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AIMS Utility values inform estimates of the cost-effectiveness of treatment for cardiovascular disease ( CVD ) , but values can vary depending on the method used . The aim of this systematic literature review ( SLR ) was to explore how methods of elicitation impact utility values for CVD . MATERIAL S AND METHODS This review identified English- language articles in Embase , MEDLINE , and the gray literature published between September 1992 and August 2015 using keywords for " utilities " and " stroke " , " heart failure " , " myocardial infa rct ion " , or " angina " . Variability in utility values based on the method of elicitation , tariff , or type of respondent was then reported . RESULTS This review screened 4,341 citations ; 290 of these articles qualified for inclusion in the SLR because they reported utility values for one or more of the cardiovascular conditions of interest listed above . Of these 290 , the 41 articles that provided head-to-head comparisons of utility methods for CVD were review ed . In this sub-set , it was found that method ological differences contributed to variation in utility values . Direct methods often yielded higher scores than did indirect methods . Within direct methods , there were no clear trends in head-to-head studies ( st and ard gamble [ SG ] vs time trade-off ) ; but general population respondents often provided lower scores than did patients with the disease when evaluating the same health states with SG methods . When comparing indirect methods , the EQ-5D typically yielded higher values than the SF-6D , but also showed more sensitivity to differences in health states . CONCLUSIONS When selecting CVD utility values for an economic model , consideration of the utility elicitation method is important , as this review demonstrates that methodology of choice impacts utility values in CVD
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"Purpose : To evaluate the use of utility-based generic quality of life measures for establishing the minimally clinical ly important difference ( MCID ) . Background : Utility-based quality of life measures place levels of wellness on a continuum anchored by death ( 0.00 ) and optimum function ( 1.00 ) . Preference measurement studies are used to define the meaning of points along the continuum . Health states that differ by less than 0.03 units can not be discriminated by panels of judges as different from one another . Thus , 0.03 is a reasonable MCID for these measures . Method : Three published studies of patients with Chronic Obstructive Pulmonary Disease ( COPD ) reported data on the Quality of Well-being Scale ( QWB ) before and after pulmonary rehabilitation . One of the studies also r and omly assigned patients to lung volume reduction surgery or to maximal medical therapy . These patients were followed for an average of 29 months . Results : All three evaluations of pulmonary rehabilitation showed changes on the QWB in excess of the proposed 0.03 MCID . QWB changes for patients assigned to lung volume reduction surgery were close to the MCID threshold at one year but grew stronger in subsequent years . Using Norman 's 0.50 st and ard deviation method , all three estimates of rehabilitation effectiveness and the outcomes one year following surgery fall below the MCID . Conclusion : Different methods for estimating MCID lead to different conclusions about the meaning of quality of life changes following pulmonary rehabilitation and lung volume reduction surgery . The preference scaling system in generic utility-based quality of life measures provides a metric that is directly interpretable and avoids many of the criticisms of MCID measures . The method is sensitive enough to suggest clinical ly meaningful benefits of rehabilitation and surgery . Further , quality adjusted life years offer a valuable metric for policy analysis . Utility-based measures of health related quality of life should gain greater use in COPD outcomes research",
"Background Little information is available regarding medical residents ' perceptions of patients ' health-related quality of life . Patients cared for by residents have been shown to receive differing patterns of care at Veterans Affairs facilities than at community or university setting s. We therefore examined : 1 ) how resident physicians value the health of patients ; 2 ) whether values differ if the patient is described as a veteran ; and 3 ) whether residency-associated variables impact values . Methods All medicine residents in a teaching hospital were asked to watch a digital video of an actor depicting a 72-year-old patient with mild-moderate congestive heart failure . Residents were r and omized to 2 groups : in one group , the patient was described as a veteran of the Korean War , and in the other , he was referred to only as a male . The respondents assessed the patient 's health state using 4 measures : rating scale ( RS ) , time tradeoff ( TTO ) , st and ard gamble ( SG ) , and willingness to pay ( WTP ) . We also ascertained residents ' demographics , risk attitudes , residency program type , post-graduate year level , current rotation , experience in a Veterans Affairs hospital , and how many days it had been since they were last on call . We performed univariate and multivariable analyses using the RS , TTO , SG and WTP as dependent variables . Results Eighty-one residents ( 89.0 % of eligible ) participated , with 36 ( 44.4 % ) viewing the video of the veteran and 45 ( 55.6 % ) viewing the video of the non-veteran . Their mean ( SD ) age was 28.7 ( 3.1 ) years ; 51.3 % were female ; and 67.5 % were white . There were no differences in residents ' characteristics or in RS , TTO , SG and WTP scores between the veteran and non-veteran groups . The mean RS score was 0.60 ( 0.14 ) ; the mean TTO score was 0.80 ( 0.20 ) ; the mean SG score was 0.91 ( 0.10 ) ; and the median ( 25th , 75th percentile ) WTP was $ 10,000 ( $ 7600 , $ 20,000 ) per year . In multivariable analyses , being a resident in the categorical program was associated with assigning higher RS scores , but no residency-associated variables were associated with the TTO , SG or WTP scores . Conclusion Physicians in training appear not to be biased either in favor of or against military veterans when judging the value of a patient 's health",
"BACKGROUND Heart failure ( HF ) is a major health problem in developed countries . HF is a progressive , lethal disorder , even with adequate treatment . There exists a vicious circle in the pathophysiology of HF that perpetuates and magnifies the problem . Concomitant fluid accumulation may worsen the congestive HF , it is responsible for numerous hospitalizations and it is an important cause of mortality . In this situation , any means of fluid removal may aid in the management of these patients . The objective of this study was to evaluate the efficacy of peritoneal dialysis ( PD ) in the treatment of refractory HF in terms of functional status , hospitalization and mortality . We also determined the improvement in health-related quality of life with the use of PD , and examined the economic consequences of its use . METHODS We conducted a single centre , prospect i ve , non-r and omized study involving patients showing symptoms and signs of congestive HF refractory to maximum tolerable drug treatment . All of them were treated with PD . We analysed physical and biochemical determinations , functional status ( according to the NYHA classification ) and echocardiogram parameters . Also , to determine the efficacy of the technique we compared the perceived state of health ( measured by the EQ5D ) to PD patients respect to those reported with conservative therapies . Finally , we carried out a cost-utility evaluation measured by the incremental cost-utility ratio between these two options . RESULTS Seventeen patients ( 65 % men , 64 + /- 9 years ) were included in the study , and 12 were still undergoing PD treatment at the end of the follow-up period ( 15 + /- 9 months ) . All patients improved their NYHA functional status ( 65 % two classes ; the rest , one ; P pulmonary artery systolic pressure ( 44 + /- 12 versus 27 + /- 9 mmHg ; P = 0.007 ) , but no changes in left ventricular ejection fraction . Hospitalization rates underwent a dramatic reduction ( from 62 + /- 16 to 11 + /- 5 days/patient/year ; P = 0.003 ) before and after PD treatment . PD treatment raised life expectancy of 82 % after 12 months of treatment , and 70 % and 56 % after 18 and 24 months , respectively , much better outcomes than those reported about conservative therapies , which only use diverse diuretic regimens . PD was associated with a higher perception state of health than the conservative therapy ( 0.6727 versus 0.4305 ; P PD is cost-effective compared with the conservative therapy . CONCLUSIONS We demonstrate that congestive HF programmes should consider offering PD in hope of seeing better functional status , reduced morbidity and mortality , better quality of life as well as reduced health care costs",
"Objective To compare two health-related quality of life measures , the preference-based EQ-5D with five questions and the profile-based R AND -36 with 36 questions , in previous critically ill patients . Design Prospect i ve observational study . Setting A ten-bed medical-surgical intensive care unit ( ICU ) in a tertiary care university hospital . Patients Of the 2,709 critically ill patients , treated during the years 1995–2000 , the 1,099 patients of the 1,443 still alive who returned both mailed measures were included in the study . Interventions None . Measurements and main results The EQ-5D and the R AND -36 correlated well ( P Ceiling effect was more obvious with the EQ-5D ; the values of the R AND -36 varied usually from 0 to 100 in all the three levels of the corresponding EQ-5D question , and the weakest statistically significant differences were between the EQ levels 2 and 3 . In particular , the R AND -36 proved to differentiate better the levels of mobility , self-care , and poor outcome . Conclusions The EQ-5D and the R AND -36 correlated well , but when more precisely stated information is needed , especially regarding mobility , self-care , or low quality of life levels of previous critically ill patients , the profile-based R AND -36 may discriminate better",
"OBJECTIVES The purpose s of this analysis were to evaluate the construct validity of the EQ-5D and compare responses on the EQ-5D with the Physical Component Summary ( PCS-12 ) and Mental Component Summary ( MCS-12 ) scores of the SF-12 Health Survey . METHODS Data were collected via a survey instrument mailed to 4,200 r and omly selected subjects in the province of Alberta , Canada . The instrument contained the EQ-5D and SF-12 health surveys , with additional questions eliciting clinical and demographic information from the respondents . RESULTS 1,555 respondents returned mailed question naires ; 606 question naires were returned undeliverable . The SF-12 summary scores were calculated for 1,380 respondents . Analysis of the EQ-5D responses by demographic variables found significant differences among categories of age , gender , and self-reported chronic medical conditions . Corresponding dimensions and summary scores were more strongly related ( eg , mobility and PCS-12 ; F ratio = 598.3 , P mobility and MCS-12 ; F ratio = 18.8 , P SF-12 summary scores ( r = 0.41 for MCS-12 and r = 0.68 for PCS-12 ) . For subjects reporting no problems on the EQ-5D , PCS-12 and MCS-12 scores were significantly lower for people reporting medical problems or feelings of depression . CONCLUSIONS The results of this investigation generally supported the validity of the EQ-5D . However , an important ceiling effect was observed for the EQ-5D in this sample . The combination of the EQ-5D and SF-12 provides relatively broad coverage of important health domains and scores for various purpose",
"Background . Preference-based measures of health-related quality of life all use the same dead = 0.00 to perfect health = 1.00 scale , but there are substantial differences among measures . Objective . The objective was to examine agreement in classifying patients as better , stable , or worse . Methods . The EQ-5D , Health Utilities Index Mark 2 and Mark 3 , Quality of Well-Being – Self-Administered scale , Short-Form 36 ( Short-Form 6D ) , and disease-targeted measures were administered prospect ively in 2 clinical cohorts . The study was conducted at academic medical centers : University of California , Los Angeles ; University of California , San Diego ; University of Wisconsin – Madison ; and University of Southern California . Patients undergoing cataract extraction surgery with lens replacement completed the 25-item National Eye Institute Visual Function Question naire ( NEI-VFQ-25 ) . Patients newly referred to congestive heart failure specialty clinics completed the Minnesota Living with Heart Failure Question naire ( MLHF ) . In both cohorts , subjects completed surveys at baseline and at 1 and 6 months . The NEI-VFQ-25 and MLHF were used as gold st and ards to assign patients to categories of change . Agreement was assessed using κ . Results . There were 376 cataract patients recruited . Complete data for baseline and the 1-month follow-up were available on all measures for 210 cases . Using criteria specified by Altman , agreement was poor for 6 of 9 pairs of comparisons and fair for 3 pairs . There were 160 heart failure patients recruited . Complete data for baseline and the 6-month follow-up were available for 86 cases . Agreement was negligible for 5 pairs and fair for 1 . The study was conducted on selected patients at a few academic medical centers . Conclusions . The results underscore the lack of interchangeability among different preference-based measures "
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Background A growing number of studies and review s have documented the impact of telemedicine on diabetes management . However , no meta- analysis has assessed whether including nutritional counseling as part of a telemedicine program has a significant impact on diabetes outcomes or what kind of nutritional counseling is most effective . Methods Original research articles examining the effect of telemedicine interventions on HbA1c levels in patients with Type 1 or Type 2 diabetes were included in this study . A literature search was performed and 92 studies were retained for analysis . We examined stratified results by differentiating interventions using no nutritional counseling from those that used nutritional counseling . We further compared between nutritional counseling administered via short message systems ( SMS ) such as email and text messages , and nutritional counseling administered via telephone or videoconference . Results Telemedicine programs that include a nutritional component show similar effect in diabetes management as those programs that do not . Furthermore , subgroup analysis reveals that nutritional intervention via SMS such as email and text messages is at least as equally effective in reducing HbA1c when compared to personal nutritional counseling with a practitioner over videoconference or telephone . Conclusion The inclusion of nutritional counseling as part of a telemedicine program does not make a significant difference to diabetes outcomes . Incorporating nutritional counseling into telemedicine programs via SMS is at least as effective as counseling via telephone or videoconference
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"OBJECTIVE This study was design ed to evaluate the impact of a teleassistance system on the metabolic control of type 2 diabetes patients . RESEARCH DESIGN AND METHODS We conducted a 1-year controlled parallel-group trial comparing patients r and omized ( 1 ) to an intervention group , assigned to a teleassistance system using real-time transmission of blood glucose results , with immediate reply when necessary , and telephone consultations , or ( 2 ) to a control group , being regularly followed-up at their healthcare center . Study subjects were type 2 diabetes patients > 30 years of age followed in the primary care setting . RESULTS A total of 328 type 2 diabetes patients were recruited from 35 family practice s in the province of Málaga , Spain . There was a reduction in hemoglobin A1c after 12 months from 7.62 + /- 1.60 % to 7.40 + /- 1.43 % ( P = 0.027 ) in the intervention group and from 7.44 + /- 1.31 % to 7.35 + /- 1.38 % ( P = 0.303 ) in the control group . The difference in the change between groups was not statistically significant . There was also a significant decrease in systolic and diastolic blood pressure , total cholesterol , low-density lipoprotein cholesterol , and body mass index in the intervention group . In the control group , the only significant decline was in low-density lipoprotein cholesterol . CONCLUSIONS A teleassistance system using real-time transmission of blood glucose results with an option to make telephone consultations is feasible in the primary care setting as a support tool for family physicians in their follow-up of type 2 diabetes patients",
"Background To determine whether an internet-based mentoring program can improve glycemic control in subjects with type 1 diabetes mellitus ( T1DM ) . Methods Subjects with T1DM on intensive insulin therapy and with hemoglobin A1c ( HbA1c ) ≥8.0 % were r and omized to mentored ( glucometer transmission with feedback from mentors ) or control ( glucometer transmission without feedback ) groups and were examined for 12 weeks . Five mentors were interviewed and selected , of which two were T1DM patients themselves and three were parents with at least one child diagnosed with T1DM since more than 5 years ago . Results A total of 57 T1DM adult subjects with a mean duration after being diagnosed with diabetes of 7.4 years were recruited from Samsung Medical Center . Unfortunately , the mentored group failed to show significant improvements in HbA1c levels or other outcomes , including the quality of life , after completion of the study . However , the mentored group monitored their blood glucose ( 1.41 vs. 0.30 ) and logged into our website ( http://ubisens.co.kr/ ) more frequently ( 20.59 times vs. 5.07 times ) than the control group . Conclusion A 12-week internet-based mentoring program for T1DM patients with inadequate glycemic control did not prove to be superior to the usual follow-up . However , the noted increase in the subjects ' frequency of blood glucose monitoring may lead to clinical benefits",
"Sustained improvement in blood glucose control is the only treatment outcome which will reduce or eliminate the long term complications of diabetes mellitus . We have design ed and evaluated an electronic information system which facilitates this task . The system is voice-interactive , physician directed and affords , to remote patients , 24 h access via touch-tone telephone . Accordingly , patients access the system each day to report self-measured blood glucose levels or hypoglycaemic symptoms together with dietary changes , planned exercise , stress , illness or other lifestyle events . In turn they receive immediate advice with respect to medication dosing changes , and other pertinent feedback . Preliminary system beta-testing for safety and efficacy was performed for one year in an open study of 204 patients derived from two independent , health-care environments . Among the two testing centres , over 60,000 telephone cells were received by the computer systems during the start-up year . Safety and efficacy expectations were met . In addition , prevalence of diabetes related crises ( hyperglycaemia or hypoglycaemia ) fell approximately 3-fold . Glycated haemoglobin fell significantly ( 1.0 - 1.3 % ) in patients actively using the system . In control groups of patients not actively using the system , there were no improvements in metabolic control while body weights were stable in all groups . The new system was safe and effective in our h and s and empowered our health professionals to provide improved diabetes care",
"BACKGROUND Telehome care has been proposed as a solution to the challenges of providing effective and affordable care for patients with diabetes . METHODS A total of 100 adult patients with type 2 diabetes-divided between insulin and noninsulin requiring-was enrolled in a r and omized , controlled trial aim ed at investigating the effects of telehome monitoring . The experimental group ( n = 50 ) received an in-home wireless glucose monitor and transmitter , whereas the control group ( n = 50 ) was instructed to follow the conventional arrangement . RESULTS There was an overall reduction in HbA1c values in both experimental and control groups after 6 months . A significant difference in HbA1c values between the groups was observed only among the noninsulin-requiring patients ( decline from 6.95 % ± 0.82 % to 6.66 % ± 0.86 % in IB vs. 7.21 % ± 2.02 % to 7.2 % ± 1.86 % in IIB ; p = 0.02 ) . The experimental group reported considerably less hyperglycemic and hypoglycemic events . The profile of the patient who benefited the most from telemonitoring consisted of older , more educated patient who had acquired the disease relatively recently , and who spends most of the time at home . The experimental group had higher overall scores on quality of life measures and sense of control over diabetes . There was a positive association between educational attainment and ability to use the telemonitoring system without help ( p = 0.045 ) . CONCLUSIONS Although not conclusive because of the small sample and short observation period , the study suggests that telehome monitoring is an effective tool in controlling type 2 diabetes in a primary care setting",
"Being able to manage and adjust insulin doses is a key part of managing type-1 diabetes . Children and adolescents with type-1 diabetes mellitus often have serious difficulties with this dosage adjustment . Therefore , this paper aims to investigate the impact of using novel mobile , web and communication technologies in assisting their therapy and treatment . A trial was conducted in the north-eastern part of Germany to evaluate the impact of the “ Mobil Diab ” , a mobile diabetes management system , on the clinical outcome . 68 subjects aged between 8 and 18 years , divided r and omly into control and intervention groups , were included into the study . Metrics such as changes in the quality of metabolic control , changes in psychological parameters , usability and acceptance of the technology were used for evaluation purpose . Metabolic control was mainly assessed by the mean HbAlc . Analysis showed a good acceptance of the proposed system . An overall improvement in mean levels of HbA1c was observed , however further studies will be conducted to prove evidence of the weight and BMI improvements . Moreover , initial indications of positive impact on the improvement in psychological parameters were presumed based on the result of the conducted study . The system appeared to be an efficient and time saving tool in diabetes management",
"OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with st and ard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS A cluster-r and omized clinical trial , the Mobile Diabetes Intervention Study , r and omly assigned 26 primary care practice s to one of three stepped treatment groups or a control group ( usual care ) . A total of 163 patients were enrolled and included in analysis . The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period . Secondary outcomes were changes in patient-reported diabetes symptoms , diabetes distress , depression , and other clinical ( blood pressure ) and laboratory ( lipid ) values . Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support . Patients received automated , real-time educational and behavioral messaging in response to individually analyzed blood glucose values , diabetes medications , and lifestyle behaviors communicated by mobile phone . Providers received quarterly reports summarizing patient ’s glycemic control , diabetes medication management , lifestyle behaviors , and evidence -based treatment options . RESULTS The mean declines in glycated hemoglobin were 1.9 % in the maximal treatment group and 0.7 % in the usual care group , a difference of 1.2 % ( P = 0.001 ) over 12 months . Appreciable differences were not observed between groups for patient-reported diabetes distress , depression , diabetes symptoms , or blood pressure and lipid levels ( all P > 0.05 ) . CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data , lifestyle behaviors , and patient self-management data individually analyzed and presented with evidence -based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year",
"OBJECTIVE To improve quality and efficiency of care for elderly patients with type 2 diabetes , we introduced elderly-friendly strategies to the clinical decision support system (CDSS)-based ubiquitous healthcare ( u-healthcare ) service , which is an individualized health management system using advanced medical information technology . RESEARCH DESIGN AND METHODS We conducted a 6-month r and omized , controlled clinical trial involving 144 patients aged > 60 years . Participants were r and omly assigned to receive routine care ( control , n = 48 ) , to the self-monitored blood glucose ( SMBG , n = 47 ) group , or to the u-healthcare group ( n = 49 ) . The primary end point was the proportion of patients achieving A1C without hypoglycemia at 6 months . U-healthcare system refers to an individualized medical service in which medical instructions are given through the patient ’s mobile phone . Patients receive a glucometer with a public switched telephone network-connected cradle that automatically transfers test results to a hospital-based server . Once the data are transferred to the server , an automated system , the CDSS rule engine , generates and sends patient-specific messages by mobile phone . RESULTS After 6 months of follow-up , the mean A1C level was significantly decreased from 7.8 ± 1.3 % to 7.4 ± 1.0 % ( P proportion of patients with A1C was 30.6 % in the u-healthcare group , 23.4 % in the SMBG group ( 23.4 % ) , and 14.0 % in the control group ( P u-healthcare service achieved better glycemic control with less hypoglycemia than SMBG and routine care and may provide effective and safe diabetes management in the elderly diabetic patients",
"Technology and improved care coordination models can help diabetes educators and providers meet national care st and ards and provide culturally sensitive diabetes education that may improve diabetes outcomes . The purpose of the study was to evaluate the clinical usefulness of a nurse-led diabetes care program ( Comprehensive Diabetes Management Program , CDMP ) for poorly controlled Hispanic type 2 diabetes ( T2DM ) patients in an urban community health center setting . Patients were r and omized to the intervention condition ( IC ; n = 21 ) or an attention control condition ( AC ; n = 18 ) . IC and AC conditions were compared on rates of adherence to national clinical practice guidelines ( blood glucose , blood pressure , foot exam , eye exam ) , and levels of diabetes distress , depression , and treatment satisfaction . IC patients had a significant improvement in A1C from baseline to 12-month follow-up compared with AC ( −1.6 % ± 1.4 % versus −0.6 % ± 1.1 % ; P = .01 ) . The proportion of IC patients meeting clinical goals at follow-up tended to be higher than AC for A1c ( IC = 45 % ; AC = 28 % ) , systolic blood pressure ( IC = 55 % ; AC = 28 % ) , eye screening ( IC = 91 % ; AC = 78 % ) , and foot screening , ( IC = 86 % ; AC = 72 % ) . Diabetes distress and treatment satisfaction also showed greater improvement for IC than AC ( P = .05 and P = .06 , respectively ) , with no differences for depression . The CDMP intervention was more effective than an attention control condition in helping patients meet evidence -based guidelines for diabetes care",
"BACKGROUND Communication of blood glucose ( BG ) results between patients and health care providers ( HCPs ) is of established benefit and remains a critical part of the diabetes management process . Currently , HCPs typically receive BG data from patients at the time of clinic visits or by telephone . The Accu-Chek Acculink modem ( Roche Diagnostics Corp. , Indianapolis , IN ) provides an additional and attractive option that can potentially facilitate this communication . METHODS To assess the impact of modem transfer of BG , we studied 47 participants with diabetes enrolled in a diabetes education program . Subjects were r and omized to weekly communication of BG data to their HCP by either telephone ( n = 23 ) or modem ( n = 24 ) for 4 weeks . Mean age ( + /- SD ) was 44 + /- 15 years , 62 % were female , 74 % used insulin , 53 % had type 1 diabetes , and mean baseline glycosylated hemoglobin ( A1C ) was 8.8 % ( range 5.2 - 13.2 % ) . RESULTS There were no differences between groups in the amount of time the HCP spent analyzing BG data and communicating with patients ( 12.6 + /- 6.1 min/week in the telephone group and 11.5 + /- 5.1 min/week in the modem group ) or in the number of patient and HCP attempts needed to make contact . There were similar improvements in A1C between groups ( change of -0.4 + /- 0.7 % in the telephone group and -0.9 + /- 1.4 % in the modem group , P = 0.18 ) . BG data provided by telephone had a 6 % error rate , in contrast to modem-sent data , which were transmitted without error . CONCLUSIONS Modem transfer of BG data can provide an accurate and clinical ly useful option for communication between patients and their HCP and has comparable effects on A1C",
"Numerous diabetes-management systems and programs for improving glycemic control to meet guideline targets have been proposed , using IT technology . But all of them allow only limited-or no-real-time interaction between patients and the system in terms of system response to patient input ; few studies have effectively assessed the systems ' usability and feasibility to determine how well patients underst and and can adopt the technology involved . DialBetics is composed of 4 modules : ( 1 ) data transmission module , ( 2 ) evaluation module , ( 3 ) communication module , and ( 4 ) dietary evaluation module . A 3-month r and omized study was design ed to assess the safety and usability of a remote health- data monitoring system , and especially its impact on modifying patient lifestyles to improve diabetes self-management and , thus , clinical outcomes . Fifty-four type 2 diabetes patients were r and omly divided into 2 groups , 27 in the DialBetics group and 27 in the non-DialBetics control group . HbA1c and fasting blood sugar ( FBS ) values declined significantly in the DialBetics group : HbA1c decreased an average of 0.4 % ( from 7.1 ± 1.0 % to 6.7 ± 0.7 % ) compared with an average increase of 0.1 % in the non-DialBetics group ( from 7.0 ± 0.9 % to 7.1 ± 1.1 % ) ( P = .015 ) ; The DialBetics group FBS decreased an average of 5.5 mg/dl compared with a non-DialBetics group average increase of 16.9 mg/dl ( P = .019 ) . BMI improvement-although not statistically significant because of the small sample size-was greater in the DialBetics group . DialBetics was shown to be a feasible and an effective tool for improving HbA1c by providing patients with real-time support based on their measurements and inputs",
"OBJECTIVE Widespread use of carbohydrate counting is limited by its complex education . In this study we compared a Diabetes Interactive Diary ( DID ) with st and ard carbohydrate counting in terms of metabolic and weight control , time required for education , quality of life , and treatment satisfaction . RESEARCH DESIGN AND METHODS Adults with type 1 diabetes were r and omly assigned to DID ( group A , n = 67 ) or st and ard education ( group B , n = 63 ) and followed for 6 months . A subgroup also completed the SF-36 Health Survey ( SF-36 ) and World Health Organization-Diabetes Treatment Satisfaction Question naire ( WHO-DTSQ ) at each visit . RESULTS Of 130 patients ( aged 35.7 ± 9.4 years ; diabetes duration 16.5 ± 10.5 years ) , 11 dropped out . Time for education was 6 h ( range 2–15 h ) in group A and 12 h ( 2.5–25 h ) in group B ( P = 0.07 ) . A1C reduction was similar in both groups ( group A from 8.2 ± 0.8 to 7.8 ± 0.8 % and group B from 8.4 ± 0.7 to 7.9 ± 1.1 % ; P = 0.68 ) . Nonsignificant differences in favor of group A were documented for fasting blood glucose and body weight . No severe hypoglycemic episode occurred . WHO-DTSQ scores increased significantly more in group A ( from 26.7 ± 4.4 to 30.3 ± 4.5 ) than in group B ( from 27.5 ± 4.8 to 28.6 ± 5.1 ) ( P = 0.04 ) . Role Physical , General Health , Vitality , and Role Emotional SF-36 scores improved significantly more in group A than in group B. CONCLUSIONS DID is at least as effective as traditional carbohydrate counting education , allowing dietary freedom for a larger proportion of type 1 diabetic patients . DID is safe , requires less time for education , and is associated with lower weight gain . DID significantly improved treatment satisfaction and several quality -of-life dimensions ",
"BACKGROUND Lifestyle changes soon after diagnosis might improve outcomes in patients with type 2 diabetes mellitus , but no large trials have compared interventions . We investigated the effects of diet and physical activity on blood pressure and glucose concentrations . METHODS We did a r and omised , controlled trial in southwest Engl and in adults aged 30 - 80 years in whom type 2 diabetes had been diagnosed 5 - 8 months previously . Participants were assigned usual care ( initial dietary consultation and follow-up every 6 months ; control group ) , an intensive diet intervention ( dietary consultation every 3 months with monthly nurse support ) , or the latter plus a pedometer-based activity programme , in a 2:5:5 ratio . The primary endpoint was improvement in glycated haemoglobin A(1c)(HbA(1c ) ) concentration and blood pressure at 6 months . Analysis was done by intention to treat . This study is registered , number IS RCT N92162869 . FINDINGS Of 593 eligible individuals , 99 were assigned usual care , 248 the diet regimen , and 246 diet plus activity . Outcome data were available for 587 ( 99 % ) and 579 ( 98 % ) participants at 6 and 12 months , respectively . At 6 months , glycaemic control had worsened in the control group ( mean baseline HbA(1c ) percentage 6·72 , SD 1·02 , and at 6 months 6·86 , 1·02 ) but improved in the diet group ( baseline-adjusted difference in percentage of HbA(1c ) -0·28 % , 95 % CI -0·46 to -0·10 ; p=0·005 ) and diet plus activity group ( -0·33 % , -0·51 to -0·14 ; p seen in bodyweight and insulin resistance between the intervention and control groups . Blood pressure was similar in all groups . INTERPRETATION An intensive diet intervention soon after diagnosis can improve glycaemic control . The addition of an activity intervention conferred no additional benefit . FUNDING Diabetes UK and the UK Department of Health",
"Background Telephone-based care management programmes have been shown to improve health outcomes in some chronic diseases . Birmingham Own Health ® is a telephone-based care service ( nurse-delivered motivational coaching and support for self-management and lifestyle change ) for patients with poorly controlled diabetes , delivered in Birmingham , UK . We used a novel method to evaluate its effectiveness in a real-life setting . Methods Retrospective cohort study in the UK . 473 patients aged ≥ 18 years with diabetes enrolled onto Birmingham Own Health ® ( intervention cohort ) and with > 90 days follow-up , were each matched by age and sex to up to 50 patients with diabetes registered with the General Practice Research Data base ( GPRD ) to create a pool of 21,052 controls ( control cohort ) . Controls were further selected from the main control cohort , matching as close as possible to the cases for baseline test levels , followed by as close as possible length of follow-up ( within + /-30 days limits ) and within + /-90 days baseline test date . The aim was to identify a control group with as similar distribution of prognostic factors to the cases as possible . Effect sizes were computed using linear regression analysis adjusting for age , sex , deprivation quintile , length of follow-up and baseline test levels . Results After adjusting for baseline values and other potential confounders , the intervention showed significant mean reductions among people with diabetes of 0.3 % ( 95%CI 0.1 , 0.4 % ) in HbA1c ; 3.5 mmHg ( 1.5 , 5.5 ) in systolic blood pressure , 1.6 mmHg ( 0.4 , 2.7 ) in diastolic blood pressure and 0.7 unit reduction ( 0.3 , 1.0 ) in BMI , over a mean follow-up of around 10 months . Only small effects were seen on average on serum cholesterol levels ( 0.1 mmol/l reduction ( 0.1 , 0.2 ) ) . More marked effects were seen for each clinical outcome among patients with worse baseline levels . Conclusions Despite the limitations of the study design , the results are consistent with the Birmingham Own Health ® telephone care management intervention being effective in reducing HbA1c levels , blood pressure and BMI in people with diabetes , to a degree comparable with r and omised controlled trials of similar interventions and clinical ly important . The effects appear to be greater in patients with poorer baseline levels and the intervention is effective in the most deprived population",
"OBJECTIVE To conduct a 1-year r and omized clinical trial to evaluate a remote comprehensive diabetes self-management education ( DSME ) intervention , Diabetes TeleCare , administered by a dietitian and nurse/certified diabetes educator ( CDE ) in the setting of a federally qualified health center ( FQHC ) in rural South Carolina . RESEARCH DESIGN AND METHODS Participants were recruited from three member health centers of an FQHC and were r and omized to either Diabetes TeleCare , a 12-month , 13-session curriculum delivered using telehealth strategies , or usual care . RESULTS Mixed linear regression model results for repeated measures showed a significant reduction in glycated hemoglobin ( GHb ) in the Diabetes TeleCare group from baseline to 6 and 12 months ( 9.4 ± 0.3 , 8.3 ± 0.3 , and 8.2 ± 0.4 , respectively ) compared with usual care ( 8.8 ± 0.3 , 8.6 ± 0.3 , and 8.6 ± 0.3 , respectively ) . LDL cholesterol was reduced at 12 months in the Diabetes TeleCare group compared with usual care . Although not part of the original study design , GHb was reduced from baseline to 12 and 24 months in the Diabetes TeleCare group ( 9.2 ± 0.4 , 7.4 ± 0.5 , and 7.6 ± 0.5 , respectively ) compared with usual care ( 8.7 ± 0.4 , 8.1 ± 0.4 , and 8.1 ± 0.5 , respectively ) in a post hoc analysis of a subset of the r and omized sample who completed a 24-month follow-up visit . CONCLUSIONS Telehealth effectively created access to successfully conduct a 1-year remote DSME by a nurse CDE and dietitian that improved metabolic control and reduced cardiovascular risk in an ethnically diverse and rural population",
"We conducted a 12-month prospect i ve interventional study of videoconferencing between primary and secondary care . A treatment network consisting of a diabetes specialist and four general practitioners was established . The communications medium was PC-based videoconferencing via ISDN at 128 kbit/s . A total of 154 type 2 diabetic patients entered the study . The specialist was contacted 94 times via videoconferencing . Metabolic and haemodynamic parameters were significantly improved over the course of the study : the mean HbA1c level fell from 8.1 % to 7.8 % , systolic blood pressure from 156 to 148 mmHg and diastolic blood pressure from 88 to 83 mmHg . The study demonstrated that therapeutic counselling by videoconferencing is feasible in diabetes care and suggests that it reduces hospital admissions and improves the quality of care",
"AIM To investigate the effectiveness of a nurse short message service ( SMS ) by cellular phone and wire Internet on plasma glucose levels in people with diabetes for six months . BACKGROUND Blood glucose management system using telemedicine approaches may maintain the appropriate blood glucose levels in type-2 diabetic patients . DESIGN A control group pre-test-post-test design was used to assess the effectiveness of nurse 's education . METHODS Twenty-five patients were r and omly assigned to an intervention group and 26 to a control group . The intervention was applied for six months . The goal of the intervention was to keep blood glucose concentrations close to the normal range . Participants were requested to input their blood glucose level , diet and exercise diary everyday in the website by cellular phone or wire Internet . The research er sends optimal recommendations to each patient using SMS by cellular phone and wire Internet weekly . RESULTS Glycosylated hemoglobin ( HbA(1)c ) decreased 1.15 % points at three months and 1.05 % points at six months compared with baseline in the intervention group . Patients in the intervention group had a decrease of two hours post meal glucose ( 2HPMG ) of 85.1 mg/dl at three months and 63.1 mg/dl at six months compared with baseline . CONCLUSION This web-based intervention using SMS of cellular phone improved HbA(1)c and 2HPMG for six months in type-2 diabetic patients . RELEVANCE TO CLINICAL PRACTICE An SMS of cellular phone intervention by a nurse can reduce HbA(1)c and 2HPMG for six months in type-2 diabetic patients",
"H istorically , nutrition principles and recommendations for diabetes and related complications have been based on scientific evidence and diabetes knowledge when available and , when evidence was not available , on clinical experience and expert consensus . Often it has been difficult to discern the level of evidence used to construct the nutrition principles and recommendations . Furthermore , in clinical practice , many nutrition recommendations that have no scientific supporting evidence have been and are still being given to individuals with diabetes . To address these problems and to incorporate the research done in the past 8 years , this 2002 technical review provides principles and recommendations classified according to the level of evidence available . It review s the evidence from r and omized , controlled trials ; cohort and case-controlled studies ; and observational studies , which can also provide valuable evidence ( 1,2 ) , and takes into account the number of studies that have provided consistent outcomes of support . In this review , nutrition principles are grade d into four categories based on the available evidence : those with strong supporting evidence , those with some supporting evidence , those with limited supporting evidence and those based on expert consensus . Evidence -based nutrition recommendations attempt to translate research data and clinical ly applicable evidence into nutrition care . However , the best available evidence must still be moderated by individual circumstances and preferences . The goal of evidence -based recommendations is to improve the quality of clinical judgments and facilitate costeffective care by increasing the awareness of clinicians and patients with diabetes of the evidence supporting nutrition services and the strength of that evidence , both in quality and quantity . Before 1994 , the American Diabetes Association ’s ( ADA ’s ) nutrition principles and recommendations attempted to define an “ ideal ” nutrition prescription that would apply to everyone with diabetes ( 3–5 ) . Although individualization was a major principle of all recommendations , it was usually done within defined limits for recommended energy intake and macronutrient composition . The 1994 nutrition recommendations shifted this focus to one that emphasized effects of nutrition therapy on metabolic control ( 6,7 ) . The nutrition prescription is determined considering treatment goals and lifestyle changes the diabetic patient is willing and able to make , rather than predetermined energy levels and percentages of carbohydrate , protein , and fat . The goal of nutrition intervention is to assist and facilitate individual lifestyle and behavior changes that will lead to improved metabolic control . This focus continues with the 2002 nutrition principles and recommendations . Medical nutrition therapy ( MNT ) is an integral component of diabetes management ( 8,9 ) and diabetes sel fmanagement education ( 10 ) . ( Medical nutrition therapy is the preferred term and should replace other terms , such as diet , diet therapy , and dietary management . ) MNT for diabetes includes the process and the system by which nutrition care is provided for diabetic individuals and the specific lifestyle recommendations for that care . However , recommendations should not only be based on scientific evidence but should also take into consideration lifestyle changes the ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●",
"AIMS We evaluate the efficacy of the \" Active Body Control ( ABC ) Program \" for weight reduction in patients with type 2 diabetes . METHODS The ABC program combines telemonitoring of the physical activity with a low-calorie diet also preferring carbohydrates with low glycemic indexes . In this 6-month , r and omized , clinical trial 35 patients ( aged 57 ± 9 years ; BMI = 35.3 ± 5.7 kg/m(2 ) ) were treated according to the ABC program and 35 control patients ( aged 58 ± 7 years ; BMI = 34.8 ± 5.9 kg/m(2 ) ) received st and ard therapy . RESULTS After 6 months the mean weight loss in the intervention group was 11.8 kg ± 8.0 kg . Glucose and HbA1c were lowered by respectively 1.0 mmol/l and 0.8 percentage points ( p=0.000 , respectively ) . The proportion of patients with HbA1c>7 % fell from 57 % to 26 % . Antidiabetic drugs were discontinued in 13 patients ( 39 % ) and reduced in 14 ( 42 % ) . The reduction of costs on medication per patient was € 83 in 6 months . In the control group , there were no relevant changes in body weight , laboratory values or drug treatment . CONCLUSIONS The ABC program effectively lowers body weight , Hb1Ac and antidiabetic drug use in patients with type 2 diabetes",
"OBJECTIVE To quantify total diabetes care received ( generalist or specialist ) from diagnosis onward and its association with the incidence of diabetes complications in a representative cohort of patients with type 1 diabetes . RESEARCH DESIGN AND METHODS A total of 429 subjects from the Pittsburgh Epidemiology of Diabetes Complications Study , a prospect i ve follow-up study of childhood-onset type 1 diabetic subjects first seen between 1986 and 1988 ( mean age 28 years , mean duration 19 years ) , followed biennially for up to 10 years were studied . Specialist care was defined as care received from a board-certified endocrinologist , diabetologist , or diabetes clinic and quantified as the percent of diabetes duration spent in specialist care . RESULTS There was a significant trend for a higher incidence of neuropathy , overt nephropathy , and coronary artery disease with lower use of specialist care . Multivariate analyses controlling for diabetes duration , demographic characteristics , health care practice s , and physiological risk factors demonstrated that higher past use of specialist care was found to be significantly protective against the development of overt nephropathy ( risk ratio 0.43 , 95 % CI 0.21 - 0.88 ) and neuropathy ( 0.54 , 0.35 - 0.83 ) and weakly protective against coronary artery disease ( 0.65 , 0.37 - 1.1 ) . CONCLUSIONS A higher proportion of diabetes duration spent in specialist care may result in delayed development of certain diabetes complications independent of other risk factors . This study thus supports the concept that the benefits of specialist care should be available to all patients with type 1 diabetes",
"OBJECTIVE To evaluate an online disease management system supporting patients with uncontrolled type 2 diabetes . MATERIAL S AND METHODS Engaging and Motivating Patients Online With Enhanced Re sources for Diabetes was a 12-month parallel r and omized controlled trial of 415 patients with type 2 diabetes with baseline glycosylated hemoglobin ( A1C ) values ≥7.5 % from primary care sites sharing an electronic health record . The intervention included : ( 1 ) wirelessly uploaded home glucometer readings with graphical feedback ; ( 2 ) comprehensive patient-specific diabetes summary status report ; ( 3 ) nutrition and exercise logs ; ( 4 ) insulin record ; ( 5 ) online messaging with the patient 's health team ; ( 6 ) nurse care manager and dietitian providing advice and medication management ; and ( 7 ) personalized text and video educational ' nuggets ' dispensed electronically by the care team . A1C was the primary outcome variable . RESULTS Compared with usual care ( UC , n=189 ) , patients in the intervention ( INT , n=193 ) group had significantly reduced A1C at 6 months ( -1.32 % INT vs -0.66 % UC ; p had improved diabetes control ( > 0.5 % reduction in A1C ) than UC patients at 12 months ( 69.9 ( 95 % CI 63.2 to 76.5 ) vs 55.4 ( 95 % CI 48.4 to 62.5 ) ; p=0.006 ) . CONCLUSIONS A nurse-led , multidisciplinary health team can manage a population of diabetic patients in an online disease management program . INT patients achieved greater decreases in A1C at 6 months than UC patients , but the differences were not sustained at 12 months . More INT than UC patients achieved improvement in A1C ( > 0.5 % decrease ) . Trial registered in clinical trials.gov : # NCT00542204",
"OBJECTIVE Despite the importance of self-management support ( SMS ) , few studies have compared SMS interventions , involved diverse population s , or entailed implementation in safety net setting s. We examined the effects of two SMS strategies across outcomes corresponding to the Chronic Care Model . RESEARCH DESIGN AND METHODS A total of 339 out patients with poorly controlled diabetes from county-run clinics were enrolled in a three-arm trial . Participants , more than half of whom spoke limited English , were uninsured , and /or had less than a high school education , were r and omly assigned to usual care , interactive weekly automated telephone self-management support with nurse follow-up ( ATSM ) , or monthly group medical visits with physician and health educator facilitation ( GMV ) . We measured 1-year changes in structure ( Patient Assessment of Chronic Illness Care [ PACIC ] ) , communication processes ( Interpersonal Processes of Care [ IPC ] ) , and outcomes ( behavioral , functional , and metabolic ) . RESULTS Compared with the usual care group , the ATSM and GMV groups showed improvements in PACIC , with effect sizes of 0.48 and 0.50 , respectively ( P improvements in IPC ( effect sizes 0.40 vs. usual care and 0.25 vs. GMV , P improvements in self-management behavior versus the usual care arm ( P fewer bed days per month than the usual care group ( −1.7 days , P = 0.05 ) and the GMV group ( −2.3 days , P less interference with daily activities than the usual care group ( odds ratio 0.37 , P = 0.02 ) . We observed no differences in A1C change . CONCLUSIONS Patient-centered SMS improves certain aspects of diabetes care and positively influences self-management behavior . ATSM seems to be a more effective communication vehicle than GMV in improving behavior and quality of life",
"OBJECTIVE We compared the short-term efficacy of home telemonitoring coupled with active medication management by a nurse practitioner with a monthly care coordination telephone call on glycemic control in veterans with type 2 diabetes and entry A1C ≥7.5 % . RESEARCH DESIGN AND METHODS Veterans who received primary care at the VA Pittsburgh Healthcare System from June 2004 to December 2005 , who were taking oral hypoglycemic agents and /or insulin for ≥1 year , and who had A1C ≥7.5 % at enrollment were r and omly assigned to either active care management with home telemonitoring ( ACM+HT group , n = 73 ) or a monthly care coordination telephone call ( CC group , n = 77 ) . Both groups received monthly calls for diabetes education and self-management review . ACM+HT group participants transmitted blood glucose , blood pressure , and weight to a nurse practitioner using the Viterion 100 TeleHealth Monitor ; the nurse practitioner adjusted medications for glucose , blood pressure , and lipid control based on established American Diabetes Association targets . Measures were obtained at baseline , 3-month , and 6-month visits . RESULTS Baseline characteristics were similar in both groups , with mean A1C of 9.4 % ( CC group ) and 9.6 % ( ACM+HT group ) . Compared with the CC group , the ACM+HT group demonstrated significantly larger decreases in A1C at 3 months ( 1.7 vs. 0.7 % ) and 6 months ( 1.7 vs. 0.8 % ; P ACM+HT group demonstrated significantly greater reductions in A1C by 3 and 6 months . However , both interventions improved glycemic control in primary care patients with previously inadequate control",
"OBJECTIVE To determine whether diabetes education can be provided as effectively through telemedicine technology as through in-person encounters with diabetes nurse and nutrition educators . RESEARCH DESIGN AND METHODS A total of 56 adults with diabetes were r and omized to receive diabetes education in person ( control group ) or via telemedicine ( telemedicine group ) and were followed prospect ively . The education consisted of three consultative visits with diabetes nurse and nutrition educators . The in-person and telemedicine groups were compared using measures of glycemic control ( HbA(1c ) ) and question naires to assess patient satisfaction and psychosocial functioning as related to diabetes . Outcome measures were obtained at baseline , immediately after the completion of diabetes education , and 3 months after the third educational visit . RESULTS Patient satisfaction was high in the telemedicine group . Problem Areas in Diabetes scale scores improved significantly with diabetes education ( adjusted P HbA(1c ) improved from 8.6 + /- 1.8 % at baseline to 7.8 + /- 1.5 % immediately after education and 7.8 + /- 1.8 % 3 months after the third educational visit ( unadjusted P glycemic control , and both methods were well accepted by patients . Reduced diabetes-related stress was observed in both groups . These data suggest that telemedicine can be successfully used to provide diabetes education to patients",
"OBJECTIVE —To determine 1 ) whether participants in the Spanish Diabetes Self-Management Program ( SDSMP ) , when compared at 6 months to r and omized control subjects , would demonstrate improvements in health status , health behaviors , and self-efficacy ; and 2 ) whether SDSMP participants receiving monthly automated telephone reinforcement would maintain improvements at 18 months better than those not receiving reinforcement . RESEARCH DESIGN AND METHODS —A total of 567 Spanish-speaking adults with type 2 diabetes were r and omized to a usual-care control group or 6-week community-based , peer-led SDSMP . SDSMP participants were re-r and omized to receive 15 months of automated telephone messages or no reinforcement . A1C was measured at baseline and 6 and 18 months . All other data were collected by self-administered question naires . RESULTS —At 6 months SDSMP participants compared with control subjects demonstrated improvements in A1C ( −0.4 % ) , health distress , symptoms of hypo- and hyperglycemia , and self-efficacy ( P SDSMP participants also demonstrated improvements in self-rated health and communication with physicians , had fewer emergency room visits ( −0.18 visits in 6 months , P fewer visits to physicians . At 18 months the only difference between reinforced and nonreinforced participants was increased glucose monitoring for the reinforcement group . CONCLUSIONS —The SDSMP demonstrated effectiveness in lowering A1C and improving health status . Reinforcement did not add to its effectiveness . Given the high needs of the Spanish-speaking population , the SDSMP deserves consideration for implementation",
"OBJECTIVE Investigate the effectiveness of an educational intervention that used both the cellular phone with a short messaging service ( SMS ) and the Internet on the glycemic control of the patients with type 2 diabetes mellitus . METHODS Twenty-five patients were r and omly assigned to an intervention group and twenty-six to a control group . The intervention was applied for 12 months . The goal of the intervention was to keep blood glucose concentrations close to the normal range ( HbA(1)c access a website by using a cellular phone or to wiring the Internet and input their blood glucose levels weekly . Participants were sent the optimal recommendations by both cellular phone and the Internet weekly . RESULTS Participants in the intervention group had lower HbA(1)c over 12 months when compared with the control group . At 12 months the change from baseline in HbA(1)c was -1.32 in the intervention group versus + 0.81 in the control group . Two hours post-meal glucose ( 2HPMG ) had a significantly greater decline in the intervention group after 12 months when compared with the control group ( -100.0 versus + 18.1mg/dl ) . CONCLUSION This educational intervention using the Internet and a SMS by cellular phone rapidly improved and stably maintained the glycemic control of the patients with type 2 diabetes mellitus",
"Objective To evaluate the effectiveness of goal focused telephone coaching by practice nurses in improving glycaemic control in patients with type 2 diabetes in Australia . Design Prospect i ve , cluster r and omised controlled trial , with general practice s as the unit of r and omisation . Setting General practice s in Victoria , Australia . Participants 59 of 69 general practice s that agreed to participate recruited sufficient patients and were r and omised . Of 829 patients with type 2 diabetes ( glycated haemoglobin ( HbA1c ) > 7.5 % in the past 12 months ) who were assessed for eligibility , 473 ( 236 from 30 intervention practice s and 237 from 29 control practice s ) agreed to participate . Intervention Practice nurses from intervention practice s received two days of training in a telephone coaching programme , which aim ed to deliver eight telephone and one face to face coaching episodes per patient . Main outcome measures The primary end point was mean absolute change in HbA1c between baseline and 18 months in the intervention group compared with the control group . Results The intervention and control patients were similar at baseline . None of the practice s dropped out over the study period ; however , patient attrition rates were 5 % in each group ( 11/236 and 11/237 in the intervention and control group , respectively ) . The median number of coaching sessions received by the 236 intervention patients was 3 ( interquartile range 1 - 5 ) , of which 25 % ( 58/236 ) did not receive any coaching sessions . At 18 months ’ follow-up the effect on glycaemic control did not differ significantly ( mean difference 0.02 , 95 % confidence interval −0.20 to 0.24 , P=0.84 ) between the intervention and control groups , adjusted for HbA1c measured at baseline and the clustering . Other biochemical and clinical outcomes were similar in both groups . Conclusions A practice nurse led telephone coaching intervention implemented in the real world primary care setting produced comparable outcomes to usual primary care in Australia . The addition of a goal focused coaching role onto the ongoing generalist role of a practice nurse without prescribing rights was found to be ineffective . Trial registration Current Controlled Trials IS RCT N50662837",
"BACKGROUND Previous studies have provided limited guidance regarding the clinical efficacy and cost-effectiveness of interventions using \" telemedicine \" models in the management of diabetes mellitus . We conducted a study to determine if routine clinical assessment s of diabetes patients could be effectively conducted via computer and telephone interaction with patients and still provide clinical results similar to traditional office care . SUBJECTS AND METHODS We enrolled 100 subjects with diabetes in this 12-month , r and omized , controlled , non-inferiority study . Subjects were r and omized ( 1:1 ratio ) to a control group ( CG ) or study group ( SG ) . Baseline characteristics were similar . CG subjects participated in quarterly office visits ; SG subjects participated in two office visits ( months 6 and 12 ) and two telemedicine interactions ( months 3 and 9 ) . Changes in clinical measurements ( hemoglobin A1c [ HbA1c ] , blood pressure , lipids , body mass index [ BMI ] , and body weight ) and clinician time requirements were assessed . RESULTS Seventy subjects completed the study ( CG , n=37 ; SG , n=33 ) . No significant between-group differences in HbA1c , blood pressure , lipids , or BMI were seen at 12 months . SG subjects showed significantly greater reductions in mean ( SD ) body weight compared with CG subjects : -5.2 ( 1.6 ) pounds versus -0.7 ( 1.5 ) pounds , respectively ( P=0.04 ) . Clinician time requirements for SG subjects were reduced by > 40 % . CONCLUSIONS Our study demonstrated that use of a telemedicine-based treatment protocol in diabetes patients is feasible and efficient and yields similar clinical outcomes compared with traditional , clinic-based protocol s. Telemedicine applications of computer software can potentially exp and access to care for patients and may reduce costs for patients , providers , and payers",
"BACKGROUND Real-time continuous glucose monitoring ( CGM ) has recently been incorporated into routine diabetes management because of the potential advantages it offers for glycemic control . The aim of our study was to evaluate the impact of the use of real-time CGM together with a telemedicine system in hemoglobin A1c and glucose variability in patients with type 1 diabetes treated with insulin pumps . METHODS Ten patients ( five women , 41.2 [ range , 21 - 62 ] years old , duration of diabetes 14.9 [ range , 3 - 52 ] years ) were included in this r and omized crossover study . Patients used the DIABTel telemedicine system throughout the study , and real-time CGM was used for 3 days every week during the intervention phase . At the end of the control phase , a blind 3-day CGM was performed . Glucose variability was evaluated using the Glucose Risk Index ( GRI ) , a comparative analysis of continuous glucose values over two consecutive hours . RESULTS Hemoglobin A1c decreased significantly ( 8.1 + /- 1.1 % vs. 7.3 + /- 0.8 % ; P = 0.007 ) after the intervention phase , while no changes were observed during the control phase . The mean number of daily capillary glucose readings was higher during the intervention phase ( 4.7 + /- 1.1 vs. 3.8 + /- 1.0 ; P mean number of bolus doses per day ( 5.23 + /- 1.1 vs. 4.4 + /- 0.8 ; P GRI was higher during the control phase than during the experimental phase ( 9.6 vs. 6.25 ; P Real-time CGM in conjunction with the DIABTel system improves glycemic control and glucose stability in pump-treated patients with type 1 diabetes",
" A total of 175 patients with Types 1 and 2 diabetes in primary care and university hospital outpatient departments were r and omized into a study group ( n = 101 ) or usual care ( n = 74 ) . The study group used an e-health application with a diabetes management system and a home care link . Usual care did not involve e-health , i.e. the patients made regular general practitioner visits about every three months . After 12 months HbA1c decreased significantly in both groups of patients . The differences were small , but HbA1c was significantly lower in the study group than the controls . Diastolic blood pressure , fasting plasma glucose , serum total cholesterol , serum LDL-cholesterol and serum triglycerides were significantly lower in the study than in the control group . This was achieved with fewer visits by study patients to doctors and nurses . Use of e-health in diabetes care for 12 months was able to provide equivalent diabetic control to usual care , and improved cardiovascular risk factors",
"ABSTRACT BACKGROUND We compared two implementation approaches for a health literacy diabetes intervention design ed for community health centers . METHODS A quasi-experimental , clinic-r and omized evaluation was conducted at six community health centers from rural , suburban , and urban locations in Missouri between August 2008 and January 2010 . In all , 486 adult patients with type 2 diabetes mellitus participated . Clinics were set up to implement either : 1 ) a clinic-based approach that involved practice re- design to routinely provide brief diabetes education and counseling services , set action-plans , and perform follow-up without additional financial re sources [ CARVE-IN ] ; or 2 ) an out source d approach where clinics referred patients to a telephone-based diabetes educator for the same services [ CARVE-OUT ] . The fidelity of each intervention was determined by the number of contacts with patients , self-report of services received , and patient satisfaction . Intervention effectiveness was investigated by assessing patient knowledge , self-efficacy , health behaviors , and clinical outcomes . RESULTS Carve-out patients received on average 4.3 contacts ( SD = 2.2 ) from the telephone-based diabetes educator versus 1.7 contacts ( SD = 2.0 ) from the clinic nurse in the carve-in arm ( p setting action plans and rated the process more positively than carve-in patients ( p in diabetes knowledge , self-efficacy , or health behaviors were found between the two approaches . However , clinical outcomes did vary in multivariable analyses ; carve-out patients had a lower HbA1c ( β = −0.31 , 95 % CI −0.56 to −0.06 , p = 0.02 ) , systolic blood pressure ( β = −3.65 , 95 % CI −6.39 to −0.90 , p = 0.01 ) , and low-density lipoprotein ( LDL ) cholesterol ( β = −7.96 , 95 % CI −10.08 to −5.83 , p feasible than clinic-based models . Patients receiving the carve-out strategy also demonstrated better clinical outcomes compared to those receiving the carve-in approach . Study limitations and unclear causal mechanisms explaining change in patient behavior suggest that further research is needed",
"PURPOSE The present study evaluated whether an intervention using the SMS by personal cellular phone and internet would improve the levels of plasma glucose of obese type 2 diabetes at 3 , 6 , 9 , and 12 months . METHODS This is a quasi-experimental design with pre- and follow-up tests . Participants were recruited from the endocrinology outpatient department of tertiary care hospital located in an urban city of South Korea . Eighteen patients were r and omly assigned to an intervention group and 16 to a control group . The goal of the intervention was to decrease body weight and keep blood glucose concentrations close to the normal range . Patients were requested to record their blood glucose level in a weekly diary on the website by personal cellular phones or computer internet . The research er sent optimal recommendations to each patient , by both the cellular phone and the Internet weekly . The intervention was applied for 1 year . RESULTS Glycosylated hemoglobin ( HbA(1)c ) decreased 1.22 percentage points at 3 months , 1.09 percentage points at 6 months , 1.47 percentage points at 9 months , and 1.49 percentage points at 12 months compared with baseline in the intervention group ( all time points , p 2-h post-pr and ial test ( 2HPPT ) of 120.1mg/dl at 3 months , 58.9 mg/dl at 6 months , 62.0mg/dl at 9 months , and 102.9 mg/dl at 12 months compared with baseline ( all time points , p web-based intervention using SMS of personal cellular phone and Internet improved HbA(1)c and 2HPPT at 3 , 6 , 9 , and 12 months in patients with obese type 2 diabetes",
"Objective To compare the American Diabetes Association st and ards for the medical care of diabetic patients with reported care patterns . Research Design and Methods These st and ards were compared with reported care patterns obtained from a stratified r and om telephone survey of general practitioners , family physicians , and general internists in Pennsylvania . A total of 610 physicians completed the survey for a response rate of 73 % . Results All primary -care physicians reported measurement of glycosylated hemoglobin , routine referrals to eye doctors , and patient self-monitoring of blood glucose foot exams , but the exams were infrequent for many of the physicians . Significant and independent differences ( P referral to eye doctors , measurement of glycosylated hemoglobin , and use of patient self-monitoring of blood glucose . General practitioners reported the lowest frequency of foot exams . Conclusions Educational programs on diabetes for primary -care physicians should focus on reported behaviors most different from recommended st and ards and may need to target subgroups of physicians to achieve a more uniform level of care for all diabetic patients",
"OBJECTIVE To determine whether a system of telemedicine support can improve glycemic control in type 1 diabetes . RESEARCH DESIGN AND METHODS A 9-month r and omized trial compared glucose self-monitoring real-time result transmission and feedback of results for the previous 24 h in the control group with real-time graphical phone-based feedback for the previous 2 weeks together with nurse-initiated support using a web-based graphical analysis of glucose self-monitoring results in the intervention group . All patients aged 18 - 30 years with HbA(1c ) ( A1C ) levels of 8 - 11 % were eligible for inclusion . RESULTS A total of 93 patients ( 55 men ) with mean diabetes duration ( means + /- SD ) 12.1 + /- 6.7 years were recruited from a young adult clinic . In total , the intervention and control groups transmitted 29,765 and 21,400 results , respectively . The corresponding median blood glucose levels were 8.9 mmol/l ( interquartile range 5.4 - 13.5 ) and 10.3 mmol/l ( 6.5 - 14.4 ) ( P reduction in A1C in the intervention group after 9 months from 9.2 + /- 1.1 to 8.6 + /- 1.4 % ( difference 0.6 % [ 95 % CI 0.3 - 1.0 ] ) and a reduction in A1C in the control group from 9.3 + /- 1.5 to 8.9 + /- 1.4 % ( difference 0.4 % [ 0.03 - 0.7 ] ) . This difference in change in A1C between groups was not statistically significant ( 0.2 % [ -0.2 to 0.7 , P = 0.3 ) . CONCLUSIONS Real-time telemedicine transmission and feedback of information about blood glucose results with nurse support is feasible and acceptable to patients , but to significantly improve glycemic control , access to real-time decision support for medication dosing and changes in diet and exercise may be required",
"BACKGROUND Obesity and its cardiovascular complications are extremely common medical problems , but evidence on how to accomplish weight loss in clinical practice is sparse . METHODS We conducted a r and omized , controlled trial to examine the effects of two behavioral weight-loss interventions in 415 obese patients with at least one cardiovascular risk factor . Participants were recruited from six primary care practice s ; 63.6 % were women , 41.0 % were black , and the mean age was 54.0 years . One intervention provided patients with weight-loss support remotely -- through the telephone , a study -specific Web site , and e-mail . The other intervention provided in-person support during group and individual sessions , along with the three remote means of support . There was also a control group in which weight loss was self-directed . Outcomes were compared between each intervention group and the control group and between the two intervention groups . For both interventions , primary care providers reinforced participation at routinely scheduled visits . The trial duration was 24 months . RESULTS At baseline , the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) for all participants was 36.6 , and the mean weight was 103.8 kg . At 24 months , the mean change in weight from baseline was -0.8 kg in the control group , -4.6 kg in the group receiving remote support only ( P lost 5 % or more of their initial weight was 18.8 % in the control group , 38.2 % in the group receiving remote support only , and 41.4 % in the group receiving in-person support . The change in weight from baseline did not differ significantly between the two intervention groups . CONCLUSIONS In two behavioral interventions , one delivered with in-person support and the other delivered remotely , without face-to-face contact between participants and weight-loss coaches , obese patients achieved and sustained clinical ly significant weight loss over a period of 24 months . ( Funded by the National Heart , Lung , and Blood Institute and others ; Clinical Trials.gov number , NCT00783315 . )",
"AIM To evaluate the effectiveness and feasibility of reinforced follow-up via telecare mediated by the local pharmacist in contact with the hospital team to improve glycaemic control in children and adolescents with type 1 diabetes ( DT1 ) . METHODS One hundred patients , aged 8 to 17 years , with a history of DT1 of more than 1 year , with HbA(1c ) > = 8 % , were r and omly assigned to either the \" reinforced follow-up \" group ( RFG ) or the \" usual follow-up \" group ( UFG ) . The intervention consisted in downloading and then printing data stored in a glucometer every two weeks , by the local pharmacist . Printouts were faxed to the hospital team which then communicated adapted instructions for better glycemic control directly to the family . RESULTS Fifty patients were assigned to each group . The two groups were comparable at the beginning . 71 children had a doctor 's visit at 6 + /- 1 months ( 36 in RFG and 35 in UFG ) . At this date , there was no significant difference between the average HbA(1c ) levels of the two groups ( 9.12 + /- 1.46 in RFG versus 9.27 + /- 1.20 in UFG ) . We had various difficulties setting up and gaining compliance with the intervention procedure , which explains why only 33 children in the RFG transmitted at least one fax . CONCLUSION At this stage , the reinforced follow-up has not proved to be superior to the usual follow-up . However , it would be possible to make numerous improvements in order to make the former more feasible and probably more efficient",
"Background : This study examined whether mobile phone-based , one-way video messages about diabetes self-care improve hemoglobin A1c ( A1C ) and self-monitoring of blood glucose ( SMBG ) . Methods : This was a 1-year prospect i ve r and omized trial with two groups . The active intervention lasted 6 months . The study enrolled 65 people with A1C > 8.0 % who were established ( > 6 months ) patients in the endocrinology clinics of the Walter Reed Health Care System . Participants were r and omized to receive “ usual care ” or self-care video messages from their diabetes nurse practitioner . Video messages were sent daily to cell phones of study participants . Hemoglobin A1c and SMBG data were collected at 0 , 3 , 6 , 9 , and 12 months . Results : Participants who received the messages had a larger rate of decline in A1C than people who received usual care ( 0.2 % difference over 12 months , adjusting for covariates ; p = .002 and p = .004 for the interaction between time and group and for the quadratic effect of time by group , respectively ) . Hemoglobin A1c decline was greatest among participants who received video messages and viewed > 10 a month ( 0.6 % difference over 12 months , adjusting for covariates ; p Self-monitoring of blood glucose metrics were not related to the intervention . Conclusions : A one-way intervention using mobile phone-based video messages about diabetes self-care can improve A1C . Engagement with the technology is an important predictor of its success . This intervention is simple to implement and sustain",
"AIM Conventional follow-up of type 1 diabetic patients treated with continuous subcutaneous insulin infusion ( CSII ) was compared with intensive coaching using the Web and the cellular phone network for retrospective data transmission and short message service ( SMS ) . METHODS Thirty poorly controlled patients ( HbA1c 7.5 - 10 % ) were enrolled in a bicenter , open-label , r and omized , 12-month , two-period , crossover study . After a 1-month run-in period , 15 patients were r and omly assigned to receive weekly medical support through SMS based upon weekly review of glucose values , while 15 patients continued to download self-monitored blood glucose ( SMBG ) values on a weekly basis without receiving SMS . After 6 months , patients crossed over to the alternate sequence for 6 additional months . Visits at the clinic were maintained every 3 months . RESULTS Patients with long-st and ing inadequately controlled diabetes ( 24 + /- 13 years ) were included . A non-significant trend to reduction in HbA(1c ) ( -0.25+/-0.94 % , P mean glucose values ( -9.2+/-25 mg/dl , P=0.06 ) during the 6-month SMS sequence was observed as compared with the no-SMS period . No safety issue ( hypoglycemia , glucose variability ) was reported . Adherence to SMBG was not affected by the trial . Quality of life analysis suggests a significant improvement in DQOL global score , as well as the DQOL satisfaction with life subscale , during the SMS sequence . CONCLUSIONS Long-term telemedical follow-up of insulin pump-treated patients using a cellular phone- , SMS- and Web-based platform is feasible , safe , does not alter quality of life and associated with a trend toward improved metabolic control",
"PURPOSE The purpose of this study was to investigate the effectiveness of an educational intervention that used both cellular phones and the Internet to provide a short messaging service ( SMS ) relating to blood glucose , blood pressure , and serum lipid levels in postmenopausal women with impaired fasting glucose ( IFG ) . METHODS Twenty-eight postmenopausal women were assigned to an intervention group and twenty-one postmenopausal women to a control group . The intervention was provided for 12 weeks . Patients in the intervention group were asked to access a web site by using a cellular phone or to use the Internet directly and input their blood glucose and blood pressure levels weekly . Participants were sent the optimal recommendations weekly by both cellular phone and Internet . RESULTS The intervention group had a mean decrease in systolic blood pressure ( SBP ) level of 8.1 mmHg but changes for the control group were not significant . There was a significant mean change in diastolic blood pressure ( DBP ) level for the intervention group ( -7.7 mmHg ) . The mean change in the control group was not significant . CONCLUSION This educational intervention using the Internet and a SMS by cellular phone improved levels of SBP and DBP in postmenopausal women with IFG",
"OBJECTIVE To assess the effect of medical nutrition therapy ( MNT ) provided by dietitians on medical and clinical outcomes for adults with non-insulin-dependent diabetes mellitus ( NIDDM ) , and to compare MNT administered according to practice guidelines nutrition care ( PGC ) to MNT administered with basic nutrition care ( BC ) . DESIGN A prospect i ve , r and omized , controlled clinical trial of two levels of MNT on metabolic control in persons newly diagnosed with or currently under treatment for NIDDM was conducted at diabetes centers in three states ( Minnesota , Florida , and Colorado ) . BC consisted of a single visit with a dietitian ; PGC involved an initial visit with a dietitian followed by two visits during the first 6 weeks of the study period . Data were collected at entry to the study and at 3 and 6 months . SUBJECTS Results are reported for 179 men and women aged 38 to 76 years : 85 assigned r and omly to BC and 94 to PGC . This represents 72 % of the 247 subjects enrolled . An additional 62 adults with NIDDM at one site who had no contact with a dietitian were identified as a nonr and om comparison group . OUTCOMES Medical outcome measures included fasting plasma glucose ( FPG ) , glycated hemoglobin ( HbA1c ) , and serum lipid levels . Clinical outcomes included weight , body mass index , waist-to-hip ratio , and changes in medical therapy . STATISTICAL ANALYSES Initial analysis of the discrete variables was done using the chi 2 statistic with Yates ' correction . Initial analysis of continuous variables was done by analysis of variance . The changes in variables between time periods were analyzed by paired t test , and comparisons between groups were analyzed using a t test for independent groups . RESULTS At 6 months , PGC result ed in significant improvements in blood glucose control as indicated by FPG and HbA1c levels and BC result ed in significant improvements in HbA1c level . Participants assigned to the PGC group had a mean FPG level at 6 months that was 10.5 % lower than the level at entry , and those in the BC group had a 5.3 % lower value . Among subjects who had diabetes for longer than 6 months , those who received PGC had a significantly better HbA1c level at 3 months compared with those receiving BC . The comparison group showed no improvement in glycemic control over a comparable 6 months . PGC subjects had significant improvements in cholesterol values at 6 months , and subjects in both the PGC and the BC groups had significant weight loss . CONCLUSIONS MNT provided by dietitians result ed in significant improvements in medical and clinical outcomes in both the BC and PGC groups and is beneficial to persons with NIDDM . Persons with a duration of diabetes longer than 6 months tended to do better with PGC than with BC . Because of the upward trend in glucose levels after 3 months , ongoing MNT by dietitians is important for long-term metabolic control",
"BACKGROUND We undertook a feasibility study to evaluate feasibility and utility of short message services ( SMSs ) to support Iraqi adults with newly diagnosed type 2 diabetes . SUBJECTS AND METHODS Fifty patients from a teaching hospital clinic in Basrah in the first year after diagnosis were recruited to receive weekly SMSs relating to diabetes self-management over 29 weeks . Numbers of messages received , acceptability , cost , effect on glycated hemoglobin ( HbA1c ) , and diabetes knowledge were documented . RESULTS Forty-two patients completed the study , receiving an average 22 of 28 messages . Mean knowledge score rose from 8.6 ( SD 1.5 ) at baseline to 9.9 ( SD 1.4 ) 6 months after receipt of SMSs ( P=0.002 ) . Baseline and 6-month knowledge scores correlated ( r=0.297 , P=0.049 ) . Mean baseline HbA1c was 79 mmol/mol ( SD 14 mmol/mol ) ( 9.3 % [ SD 1.3 % ] ) and decreased to 70 mmol/mol ( SD 13 mmol/mol ) ( 8.6 % [ SD 1.2 % ] ) ( P=0.001 ) 6 months after the SMS intervention . Baseline and 6-month values were correlated ( r=0.898 , P=0.001 ) . Age , gender , and educational level showed no association with changes in HbA1c or knowledge score . Changes in knowledge score were correlated with postintervention HbA1c ( r=-0.341 , P=0.027 ) . All patients were satisfied with text messages and wished the service to be continued after the study . The cost of SMSs was € 0.065 per message . CONCLUSIONS This study demonstrates SMSs are acceptable , cost-effective , and feasible in supporting diabetes care in the challenging , re source -poor environment of modern-day Iraq . This study is the first in Iraq to demonstrate similar benefits of this technology on diabetes education and management to those seen from its use in better-re source d parts of the world . A r and omized controlled trial is needed to assess precise benefits on self-care and knowledge ",
"RATIONALE , AIMS AND OBJECTIVES Utilizing information technology , such as Internet and cellphones , holds great promise in enhancing diabetic care . Yet few studies have examined the impact of cellphone technology on type 2 diabetics ' self-care . The primary aim of the study is to examine the feasibility of utilizing this technology to assist with diabetes self-care in a clinic population as well as its impact on clinical outcomes . METHODS Thirty patients with a diagnosis of type 2 diabetes at two Community Health Centers were r and omized to intervention or control . Intervention patients participated in a brief intervention and received tailored daily messages via cellphone prompting them to enhance their diabetic self-care behaviour . Patients at the control site continued with their st and ard diabetes self-management . RESULTS A mean improvement in HbA1c levels was apparent ( -0.1 , SD = 0.3 % ; P = 0.1534 ) in the intervention group , compared with a mean deterioration in the control ( 0.3 , SD = 1.0 % ; P = 0.3813 ) , yet without statistical significance . Self-efficacy scores improved significantly in the intervention group ( -0.5 , SD = 0.6 ; P = 0.0080 ) compared with no improvement in the control ( 0.0 , SD = 1.0 ; P = 0.9060 ) . Participants encountered numerous technological barriers when attempting to adhere to the intervention protocol . CONCLUSION The results indicate the intervention had a positive impact on some clinical outcome and self-efficacy . Although the technology appears feasible in a clinical setting technology must be made more user-friendly before a larger phase II trial is conducted",
"OBJECTIVE To determine if scheduled telephone calls from a pediatric diabetes educator to children who have type 1 diabetes improve hemoglobin A1c ( HbA1c ) level , hospital admissions , diabetes knowledge , compliance , and psychological well-being . RESEARCH DESIGN AND METHODS A r and omized controlled trial of 123 young subjects ( mean age 11.9 yr , 69 male ) with type 1 diabetes ( mean duration 3.65 yr ) . For 7 months , the intervention group held bimonthly 15 - 30 min scheduled supportive telephone discussion s. The primary outcome was change in the HbA1c level . Admission rates and changes in diabetes knowledge , psychological parameters , compliance , and patient perception were measured . RESULTS There was no significant difference between the treatment and control groups either before or after the intervention . The mean HbA1c level in the control group increased from 8.32 to 8.82 % and in the intervention group from 8.15 to 8.85 % ( p = 0.24 ) . Both groups showed an increase in admissions of 0.2 per yr ( p = 0.57 ) . There was no improvement in diabetes knowledge ( p = 0.34 ) , compliance , or psychological function . The intervention group viewed their contact with the clinic as more helpful ( p = 0.003 ) . Analysis of family function did not reveal subgroups with statistically significant differences . A mean of 13 calls was made to each subject at a cost of 36 Australian dollars per child per month . CONCLUSIONS Scheduled bimonthly phone support does not improve the HbA1c level , admission rates , diabetes knowledge , psychological function , or self-management but is perceived by patients as helpful . Further study into the effects of more frequent but shorter periods of support for patients experiencing specific difficulties is needed",
"Patients with Type 2 ( non-insulin-dependent ) diabetes mellitus ( DM ) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas ' fail ' . The rate of failure and the features of those who fail have been poorly described . To assess secondary failure rates of sulphonylureas , we report on the responses in 1305 patients with newly diagnosed Type 2 DM r and omly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospect i ve Diabetes Study ( UKPDS ) . These patients were initially treated by diet for 3 months and had a fasting plasma glucose > 6 mmol l(-1 ) ; mean age 53 ( SD 9 ) years ; BMI 26.8 ( SD 5.0 ) kg m(-2 ) ; and median fasting plasma glucose 9.1 ( 7.6 - 12.5 quartiles ) mmol l(-1 ) . If their fasting plasma glucose subsequently rose above 15.0 mmol l(-1 ) , or they developed hyperglycaemic symptoms , additional hypoglycaemic therapy was given : metformin , ultratard insulin , and soluble insulin as required . By 6 years , 44 % had required additional therapy . Of those r and omized to glibenclamide , 48 % required additional therapy by 6 years , compared with 40 % of those allocated to chlorpropamide ( p fasting plasma glucose > or = 10.0 mmol l(-1 ) , > or = 7.8 mmol l(-1 ) to additional therapy ( p additional therapy than obese patients ( BMI > or = 30 kg m(-2 ) ) ( 43 % vs 53 % at 6 years ; p beta-cell function showed that those with lower function were more likely to fail ( p sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially . Higher failure rates were found in those with higher glucose concentrations , those who were younger , those with lower beta-cell reserve and those r and omized to glibenclamide compared with chlorpropamide",
"Background : The DIABTel system , a Web-based telemedicine application , integrates a whole communication system ( glucometer , insulin pump , wireless h and -held assistant ) for medical remote advice . We sought to evaluate , in terms of glycemic control , the DIABTel system in a r and omized crossover clinical study . Methods : Ten patients with type 1 diabetes [ 5 women , age 40.6 ( 21–62 ) years , diabetes duration 14.7 ( 3–52 ) years ] were included . During the 4-week active phase , data sent by patients were analyzed by the physician and modifications of the basal rate and bolus were advised in the following 24 hours . During the control phase , patients sent glucose data without any feedback from the medical center . Results : The mean numbers of daily glucose values and bolus sent by patients during the active period were 4.46 ± 0.91 and 4.58 ± 0.89 , respectively . The personal digital assistant functionalities used more frequently by patients were ( times per week ) data visualization ( 8.1 ± 6.8 ) , data download from the insulin pump ( 6.8 ± 3.3 ) , and synchronization with the telemedicine server ( 8.5 ± 4.9 ) . After the experimental phase , serum fructosamine decreased significantly ( 393 ± 32 vs 366 ± 25 μmol/liter ; p and hemoglobin A1c ( HbA1c ) tended to decrease ( 8.0 ± 0.6 vs 7.78 ± 0.6 ; p = 0.073 ) , whereas no changes were observed during the control phase . The number of treatment modifications proposed and performed by the patients correlated with the change observed in HbA1c during the active phase ( r = −0.729 , p = 0.017 ) . Conclusions : The DIABTel system , a telemedicine system that includes a wireless personal assistant for remote treatment advising , allows better glycemic control in pump-treated patients with type 1 diabetes . To our knowledge , this is the first study that demonstrates improved glycemic control with the use of a telemedicine system that incorporates insulin delivery data",
"AIM The aim of this paper was to test in teenagers with type 1 diabetes mellitus ( T1DM ) the Glucobeeb ( Gb ) , a web based tool to support the diabetes care . METHODS Gb transfers glucometer 's data by phone and Internet to the PC of practitioner in files dedicated to each patient ; the response returns to patient as 1-min vocal message . From out patients paediatric clinic 28 teenagers ( mean 14.8 years , range 10 - 20 , male 14 ) with T1DM on multiple daily injections insulin therapy , with glicated haemoglobin ( HbA1c ) over 7 % and > 2 years ' duration of the disease ( 9.1 years , range 2 - 15 ) , were consequently r and omized to telecare ( glucometer transmission with feedback , group A ) or control ( st and ard communication by phone and face-to-face visits , group B ) . Glycaemia was tested four times per day and data transmitted every 2 weeks ; clinician feedback returned within the following week . Two controls were excluded after r and omization . Outcomes of 14 patients of A were compared with 12 of B. RESULTS In intervention group average HbA1c% decreased from baseline at 3 and 6 months in comparison with controls ( 9.5 , 9.0 , 9.1 , vs 9.1 , 9.4 , 9.4 respectively ) . Controls after 6 months were introduced to Gb , and similar trend of HbA1c was observed in the following examinations at 3 and 6 month ( 9.4 , 8.9 , 8.7 ) . Then , in both groups HbA1c after 12 months of Gb increased , and after 18 reduced ( A : 9.2 , and 8.8 , B 9.1 and 8.5 respectively ) . The enhancement of HbA1c from baseline to end was significant ( P=0.01 ) . CONCLUSION The tool improves metabolic control in teenagers with T1DM",
"OBJECTIVE To compare the effects of real-time continuous glucose monitoring ( RT-CGM ) and an Internet blood glucose monitoring system ( IBGMS ) on glycated hemoglobin levels in patients with type 2 diabetes mellitus treated with insulin . METHODS Fifty-seven patients with type 2 diabetes treated with insulin were assigned r and omly to 1 of 2 groups . Group 1 had the results of their self-monitoring of blood glucose level monitored biweekly using an IBGMS . Group 2 used RT-CGM and were monitored biweekly . Both groups used a secure website to upload data and to receive feedback from their endocrinologist . A1C and laboratory test results were collected at 0 , 3 and 6 months . RESULTS The baseline parameters were not significantly different . After a 6-month follow-up period , both IBGMS and RT-CGM showed significant within-group improvements in A1C level . In the IBGMS group , the A1C level decreased from 8.79%±1.25 % to 7.96%±1.30 % ( p ) . The RT-CGM group decreased from 8.80%±1.37 % to 7.49%±0.70 % ( p ) . IBGMS and RT-CGM did not show significantly different A1C levels at baseline , 3 and 6 months ( p>0.05 ) . CONCLUSIONS The use of both IBGMS and RT-CGM significantly improved A1C levels in patients with type 2 diabetes treated with insulin in a r and omized trial over a 6-month period . There were no significant differences in A1C values between groups after 6 months",
"BACKGROUND Patients with insulin dependent diabetes require frequent advice if their metabolic control is not optimal . This study focuses on the fiscal and administrative aspects of telemanagement , which was used to establish a supervised autonomy of patients on intensified insulin therapy . METHODS A prospect i ve , r and omised trial with 43 patients on intensified insulin therapy was conducted . Travelling distance to the diabetes centre was 50 min one way ; all patients had undergone a diabetes education course with lessons in dose adaptation . Patients were r and omly assigned to telecare ( n=27 ) or conventional care ( n=16 ) . They used BG-meters with a storage capacity of 120 values ( Precision QID Abbott/Medisense ) and transmitted their data over a combined modem/interface via telephone line to the diabetes centre . Data were displayed and stored by a customised software ( Precision Link Plus , Abbott/Medisense ) . Advice for proper dose adjustment was given by telephone . RESULTS Average time needed for instruction in the telemedical system was 15 min . Data were transmitted every 1 - 3 weeks and a teleconsultation was performed by phone every 2 - 4 weeks , depending on the extent of specific problems . On average , personal visits in the control group were performed once a month . Physician 's time expenditure for telemanagement , compared to conventional advice was moderately higher ( 50 vs. 42 min per month ) . A substantial amount of time on the patients side could be saved through replacing personal communications by telephone contacts and data transmission reduction ( 96 vs. 163 min/month including data transmission time ) . Setting up an optimal telemanagement scenario , a cost analysis was carried out yielding savings of approximately 650 euro per year per patient . HbA(1c ) dropped significantly from 8.2 to 7.0 % after 8 months of observation , but there was no significant difference between the intervention and control groups . Major technical problems with the telematic system did not occur during the study . CONCLUSIONS Telemanagement of insulin-requiring diabetic patients is a cost and time saving procedure for the patients and results in metabolic control comparable to conventional outpatient management",
"This study was performed to investigate the effect of a telephone-delivered intervention on glycemic control and body mass index in Korean type 2 diabetic patients . 38 patients were r and omly selected , with 20 assigned to a telephone group and 18 to a control group . The goal of the intervention was to keep blood glucose concentrations close to the normal range . The intervention was applied to the telephone group for 12 weeks . It consisted of continuous education and reinforcement of diet , exercise and medication adjustment , as well as frequent self-monitoring of blood glucose levels . Telephone intervention was performed twice per week for the first month , and then weekly for the second and third months . Subjects were requested to write self- management logs , including blood glucose , diet and an exercise diary . The diet diaries were analyzed by a dietitian , and subjects instructed about the results by telephone counseling or mail . All medication adjustments were communicated to the subjects ' diabetes specialist . Glycosylated hemoglobin ( HbA1c ) , fasting blood glucose ( FBG ) and 2-hour postpr and ial glucose were measured before , and after , the intervention . Patients in the telephone group had a mean decrease of 1.2 % , with those in the control group having a mean increase of 0.6 % , in HbA1c . There were no significant differences in the body mass index ( BMI ) between the two groups . These findings indicated that a telephone-delivered intervention would improve HbA1c , but would not affect BMI",
"BACKGROUND Today 's generation of young adults are gaining weight faster than their parents ; however , there remains insufficient evidence to inform interventions to prevent this weight gain . Mobile phones are a popular means of communication that may provide a convenient , inexpensive means to deliver health intervention programmes . This pilot study aim ed to measure the effect of a 12-week mobile health ( mHealth ) intervention on body weight , body mass index and specific lifestyle behaviours addressed by the programme . METHODS University students and staff aged 18 - 35 years ( n = 51 ) were r and omised ( ratio 1 : 1 , intervention : control ) . Both groups received a printed diet booklet with instructions prepared by a dietitian . The intervention group also received Short Message Service ( SMS ) text messages ( four per week ) , e-mails ( four per week ) , and had access to smartphone applications and Internet forums . RESULTS Pre- to post-intervention , participants in the intervention group decreased their body weight [ mean ( SD ) ] [ -1.6 ( 2.6 ) kg ] , increased their light intensity activity [ 34 ( 35 ) min day(-1 ) ] and reported an increased vegetable ( 1.0 median serving day(-1 ) ) and decreased sugar-sweetened beverage intake [ -355 ( 836 ) mL week(-1 ) ] . Despite this , post-intervention changes in outcomes were not significantly different from controls . CONCLUSIONS The piloted mHealth programme provided some short-term positive changes in weight , nutrition and physical activity using a low cost , convenient delivery method for this population . However , changes were no different from those observed among controls . This might partly be explained by intervention participants ' low engagement with the programme , which is likely to require further modification to provide more regular , personalised , monitored support",
"Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions who experience barriers to access to care or a high burden of illness . We conducted a r and omized controlled trial comparing telemedicine case management to usual care , with blinding of those obtaining outcome data , in 1,665 Medicare recipients with diabetes , aged 55 years or greater , and living in federally design ated medically underserved areas of New York State . In New York City , 98 % of participants were black or Hispanic , 69 % were Medicaid-eligible , and 93 % reported annual household income A baseline survey found that 95 % of participants in New York City and 67 % in upstate New York reported that they did not know how to use a computer . The primary endpoints were HgbA1c , blood pressure , and low density lipoprotein ( LDL ) cholesterol levels . In the intervention group ( N = 844 ) , mean HgbA1c improved over 1 year from 7.35 % to 6.97 % , and from 8.35 % to 7.42 % in the subgroup with baseline HgbA1c > or = 7 % ( N = 353 ) . In the usual care group ( N = 821 ) , mean HgbA1c improved over 1 year from 7.42 % to 7.17 % . Adjusted net reductions ( 1-year minus baseline mean values in each group , compared between groups ) favoring the intervention were as follows : HgbA1c , 0.18 % ( p = 0.006 ) , systolic and diastolic blood pressure , 3.4 ( p = 0.001 ) and 1.9 mmHg ( p LDL cholesterol , 9.5 mg/dl ( p or = 7 % , net adjusted reduction in HgbA1c favoring the intervention group was 0.32 % ( p = 0.002 ) . Mean LDL cholesterol level in the intervention group at one year was 95.7 mg/dl . The intervention effects were similar in magnitude in the subgroups living in New York City and upstate New York . A satisfaction survey of intervention group participants ( N = 346 respondents ) showed high levels of satisfaction with major intervention components . A satisfaction survey of participating primary care physicians ( N = 116 respondents ) showed positive perceptions for acceptability , impact on patients and communication . Telemedicine case management improved glycemic control , blood pressure levels , and total and LDL-cholesterol levels at 1 year of follow-up . Telemedicine is an effective method for translating modern approaches to disease management into effective care for underserved population",
"BACKGROUND Type 2 diabetes mellitus is increasing in incidence and research has shown that normalization of blood glucose levels can moderate the risk of microvascular and neurological complications . AIM The purpose of this study was to investigate the effect of nurse telephone calls on glycosylated haemoglobin ( HbA1c ) levels and adherence to diabetes control recommendations . METHODS A r and omized design with control and experimental groups being assessed pre- and post intervention was used to assess the effectiveness of nurse telephone calls . Twenty patients were r and omly assigned to an intervention group and 16 to a control group . The goal of the intervention was to keep blood glucose concentrations close to the normal range ( HbA1c continued education and reinforcement of diet , exercise , medication adjustment recommendations , as well as frequent self-monitoring of blood glucose levels . Telephone intervention was performed twice per week for the first month and then weekly for the second and third month . Participants were requested to write self-management logs including blood glucose levels , diet and an exercise diary . A dietitian analysed the diet diaries and participants were informed about their results by telephone or mail . All medication adjustments were communicated to participants ' doctors . The HbA1c and diabetes adherence were measured before and after the intervention . RESULTS Patients in the intervention group had a mean decrease of 1.2 % in HbA1c levels and those in the control group had a mean increase of 0.6 % in HbA1c levels . The intervention group had greater diet and blood glucose testing adherence than the control group . CONCLUSION These findings indicate that a nurse telephone intervention can improve HbA1c , and diet and blood glucose testing adherence",
"We conducted a pilot study of the effectiveness of individual counselling sessions provided by a dietician through telemedicine for patients with diabetes . All participants received a single group education session via videoconference . Those who were r and omized to the intervention also received two additional follow-up sessions , four and eight weeks later . Glycosylated haemoglobin and total cholesterol were measured at the start and again 16 weeks later . The patients completed diabetes quality -of-life and telemedicine patient satisfaction surveys . Thirty-two participants consented to participate . Complete data were collected on 13 intervention and 13 control patients . There was a 1 % fall in HbA1c in the intervention group from pre- to post- assessment , although this was not significant . The control group showed a significantly larger fall in HbA1c levels than the intervention group ( P = 0.043 ) . Total cholesterol decreased in both groups , although not significantly . All control and intervention group participants indicated that they would participate in videoconferencing nutritional counselling again . The results suggest that providing nutritional therapy via videoconferencing may be useful in assisting patients to manage their conditions",
"BACKGROUND Daily weighing is emerging as the recommended self-weighing frequency for weight loss . This is likely because it improves adoption of weight control behaviors . OBJECTIVE To examine whether weighing every day is associated with greater adoption of weight control behaviors compared with less frequent weighing . DESIGN Longitudinal analysis of a previously conducted 6-month r and omized controlled trial . PARTICIPANTS / SETTING Overweight men and women in Chapel Hill , NC , participated in the intervention arm ( N=47 ) . INTERVENTION The intervention focused on daily weighing for weight loss using an e-scale that transmitted weights to a study website , along with weekly e-mailed lessons and tailored feedback on daily weighing adherence and weight loss progress . MAIN OUTCOME MEASURES We gathered objective data on self-weighing frequency from the e-scales . At baseline and 6 months , weight change was measured in the clinic and weight control behaviors ( total items=37 ) , dietary strategies , and calorie expenditure from physical activity were assessed via question naires . Calorie intake was assessed using an online 24-hour recall tool . STATISTICAL ANALYSES We used χ(2 ) tests to examine variation in discrete weight control behaviors and linear regression models to examine differences in weight , dietary strategies , and calorie intake and expenditure by self-weighing frequency . RESULTS Fifty-one percent of participants weighed every day ( n=24 ) over 6 months . The average self-weighing frequency among those weighing less than daily ( n=23 ) was 5.4±1.2 days per week . Daily weighers lost significantly more weight compared with those weighing less than daily ( mean difference=-6.1 kg ; 95 % CI -10.2 to -2.1 ; P=0.004 ) . The total number of weight control behaviors adopted was greater among daily weighers ( 17.6±7.6 vs 11.2±6.4 ; P=0.004 ) . There were no differences by self-weighing frequency in dietary strategies , calorie intake , or calorie expenditure . CONCLUSIONS Weighing every day led to greater adoption of weight control behaviors and produced greater weight loss compared with weighing most days of the week . This further implicates daily weighing as an effective weight loss tool",
"BACKGROUND Control of serum glucose levels is essential for the reduction of complications of diabetes . Telemedicine is one strategy through which serum glucose control can be improved . METHODS A total of 35 adult , insulin-treated patients with diabetes ( type 1 and type 2 ) were enrolled in the present study ( 63.0 + /- 10 years of age , 63 % female ) and r and omized to telemedicine monitoring ( including cordless , remote glucose monitor , and transmitter , n = 17 ) , or conventional follow-up ( n = 18 ) . Metabolic parameters were evaluated , and a quality of life question naire was administered both pre- and post-treatment . RESULTS Groups were similar at baseline in terms of demographic , quality of life , and metabolic parameters . Significant differences in post-treatment metabolic parameters were not observed , although serum glucose was marginally elevated in the control group compared to the telemedicine group ( 214 + /- 65 mg/dL vs. 171 + /- 77 mg/dL , P = 0.09 ) . On the other h and , being clinical ly symptom-free ( 71 % vs. 11 % , P = 0.003 ) , having no hypoglycemic events ( 82 % vs. 17 % , P = 0.0001 ) , and having no hyperglycemic events ( 65 % vs. 17 % , P = 0.004 ) were all significantly more frequently reported in the telemedicine group compared to the control group . Compared to the control group , the telemedicine group reported experiencing significantly less anxiety , treatment difficulty , depression , disease-associated life complications , and feelings of impotence or ineptitude and significantly greater improvement in personal control over glucose , weight , and overall diabetes . CONCLUSIONS Though post-treatment metabolic differences were not observed between treatment groups , the telemedicine group reported significantly greater post-treatment experiences of improved quality of life and sense of control over the disease . Thus patient satisfaction can be enhanced through the use of telemedicine",
"BACKGROUND The aim of this study is to evaluate the effect of a web-based comprehensive information system , consisting of Internet and cellular phone use , on blood glucose control . METHODS We established eMOD ( electronic Management of Diabetes ) , a web-based ubiquitous information system , for cell phone users along with a website for Internet users to provide diabetes education . We examined whether this information system has the same impact on glycemic control as conventional education for the diabetes patient . Forty volunteers were enrolled and r and omly assigned to either the eMOD experimental group ( n = 20 ) or the control group ( n = 20 ) . Blood glucose and glycated hemoglobin ( A1C ) levels were evaluated at baseline and after 6 months . RESULTS The two groups were homogeneous in terms of age , sex , and diabetes ' duration at baseline . A1C ( from 9.0 + /- 2.3 % to 7.5 + /- 1.4 % , P = 0.031 ) and postpr and ial glucose level ( 228.1 + /- 79.7 to 173.5 + /- 50.2 mg/dL , P = 0.030 ) were significantly decreased over time in the intervention group but not in the control group . There was a significant relationship between the change in A1C and the frequency of access to the eMOD system via cellular phone ( r = 0.766 , P = 0.03 ; coefficient -0.147 ) . CONCLUSIONS A1C was improved by a web-based intervention not only via computer but also via cellular phone at 6 months post-initiation in patients with type 2 diabetes . These results indicate that the use of a convenient web-based education system could be more effective for glycemic control than traditional education for diabetes patients"
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Background Many preschoolers spend a substantial portion of their day enrolled in centre-based childcare ; the amounts of physical activity and sedentary time accumulated in this environment are critical to preschoolers ’ ability to meet movement guidelines . The purpose of this systematic review was to provide a comprehensive overview of the objective ly assessed physical activity and sedentary time of preschoolers in centre-based childcare ( registration no. CRD42016033502 ) . Methods Eight online data bases were search ed using terms related to physical activity , sedentary time , preschoolers and centre-based childcare . Published , peer- review ed primary studies written in English that objective ly assessed ( via accelerometry ) the physical activity and sedentary time of preschoolers ( 2 - 5 years ) in centre-based childcare were included . Results Fifty-five studies ( published 2004 - 2017 ) from 11 countries , representing 13,956 participants were included . Studies reported light physical activity ( n=38 ) ranging from 2.94 to 29.96 mins/hr , moderate-to-vigorous physical activity ( n=46 ) which ranged from 1.29 to 22.66 mins/hr , and total physical activity ( n=42 ) ranging from 4.23 to 47.17 mins/hr . Sedentary time ( n=47 ) ranged from 12.38 to 55.77 mins/hr . Conclusion Physical activity and sedentary time were highly varied and inconsistent between studies ; therefore , it is difficult to determine preschoolers ’ true amount of physical activity and sedentary time during childcare hours . Despite this variability , preschoolers were noted to participate in high rates of sedentary time in this setting . The lack of homogeneity is an important finding in and of itself as it highlights the lack of consistency in measuring , processing , and reporting paediatric physical activity data
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"INTRODUCTION This study evaluated whether intervening with child care providers would increase physical activity ( PA ) and reduce adiposity in preschoolers . METHODS This was a two-arm , parallel group , cluster RCT whereby six child care centers were r and omly assigned in equal numbers to intervention ( n=40 children ) or control ( n=43 children ) . Participants were aged 3 - 5 years and attended licensed child care centers . Child care providers received two 3-hour train-the-trainer workshops and a training manual at program initiation aim ed at increasing structured and unstructured PA through active play . Control child care centers implemented their st and ard curriculum . PA and sedentary behavior were measured by accelerometry , and body composition was measured using bioelectrical impedance at baseline and 6 months . Data were collected in 2011 - 2012 and analyzed in April 2015 . RESULTS Linear mixed-effects modeling showed that at 6 months , children in the intervention group demonstrated greater increases in minutes per preschool day spent in overall PA ( 22.5 minutes , 95 % CI=8.9 , 36.1 , p=0.002 ) , and light-intensity PA ( 16.1 minutes , 95 % CI=5.2 , 26.7 , p=0.004 ) , but changes between groups in moderate to vigorous PA did not differ . The intervention group showed greater reductions in body fat percentage ( -1.9 % , 95 % CI=-3.5 , -0.3 , p=0.023 ) and fat mass ( -0.3 kg , 95 % CI=-0.7 , -0.1 , p=0.018 ) , but groups did not differ on fat-free mass , BMI , or z- BMI . CONCLUSIONS Provider-led intervention in child care centers increased preschoolers ' PA and reduced adiposity , therefore may represent a viable approach to promoting PA and related health benefits in preschool-aged children . TRIAL REGISTRATION This study is registered at www . clinical trials.gov NCT02293278",
"This pilot study examined the effects of a teacher-taught , locomotor skill (LMS)-based physical activity ( PA ) program on the LMS and PA levels of minority preschooler-aged children . Eight low-socioeconomic status preschool classrooms were r and omized into LMS-PA ( LMS-oriented lesson plans ) or control group ( supervised free playtime ) . Interventions were delivered for 30 min/day , five days/week for six months . Changes in PA ( accelerometer ) and LMS variables were assessed with MANCOVA . LMS-PA group exhibited a significant reduction in during-preschool ( F ( 1,16 ) = 6.34 , p = .02 , d = 0.02 ) and total daily ( F ( 1,16 ) = 9.78 , p = .01 , d = 0.30 ) percent time spent in sedentary activity . LMS-PA group also exhibited significant improvement in leaping skills , F ( 1 , 51 ) = 7.18 , p = .01 , d = 0.80 ) . No other , significant changes were observed . The implementation of a teacher-taught , LMS-based PA program could potentially improve LMS and reduce sedentary time of minority preschoolers",
"OBJECTIVE : To identify correlates of objective ly measured moderate and vigorous physical activity ( MVPA ) in children during preschool attendance . METHODS : This cross-sectional study included data from 426 apparently healthy Danish children ( 49.5 % boys ) , 5 to 6 years of age enrolled in 42 r and omly selected preschools . The percentage of time spent in MVPA ( ≥574 counts/15 second ) during preschool attendance was measured using ActiGraph accelerometers over 4.3 preschool days in May and June in 2009 . Thirty-seven potential correlates across the child , preschool staff , and preschool environment domains were tested for associations with MVPA . RESULTS : The final multivariate model identified 9 significant correlates of MVPA . Preterm birth , vegetation on the playground , and rainy days were negatively associated with MVPA , whereas child motor coordination , location of preschool building on the playground , gender ( boys ) , percentage afternoon hours , and size of indoor area per child were positively associated with MVPA . The direction of the significant association with the parental mean education level was unclear . CONCLUSIONS : We identified a number of new modifiable correlates of MVPA during preschool attendance . The positive association with size of indoor area per child and location of the preschool building on the playground seem important correlates to be targeted in future studies",
"Background In preschoolers , high levels of sedentary behaviour are associated with several adverse health outcomes . The purpose of this study is to report the effects of the ToyBox-intervention ( a European 24-week cluster r and omised controlled trial ) on sedentary behaviour in preschoolers . Methods In Belgium , 859 preschoolers from 27 kindergartens ( 15 intervention and 12 control ) wore an accelerometer to objective ly measure their sedentary time and 1715 parents/caregivers completed a question naire to assess sedentary activities in which preschoolers participate at home . Main outcomes were objective ly measured sedentary time , time spent watching TV , using the computer and time spent in quiet play . Multilevel repeated measures analyses were conducted to take clustering into account . Intention to treat analysis was used to h and le missing data . Results A sample of 859 ( 29.5 % of all contacted children ) preschoolers ( 4.4 ± 0.6 years , 54.4 % boys ) provided valid accelerometer data at either baseline or follow-up and parents of 1715 ( 58.9 % of all contacted children ) preschoolers ( 4.4 ± 0.5 years , 52.5 % boys ) completed a question naire at either baseline or follow-up . No intervention effects were found on objective ly and subjectively measured total sedentary time in the total sample . However , some effects on objective ly and subjectively measured sedentary time were found in specific subgroups . Preschoolers from the intervention group from high SES kindergartens and preschoolers with high levels of sedentary time at baseline decreased their sedentary time , while preschoolers from the control group increased their sedentary time . Girls in the intervention group decreased their TV viewing time during weekend days ( -5.83 min/day ) , while girls ’ & TV viewing in the control group increased ( + 4.15 min/day ) . In low SES kindergartens , a smaller increase for computer time during weekend days was found in preschoolers in intervention kindergartens ( + 6.06 min/day ) than in control kindergartens ( + 12.49 min/day ) . Conclusion While some small positive effects were found in some sub-groups , the ToyBox-intervention had no effect on objective ly and subjectively measured sedentary time in the total sample . A longer period to implement the intervention and a more active involvement of parents/caregivers might enhance intervention effects . The ToyBox- study is registered with the clinical trials registry clinical trials.gov , ID : NCT02116296",
"The aim of this study was to assess the feasibility , acceptability and potential efficacy of a physical activity program for preschool children . A 20-week , 2-arm parallel cluster r and omized controlled pilot trial was conducted . The intervention comprised structured activities for children and professional development for staff . The control group participated in usual care activities , which included design ated inside and outside playtime . Primary outcomes were movement skill development and objective ly measured physical activity . At follow-up , compared with children in the control group , children in the intervention group showed greater improvements in movement skill proficiency , with this improvement statically significant for overall movement skill development ( adjust diff . = 2.08 , 95 % CI 0.76 , 3.40 ; Cohen 's d = 0.47 ) and significantly greater increases in objective ly measured physical activity ( counts per minute ) during the preschool day ( adjust diff . = 110.5 , 95 % CI 33.6 , 187.3 ; Cohen 's d = 0.46 ) . This study demonstrates that a physical activity program implemented by staff within a preschool setting is feasible , acceptable and potentially efficacious",
"Background Most preschool centers provide two 30-min sessions of gross-motor/outdoor playtime per preschool day . Within this time frame , children accumulate most of their activity within the first 10 min . This paper describes the design and baseline participant characteristics of the Short bouTs of Exercise for Preschoolers ( STEP ) study . The STEP study is a cluster r and omized controlled study design ed to examine the effects of short bouts of structured physical activity ( SBS-PA ) implemented within the classroom setting as part of design ated gross-motor playtime on during-school physical activity ( PA ) in preschoolers . Methods / Design Ten preschool centers serving low-income families were r and omized into SBS-PA versus unstructured PA ( UPA ) . SBS-PA schools were asked to implement age-appropriate 10 min structured PA routines within the classroom setting , twice daily , followed by 20 min of usual unstructured playtime . UPA intervention consisted of 30 min of supervised unstructured free playtime twice daily . Interventions were implemented during the morning and afternoon design ated gross-motor playtime for 30 min/session , five days/week for six months . Outcome measures were between group difference in during-preschool PA ( accelerometers and direct observation ) over six-months . Ten preschool centers , representing 34 classrooms and 315 children , enrolled in the study . The average age and BMI percentile for the participants was 4.1 ± 0.8 years and 69th percentile , respectively . Participants spent 74 % and 6 % of their preschool day engaged in sedentary and MVPA , respectively . Discussion Results from the STEP intervention could provide evidence that a PA policy that exposes preschoolers to shorter bouts of structured PA throughout the preschool day could potentially increase preschoolers ’ PA levels . Trial registration Clinical trials.gov ,",
"INTRODUCTION Despite children spending long hours in child care centers , it is unknown what center characteristics are associated with children 's moderate to vigorous physical activity ( MVPA ) at the center and over the 24-hour day . METHODS Mixed model ANOVA evaluated associations between 23 center characteristics ( e.g. , policies , facilities , practice s , and staff training ) and time in MVPA , measured with accelerometers , at the child care center and over the 24-hour day among 388 preschoolers from 30 r and omly selected child care centers in Cincinnati , Ohio . Data collection occurred from November 2009 through January 2011 ; data analyses occurred in 2012 - 2014 . RESULTS Ninety percent of centers reported scheduling two or more outdoor sessions daily , yet only 40 % of children had two or more outdoor sessions ; 32 % had no time outdoors . Eighty-three percent of centers reported scheduling ≥60 minutes outdoors ; 28 % of children experienced this during observation . Children spent a mean ( SE ) of 2.0 ( 0.06 ) minutes/hour in MVPA . Children with ≥60 minutes outdoor time had 0.6 minutes/hour more MVPA in child care ( p=0.001 ) , and 0.5 minutes/hour over the 24-hour day ( p=0.001 ) than those who did not . Presence of an indoor play space , large outdoor playground , portable or fixed play equipment , staff PA training , weather and clothing policies , and TV/computer use were not related to children 's MVPA . CONCLUSIONS Outdoor time occurred less frequently than scheduled . Children with ≥60 minutes of outdoor time at the center were more active than children without . Centers may increase preschoolers ' PA by adhering to the scheduled ≥60 minutes of outdoor time daily",
"OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity",
"OBJECTIVE A r and omized controlled pilot study to test the hypothesis that increasing preschool children 's outdoor free play time increases their daily physical activity levels . METHODS Physical activity was assessed by accelerometers for four consecutive school days in thirty-two Latino children ( 3.6+/-0.5 years ) attending a preschool for low-income families . After two days of baseline physical activity assessment , participants were r and omly assigned to an intervention ( RECESS ; n = 17 ) or control ( CON ; n = 15 ) group . The RECESS group received two additional 30-minute periods of outdoor free play time per day for two days . The CON group followed their normal classroom schedule . Between group differences in physical activity variables were tested with a Wilcoxon rank-sum test . RESULTS There were no statistically significant differences between groups in changes from baseline in average total daily ( CON , 48.2+/-114.5 ; RECESS , 58.2+/-74.6 ) and during school day ( CON , 64.6+/-181.9 ; RECESS , 59.7+/-79.1 ) counts per minute , or total daily ( CON , 0.4+/-1.3 ; RECESS , 0.3+/-0.8 ) and during school day ( CON , 0.6+/-2.1 ; RECESS , 0.5+/-0.8 ) percent of time spent in moderate to vigorous physical activity . CONCLUSIONS Substantially increasing preschoolers ' outdoor free play time did not increase their physical activity levels",
"BACKGROUND We examined the effects of short bouts of structured physical activity ( SBS-PA ) implemented within the classroom setting as part of design ated gross-motor playtime on preschoolers PA . METHODS Preschools were r and omized to SBS-PA ( centers , N = 5 ; participants , N = 141 ) or unstructured free playtime ( UPA ) ( centers , N = 5 ; participants , N = 150 ) . SBS-PA consisted of structured PA implemented in the classroom during the first 10 minutes of gross-motor playtime followed by 20 minutes of free playtime . UPA consisted of 30 minutes of unstructured free playtime . Teachers implemented both conditions for 5 days/week for 6 months . PA was assessed with accelerometers ( preschool-day ) and direct observation ( 30-minute sessions ) . Generalized linear mixed models were used to examine the impact of the intervention . RESULTS Regarding the 30-minute sessions , significant group main effects were observed for intervals spent at light ( p and moderate-to-vigorous PA ( MVPA , p preschool-day PA , significant group by visit interaction was observed for percent time spent in total preschool-day MVPA ( F ( 2 , 254 ) = 3.54 , p = .03 ) . Percent of time spent in MVPA significantly decreased in both groups at 3 months and at 6 months . CONCLUSION SBS-PA can be implemented in classroom setting s ; however , further research is needed to examine its impact on preschoolers PA levels",
"INTRODUCTION A majority of preschool-aged children spend a significant portion of every weekday in a preschool or child care setting , where they typically participate in limited physical activity . This study determined if an ecologic physical activity intervention in preschools increases children 's moderate- to vigorous-intensity physical activity ( MVPA ) . DESIGN RCT , with preschool as the unit of r and omization and analysis . Child physical activity was measured by accelerometry . Mixed model analysis of covariance with preschool as a r and om variable was used to test the effects of the intervention on physical activity in the total group and in sex-specific subgroups . Data were collected in 2008 - 2010 and analyzed in 2012 - 2014 . SETTING / PARTICIPANTS Children in 4-year-olds ' classrooms in 16 preschools , pair matched and assigned to intervention or control groups . INTERVENTION The intervention focused on increasing children 's physical activity by changing instructional practice s. Research ers trained preschool teachers to engage children in physical activity during ( 1 ) structured , teacher-led physical activity opportunities in the classroom ; ( 2 ) structured and unstructured physical activity opportunities at recess ; and ( 3 ) physical activity integrated into pre-academic lessons . Research staff encouraged teachers to adapt the intervention to their classrooms . MAIN OUTCOME MEASURES Minutes/hour of MVPA during the preschool day . RESULTS In an analytic sample of 379 children ( 188 intervention , 191 control ) , those in the intervention schools engaged in significantly more MVPA than children in control schools ( 7.4 and 6.6 minutes/hour , respectively ) . This difference remained significant after adjusting for parent education and length of the school day ( half versus full day ) . In the sex-specific analyses , the difference was significant for girls ( 6.8 vs 6.1 minutes/hour of MVPA , respectively ) but not for boys ( 7.9 vs 7.2 minutes/hour , respectively ) . CONCLUSIONS A flexible ecologic physical activity intervention that trains teachers to provide children with opportunities to be active throughout the school day increased MVPA in preschool children",
"The purpose of this study was twofold : first to document the gender differences in Moderate to Vigorous Physical Activity ( MVPA ) according to two epoch systems ( 5 vs. 60 s ) in preschoolers , and , second to document the differences in physical activity ( PA ) patterns according to two different epoch choices . The sample comprised 59 preschoolers ( 31 girls ) aged 2 - 5 years old . PA was assessed by accelerometer during school hours . The time spent in MVPA was significantly higher ( p MVPA . Different epoch times might affect the time spent in MVPA among preschool children",
"OBJECTIVES The purpose of this study was to examine the convergent validity of the Actical and activPAL to measure sedentary behaviour ( SB ) and non-SB in preschoolers in a free-living environment . DESIGN A convenience sample of 49 preschoolers ( 22 boys ; 4.0 ± 0.5 years ) from six early childhood centres in Auckl and , New Zeal and were included in data analysis . METHODS Participants wore a hip-mounted Actical and a thigh-mounted activPAL accelerometer simultaneously during centre attendance for one day and data were collected in 15s epochs . Bl and -Altman tests were used to assess differences in group mean minutes and percentage of time in (non-)SB between both monitors . Agreement between binary coded ( SB vs. non-SB ) 15s-by-15s Actical and activPAL data was evaluated by calculating percentage agreement and κ statistic . RESULTS The monitors were worn on average for 294.8 ± 46.3 min result ing in a total of 57,780 15s epochs . Bl and -Altman tests suggested a small group mean difference in (non-)SB ( 1.3 min ; 0.1 % ) and a wide prediction interval ( 121.3 min ; 39.2 % ) . No obvious systematic bias was observed in the Bl and -Altman plot . Percentage agreement between the 15s-by-15s Actical and activPAL data of all participants was 73.0 % ( inter-child range : 36.8 - 93.8 % ) . The κ statistic showed moderate agreement with a value of 0.46 ( 95 % CI : 0.45 - 0.47 ) . CONCLUSIONS Although the group mean estimate of (non-)SB was similar between the Actical and activPAL , the output of both monitors can not be considered convergent as meaningful r and om disagreement was found between both monitors"
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Abstract de la Motte , SJ , Gribbin , TC , Lisman , P , Murphy , K , and Deuster , PA . A systematic review of the association between physical fitness and musculoskeletal injury risk : part 2—muscular endurance and muscular strength . J Strength Cond Res 31(11 ) : 3218–3234 , 2017—This is a systematic review and evaluation of the current evidence on the association between both muscular endurance ( ME ) and muscular strength ( MS ) and musculoskeletal injury ( MSK-I ) risk in military and civilian population s. MEDLINE , EBSCO , EMBASE , and the Defense Technical Information Center were search ed for original studies published from 1970 through 2015 which examined associations between physical fitness ( ME and MS ) and MSK-I in military or civilian population s. Method ological quality and strength of the evidence were determined following criteria adapted from previously published systematic review s. Forty-five of 4,229 citations met our inclusion criteria . Although results for some tests did vary by sex , taken together , our primary findings indicate there is ( a ) a strong evidence that poor performance in a push-up test is associated with MSK-I risk ; ( b ) moderate evidence that poor performance in sit-up test is associated with MSK-I risk ; ( c ) moderate evidence that isokinetic ankle and knee flexion strength , and isometric strength assessment s at the back , elbow , or knee are associated with MSK-I risk ; and ( d ) limited evidence that poor performance in a pull-up test and isotonic assessment s of muscular strength are associated with MSK-I. Several measures of ME/MS are moderately or strongly associated with risk of MSK-I , but additional research is needed to identify and recommend specific assessment s of ME/MS that predict MSK-I in both men and women . Future studies should also consider measures of ME and MS as a function of upper body , lower body , and core strength , and their potential association with specific , rather than general ,
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"Background Military service in Finl and is compulsory for all male citizens and annually about 80 % of 19-year-old men enter into the service . The elevated risk for many chronic diseases and loss of function among those who are inactive and unfit can be often detected already in youth . On the other h and , activity-induced injuries among young are true public health issue . The purpose of the present prospect i ve cohort follow-up study was to evaluate predictive associations between acute or overuse injuries and their various intrinsic risk factors . Methods Four successive cohorts of conscripts who formed a representative sample of Finnish young men were followed for 6 months . At the beginning of the service , the risk factors of injuries were measured and recorded and then the acute and overuse injuries treated at the garrison clinic were identified . Predictive associations between injuries and their risk factors were examined by multivariate Cox ’s proportional hazard models . Results Of the 1411 participants , 27 % sustained an acute injury and 51 % suffered from overuse injury . Concerning acute injuries , highest risk for severe injuries were detected among conscripts with low fitness level in both the st and ing long-jump and push-up tests ( hazard rate , HR=5.9 ; 95 % CI : 1.6‒21.3 ) . A history of good degree in school sports was not a protective factor against acute injuries . High waist circumference and , on the other h and , being underweight according to BMI increased the HR for overuse injuries . Brisk leisure time physical activity before military entry was a protective factor against overuse injuries . Poor result in Cooper ’s test was a warning signal of elevated risk of overuse injuries . Conclusion We confirmed previous findings that low level of physical fitness is predictor for musculoskeletal injuries during intensive physical training . The U-shaped relationship between body composition and overuse injuries was noticed indicating that both obesity and underweight are risk factors for overuse injuries . Persons with excellent sports skills according to their earlier degrees in school sports had similar HR for acute injuries than those with poorer degrees . This indicates that school-age sports skills and fitness do not carry far and therefore preventive programmes are needed to prevent activity-induced injuries",
"This prospect i ve study was conducted to determine whether hip muscle strength and flexibility play a role in the incidence of adductor and hip flexor strains in National Hockey League ice hockey team players . Hip flexion , abduction , and adduction strength were measured in 81 players before two consecutive seasons . Thirty-four players were cut , traded , or sent to the minor league before the beginning of the season . Injury and individual exposure data were recorded for the remaining 47 players . Eight players experienced 11 adductor muscle strains , and there were 4 hip flexor strains . Preseason hip adduction strength was 18 % lower in the players who subsequently sustained an adductor muscle strain compared with that of uninjured players . Adduction strength was 95 % of abduction strength in the uninjured players but only 78 % of abduction strength in the injured players . Preseason hip adductor flexibility was not different between players who sustained adductor muscle strains and those who did not . These results indicate that preseason hip strength testing of professional ice hockey players can identify players at risk of developing adductor muscle strains . A player was 17 times more likely to sustain an adductor muscle strain if his adductor strength was less than 80 % of his abductor strength",
"BACKGROUND This study examined whether assigning running shoes based on the shape of the bottom of the foot ( plantar surface ) influenced injury risk in Air Force Basic Military Training ( BMT ) and examined risk factors for injury in BMT . METHODS Data were collected from BMT recruits during 2007 ; analysis took place during 2008 . After foot examinations , recruits were r and omly consigned to either an experimental group ( E , n=1042 men , 375 women ) or a control group ( C , n=913 men , 346 women ) . Experimental group recruits were assigned motion control , stability , or cushioned shoes for plantar shapes indicative of low , medium , or high arches , respectively . Control group recruits received a stability shoe regardless of plantar shape . Injuries during BMT were determined from outpatient visits provided from the Defense Medical Surveillance System . Other injury risk factors ( fitness , smoking , physical activity , prior injury , menstrual history , and demographics ) were obtained from a question naire , existing data bases , or BMT units . RESULTS Multivariate Cox regression controlling for other risk factors showed little difference in injury risk between the groups among men ( hazard ratio [E/C]=1.11 , 95 % CI=0.89 - 1.38 ) or women ( hazard ratio [E/C]=1.20 , 95 % CI= 0.90 - 1.60 ) . Independent injury risk factors among both men and women included low aerobic fitness and cigarette smoking . CONCLUSIONS This prospect i ve study demonstrated that assigning running shoes based on the shape of the plantar surface had little influence on injury risk in BMT even after controlling for other injury risk factors",
"Background : Hamstring injuries are common in sprinters . Identifying preseason risk factors is essential to target injury-prone athletes and develop injury preventive measures . Objective : To investigate the incidence of hamstring muscle injury in sprinters over an athletic season and to explore the preseason predictor of this injury . Design : Prospect i ve cohort study . Participants : 44 sprinters from the Hong Kong Sports Institute , the Hong Kong Amateur Athletic Association and intercollegiate athletic teams were recruited . Methods : Preseason assessment of hamstring flexibility , concentric and eccentric isokinetic peak torque and peak torque angle were obtained at the beginning of an athletic season . The athletes were followed over 12 months and were asked to report all injuries result ing from training and competition . Results : Eight athletes sustained hamstring injuries over the season . The injury rate was 0.87 per 1000 h of exposure . The incidence of injuries was higher at the beginning of the season , with 58.3 % injuries occurring in the first 100 h of exposure . Cox regression analysis revealed that athletes with a decrease in the hamstring : quadriceps peak torque ratio of less than 0.60 at an angular velocity of 180 ° /s have a 17-fold increased risk of hamstring injury . Conclusion : Performing preseason hamstring : quadriceps peak torque ratio assessment s may be useful to identify sprinters susceptible to hamstring injury",
"Physical training-related injuries are common among army recruits and other vigorously active population s , but little is known about their causation . To identify intrinsic risk factors , we prospect ively measured 391 army trainees . For 8 weeks of basic training , 124 men and 186 women ( 79.3 % ) were studied . They answered question naires on past activities and sports participa tion , and were measured for height , weight , and body fat percentage ; 71 % of the subjects took an initial army physical training test . Women had a significantly higher incidence of time-loss injuries than men , 44.6 % com pared with 29.0 % . During training , more time-loss in juries occurred among the 50 % of the men who were slower on the mile run , 29.0 % versus 0.0 % . Slower women were likewise at greater risk than faster ones , 38.2 % versus 18.5 % . Men with histories of inactivity and with higher body mass index were at greater injury risk than other men , as were the shortest women . We conclude that female gender and low aerobic fitness measured by run times are risk factors for training injuries in army trainees , and that other factors such as prior activity levels and stature may affect men and women differently",
"Background A one-year prospect i ve examination of injury rates and injury risk factors was conducted in Federal Bureau of Investigation ( FBI ) new agent training . Methods Injury incidents were obtained from medical records and injury compensation forms . Potential injury risk factors were acquired from a lifestyle question naire and existing data at the FBI Academy . Results A total of 426 men and 105 women participated in the project . Thirty-five percent of men and 42 % of women experienced one or more injuries during training . The injury incidence rate was 2.5 and 3.2 injuries/1,000 person-days for men and women , respectively ( risk ratio ( women/men ) = 1.3 , 95 % confidence interval = 0.9 - 1.7 ) . The activities most commonly associated with injuries ( % of total ) were defensive tactics training ( 58 % ) , physical fitness training ( 20 % ) , physical fitness testing ( 5 % ) , and firearms training ( 3 % ) . Among the men , higher injury risk was associated with older age , slower 300-meter sprint time , slower 1.5-mile run time , lower total points on the physical fitness test ( PFT ) , lower self-rated physical activity , lower frequency of aerobic exercise , a prior upper or lower limb injury , and prior foot or knee pain that limited activity . Among the women higher injury risk was associated with slower 300-meter sprint time , slower 1.5-mile run time , lower total points on the PFT , and prior back pain that limited activity . Conclusion The results of this investigation supported those of a previous retrospective investigation emphasizing that lower fitness and self-reported pain limiting activity were associated with higher injury risk among FBI new agents",
"Background : Injuries in collegiate ice hockey can result in significant time lost from play . The identification of modifiable risk factors relating to a player ’s physical fitness allows the development of focused training and injury prevention programs targeted at reducing these risks . Purpose : To determine the ability of preseason fitness outcomes to predict in-season on-ice injury in male collegiate ice hockey players . Study Design : Prognostic cohort study . Level of Evidence : Level 3 . Methods : Athlete demographics , percentage body fat , aerobic capacity ( 300-m shuttle run ; 1- , 1.5- , 5-mile run ) , and strength assessment ( sit-ups , push-ups , grip strength , bench press , Olympic cleans , squats ) data were collected at the beginning of 8 successive seasons for 1 male collegiate ice hockey team . Hockey-related injury data and player-level practice /game athlete exposure ( AE ) data were also prospect ively collected . Seventy-nine players participated ( 203 player-years ) . Injury was defined as any event that result ed in the athlete being unable to participate in 1 or more practice s or games following the event . Multivariable logistic regression was performed to determine the ability of the independent variables to predict the occurrence of on-ice injury . Results : There were 132 injuries ( mean , 16.5 per year ) in 55 athletes . The overall injury rate was 4.4 injuries per 1000 AEs . Forwards suffered 68 % of the injuries . Seventy percent of injuries occurred during games with equal distribution between the 3 periods . The mean number of days lost due to injury was 7.8 ± 13.8 ( range , 1 - 127 days ) . The most common mechanism of injury was contact with another player ( 54 % ) . The odds of injury in a forward was 1.9 times ( 95 % CI , 1.1 - 3.4 ) that of a defenseman and 3 times ( 95 % CI , 1.2 - 7.7 ) that of a goal ie . The odds of injury if the player ’s body mass index ( BMI ) was ≥25 kg/m2 was 2.1 times ( 95 % CI , 1.1 - 3.8 ) that of a player with a BMI odds ratios for bench press , maximum sit-ups , and Olympic cleans were statistically significant but close to 1.0 , and therefore the clinical relevance is unknown . Conclusion : Forwards have higher odds of injury relative to other player positions . BMI was predictive of on-ice injury . Aerobic fitness and maximum strength outcomes were not strongly predictive of on-ice injury",
"Reliable data on the impact of physical training on light infantry units in terms of injuries and time loss are sparse . This study evaluated a light infantry unit ( n = 181 ) prospect ively and followed it throughout one year of infantry training and operations . Fifty-five percent of the soldiers ( n = 101 ) experienced one or more injuries . Eighty-eight percent of the injuries were training-related conditions , which result ed in 1,103 days of limited duty . Lower extremity overuse injuries were the most common type of injury documented . Fractures accounted for the greatest number of days of limited duty . Risk factors for training-related injuries identified by this study were cigarette smoking , high percentage of body fat , extremely high or low body mass index , low endurance levels , and low muscular endurance levels ( sit-ups ) . Logistic regression showed that cigarette smoking and low endurance levels were independent risk factors for training injuries . These data indicate that the incidence of training-related injuries in infantry units is high . A number of modifiable injury risk factors were identified , suggesting that many of these injuries may be preventable",
"PURPOSE This study aim ed to prospect ively analyze the role of factors on the contralateral side of the kinetic chain in the development of exertional medial tibial pain ( EMTP ) . METHODS Eighty-one female physical education students were tested at the beginning of their first academic year . Within the testing protocol , contralateral isokinetic hip muscle strength and full-body kinematic parameters during a single-leg drop jump were evaluated . Online question naires were administered weekly , and personal interviews were conducted every 3 months to assess injury follow-up . EMTP was diagnosed by an experienced medical doctor . Cox regression analysis was used to identify the potential risk factors for the development of EMTP . RESULTS After exclusion of subjects with diagnosed bilateral EMTP , 11 subjects were included in the EMTP group . Fifty-three subjects did not develop any lower extremity overuse injury and were included in the control group . The leg not at risk within subjects who developed EMTP was compared with an uninjured leg of those in the control group . Increased transverse plane motion for the contralateral lower leg segment during l and ing phase was found to be a significant predictor ( P = 0.012 ) for EMTP . Analysis of the isokinetic data did not reveal altered hip muscle strength parameters for the leg not at risk within the EMTP group . CONCLUSIONS Impaired dynamic joint stability or accessory movements were found in the transverse plane of the contralateral lower leg segment of EMTP subjects . This contralateral instability might have contributed to altered movement patterns within the kinetic chain function of EMTP subjects . No contralateral hip muscle strength parameters were found to predict EMTP in this study",
"Knapik , JJ , Swedler , DI , Grier , TL , Hauret , KG , Bullock , SH , Williams , KW , Darakjy , SS , Lester , ME , Tobler , SK , and Jones , BH . Injury reduction effectiveness of selecting running shoes based on plantar shape . J Strength Cond Res 23(3 ) : 685 - 697 , 2009-Popular running magazines and running shoe companies suggest that imprints of the bottom of the feet ( plantar shape ) can be used as an indication of the height of the medial longitudinal foot arch and that this can be used to select individually appropriate types of running shoes . This study examined whether or not this selection technique influenced injury risk during United States Army Basic Combat Training ( BCT ) . After foot examinations , BCT recruits in an experimental group ( E : n = 1,079 men and 451 women ) selected motion control , stability , or cushioned shoes for plantar shapes judged to represent low , medium , or high foot arches , respectively . A control group ( C : n = 1,068 men and 464 women ) received a stability shoe regardless of plantar shape . Injuries during BCT were determined from outpatient medical records . Other previously known injury risk factors ( e.g. , age , fitness , and smoking ) were obtained from a question naire and existing data bases . Multivariate Cox regression controlling for other injury risk factors showed little difference in injury risk between the E and C groups among men ( risk ratio ( E/C ) = 1.01 ; 95 % confidence interval = 0.88 - 1.16 ; p = 0.87 ) or women ( risk ratio ( E/C ) = 1.07 ; 95 % confidence interval = 0.91 - 1.25 ; p = 0.44 ) . In practical application , this prospect i ve study demonstrated that selecting shoes based on plantar shape had little influence on injury risk in BCT . Thus , if the goal is injury prevention , this selection technique is not necessary in BCT",
"INTRODUCTION / PURPOSE Decreased lumbo-pelvic ( or core ) stability has been suggested to contribute to the etiology of lower extremity injuries , particularly in females . This prospect i ve study compares core stability measures between genders and between athletes who reported an injury during their season versus those who did not . Finally , we looked for one or a combination of these strength measures that could be used to identify athletes at risk for lower extremity injury . METHODS Before their season , 80 female ( mean age = 19.1 + /- 1.37 yr , mean weight 65.1 + /- 10.0 kg ) and 60 male ( mean age = 19.0 + /- 0.90 yr , mean weight 78.8 + /- 13.3 kg ) intercollegiate basketball and track athletes were studied . Hip abduction and external rotation strength , abdominal muscle function , and back extensor and quadratus lumborum endurance was tested for each athlete . RESULTS Males produced greater hip abduction ( males = 32.6 + /- 7.3%BW , females = 29.2 + /- 6.1%BW ) , hip external rotation ( males = 21.6 + /- 4.3%BW , females = 18.4 + /- 4.1%BW ) , and quadratus lumborum measures ( males = 84.3 + /- 32.5 s , females = 58.9 + /- 26.0 s ) . Athletes who did not sustain an injury were significantly stronger in hip abduction ( males = 31.6 + /- 7.1%BW , females = 28.6 + /- 5.5%BW ) and external rotation ( males = 20.6 + /- 4.2%BW , females = 17.9 + /- 4.4%BW ) . Logistic regression analysis revealed that hip external rotation strength was the only useful predictor of injury status ( OR = 0.86 , 95 % CI = 0.77 , 0.097 ) . CONCLUSION Core stability has an important role in injury prevention . Future study may reveal that differences in postural stability partially explain the gender bias among female athletes",
"PURPOSE The purpose of this prospect i ve study was to investigate the epidemiology of overuse injuries and to identify common risk factors for stress fractures among female and male recruits in a new light infantry basic training design ed to minimize the incidence of overuse injuries . METHODS Study subjects were male and female recruits in the 16-wk light infantry basic training . A control group of noncombat female medics whose military service did not include dem and ing physical activities was recruited to assess the female recruits ' preinduction physical preparedness . Pretraining survey of all participants ' medical and sports participation histories was conducted . Anthropometric measurements were performed . Subjects were followed every 3 wk for overuse injuries . Stress fractures were diagnosed by radiography or scintigraphy . RESULTS Ninety-nine female recruits , 36 male recruits , and 55 controls participated . Although 31 % of the controls reported regular preinduction sports participation , less than 25 % of both male and female recruits did . Stress fractures incidence was 0 % among males and controls but 12 % among female recruits ( P = 0.03 ) . The mean body mass index of female recruits with stress fractures was 19.2 + /- 2.6 versus 22.5 + /- 3.3 kg x m of female recruits without stress fractures ( P = 0.02 , odds ratio = 1.397 , 95 % confidence interval = 1.065 - 1.833 ) . No statistically significant difference was found between female and male military trainees in the incidence of other overuse injuries , but there was a statistical trend ( P = 0.07 ) for more back pain among females . CONCLUSIONS Lower body mass index was the only variable identified as a risk factor for stress fractures among female recruits in the present study . It does not explain the markedly different response of female and male recruits ' bones to the low dem and training . There may be an intrinsic difference between male and female bone resistance to fatigue",
"Background Musculoskeletal injury is the most common reason that soldiers are medically not ready to deploy . Underst and ing intrinsic risk factors that may place an elite soldier at risk of musculoskeletal injury may be beneficial in preventing musculoskeletal injury and maintaining operational military readiness . Findings from this population may also be useful as hypothesis-generating work for particular civilian setting s such as law enforcement officers ( SWAT teams ) , firefighters ( smoke jumpers ) , or others in physically dem and ing professions . Questions / purpose sThe purpose s of this study were ( 1 ) to examine whether using baseline measures of self-report and physical performance can identify musculoskeletal injury risk ; and ( 2 ) to determine whether a combination of predictors would enhance the accuracy for determining future musculoskeletal injury risk in US Army Rangers . Methods Our study was a planned secondary analysis from a prospect i ve cohort examining how baseline factors predict musculoskeletal injury . Baseline predictors associated with musculoskeletal injury were collected using surveys and physical performance measures . Survey data included demographic variables , injury history , and biopsychosocial questions . Physical performance measures included ankle dorsiflexion , Functional Movement Screen , lower and upper quarter Y-balance test , hop testing , pain provocation , and the Army Physical Fitness Test ( consisting of a 2-mile run and 2 minutes of sit-ups and push-ups ) . A total of 320 Rangers were invited to enroll and 211 participated ( 66 % ) . Occurrence of musculoskeletal injury was tracked for 1 year using monthly injury surveillance surveys , medical record review s , and a query of the Department of Defense healthcare utilization data base . Injury surveillance data were available on 100 % of the subjects . Receiver operator characteristic curves and accuracy statistics were calculated to identify predictors of interest . A logistic regression equation was then calculated to find the most pertinent set of predictors . Of the 188 Rangers ( age , 23.3 ± 3.7 years ; body mass index , 26.0 ± 2.4 kg/m2 ) remaining in the cohort , 85 ( 45.2 % ) sustained a musculoskeletal injury of interest . Results Smoking , prior surgery , recurrent prior musculoskeletal injury , limited-duty days in the prior year for musculoskeletal injury , asymmetrical ankle dorsiflexion , pain with Functional Movement Screen clearing tests , and decreased performance on the 2-mile run and 2-minute sit-up test were associated with increased injury risk . Presenting with one or fewer predictors result ed in a sensitivity of 0.90 ( 95 % confidence interval [ CI ] , 0.83–0.95 ) , and having three or more predictors result ed in a specificity of 0.98 ( 95 % CI , 0.93–0.99 ) . The combined factors that contribute to the final multivariable logistic regression equation yielded an odds ratio of 4.3 ( 95 % CI , 2.0–9.2 ) , relative risk of 1.9 ( 95 % CI , 1.4–2.6 ) , and an area under the curve of 0.64 . Conclusions Multiple factors ( musculoskeletal injury history , smoking , pain provocation , movement tests , and lower scores on physical performance measures ) were associated with individuals at risk for musculoskeletal injury . The summation of the number of risk factors produced a highly sensitive ( one or less factor ) and specific ( three or more factors ) model that could potentially be used to effectively identify and intervene in those persons with elevated risk for musculoskeletal injury . Future research should establish if screening and intervening can improve musculoskeletal health and if our findings among US Army Rangers translate to other occupations or athletes . Level of Evidence Level II , prognostic study",
"PURPOSE The aim of the present study was to assess the risk factors for magnetic resonance imaging (MRI)-detected bone stress injuries in the pelvis , hip , thigh , and knee in a large cohort of Finnish conscripts during a follow-up of 102,515 person-years . METHODS An epidemiologic prospect i ve cohort study of 152,095 conscripts , including 2345 ( 1.5 % ) females , was conducted . Localized pain in the pelvis , hip , thigh , or knee result ed in an orthopedic surgeon 's consultation and subsequent MRI examination at the Central Military Hospital , Helsinki , Finl and . Risk factors were systematic ally collected from 1998 to 2004 , including data on conscripts ' physical fitness and body composition measured at the beginning of their military service . RESULTS Altogether , 319 MRI-detected bone stress injuries of the pelvis , hip , thigh , or knee were identified in our cohort ; thus , the incidence was 311 ( 95 % CI : 277 - 345 ) per 100,000 person-years . The female : male ratio varied substantially , depending on the anatomic location of the injury ; it was highest for sacral injuries ( female : male ratio = 51.1 ) and lowest for injuries of the femoral condyle ( female : male ratio = 0.8 ) . In univariate Cox regression analysis , poor muscle strength and a poor result in a 12-min run were significantly associated with bone stress injuries . In multivariable analysis , the strongest risk factors for bone stress injuries were female gender ( hazard ratio 8.2 ; 95 % CI : 4.8 - 14.2 ) and higher age ( hazard ratio 2.1 ; 95 % CI : 1.4 - 3.1 ) . CONCLUSIONS Female military trainees have a highly increased risk of bone stress injuries of the pelvis and hip compared with male conscripts . Sacral stress fractures are typical bone stress injuries in female military recruits . Physicians should remember the possibility of bone stress injury , especially when examining stress-related pain symptoms of the pelvic area in physically active young adult females",
"Ankle sprains are extremely common . However , very little is known about the variables that predispose individuals to these injuries . The purpose of this study was to examine prospect ively intrinsic risk factors for inversion sprains in a young physically active female population . One hundred and fifty-nine female physical education students were evaluated for several possible intrinsic risk factors for inversion sprains at the beginning of their academic study . The evaluated intrinsic risk factors included anthropometrical and physical characteristics , ankle joint position sense , isokinetic ankle muscle strength , lower leg alignment characteristics , postural control and muscle reaction time during a sudden inversion perturbation . All sports injuries were registered during 1 - 3 years and exposure to sport was recorded ( mean : 15.33+/-4.33 h a week ) . Thirty-two ( 20 % ) of the 159 females sprained their ankle . The number of ankle sprains per 1000 h of sports exposure was 0.75 . The Cox regression analysis revealed that females with less accurate passive joint inversion position sense [ hazard ratio ( HR ) : 1.08 , 95 % confidence interval ( CI ) : 1.02 - 1.14 for absolute error at 15 degrees inversion ] , a higher extension range of motion at the first metatarsophalangeal joint ( HR : 1.03 , 95 % CI : 1.00 - 1.06 ) and less coordination of postural control ( HR : 0.96 , 95 % CI : 0.93 - 1.00 for endpoint excursion ; HR : 0.94 , 95 % CI : 0.89 - 0.99 for maximal endpoint excursion ) are at greater risk of an ankle sprain . The findings of this study suggest that effective prevention and conservative rehabilitation of ankle inversion sprains should include attention to these variables",
"Background : Ankle sprain is an extremely common injury in soccer players . Despite extensive research , the intrinsic cause of this injury under noncontact conditions remains unclear . Purpose : To identify intrinsic risk factors for noncontact ankle sprains in professional soccer players . Study Design : Cohort study ; Level of evidence , 2 Methods : One hundred professional soccer players were assessed in the preseason for potential risk factors of noncontact ankle sprains . The assessment included ( A ) ankle joint asymmetries ( right-left ) in isokinetic muscle strength , flexibility , proprioception , and stability ; ( B ) somatometric asymmetries ; ( C ) previous injuries ; and ( D ) lateral dominance traits . Noncontact ankle sprains were prospect ively recorded and diagnosed for a full competition period ( 10 months ) . Results : Seventeen of the players sustained at least 1 noncontact ankle sprain . Logistic regression revealed that players with ( A ) eccentric isokinetic ankle flexion strength asymmetries ( odds ratio [ OR ] = 8.88 ; 95 % confidence interval [ CI ] , 1.95 - 40.36 , P = .005 ) , ( B ) increased body mass index ( OR = 8.16 ; 95 % CI , 1.42 - 46.63 , P = .018 ) , and ( C ) increased body weight ( OR = 5.72 ; 95 % CI , 1.37 - 23.95 , P = .017 ) each had a significantly higher risk of a noncontact ankle sprain . A trend for younger players ( OR = 0.28 ; 95 % CI , 0.061 - 1.24 , P = .092 ) and for players with ankle laxity asymmetries ( OR = 3.38 ; 95 % CI , 0.82 - 14.00 , P = .093 ) to be at greater risk for ankle sprain was also apparent to the limit of statistical significance ( .05 increased body mass index and body weight raise the propensity for ankle sprains in professional soccer players . Age and asymmetries in ankle laxity are potential factors worth revisiting , as there was an indication for younger players and players with ankle instability to be at higher risk for ankle injury . Proper preseason evaluation may improve prevention strategies for this type of injury in soccer",
"Objectives : ( 1 ) To characterize the demographics and external causes of pediatric sports injury-related visits ( SIRVs ) to emergency departments ( EDs ) . ( 2 ) To analyze the effect of race/ethnicity and insurance on SIRVs to EDs . Methods : A stratified r and om- sample cross-sectional survey of EDs in the National Hospital Ambulatory Medical Care Survey was conducted from 1997 - 2001 ; for patients younger than 19 years , we used all visits [ n = 33,654 ; injury-related visits ( IRVs ) = 13,496 , SIRVs = 2990 ] . We examined both the external cause codes and the actual verbatim text of all IRVs . National estimates of pediatric IRVs were obtained using the assigned patient visit weights in the National Hospital Ambulatory Medical Care Survey data bases and SUDAAN 9.1 software ( SAS Institute , Inc. , Cary , NC ) . Results : Sports injuries result ed in 2.5 million visits annually , or 23 % of ED IRVs . Male sex , older age ( 6 - 18 years ) , and white race/ethnicity are associated with higher rates of SIRVs . Cycling , basketball , playground injuries , and football result ed in the largest numbers of ED SIRVs . Leading diagnoses for SIRVs included fractures and dislocations , sprains and strains , open wounds , and contusions . Hispanic race/ethnicity was associated with lower rates of SIRVs across all insurance types . After controlling for demographic factors and insurance , Hispanic children were less likely to have an SIRV than white children ( odds ratio , 0.7 ; 95 % confidence interval , 0.6 - 0.9 ) . Conclusions : Sports and recreation are the leading causes of pediatric ED IRVs . Hispanic children , regardless of insurance status , had lower rates of SIRVs than white children , which helps explain the lower rate of nonfatal IRVs to EDs among Hispanic youth",
"OBJECTIVES Well-developed physical qualities may protect against contact injuries . However , the potential contribution of physical qualities as risk or protective factors to contact injury risk is yet to be determined for rugby league . This study applied a frailty survival model that accounts for recurrent injury to identify risk factors for all physiotherapist-reported contact injury in professional rugby league players . DESIGN Prospect i ve cohort study . METHODS Sixty-six professional rugby league players participated in this three successive year prospect i ve study . At the start of each season , all players underwent measurements of st and ard anthropometry ( height , body mass , and sum of seven skinfolds ) , speed ( 10 m and 40 m sprint ) , muscular strength ( 1 repetition maximum [ RM ] bench press , 1RM squat , 1RM weighted chin-ups ) , power ( vertical jump , bench throw , 1RM power clean , jump squat ) , and endurance ( maximum repetition bench press with 60 kg resistance ) , repeated-sprint ability ( 12 × 20 m sprints performed on a 20s cycle ) , prolonged high-intensity intermittent running ability ( 8 × 12 s maximal effort shuttles performed on a 48 s cycle ) , and maximal aerobic power ( multi-stage fitness test ) . Data was used to demonstrate the application of the frailty model extension of the Cox proportional regression model for recurrent events to identify factors associated with a high hazard ratio ( HR ) of injury . RESULTS Heavier ( body mass , HR=2.6 , 95 % CI=1.2 - 5.7 ) , and faster ( 40 m sprint , HR=2.1 , 95 % CI=1.0 - 4.2 ) players , and those with poorly developed prolonged high-intensity intermittent running ability ( HR=2.9 , 95 % CI=1.7 - 5.0 ) and upper-body strength ( chin-up , HR=2.2 , 95 % CI=1.3 - 3.7 ) had a higher incidence of contact injuries . CONCLUSIONS This study demonstrates application of a novel statistical approach for the analysis of injury data that is recurrent in nature . This approach identified that the greater impact forces generated from heavier players with faster speed may result in an increase in recurrent contact injury rates . However , the development of prolonged high-intensity intermittent running ability and upper-body strength and power may assist to reduce the risk of contact injury in professional rugby league players",
"Purpose This prospect i ve cohort study examined injuries and injury risk factors in 660 British Army infantry soldiers during a predeployment training cycle . Methods Soldiers completed a question naire concerning physical characteristics , occupational factors , lifestyle characteristics ( including physical training time ) and previous injury . Direct measurements included height , body mass , sit-ups , push-ups and run time . Electronic medical records were screened for injuries over a 1-year period before operational deployment . Backward-stepping Cox regression calculated HR and 95 % CI to quantify independent injury risk factors . Results One or more injuries were experienced by 58.5 % of soldiers . The new injury diagnosis rate was 88 injuries/100 person-years . Most injuries involved the lower body ( 71 % ) , especially the lower back ( 14 % ) , knee ( 19 % ) and ankle ( 15 % ) . Activities associated with injury included sports ( 22 % ) , physical training ( 30 % ) and military training/work ( 26 % ) . Traumatic injuries accounted for 83 % of all injury diagnoses . Independent risk factors for any injury were younger age ( 17–19 years ( HR 1.0 ) , 20–24 years ( HR 0.71 , 95 % CI 0.55 to 0.93 ) , 25–29 years ( HR 0.89 , 95 % CI 0.66 to 1.19 ) and 30–43 years ( HR 0.41 , 95 % CI 0.27 to 0.63 ) , previous lower limb injury ( yes/no HR 1.49 , 95 % CI 1.19 to 1.87 ) and previous lower back injury ( yes/no HR 1.30 , 95 % CI 1.03 to 1.63 ) . Conclusion British infantry injury rates were lower than those reported for US infantry ( range 101–223 injuries/100 soldier-years ) , and younger age and previous injury were identified as independent risk factors . Future efforts should target reducing the incidence of traumatic injuries , especially those related to physical training and /or sports"
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Background Probiotics are living microorganisms that , when administered in adequate amounts , confer a health benefit . It has been speculated that probiotics might help prevent preterm birth , but in two previous systematic review s possible major increases in this risk have been suggested . Our objective was to perform a systematic review and meta- analysis of the risk of preterm birth and other adverse pregnancy outcomes in pregnant women taking probiotics , prebiotics or synbiotics . Methods We search ed six electronic data bases ( MEDLINE , EMBASE , CINAHL , Cochrane Central Register of Controlled Trials , Web of Science ’s Core collection and BIOSIS P review ) up to September 2016 and contacted authors for additional data . We included r and omized controlled trials in which women with a singleton pregnancy received a probiotic , prebiotic or synbiotic intervention . Two independent review ers extracted data using a piloted form and assessed the risk of bias using the Cochrane risk of bias tool . We used r and om-effects meta-analyses to pool the results . Results We identified 2574 publications , screened 1449 non-duplicate titles and abstract s and read 160 full text articles . The 49 publications that met our inclusion criteria represented 27 studies . No study used synbiotics , one used prebiotics and the rest used probiotics . Being r and omized to take probiotics during pregnancy neither increased nor decreased the risk of preterm birth preterm birth gestational diabetes mellitus . Conclusions We found no evidence that taking probiotics or prebiotics during pregnancy either increases or decreases the risk of preterm birth or other infant and maternal adverse pregnancy outcomes .Trial registration We prospect ively published the protocol for this study in the PROSPERO data base ( CRD42016048129 )
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"Balanced glucose metabolism ensures optimal fetal growth with long-term health implication s conferred on both mother and child . We examined whether supplementation of probiotics with dietary counselling affects glucose metabolism in normoglycaemic pregnant women . At the first trimester of pregnancy 256 women were r and omised to receive nutrition counselling to modify dietary intake according to current recommendations or as controls ; the dietary intervention group was further r and omised to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) in a double-blind manner , whilst the control group received placebo ( control/placebo ) . Blood glucose concentrations were lowest in the diet/probiotics group during pregnancy ( baseline-adjusted means 4.45 , 4.60 and 4.56 mmol/l in diet/probiotics , diet/placebo and control/placebo , respectively ; P = 0.025 ) and over the 12 months ' postpartum period ( baseline-adjusted means 4.87 , 5.01 and 5.02 mmol/l ; P = 0.025 ) . Better glucose tolerance in the diet/probiotics group was confirmed by a reduced risk of elevated glucose concentration compared with the control/placebo group ( OR 0.31 ( 95 % CI 0.12 , 0.78 ) ; P = 0.013 ) as well as by the lowest insulin concentration ( adjusted means 7.55 , 9.32 and 9.27 mU/l ; P = 0.032 ) and homeostasis model assessment ( adjusted means 1.49 , 1.90 and 1.88 ; P = 0.028 ) and the highest quantitative insulin sensitivity check index ( adjusted means 0.37 , 0.35 and 0.35 ; P = 0.028 ) during the last trimester of pregnancy . The effects observed extended over the 12-month postpartum period . The present study demonstrated that improved blood glucose control can be achieved by dietary counselling with probiotics even in a normoglycaemic population and thus may provide potential novel means for the prophylactic and therapeutic management of glucose disorders",
"Background Although several studies have found probiotics encouraging in prevention of gestational diabetes mellitus ( GDM ) , the evidence for the use of probiotics in diagnosed GDM is largely limited . The aim of this study was to assess the effect of a probiotic supplement capsule containing four bacterial strains on glucose metabolism indices and weight changes in women with newly diagnosed GDM . Methods Sixty-four pregnant women with GDM were enrolled into a double-blind placebo-controlled r and omized clinical trial . They were r and omly assigned to receive either a probiotic or placebo capsule along with dietary advice for eight consecutive weeks . The trend of weight gain along with glucose metabolism indices was assayed . Results During the first 6 weeks of the study , the weight gain trend was similar between the groups . However , in the last 2 weeks of the study , the weight gain in the probiotic group was significantly lower than in the placebo group ( p Fasting blood sugar ( FBS ) decreased in both intervention ( from 103.7 to 88.4 mg/dl ) and control ( from 100.9 to 93.6 mg/dl ) groups significantly , and the decrease in the probiotic group was significantly higher than in the placebo group ( p Insulin resistance index in the probiotic group had 6.74 % reduction over the study period ( p insulin resistance index ( 6.45 % ) , but the observed change in insulin resistance was not statistically significant . Insulin sensitivity index was increased in both groups . The post-intervention insulin sensitivity index in the probiotic group was not significantly different from placebo when adjusted for the baseline levels . Conclusions The probiotic supplement appeared to affect glucose metabolism and weight gain among pregnant women with GDM . This needs to be confirmed in other setting s before a therapeutic value could be approved",
"Objective : This study was performed to determine the comparative efficacy of probiotic yoghurt and clindamycin in the treatment of bacterial vaginosis in pregnant women in the third trimester . Methods and material s : This r and omized clinical trial was performed as an open-label study . 310 symptomatic patients with BV were recruited . Diagnosis of BV was through Amsel criteria . The patients were r and omly assigned to receive either probiotic yoghurt ( 100 g twice a day/week ) or orally administered clindamycin ( 300 mg twice a day/week ) . Results : Ten patients in probiotic group and 9 subjects in clindamycin group had symptom recurrence ( p > 0.05 ) . 132 patients in probiotic group and 105 subjects in clindamycin group had pH decrease ( p clindamycin group had complete symptomatic cure ( p > 0.05 ) . Twelve patients in probiotic group and seven subjects in clindamycin group had preterm birth . Nine women in probiotic group and five subjects in clindamycin group had PROM ( p > 0.05 ) . Conclusions : According to the obtained results , it may be concluded that probiotics would have a good efficacy in the treatment of bacterial vaginosis in pregnancy leading to decreased burden of subsequent preterm birth",
"OBJECTIVE This study is to examine the effect of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 taken orally before bedtime on Group B Streptococcus (GBS)-positive pregnant women with respect to becoming GBS negative . MATERIAL S AND METHODS In total , 110 pregnant women at 35 - 37 weeks of gestation who were diagnosed by GBS culture as being GBS positive for both vaginal and rectal GBS colonization were r and omly assigned to be orally treated with two placebo capsules or two probiotic capsules ( containing L. rhamnosus GR-1 and L. reuteri RC-14 ) before bedtime until delivery . All women were tested for vaginal and rectal GBS colonization again by GBS culture on admission for delivery . RESULTS Of the 110 participants , 99 completed the study ( 49 in the probiotic group and 50 in the placebo group ) . The GBS colonization results changed from positive to negative in 21 women in the probiotic group ( 42.9 % ) and in nine women in the placebo group ( 18.0 % ) during this period ( Chi-square p=0.007 ) . CONCLUSION Oral probiotic containing L. rhamnosus GR-1 and L. reuteri RC-14 could reduce the vaginal and rectal GBS colonization rate in pregnant women",
"BACKGROUND Galactooligosaccharides ( GOS ) and long-chain fructooligosaccharides ( lcFOS ) proliferate bifidobacteria in infant gut microbiota . However , it is not known how GOS and FOS influence the microbiota of pregnant women and whether a potential prebiotic effect is transferred to the offspring . OBJECTIVES We aim ed to test how supplementation with GOS and lcFOS ( GOS/lcFOS ) in the last trimester of pregnancy affects maternal and neonatal gut microbiota . Variables of fetal immunity were assessed as a secondary outcome . DESIGN In a r and omized , double-blind , placebo-controlled pilot study , 48 pregnant women were supplemented 3 times/d with 3 g GOS/lcFOS ( at a ratio of 9:1 ) or maltodextrin ( placebo ) from week 25 of gestation until delivery . Percentages of bifidobacteria and lactobacilli within total bacterial counts were detected by fluorescent in situ hybridization and quantitative polymerase chain reaction in maternal and neonatal ( days 5 , 20 , and approximately 182 ) stool sample s. Variables of fetal immunity were assessed in cord blood by using flow cytometry and cytokine multiplex-array analysis . RESULTS The proportions of bifidobacteria in the maternal gut were significantly higher in the supplemented group than in the placebo group ( 21.0 % and 12.4 % , respectively ; P = 0.026 ) ; the proportion of lactobacilli did not differ between the groups . In neonates , bifidobacteria and lactobacilli percentages , diversity and similarity indexes , and fetal immune parameters did not differ significantly between the 2 groups . Mother-neonate similarity indexes of bifidobacteria decreased over time . CONCLUSIONS GOS/lcFOS supplementation has a bifidogenic effect on maternal gut microbiota that is not transferred to neonates . The increased maternal bifidobacteria did not affect fetal immunity as measured by a comprehensive examination of cord blood immunity variables",
"OBJECTIVE : The aim of this study was to determine the effects of synbiotic food consumption on glycemic status and serum high sensitivity C-reactive protein ( hs-CRP ) levels of Iranian pregnant women . DESIGN : This r and omized placebo-controlled clinical trial was performed among 52 pregnant women , primigravida , aged 18–35 year old , in their third trimester . After a 2-wk run-in period , subjects were r and omly assigned to consume either a synbiotic ( n=26 ) or control food ( n=26 ) for 9 weeks . The synbiotic food consisted of a probiotic Lactobacillus sporogenes ( 1 × 107 CFU ) , 0.04 g inulin as prebiotic with 0.38 g isomalt , 0.36 g sorbitol and 0.05 g stevia as sweetener per 1 g. Control food ( the same substance without probiotic bacteria and inulin ) was packed in identical 9-gram packages . Patients were asked to consume the synbiotic and control foods two times a day . Fasting blood sample s were taken at baseline and after a 9-wk intervention for quantification of related factors . RESULTS : Consumption of a synbiotic food did not show any significant change regarding the impact of insulin actions in the synbiotic group ; nonetheless , compared to the control food , it result ed in a significant decrease in serum insulin levels ( −0.26 vs. 6.34 µIU/mL , P=0.014 ) and HOMA-IR ( −0.13 vs. 1.13 , P=0.033 ) , a significant difference in HOMA-B ( 5.30 vs. 34.22 , P=0.040 ) and a significant rise in QUICKI score ( 0.002 vs. −0.02 , P=0.022 ) . CONCLUSIONS : Consumption of a synbiotic food for 9 weeks by pregnant women had beneficial effects on insulin actions compared to the control food , but did not affect FPG and serum hs-CRP concentrations ",
"Background Bacterial vaginosis increases the risk of spontaneous preterm delivery at less than 34 weeks of gestation . Objective The purpose of this study was to evaluate the efficacy of the early administration of selected lactobacilli strains ( probiotics ) to pregnant women with asymptomatic bacterial vaginosis/intermediate-degree infections to prevent spontaneous premature delivery and associated neonatal morbidity . Methods / Design Asymptomatic pregnant women at less than 20 weeks of gestation , with no indication of elective preterm delivery , with a vaginal pH ≥ 4.5 and Nugent score > 3 were r and omly assigned to the placebo or intervention group ( oral administration of selected lactobacilli up to the 24th to 26th week of gestation ) . The r and omisation was stratified for the history of premature delivery ( HPD ) and blocked . The allocation was concealed , and the participating health professionals and patients were blinded . The primary outcome was preterm delivery ( , and the secondary outcomes were associated neonatal complications . Results In total , 4,204 pregnant women were screened ; 320 and 324 individuals were respectively r and omly assigned to the placebo and intervention groups , and 62 % finished the trial . None of the r and omised patients were lost to follow-up . For the non-HPD stratum , the intent-to-treat relative risks of spontaneous premature birth at The intent-to-treat relative risk of spontaneous premature birth at ns ) . The neonatal complications under evaluation occurred in only one infant ( with respiratory distress syndrome and suspected early neonatal sepsis . The recorded adverse events were minor and relatively non-specific . Conclusions The efficacy of the tested probiotics to prevent preterm delivery among women without a history of preterm delivery was not determined because the study sample was insufficient to estimate statistically significant intent-to-treat effects ; additional studies are needed to evaluate this intervention among these women . Trial registration Trial registration at NIH register : NCT00303082 . Sources of funding : the Brazilian Health Ministry and the State of Rio de Janeiro Research Foundation",
"BACKGROUND Reversal of the progressive increase in frequency of atopic disease would be an important breakthrough for health care and wellbeing in western societies . In the hygiene hypothesis this increase is attributed to reduced microbial exposure in early life . Probiotics are cultures of potentially beneficial bacteria of the healthy gut microflora . We assessed the effect on atopic disease of Lactobacillus GG ( which is safe at an early age and effective in treatment of allergic inflammation and food allergy ) . METHODS In a double-blind , r and omised placebo-controlled trial we gave Lactobacillus GG prenatally to mothers who had at least one first-degree relative ( or partner ) with atopic eczema , allergic rhinitis , or asthma , and postnatally for 6 months to their infants . Chronic recurring atopic eczema , which is the main sign of atopic disease in the first years of life , was the primary endpoint . FINDINGS Atopic eczema was diagnosed in 46 of 132 ( 35 % ) children aged 2 years . Asthma was diagnosed in six of these children and allergic rhinitis in one . The frequency of atopic eczema in the probiotic group was half that of the placebo group ( 15/64 [ 23 % ] vs 31/68 [ 46 % ] ; relative risk 0.51 [ 95 % CI 0.32 - 0.84 ] ) . The number needed to treat was 4.5 ( 95 % CI 2.6 - 15.6 ) . INTERPRETATIONS Lactobacillus GG was effective in prevention of early atopic disease in children at high risk . Thus , gut microflora might be a hitherto unexplored source of natural immunomodulators and probiotics , for prevention of atopic disease",
"Controversy exists regarding the preventive effect of probiotics on the development of eczema or atopic dermatitis . We investigated whether supplementation of probiotics prevents the development of eczema in infants at high risk . In a r and omized , double-blind , placebo-controlled trial , 112 pregnant women with a family history of allergic diseases received a once-daily supplement , either a mixture of Bifidobacterium bifidum BGN4 , B. lactis AD011 , and Lactobacillus acidophilus AD031 , or placebo , starting at 4 - 8 wks before delivery and continuing until 6 months after delivery . Infants were exclusively breast-fed during the first 3 months , and were subsequently fed with breastmilk or cow 's milk formula from 4 to 6 months of age . Clinical symptoms of the infants were monitored until 1 yr of age , when the total and specific IgE against common food allergens were measured . A total of 68 infants completed the study . The prevalence of eczema at 1 yr in the probiotic group was significantly lower than in the placebo group ( 18.2 % vs. 40.0 % , p=0.048 ) . The cumulative incidence of eczema during the first 12 months was reduced significantly in probiotic group ( 36.4 % vs. 62.9 % , p=0.029 ) ; however , there was no difference in serum total IgE level or the sensitization against food allergens between the two groups . Prenatal and postnatal supplementation with a mixture of B. bifidum BGN4 , B. lactis AD011 , and L. acidophilus AD031 is an effective approach in preventing the development of eczema in infants at high risk of allergy during the first year of life",
"Production and manufacturing methods and the food carrier may influence the properties of probiotic strains , and have an impact on the outcome of clinical intervention studies . The aim of the present study was to establish whether the properties of a specific probiotic strain , Lactobacillus rhamnosus GG , may differ depending on the product and source of the strain . In total , fifteen different L. rhamnosus isolates , among them fourteen labelled as L. rhamnosus GG , were isolated from specific probiotic products . The micro-organisms were phenotypically and genotypically characterised . Their adhesion properties were compared using the human intestinal mucus model , and the ability of the isolates to influence model pathogen adhesion to human colonic mucus was assessed . All L. rhamnosus isolates used were confirmed as members of the species L. rhamnosus . Except the reference strain OL , all L. rhamnosus isolates showed r and omly amplified polymorphic DNA , enterobacterial repetitive intergenic consensus and pulsed-field gel electrophoresis profiles identical to that of L. rhamnosus GG ( ATCC 53103 ) . All L. rhamnosus isolates showed similar tolerance to acid and were able to bind to human colonic mucus . However , pathogen exclusion by inhibition and competition varied significantly among the different L. rhamnosus isolates and pathogens tested . The results suggest that different sources of the same probiotic may have significantly altered strain properties . This should be considered in in vivo studies on human subjects and also for quality control of probiotic products",
"Probiotic supplementation to a mother during the perinatal period can have a positive impact on the breast milk composition . The aim of our study was to evaluate the effect of oral supplementation with the probiotic VSL#3 , during late pregnancy and lactation , on breast milk levels of beneficial bacteria and some functional components ( oligosaccharides and lactoferrin ) potentially able to have a positive influence on the microbiota . Breast milk microbiota was analyzed by conventional and quantitative real-time PCR . In a double-blind , placebo-controlled , r and omized trial , 66 women took daily either the probiotic ( n=33 ) or a placebo ( n=33 ) . Intergroup analysis demonstrated that the amounts of both lactobacilli and bifidobacteria were significantly higher in the colostrum and mature milk of the mothers taking VSL#3 in comparison to those taking placebo . The analysis of bacterial strains and species present in breast milk of VSL#3 supplemented mothers indicated that the administered probiotic microorganisms did not pass from maternal gut to mammary gl and . In women with vaginal delivery , significantly higher amounts of lactobacilli and bifidobacteria were detected in colostrum and mature milk of probiotic treated group in comparison to placebo group , whereas no significant difference was observed between groups in women who had caesarean section , neither in colostrum nor in mature milk . Milk levels of oligosaccharides and lactoferrin were similar in placebo and probiotic supplemented groups at all timepoints and regardless of the mode of delivery . Our results indicate a probiotic-dependent modulation of breast milk microbiota in vaginally delivering women , possibly exerted through a systemic effect",
"Objective . This trial aims to examine the effects of a Probiotic Mixture ( VSL#3 ) on glycemic status and inflammatory markers , in women with GDM . Material s and Methods . Over a period of 8 weeks , 82 women with gestational diabetes were r and omly assigned to either an intervention group ( n = 41 ) which were given VSL#3 capsule or to a control group which were given placebo capsule ( n = 41 ) . Fasting plasma glucose , homeostatic model assessment of insulin resistance , glycosylated hemoglobin , high-sensitivity C-reactive protein , tumor necrosis factor-α , interleukin-6 , Interferon gamma , and interleukin-10 were measured before and after the intervention . Results . After 8 wk of supplementation FPG , HbA1c , HOMA-IR , and insulin levels remained unchanged in the probiotic and placebo groups . The comparison between the two groups showed no significant differences with FPG and HbA1c , but there were significant differences in insulin levels and HOMA-IR ( 16.6 ± 5.9 ; 3.7 ± 1.5 , resp . ) . Unlike the levels of IFN-g ( 19.21 ± 16.6 ) , there was a significant decrease in levels of IL-6 ( 3.81 ± 0.7 ) , TNF-α ( 3.10 ± 1.1 ) , and hs-CRP ( 4927.4 ± 924.6 ) . No significant increase was observed in IL-10 ( 3.11 ± 5.7 ) in the intervention group as compared with the control group . Conclusions . In women with GDM , supplementation with probiotics ( VSL#3 ) may help to modulate some inflammatory markers and may have benefits on glycemic control ",
"BACKGROUND An altered microbial exposure may underlie the increase of allergic diseases in affluent societies . Probiotics may alleviate and even prevent eczema in infants . OBJECTIVE To prevent eczema and sensitization in infants with a family history of allergic disease by oral supplementation with the probiotic Lactobacillus reuteri . METHODS Double-blind , r and omized , placebo-controlled trial , which comprised 232 families with allergic disease , of whom 188 completed the study . The mothers received L reuteri ATCC 55730 ( 1 x 10(8 ) colony forming units ) daily from gestational week 36 until delivery . Their babies then continued with the same product from birth until 12 months of age and were followed up for another year . Primary outcome was allergic disease , with or without positive skin prick test or circulating IgE to food allergens . RESULTS The cumulative incidence of eczema was similar , 36 % in the treated versus 34 % in the placebo group . The L reuteri group had less IgE-associated eczema during the second year , 8 % versus 20 % ( P = .02 ) , however . Skin prick test reactivity was also less common in the treated than in the placebo group , significantly so for infants with mothers with allergies , 14 % versus 31 % ( P = .02 ) . Wheeze and other potentially allergic diseases were not affected . CONCLUSION Although a preventive effect of probiotics on infant eczema was not confirmed , the treated infants had less IgE-associated eczema at 2 years of age and therefore possibly run a reduced risk to develop later respiratory allergic disease . CLINICAL IMPLICATION Probiotics may reduce the incidence of IgE-associated eczema in infancy",
"BACKGROUND Probiotics have shown promising potential in reducing the risk of eczema in infants . Optimal probiotic intervention regimen remains to be determined . OBJECTIVE We investigated whether maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of developing eczema in high-risk infants . METHODS This was a parallel , double-blind placebo-controlled trial of 241 mother-infant pairs . Mothers with allergic disease and atopic sensitization were r and omly assigned to receive ( 1 ) Lactobacillus rhamnosus LPR and Bifidobacterium longum BL999 ( LPR+BL999 ) , ( 2 ) L paracasei ST11 and B longum BL999 ( ST11+BL999 ) , or ( 3 ) placebo , beginning 2 months before delivery and during the first 2 months of breast-feeding . The infants were followed until the age of 24 months . Skin prick tests were performed at the ages of 6 , 12 , and 24 months . RESULTS Altogether 205 infants completed the follow-up and were included in the analyses . The risk of developing eczema during the first 24 months of life was significantly reduced in infants of mothers receiving LPR+BL999 ( odds ratio [ OR ] , 0.17 ; 95 % CI , 0.08 - 0.35 ; P chronically persistent eczema were 0.30 ( 95 % CI , 0.12 - 0.80 ; P = .016 ) and 0.17 ( 95 % CI , 0.05 - 0.56 ; P = .003 ) . Probiotics had no effect on the risk of atopic sensitization in the infants . No adverse effects were related to the use of probiotics . CONCLUSION Prevention regimen with specific probiotics administered to the pregnant and breast-feeding mother , that is , prenatally and postnatally , is safe and effective in reducing the risk of eczema in infants with allergic mothers positive for skin prick test",
"To cite this article : Boyle RJ , Ismail IH , Kivivuori S , Licciardi PV , Robins‐Browne RM , Mah L‐J , Axelrad C , Moore S , Donath S , Carlin JB , Lahtinen SJ , Tang MLK . Lactobacillus GG treatment during pregnancy for the prevention of eczema : a r and omized controlled trial . Allergy 2011 ; 66 : 509–516",
"BACKGROUND Recent studies have reported beneficial effects of probiotics on maternal glycemia in healthy pregnant women . Obesity significantly increases risk of impaired glucose tolerance in pregnancy , but glycemic effects of probiotics in this specific obstetric group require additional investigation . OBJECTIVE The aim of the Probiotics in Pregnancy Study was to investigate the effect of a probiotic capsule on maternal fasting glucose in obese pregnant women . DESIGN In this placebo-controlled , double-blind , r and omized trial , 175 pregnant women with an early pregnancy body mass index ( BMI ; in kg/m² ) from 30.0 to 39.9 were recruited from antenatal clinics at the National Maternity Hospital , Dublin , Irel and . Exclusion criteria were BMI 39.9 , prepregnancy or gestational diabetes , age Women were r and omly assigned to receive either a daily probiotic or a placebo capsule from 24 to 28 wk of gestation in addition to routine antenatal care . The primary outcome was the change in fasting glucose between groups from preintervention to postintervention . Secondary outcomes were the incidence of gestational diabetes and neonatal anthropometric measures . RESULTS In 138 women who completed the study ( 63 women in the probiotic group ; 75 women in the placebo group ) , mean ( ±SD ) early pregnancy BMI was 33.6 ± 2.6 , which differed significantly between probiotic ( 32.9 ± 2.4 ) and placebo ( 34.1 ± 2.7 ) groups . With adjustment for BMI , the change in maternal fasting glucose did not differ significantly between treated and control groups [ -0.09 ± 0.27 compared with -0.07 ± 0.39 mmol/L ; P = 0.391 ; B = -0.05 ( 95 % CI : -0.17 , 0.07 ) ] . There were also no differences in the incidence of impaired glycemia ( 16 % in the probiotic group compared with 15 % in the placebo group ; P = 0.561 ) , birth weight ( 3.70 kg in the probiotic group compared with 3.68 kg in the placebo group ; P = 0.723 ) , or other metabolic variables or pregnancy outcomes . A secondary analysis of 110 women , excluding antibiotic users and poor compliers , also revealed no differences in maternal glucose or other outcomes between groups . CONCLUSION Probiotic treatment of 4 wk during pregnancy did not influence maternal fasting glucose , the metabolic profile , or pregnancy outcomes in obese women",
"BACKGROUND The role of probiotics in prevention of allergic disease is still not clearly established , although early reports suggested Lactobacillus GG halved the risk of eczema at 2 years . OBJECTIVE To determine whether probiotic supplementation in early life could prevent development of eczema and atopy at 2 years . METHODS Double-blind , r and omized placebo-controlled trial of infants at risk of allergic disease . Pregnant women were r and omized to take Lactobacillus rhamnosus HN001 ( L rhamnosus ) , Bifidobacterium animalis subsp lactis strain HN019 or placebo daily from 35 weeks gestation until 6 months if breast-feeding , and their infants were r and omized to receive the same treatment from birth to 2 years ( n = 474 ) . The infant 's cumulative prevalence of eczema and point prevalence of atopy , using skin prick tests to common allergens , was assessed at 2 years . RESULTS Infants receiving L rhamnosus had a significantly ( P = .01 ) reduced risk of eczema ( hazard ratio [ HR ] , 0.51 ; 95 % CI , 0.30 - 0.85 ) compared with placebo , but this was not the case for B animalis subsp lactis ( HR , 0.90 ; 95 % CI , 0.58 - 1.41 ) . There was no significant effect of L rhamnosus ( HR , 0.74 ; 95 % CI , 0.46 - 1.18 ) or B animalis subsp lactis ( HR , 0.82 ; 95 % CI , 0.52 - 1.28 ) on atopy . L rhamnosus ( 71.5 % ) was more likely than B animalis subsp lactis ( 22.6 % ) to be present in the feces at 3 months , although detection rates were similar by 24 months . CONCLUSION We found that supplementation with L rhamnosus , but not B animalis subsp lactis , substantially reduced the cumulative prevalence of eczema , but not atopy , by 2 years . Underst and ing how Lactobacilli act to prevent eczema requires further investigation",
"BACKGROUND To our knowledge , data on the effects of probiotic supplementation on glycaemic control and lipid concentrations in patients with gestational diabetes mellitus ( GDM ) are scarce . AIM The aim of the present study was to determine the effects of probiotic supplementation on glycaemic control and lipid profiles in GDM patients . METHODS Sixty pregnant women with GDM , primigravida and aged 18 - 40years , were divided into two groups to receive either probiotic capsules ( n=30 ) or a matching placebo ( n=30 ) in this r and omized double-blind , placebo-controlled trial . The patients in the probiotic group took a daily capsule that contained three viable freeze-dried strains : Lactobacillus acidophilus ( 2 × 10(9)CFU/g ) , L. casei ( 2 × 10(9)CFU/g ) and Bifidobacterium bifidum ( 2 × 10(9)CFU/g ) for 6weeks . The placebo group took capsules filled with cellulose for the same time period . Fasting blood sample s were taken at the beginning and end of the study to quantify the relevant markers . RESULTS After 6weeks of intervention , probiotic supplementation vs a placebo result ed in significant decreases in fasting plasma glucose ( -9.2±9.2mg/dL vs + 1.1±12.2mg/dL , P ) , serum insulin levels ( -0.8±3.1μIU/mL vs + 4.5±10.6μIU/mL , P=0.01 ) , homoeostasis model assessment ( HOMA ) for insulin resistance ( -0.4±0.9 vs + 1.1±2.5 , P=0.003 ) and HOMA for β-cell function ( + 1.1±9.8 vs + 18.0±42.5 , P=0.03 ) , and a significant increase in the quantitative insulin sensitivity check index ( + 0.007±0.01 vs -0.01±0.02 , P=0.007 ) . In addition , significant decreases in serum triglycerides ( -1.6±59.4mg/dL vs + 27.1±37.9mg/dL , P=0.03 ) and VLDL cholesterol concentrations ( -0.3±11.9mg/dL vs + 5.4±7.6mg/dL , P=0.03 ) were seen following supplementation with the probiotics compared with the placebo . However , no significant changes in other lipid profiles were seen with the intervention . CONCLUSION Overall , the results of our study have demonstrated that taking probiotic supplements for 6weeks in patients with GDM had beneficial effects on glycaemic control , triglycerides and VLDL cholesterol concentrations , although there was no effect on other lipid profiles",
"Lactic acid bacteria and bifidobacteria are increasingly being administered to pregnant women and infants with the intention of improving health . Although these organisms have a long record of safe use , it is important to identify any adverse effects in potentially vulnerable population s. In a r and omized , double-blinded , placebo-controlled trial , we evaluated the safety of a bacterial dietary supplement for the prevention of atopy in infants . Two strains of lactobacilli ( Lactobacillus salivarius CUL61 and Lactobacillus paracasei CUL08 ) and bifidobacteria ( Bifidobacterium animalis subsp . lactis CUL34 and Bifidobacterium bifidum CUL20 ) with a total of 1 x 10(10 ) colony-forming units were administered daily to women during the last month of pregnancy and to infants aged 0 - 6 mo . Adverse events ( AE ) were classified according to WHO International Statistical Classification of Diseases criteria . Common symptoms were recorded by regular question naires . Baseline characteristics of 220 mother-infant dyads in the treatment and 234 in the placebo group were similar . Compliance with the trial interventions , loss to follow-up , symptoms , drug usage , infant growth , method of feeding , visits to the doctor , and mothers ' assessment of infant health were similar in the 2 groups . Fifteen ( 6.8 % ) mothers and 73 ( 33.2 % ) infants in the treatment group and 21 ( 9.0 % ) mothers and 75 ( 32.1 % ) infants in the placebo group reported AE ( P = 0.49 and P = 0.84 , respectively ) . Severe AE occurred in 18 mothers and 63 infants with a similar frequency in each group . None of the AE were attributed to the intervention . Our findings support the safe use of this consortium of organisms during pregnancy and early infancy",
"We evaluated the effects of Bifidobacterium breve-fermented soymilk on probiotic function . An administered strain of B. breve strain Yakult was capable of growing in soymilk with no additives as high as 10(9 ) CFU/ml . During storage of the fermented soymilk at 10 degrees C for 20 days , viable counts of the strain did not change . The growth inhibition of the strain in a bile-containing medium was lessened by the addition of soy protein . In human feeding experiments , the administered B. breve was recovered at a level of over 10(9 ) CFU/g faeces , accompanied by an increase in the total number of bifidobacteria . These results indicate that fermented soymilk with B. breve strain Yakult could be a novel type of probiotic food",
"Background / Aims : The supply of docosahexaenoic acid ( DHA , 22:6ω–3 ) , important for fetal/infant neurodevelopment , depends on the maternal fatty acid ( FA ) status , which may be marginal in central Europe . Therefore , we investigated the effect of a daily vitamin/mineral supplement with and without 200 mg DHA from mid-pregnancy through lactation on the DHA concentrations in maternal and infant red blood cell phospholipids ( RBC% ) , and in breast milk FA ( % ) . Methods : At 21 weeks ’ gestation , 144 women were enrolled into a r and omised , double-blind clinical trial receiving daily : ( 1 ) a basic vitamin-mineral supplement ( Vit/Min group ) , ( 2 ) Vit/Min plus 4.5 g fructo-oligosaccharide ( FOS group ) , or ( 3 ) Vit/Min plus 4.5 g FOS plus 200 mg fish oil-derived DHA ( DHA-FOS group ) . FAs were determined by capillary gas-liquid chromatography . Results : While maternal RBC-DHA% at enrolment was not different , at 37 weeks gestation , and 3 months after delivery RBC-DHA% were significantly higher in the DHA-FOS group . The breast milk DHA% was twice as high in the DHA-FOS group ( 0.50 % ) than in the two others ( 0.25 % ) ( p ) . The RBC-DHA% of the infants in the DHA-FOS group was also significantly higher , and correlated significantly with maternal RBC-DHA% before and 3 months after delivery . Conclusions : In central Europe , a dose of 200 mg/day DHA from mid-pregnancy through lactation seems appropriate to improve the DHA status of mothers and infants ",
"BACKGROUND . The value of probiotics for primary prevention is controversial . Published trials vary considerably in study design and the applied probiotics , thereby limiting comparability of the results . OBJECTIVE . The purpose of this trial was to study the preventive effect of the probiotic Lactobacillus GG on the development of atopic dermatitis . METHODS . In a double-blind , placebo-controlled prospect i ve trial , 105 pregnant women from families with ≥1 member ( mother , father , or child ) with an atopic disease were r and omly assigned to receive either the probiotic Lactobacillus GG ( American Type Culture Collection 53103 ; 5 × 109 colony-forming units of Lactobacillus GG twice daily ) or placebo . Ninety-four families ( 89.5 % ) completed the trial . The supplementation period started 4 to 6 weeks before expected delivery , followed by a postnatal period of 6 months . The primary end point was the occurrence of atopic dermatitis at the age of 2 years . Secondary outcomes were severity of atopic dermatitis , recurrent episodes of wheezing bronchitis , and allergic sensitization at the age of 2 years . RESULTS . Atopic dermatitis was diagnosed in 14 ( 28 % ) of 50 in the Lactobacillus GG group and in 12 ( 27.3 % ) of 44 in the placebo group . The risk of atopic dermatitis in children on probiotics relative to placebo was 0.96 ( confidence interval 0.38–2.33 ) . Severity of atopic dermatitis was comparable between the 2 groups . Notably , children with recurrent ( ≥5 ) episodes of wheezing bronchitis were more frequent in the Lactobacillus GG group ( 26 % ; n = 13 ) , as compared with the placebo group ( 9.1 % ; n = 4 ) . No difference was observed between both groups in total immunoglobulin E concentrations or numbers of specific sensitization to inhalant allergens . CONCLUSIONS . Supplementation with Lactobacillus GG during pregnancy and early infancy neither reduced the incidence of atopic dermatitis nor altered the severity of atopic dermatitis in affected children but was associated with an increased rate of recurrent episodes of wheezing bronchitis . Therefore , Lactobacillus GG can not be generally recommended for primary prevention",
"OBJECTIVE In an effort to eluci date possible causes of preterm labor , we undertook a prospect i ve study of 50 patients consecutively admitted with intact membranes and preterm labor who eventually had a preterm delivery despite the use of tocolysis . STUDY DESIGN A comprehensive evaluation plan was instituted . This included a detailed history and physical examination , targeted ultrasonography , amniocentesis for Gram stain , culture , and glucose determination , laboratory analysis for infection ( complete blood cell count , urinalysis , and cervical and urine cultures ) and for antiphospholipid antibody syndrome ( antinuclear antibody , lupus anticoagulant , anticardiolipin antibody ) , pathologic examination of the placenta , and a urine toxicology screen . RESULTS The following groups of possible causes of preterm labor were identified : ( 1 ) faulty placentation , 50 % ( 25/50 ) ; ( 2 ) intrauterine infection 38 % ( 19/50 ) ; ( 3 ) immunologic factors , 30 % ( 15/50 ) ; ( 4 ) cervical incompetence , 16 % ( 8/50 ) ; ( 5 ) uterine factors , 14 % ( 7/50 ) ; ( 6 ) maternal factors 10 % ( 5/50 ) ; ( 7 ) trauma and surgery , 8 % ( 4/50 ) ; ( 8) fetal anomalies , 6 % ( 3/50 ) ; and ( 9 ) idiopathic conditions , 4 % ( 2/50 ) . Among the 50 patients two or more possible causes were identified in 58 % ( 29/50 ) . CONCLUSION We suggest that an exhaustive evaluation plan can identify possible causes in the majority ( 96 % ) of cases of \" idiopathic \" preterm labor that result in preterm delivery",
"Previous studies have shown that inflammatory factors increases in pregnancy and is associated with several complications of pregnancy . The aim of this study was to assess effects of daily consumption of probiotic yoghurt on inflammatory factors in pregnant women . In a r and omized clinical trial , seventy primigravid ( the first pregnancy ) and singleton pregnant women aged 18 - 30 years were assigned to two groups . Subjects consumed daily 200 g probiotic yoghurt containing Lactobacillus acidophilus La5 and Bifidobacterium animalis BB12 ( 10(7 ) CFU g(-1 ) for each ) or 200 g conventional yoghurt for 9 weeks . Fasting blood sample s were collected at baseline ( 28 weeks of gestation ) and after intervention ( 37 weeks of gestation ) . Inflammatory factors , hs-CRP and TNF-alpha , were measured by Enzyme-linked Immunosorbent Assay ( ELISA ) . Independent t-test was used to compare the two groups after intervention and paired- sample t-test compared variables before and after treatment . The results showed that the probiotic yogurt brought about a decrease in the serum hs-CRP level , from 10.44 + /- 1.56 to 7.44 + /- 1.03 microg mL(-1 ) ( p = 0.041 ) . There was no significant change in the conventional yogurt group in the serum hs-CRP level ( 12.55 + /- 1.57 to 14.51 + /- 1.62 microg mL(-1 ) , p = 0.202 ) . The probiotic yogurt had no effect on TNF-alpha ( from 73.75 + /- 6.59 to 77.91 + /- 5.61 pg mL(-1 ) , p = 0.633 ) . Serum TNF-alpha did not change in the conventional yogurt group ( p = 0.134 ) . In conclusion probiotic yogurt significantly decreased hs-CRP in pregnant women but had no effect on TNF-alpha",
"BACKGROUND The increase in allergic diseases is attributed to a relative lack of microbial stimulation of the infantile gut immune system . Probiotics , live health-promoting microbes , might offer such stimulation . OBJECTIVE We studied the effect of a mixture of 4 probiotic bacterial strains along with prebiotic galacto-oligosaccharides in preventing allergic diseases . METHODS We r and omized 1223 pregnant women carrying high-risk children to use a probiotic preparation or a placebo for 2 to 4 weeks before delivery . Their infants received the same probiotics plus galacto-oligosaccharides ( n = 461 ) or a placebo ( n = 464 ) for 6 months . At 2 years , we evaluated the cumulative incidence of allergic diseases ( food allergy , eczema , asthma , and allergic rhinitis ) and IgE sensitization ( positive skin prick test response or serum antigen-specific IgE level > 0.7 kU/L ) . Fecal bacteria were analyzed during treatment and at age 2 years . RESULTS Probiotic treatment compared with placebo showed no effect on the cumulative incidence of allergic diseases but tended to reduce IgE-associated ( atopic ) diseases ( odds ratio [ OR ] , 0.71 ; 95 % CI , 0.50 - 1.00 ; P = .052 ) . Probiotic treatment reduced eczema ( OR , 0.74 ; 95 % CI , 0.55 - 0.98 ; P = .035 ) and atopic eczema ( OR , 0.66 ; 95 % CI , 0.46 - 0.95 ; P = .025 ) . Lactobacilli and bifidobacteria more frequently ( P treatment showed no effect on the incidence of all allergic diseases by age 2 years but significantly prevented eczema and especially atopic eczema . The results suggest an inverse association between atopic diseases and colonization of the gut by probiotics . CLINICAL IMPLICATION S The prevention of atopic eczema in high-risk infants is possible by modulating the infant 's gut microbiota with probiotics and prebiotics"
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BACKGROUND Calcium channel blockers ( CCBs ) are a relatively new antihypertensive class . The effect of first-line CCBs on the prevention of cardiovascular events , as compared with other antihypertensive drug classes , is unknown . OBJECTIVES To determine whether CCBs used as first-line therapy for hypertension are different from other first-line drug classes in reducing the incidence of major adverse cardiovascular events . SEARCH STRATEGY Electronic search es of the Cochrane Central Register of Controlled Trials , MEDLINE , EMBASE and the WHO-ISH Collaboration Register ( up to May 2009 ) were performed . We also checked the references of published studies to identify additional trials . SELECTION CRITERIA R and omized controlled trial ( RCT ) comparing first-line CCBs with other antihypertensive classes , with at least 100 r and omized hypertensive participants and with a follow-up of at least two years . DATA COLLECTION AND ANALYSIS Two authors independently selected the included trials , evaluated the risk of bias and entered the data for analysis . MAIN RESULTS Eighteen RCTs ( 14 dihydropyridines , 4 non-dihydropyridines ) with a total of 141,807 participants were included . All-cause mortality was not different between first-line CCBs and any other first-line antihypertensive classes . CCBs reduced the following outcomes as compared to beta-blockers : total cardiovascular events ( RR 0.84 , 95 % CI [ 0.77 , 0.92 ] ) , stroke ( RR 0.77 , 95 % CI [ 0.67 , 0.88 ] ) and cardiovascular mortality ( RR 0.90 , 95 % CI [ 0.81 , 0.99 ] ) . CCBs increased total cardiovascular events ( RR 1.05 , 95 % CI [ 1.00 , 1.09 ] , p = 0.03 ) and congestive heart failure events ( RR 1.37 , 95 % CI [ 1.25 , 1.51 ] ) as compared to diuretics . CCBs reduced stroke ( RR 0.89 , 95 % CI [ 0.80 , 0.98 ] ) as compared to ACE inhibitors and reduced stroke ( RR 0.85 , 95 % CI [ 0.73 , 0.99 ] ) and MI ( RR 0.83 , 95 % CI [ 0.72 , 0.96 ] ) as compared to ARBs . CCBs also increased congestive heart failure events as compared to ACE inhibitors ( RR 1.16 , 95 % CI [ 1.06 , 1.27 ] ) and ARBs ( RR 1.20 , 95 % CI [ 1.06 , 1.36 ] ) . The other evaluated outcomes were not significantly different . AUTHORS ' CONCLUSIONS Diuretics are preferred first-line over CCBs to optimize reduction of cardiovascular events . The review does not distinguish between CCBs , ACE inhibitors or ARBs , but does provide evidence supporting the use of CCBs over beta-blockers . Many of the differences found in the current review are not robust and further trials might change the conclusions . More well- design ed RCTs study ing the mortality and morbidity of patients taking CCBs as compared with other antihypertensive drug classes are needed for patients with different stages of hypertension , different ages , and with different co-morbidities such as diabetes
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"CONTEXT Incidence of end-stage renal disease due to hypertension has increased in recent decades , but the optimal strategy for treatment of hypertension to prevent renal failure is unknown , especially among African Americans . OBJECTIVE To compare the effects of an angiotensin-converting enzyme ( ACE ) inhibitor ( ramipril ) , a dihydropyridine calcium channel blocker ( amlodipine ) , and a beta-blocker ( metoprolol ) on hypertensive renal disease progression . DESIGN , SETTING , AND PARTICIPANTS Interim analysis of a r and omized , double-blind , 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( glomerular filtration rate [ GFR ] of 20 - 65 mL/min per 1.73 m(2 ) ) enrolled between February 1995 and September 1998 . This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000 . INTERVENTIONS Participants were r and omly assigned to receive amlodipine , 5 to 10 mg/d ( n = 217 ) , ramipril , 2.5 to 10 mg/d ( n = 436 ) , or metoprolol , 50 to 200 mg/d ( n = 441 ) , with other agents added to achieve 1 of 2 blood pressure goals . MAIN OUTCOME MEASURES The primary outcome measure was the rate of change in GFR ; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50 % or 25 mL/min per 1.73 m(2 ) , end-stage renal disease , or death . RESULTS Among participants with a urinary protein to creatinine ratio of > 0.22 ( corresponding approximately to proteinuria of more than 300 mg/d ) , the ramipril group had a 36 % ( 2.02 [ SE , 0.74 ] mL/min per 1.73 m(2)/y ) slower mean decline in GFR over 3 years ( P = .006 ) and a 48 % reduced risk of the clinical end points vs the amlodipine group ( 95 % confidence interval [ CI ] , 20%-66 % ) . In the entire cohort , there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups ( P = .38 ) . However , compared with the amlodipine group , after adjustment for baseline covariates the ramipril group had a 38 % reduced risk of clinical end points ( 95 % CI , 13%-56 % ) , a 36 % slower mean decline in GFR after 3 months ( P = .002 ) , and less proteinuria ( P renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria",
"CONTEXT Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients , safety and efficacy of antihypertensive agents for coronary artery disease ( CAD ) have been discerned only from subgroup analyses in large trials . OBJECTIVE To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy ( CAS ) or a non-calcium antagonist strategy ( NCAS ) . DESIGN , SETTING , AND PARTICIPANTS R and omized , open label , blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older , which was conducted September 1997 to February 2003 at 862 sites in 14 countries . INTERVENTIONS Patients were r and omly assigned to either CAS ( verapamil sustained release ) or NCAS ( atenolol ) . Strategies specified dose and additional drug regimens . Tr and olapril and /or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) of less than 140 mm Hg ( systolic ) and less than 90 mm Hg ( diastolic ) ; and less than 130 mm Hg ( systolic ) and less than 85 mm Hg ( diastolic ) if diabetes or renal impairment was present . Tr and olapril was also recommended for patients with heart failure , diabetes , or renal impairment . MAIN OUTCOME MEASURES Primary : first occurrence of death ( all cause ) , nonfatal myocardial infa rct ion , or nonfatal stroke ; other : cardiovascular death , angina , adverse experiences , hospitalizations , and blood pressure control at 24 months . RESULTS At 24 months , in the CAS group , 6391 patients ( 81.5 % ) were taking verapamil sustained release ; 4934 ( 62.9 % ) were taking tr and olapril ; and 3430 ( 43.7 % ) were taking hydrochlorothiazide . In the NCAS group , 6083 patients ( 77.5 % ) were taking atenolol ; 4733 ( 60.3 % ) were taking hydrochlorothiazide ; and 4113 ( 52.4 % ) were taking tr and olapril . After a follow-up of 61 835 patient-years ( mean , 2.7 years per patient ) , 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies ( 9.93 % in CAS and 10.17 % in NCAS ; relative risk [ RR ] , 0.98 ; 95 % confidence interval [ CI ] , 0.90 - 1.06 ) . Two-year blood pressure control was similar between groups . The JNC VI blood pressure goals were achieved by 65.0 % ( systolic ) and 88.5 % ( diastolic ) of CAS and 64.0 % ( systolic ) and 88.1 % ( diastolic ) of NCAS patients . A total of 71.7 % of CAS and 70.7 % of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg . CONCLUSION The verapamil-tr and olapril-based strategy was as clinical ly effective as the atenolol-hydrochlorothiazide-based strategy in hypertensive CAD patients",
"SUMMARY Background : Hypertension is one of the most important causes of cardiovascular disease , and treatment of hypertension leads to a significant reduction in cardiovascular mortality and morbidity . Although calcium channel blockers are regarded as an important part of the therapeutic armamentarium against cardiovascular diseases , and are among the most frequently prescribed antihypertensive medications , concern has been aroused about these drugs , particularly the short-acting dihydropyridine derivatives . However , the value of nifedipine GITS ( Adalat-Crono * ) , the long-acting dihydropyridine , is in need of being re-established . * Adalat-Crono is a registered tradename of Bayer AG , Leverkusen , Germany Objective : To compare the effectiveness , safety and tolerability of once-daily nifedipine and amlodipine treatment in patients with mild-to-moderate essential hypertension . Design : R and omised multicentre trial with an open comparison of treatments for 12 weeks , with a preceding placebo run-in period of 2 weeks ( patients on beta-blockers at the time of enrolment entered a m and atory 2-week wash-out period before being allowed in the placebo run-in period ; this wash-out period was one week for patients using any antihypertensive medication other than beta-blockers ) . Setting : Nine centres ( all university hospitals ) in Turkey . Patients : 155 patients with essential hypertension ( diastolicblood pressure 95 - 109 mmHg ) . Interventions : Initial treatment ( step 1 ) consisted of 30 mg nifedipine GITS ( n = 76 ; ( Adalat-Crono tablets ) , or 5 mg amlodipine ( n = 79 ; Norvasc * 5-mg tablets ) , either administered once daily , as a morning dose , or if the blood pressure was not below 140/90 mmHg , or the reduction in diastolic blood pressure was lower than 10 mmHg after a treatment period of 6 weeks , the dose was increased ( Step 2 ) to 60 mg once daily in the nifedipine group , or 10 mg once daily in the amlodipine group . Main efficacy parameter : Diastolic blood pressure at trough after 12 weeks of active compound therapy adjusted to baseline . Results : After 12 weeks of treatment , the mean diastolic blood pressure was 83.1 and 81.9 mmHg , in the nifedipine and amlodipine groups , respectively ( p = 0.436 ) . The mean decrease in systolic blood pressure ( 28.5 ± 11.9 and 28.2 ± 11.2 mmHg in the nifedipine and amlodipine groups , respectively ) and the mean decrease in diastolic blood pressure ( 16.4 ± 7.0 and 17.5 ± 6.9 mmHg in the nifedipine and amlodipine groups , respectively ) , as well as the responder rates ( 88.1 % and 92.1 % , in the nifedipine and amlodipine groups , respectively ) were comparable at the end of the study . No significant differences between groups were detected in the efficacy parameters assessed in this study . Both drugs were well tolerated . The overall incidence of adverse events was 7.9 % in the nifedipine group and 10.1 % in the amlodipine group . However , more patients discontinued treatment prematurely in the amlodipine group ( 13 patients ; 19.7 % ) , than in the nifedipine group ( four patients ; 5.6 % ) . Conclusions : The results of this study demonstrated that once-daily nifedipine in GITS formulation and amlodipine are comparably safe and effective treatment options in patients with mild-to-moderate essential hypertensi on",
"NORDIL -- the Nordic Diltiazem Study (NORDIL)--is a prospect i ve , r and omized , open blinded-endpoint ( PROBE ) , multicenter , parallel-group morbidity/mortality outcome study in hypertensive patients design ed to compare an intervention strategy based on the calcium antagonist diltiazem with a strategy based on conventional antihypertensive drug treatment ( diuretics or beta-adrenergic blockers ) . Patient recruitment was started in Norway and Sweden in September 1992 , and ended on December 15 , 1996 , when 10.896 male and female patients , aged 50 - 74 years , with essential hypertension had been r and omized . In this paper we describe the baseline data of the patient cohort and blood pressures achieved in the two treatment groups during the early part of the study . The patient cohort consists of 5294 males and 5602 females with a mean age of 59.6 and 60.3 years , respectively . Concomitant disorders and risk factors in the cohort are : smoking 22 % , ischemic heart disease 3.0 % , previous myocardial infa rct ion ( MI ) 2.0 % , previous stroke 1.5 % , diabetes mellitus 7.0 % , and renal impairment 0.3 % . There were no differences between the treatment groups in these respects . The blood pressure treatment goal is a target diastolic blood pressure of diastolic blood pressure reduction from the inclusion pressure . In the treatment group r and omized to a diltiazem-based treatment strategy , blood pressure was 174/106 mmHg at baseline and 156/90 mmHg after 12 months of follow-up on active treatment . In the group r and omized to a conventional treatment strategy , baseline blood pressure at r and omization was 173/106 mmHg and 153/90 mmHg after 12 months on active therapy . The NORDIL study will terminate on October 31 , 1999 and the final results should be available by mid-2000",
"Background —The Prospect i ve R and omized Enalapril Study Evaluating Regression of Ventricular Enlargement ( PRESERVE ) study was design ed to test whether enalapril achieves greater left ventricular ( LV ) mass reduction than does a nifedipine gastrointestinal treatment system by a prognostically meaningful degree on a population basis ( 10 g/m2 ) . Methods and Results —An ethnically diverse population of 303 men and women with essential hypertension and increased LV mass at screening echocardiography were enrolled at clinical centers on 4 continents and studied by echocardiography at baseline and after 6- and 12-month r and omized therapy . Clinical examination and blinded echocardiogram readings 48 weeks after study entry in an intention-to-treat analysis of 113 enalapril-treated and 122 nifedipine-treated patients revealed similar reductions in systolic/diastolic pressure ( −22/12 versus −21/13 mm Hg ) and LV mass index ( −15 versus −17g/m2 , both P > 0.20 ) . No significant between-treatment difference was detected in population subsets defined by monotherapy treatment , sex , age , race , or severity of baseline hypertrophy . Similarly , there was no between-treatment difference in change in velocities of early diastolic or atrial phase transmitral blood flow . More enalapril-treated than nifedipine-treated patients required supplemental treatment with hydrochlorothiazide ( 59 % versus 34 % , P atenolol ( 27 % versus 22 % , NS ) . Conclusions —Once-daily antihypertensive treatment with enalapril or long-acting nifedipine , plus adjunctive hydrochlorothiazide and atenolol when needed to control blood pressure , both had moderately beneficial and statistically indistinguishable effects on regression of LV hypertrophy",
"The Multicenter Isradipine Diuretic Atherosclerosis Study is a r and omized , double-blind , clinical trial design ed to compare the effectiveness of isradipine against hydrochlorothiazide in retarding the rate of progression of atherosclerotic lesions in the carotid arteries of hypertensive subjects . Eight hundred hypertensive men and women , 40 years of age or older , with minor plaques , are being recruited at eight clinical centers in the United States and will be followed for three years . Quantification of the atherosclerotic lesions at baseline and semiannually is done using B-mode ultrasonography . The background of the trial and its design features are discussed",
"The African American Study of Kidney Disease and Hypertension ( AASK ) Pilot Study evaluated the feasibility of carrying out a r and omized , multicenter , 7-year clinical trial to determine the effects of two goal levels of blood pressure control and three antihypertensive drug regimens on decline in glomerular filtration rate in African Americans with clinical ly diagnosed hypertensive nephrosclerosis . Participants were r and omized to either a usual mean arterial blood pressure ( MAP ) goal group ( 102 - 107 mm Hg ) or a low-MAP goal group ( drug regimen ( initial therapy with either atenolol , amlodipine , or enalapril ) . Quality of life was assessed by the Medical Outcomes Short-Form 36 ( MOS SF-36 ) at baseline and the last follow-up visit for 84 of the 94 participants of the AASK Pilot Study . Symptoms were assessed at baseline and throughout the course of therapy by participant self-report . Mean SF-36 scores increased significantly on physical functioning ( 9.2 ) , role limitations ( physical ) ( 19.0 ) , social functioning ( 9.0 ) , and vitality dimensions ( 5.6 ) from baseline to the last follow-up visit in the usual MAP goal group . Scores for the eight health dimensions assessed by the MOS SF-36 did not change significantly during the same time period either in the low-MAP goal group or in any of the drug regimens . The mean score for general health perception was significantly lower at the last follow-up visit in the enalapril drug regimen ( 49.9 ) compared to drug regimens with atenolol ( 65.4 ) or amlodipine ( 63.9 ) . Physical functioning , role limitations ( emotional ) , social functioning , mental health , vitality , and general health perception scores were negatively correlated with self-reported symptoms during treatment . We conclude that selected dimensions of quality of life improved during the AASK Pilot Study only in participants r and omized to the usual MAP goal group . Significant differences between MAP goal groups and drug regimens at the end of follow-up were observed for only a few health dimensions",
"Hypertension and end-stage renal disease ( ESRD ) are major causes of morbidity and mortality in the United States , especially among African Americans . The African American Study of Kidney Disease and Hypertension ( AASK ) Pilot Study evaluated the feasibility of conducting a long-term clinical trial to compare the effects of two levels of blood pressure control and three different antihypertensive drug regimens on the rate of decline in glomerular filtration rate ( GFR ) in African Americans with clinical ly diagnosed hypertensive renal disease . African American men and women aged 18 - 70 years with a GFR of 25 - 70 ml/min/ 1.73m2 and hypertension were r and omized in a 3 x 2 factorial design to initial treatment with either an angiotensin-converting enzyme inhibitor ( enalapril ) , a calcium channel blocker ( amlodipine ) , or a beta blocker ( atenolol ) and to a mean arterial blood pressure ( goal MAP ) of either 102 - 107 mm Hg or Furosemide , doxazosin , clonidine , hydralazine , and minoxidil were added sequentially until goal MAP was achieved . To compare the pathologic diagnosis with the clinical diagnosis of renal disease , study participants without contraindication were also asked to undergo a renal biopsy . The goals of the AASK Pilot Study were to evaluate recruitment techniques , adherence to prescribed antihypertensive drug regimens , ability of the antihypertensive regimens to achieve blood pressure goals , rates of participation in scheduled clinic visits and procedures , and variability of GFR measurements . A further goal was to obtain renal biopsy data in at least 75 % of the r and omized study participants . Compared to the ESRD patient population whose renal disease is caused by hypertension , women were underrepresented in the AASK Pilot Study . AASK Pilot Study participants had higher unemployment rates and lower income levels than African Americans in the general U.S. population",
"BACKGROUND Several recent studies have suggested that calcium antagonist drugs , which are widely used for the treatment of hypertension , are associated with increased risk of cardiovascular disease . These studies have cast doubts on the long-term safety of calcium antagonists . OBJECTIVE To examine the association of calcium antagonist use with mortality in subjects with hypertension followed up in the Framingham Heart Study . SUBJECTS AND METHODS We stratified 3539 subjects ( mean+/-SD age , 64+/-13 years ) from the Framingham Heart Study who had hypertension at routine clinic examinations , according to the use of calcium antagonists and presence of coronary heart disease at the baseline examination . At each follow-up examination ( every 2 - 4 years ) , subjects were reclassified with regard to the use of calcium antagonists . The end point of the study was all-cause mortality . Hazard ratios and 95 % confidence intervals associated with the use of calcium antagonists were obtained using Cox proportional hazards regression models . RESULTS There were 970 deaths during follow-up . Hazard ratios for mortality associated with the use of calcium antagonists were 0.93 ( 95 % confidence interval , 0.72 - 1.21 ; P=.59 ) for subjects with hypertension without coronary heart disease , and 0.92 ( 95 % confidence interval , 0.69 - 1.24 ; P=.58 ) for those with coronary heart disease at baseline . All models were adjusted for age , sex , current smoking , systolic and diastolic blood pressure , use of beta-blockers , and use of other antihypertensive medications . CONCLUSIONS In this cohort of 3539 subjects with hypertension there were no differences in mortality among subjects with hypertension using a calcium antagonist compared with those who were not . Results were similar among subjects with hypertension with and without coronary heart disease . The results of ongoing long-term , r and omized clinical trials will provide more definitive data on the safety of calcium antagonists",
"OBJECTIVES The primary objective of the International Verapamil SR/Tr and olapril Study ( INVEST ) is to compare the risk for adverse outcomes ( all-cause mortality , nonfatal myocardial infa rct ion [ MI ] or nonfatal stroke ) in hypertensive patients with coronary artery disease ( CAD ) treated with either a calcium antagonist-based or a noncalcium antagonist-based strategy . BACKGROUND Treatment recommendations for hypertension include initial therapy with a diuretic or beta-adrenergic blocking agent , for which reductions in morbidity and mortality are documented from r and omized trials but are less than expected from epidemiologic data . For this reason , recent attention has focused on calcium antagonists or angiotensin-converting enzyme inhibitors . While these agents reduce blood pressure , outcome data from large r and omized trials are lacking , but some case-control data , dominated by short-acting dihydropyridines , suggest an increased risk of cardiovascular events . These studies had method ologic limitations and did not differentiate among calcium antagonist types and formulations . Several studies differentiating among calcium antagonist types and an overview of published r and omized trials show no increased risk with verapamil and suggestion for benefit in CAD patients . METHODS A total of 27,000 CAD patients with hypertension will be r and omized at 1,500 primary care sites to receive either a calcium antagonist-based ( verapamil ) or beta-blocker/diuretic-based ( atenolol/hydrochlorothiazide ) antihypertensive care strategy . The study uses a novel , electronic \" paper-less \" system for direct on-screen data entry , r and omization and drug distribution from a mail pharmacy linked to the coordination center via the Internet . RESULTS Contract negotiations with the United States and international sites are ongoing . Patients being enrolled are predominantly elderly ( 72 % aged 60 years or older ) men ( 54 % ) , with either an abnormal coronary angiogram or prior MI ( 71 % ) . In addition to hypertension , CAD and elderly age , most patients ( 89 % ) have one or more associated conditions ( diabetes , dyslipidemia , smoking , cerebral or peripheral vascular disease , etc . ) contributing to increased risk for adverse outcome . While 26 % have diabetes , most of these are noninsulin dependent . Using the protocol strategies , target blood pressures ( according to JNC VI ) have been reached in 58 % at the fourth visit , and as expected most ( 89 % ) are requiring multiple antihypertensive drugs . CONCLUSION The design and baseline characteristics of the initial patients recruited for a prospect i ve , r and omized , international , multicenter study comparing two therapeutic strategies to control hypertension in CAD patients are described",
"Background —ACE inhibitors and calcium antagonists may modulate fibrinolysis . We conducted a r and omized controlled trial to assess the effects of these drugs on plasminogen activator inhibitor-1 ( PAI-1 ) antigen , an inhibitor of fibrinolysis . Methods and Results — Participants with hypertension and type 2 diabetes mellitus ( n=96 , 51 % black ) were r and omized after an initial 4 weeks of placebo to double-blind 20 or 40 mg fosinopril or 5 or 10 mg amlodipine daily for 4 weeks in a fixed-dose regimen . After 4 weeks of placebo washout , the patients received 4 weeks of crossover treatments . After treatment with placebo , systolic and diastolic blood pressure were 143±2 and 86±1 mm Hg and plasma PAI-1 was 43.4±2.3 ng/mL. Amlodipine achieved a greater systolic and diastolic blood pressure reduction than fosinopril ( 10 mm Hg versus 8 mm Hg , P = 0.029 , and 5 mm Hg versus 3 mm Hg , P = 0.040 , respectively ) but tended to increase PAI-1 , whereas fosinopril tended to decrease PAI-1 ( 5.4±3.6 versus −3.8±2.5 ng/mL , P = 0.045 ) . The PAI-1 changes depended on drug dose ( 6.5±6.1 and 3.4±3.9 ng/mL with amlodipine 10 and 5 mg , respectively , and −0.4±3.1 and −7.4±4.0 ng/mL with fosinopril 20 and 40 mg , respectively , P for trend 0.024 ) . No significant differences between fosinopril and amlodipine were found for short-term changes in tissue plasminogen activator antigen , fibrinogen , C-reactive protein , and interleukin-6 . The findings were similar in black and white participants . Conclusions —Short-term treatment with fosinopril significantly reduced PAI-1 compared with amlodipine in a dose-dependent fashion . This effect , which was independent of blood pressure reduction , may account for the improved clinical outcomes achieved with ACE inhibitors compared with calcium antagonists",
"beta-Blockers are known to slow the progression of diabetic nephropathy by lowering arterial pressure . Moreover , in individuals with diabetic nephropathy , antihypertensive agents that provide sustained reductions in proteinuria slow the rate of decline in renal function compared with agents without this antiproteinuric effect . To examine whether differential effects on proteinuria affect the progression of diabetic nephropathy , we conducted a r and omized study that compared the effects of a heart rate-lowering calcium channel blocker , sustained-release verapamil , with those of a beta-blocker , atenolol , on the progression of diabetic renal disease . The primary end point of the study was a change in creatinine clearance slope . Thirty-four African Americans with the following inclusion criteria were r and omized to one of the two groups : serum creatinine greater than 1.4 mg/dL , proteinuria greater than 1500 mg/d , longer than a 5-year history of both non-insulin-dependent diabetes mellitus and hypertension , and exclusion of other renal diseases . Goal blood pressure was less than 140/90 mm Hg . All subjects received loop diuretics as second line agents to help achieve the blood pressure goal . Twenty-four-hour urinary protein and sodium excretions as well as creatinine clearance were measured at 6-month intervals . Blood pressure was measured every 3 months . After a mean follow-up of 54+/-6 months , the calcium channel blocker group demonstrated both a slower rate of decline in creatinine clearance ( -1.7+/-0.9 versus -3.7+/-1.4 mL/min per year per 1.73 m2 , P proteinuria compared with the atenolol group . Additionally , a greater proportion of the atenolol group had a 50 % or more increase in serum creatinine compared with the verapamil group ( 32+/-9 % versus 16+/-7 % , P blood pressure control . These data support the concept that antihypertensive agents that persistently maintain reductions in both arterial pressure and proteinuria slow the progression of diabetic renal disease in African Americans to a greater extent than those agents without these effects",
"In the double-blind Systolic Hypertension in Europe ( Syst-Eur ) Trial , active treatment was initiated with nitrendipine ( 10 to 40 mg/d ) with the possible addition of enalapril ( 5 to 20 mg/d ) and /or hydrochlorothiazide ( 12.5 to 25 mg/d ) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to placebos were used similarly . In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs , this report explored to what extent nitrendipine , administered alone , prevented cardiovascular complications . Age at r and omization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg . Of 2398 actively treated patients , 1327 took only nitrendipine ( average dose , 23.4 mg/d ) , and 1042 progressed to other treatments including nitrendipine ( n=757 ; 35.7 mg/d ) , enalapril ( n=783 ; 13.4 mg/d ) , and /or hydrochlorothiazide ( n=294 ; 21.0 mg/d ) . Compared with the whole placebo group ( n=2297 ) , patients receiving monotherapy with nitrendipine had 25 % ( P=0.05 ) fewer cardiovascular end points , and those progressing to other active treatments showed decreases ( P total mortality ( 40 % ) , stroke ( 59 % ) , and all cardiovascular end points ( 39 % ) . Among the control patients , 863 used only the first-line placebo . Compared with this subgroup , patients receiving monotherapy with nitrendipine showed a nearly 50 % ( P of end points , including total and cardiovascular mortality . The full relative benefit from nitrendipine was seen as early as 6 months after r and omization . To ascertain that the benefit conferred by the dihydropyridine was not due to selection bias , the 1327 patients remaining on monotherapy with nitrendipine were matched by gender , age , previous cardiovascular complications , and systolic blood pressure at entry with an equal number of placebo patients . In this analysis , nitrendipine reduced ( P cardiovascular mortality by 41 % , all cardiovascular end points by 33 % , and fatal and nonfatal cardiac end points by 33 % . Despite the limitations inherent in post hoc analyses , the present findings suggest that the calcium channel blocker nitrendipine , given as a single antihypertensive medication , prevents cardiovascular complications in older patients with isolated systolic hypertension",
"BACKGROUND Calcium antagonists are a first-line treatment for hypertension . The effectiveness of diltiazem , a non-dihydropyridine calcium antagonist , in reducing cardiovascular morbidity or mortality is unclear . We compared the effects of diltiazem with that of diuretics , beta-blockers , or both on cardiovascular morbidity and mortality in hypertensive patients . METHODS In a prospect i ve , r and omised , open , blinded endpoint study , we enrolled 10,881 patients , aged 50 - 74 years , at health centres in Norway and Sweden , who had diastolic blood pressure of 100 mm Hg or more . We r and omly assigned patients diltiazem , or diuretics , beta-blockers , or both . The combined primary endpoint was fatal and non-fatal stroke , myocardial infa rct ion , and other cardiovascular death . Analysis was done by intention to treat . FINDINGS Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups ( reduction 20.3/18.7 vs 23.3/18.7 mm Hg ; difference in systolic reduction p Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group ( 6.4 vs 7.9 events per 1000 patient-years ; 0.80 [ 0.65 - 0.99 ] , p=0.04 ) and fatal and non-fatal myocardial infa rct ion in 183 and 157 patients ( 7.4 vs 6.3 events per 1000 patient-years ; 1.16 [ 0.94 - 1.44 ] , p=0.17 ) . INTERPRETATION Diltiazem was as effective as treatment based on diuretics , beta-blockers , or both in preventing the combined primary endpoint of all stroke , myocardial infa rct ion , and other cardiovascular death",
"BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or placebo . The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes",
"Twenty patients with acute severe hypertension were r and omised to therapy with either nifedipine capsules ( 10 mg ) or captopril tablets ( 25 mg ) given sublingually and the blood pressure recorded for 240 minutes . Oral monotherapy with either agent followed for 3 weeks , then the agents were combined for a further 2 weeks and in the final 6 weeks of the trial a beta-blocker and diuretic were added , if needed . Thirteen patients completed the trial . The major results were : ( i ) nifedipine decreased blood pressure more rapidly than captopril 60 minutes after first ingestion but at 240 minutes equal degrees of fall in blood pressure had been obtained ; ( ii ) neither agent given as sustained monotherapy was able to reduce blood pressure adequately , although nifedipine was better than captopril ; and ( iii ) combination therapy with both agents was conspicuously successful in achieving reduction in blood pressure . It is suggested that combination nifedipine-captopril therapy be subject to a formal trial for early therapy in acute severe hypertension",
"Summary The Syst-Eur Trial is a concerted action of the European Community ’s Medical and Health Research Programme . The trial is carried out in consultation with the World Health Organization , the International Society of Hypertension , the European Society of Hypertension and the World Hypertension League . This article describes the objectives and the protocol of Syst-Eur , a multicentre trial design ed by the European Working Party on High Blood . Pressure in the Elderly ( EWPHE ) , to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality . Secondary endpoints include cardiovascular events , such as myocardial infa rct ion and congestive heart failure . To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160–219 mmHg with a diastolic pressure less than 95 mmHg . Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry . The patients are r and omized to active treatment or placebo . Active treatment consists of nitrendipine ( 10–40 mg/day ) , combined with enalapril ( 5–20 mg/day ) and hydrochlorothiazide ( 12.5–25 mg/day ) , as necessary . The patients of the control group receive matching placebos . The drugs ( or matching placebos ) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg . Morbidity and mortality are monitored to enable an intention-to-treat and per protocol comparison of the outcome in the 2 treatment groups . A one-year pilot trial ( 1989 ) showed that the protocol is practicable . The Ethics Committee therefore decided to start the definite study ( 1990 ) , in which r and omized patients will be followed for 5 years . Recruitment of new centres and of the required 3,000 patients will last 3 years ( until 1993 )",
"OBJECTIVE ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism . The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events R and omized Trial ( FACET ) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension . Prospect ively defined cardiovascular events were assessed as secondary outcomes . RESEARCH DESIGN AND METHODS Inclusion criteria included a diagnosis of NIDDM and hypertension ( systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg ) . Exclusion criteria included a history of coronary heart disease or stroke , serum creatinine > 1.5 mg/dl , albuminuria > 40 μg/min , and use of lipid-lowering drugs , aspirin , or antihypertensive agents other than beta-blockers or diuretics . A total of 380 hypertensive diabetics were r and omly assigned to open-label fosinopril ( 20 mg/day ) or amlodipine ( 10 mg/day ) and followed for up to 3.5 years . If blood pressure was not controlled , the other study drug was added . RESULTS Both treatments were effective in lowering blood pressure . At the end of followup , between the two groups there was no significant difference in total serum cholesterol , HDL cholesterol , HbA1c , fasting serum glucose , or plasma insulin . The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infa rct ion , stroke , or hospitalized angina than those receiving amlodipine ( 14/189 vs. 27/191 ; hazards ratio = 0.49 , 95 % CI = 0.26–0.95 ) . CONCLUSIONS Fosinopril and amlodipine had similar effects on biochemical measures , but the patients r and omized to fosinopril had a significantly lower risk of major vascular events , compared with the patients r and omized to amlodipine ",
"Background —Most cardiovascular events associated with hypertension are complications of atherosclerosis . Some antihypertensive agents influence experimental models of atherosclerosis through mechanisms independent of blood pressure lowering . Methods and Results —The European Lacidipine Study on Atherosclerosis ( ELSA ) was a r and omized , double-blind trial in 2334 patients with hypertension that compared the effects of a 4-year treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis , the mean of the maximum intima-media thicknesses ( IMT ) in far walls of common carotids and bifurcations ( CBMmax ) . This index has been shown by epidemiological studies to be predictive of cardiovascular events . A significant ( P lacidipine was found compared with atenolol , with a treatment difference in 4-year CBMmax progression of −0.0227 mm ( intention-to-treat population ) and −0.0281 mm ( completers ) . The yearly IMT progression rate was 0.0145 mm/y in atenolol-treated and 0.0087 mm/y in lacidipine-treated patients ( completers , 40 % reduction;P = 0.0073 ) . Patients with plaque progression were significantly less common , and patients with plaque regression were significantly more common in the lacidipine group . Clinic blood pressure reductions were identical with both treatments , but 24-hour ambulatory systolic/diastolic blood pressure changes were greater with atenolol ( −10/−9 mm Hg ) than with lacidipine ( −7/−5 mm Hg ) . No significant difference between treatments was found in any cardiovascular events , although the relative risk for stroke , major cardiovascular events , and mortality showed a trend favoring lacidipine . Conclusion —The greater efficacy of lacidipine on carotid IMT progression and number of plaques per patient , despite a smaller ambulatory blood pressure reduction , indicates an antiatherosclerotic action of lacidipine independent of its antihypertensive action",
"BACKGROUND The efficacy of new antihypertensive drugs has been question ed . We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients . METHODS We did a prospect i ve , r and omised trial in 6614 patients aged 70 - 84 years with hypertension ( blood pressure > or = 180 mm Hg systolic , > or = 105 mm Hg diastolic , or both ) . Patients were r and omly assigned conventional antihypertensive drugs ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) or newer drugs ( enalapril 10 mg or lisinopril 10 mg , or felodipine 2.5 mg or isradipine 2 - 5 mg daily ) . We assessed fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease . Analysis was by intention to treat . FINDINGS Blood pressure was decreased similarly in all treatment groups . The primary combined endpoint of fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group ( 19.8 events per 1000 patient-years ) and in 438 of 4401 in the newer drugs group ( 19.8 per 1000 ; relative risk 0.99 [ 95 % CI 0.84 - 1.16 ] , p=0.89 ) . The combined endpoint of fatal and non-fatal stroke , fatal and non-fatal myocardial infa rct ion , and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs ( 0.96 [ 0.86 - 1.08 ] , p=0.49 ) . INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events . Decrease in blood pressure was of major importance for the prevention of cardiovascular events",
"CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline",
"BACKGROUND The Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) trial was design ed to test the hypothesis that for the same blood-pressure control , valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk . METHODS 15?245 patients , aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a r and omised , double-blind , parallel-group comparison of therapy based on valsartan or amlodipine . Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint , defined as a composite of cardiac mortality and morbidity . Patients from 31 countries were followed up for a mean of 4.2 years . FINDINGS Blood pressure was reduced by both treatments , but the effects of the amlodipine-based regimen were more pronounced , especially in the early period ( blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month ; 1.5/1.3 mm Hg after 1 year ; p valsartan group ( 10.6 % , 25.5 per 1000 patient-years ) and 789 in the amlodipine group ( 10.4 % , 24.7 per 1000 patient-years ; hazard ratio 1.04 , 95 % CI 0.94 - 1.15 , p=0.49 ) . INTERPRETATION The main outcome of cardiac disease did not differ between the treatment groups . Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes . The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk",
"BACKGROUND Antihypertensive drugs may differ in their ability to reduce LV mass . Covariates other than drug selection , such as pretreatment LV mass , body weight , the magnitude of blood pressure reduction , race , and age may modify the response of LV mass to therapy . METHODS AND RESULTS Patients with mild to moderate hypertension ( diastolic blood pressure , 95 to 109 mm Hg ) were r and omly allocated to treatment with atenolol , captopril , clonidine , diltiazem , hydrochlorothiazide , or prazosin in a double-masked trial . Patients achieving the goal diastolic blood pressure of entered a 1-year maintenance period . Longitudinal analysis examined changes from baseline echocardiogram in LV mass at 8 weeks and at 1 year , statistically adjusted for pretreatment LV mass , systolic blood pressure , body weight , sodium excretion , physical activity , race , and age . Significant reductions at 1 year in adjusted LV mass were seen for patients in the highest tertile of pretreatment LV mass treated with hydrochlorothiazide ( mean , -42.9 ; 95 % confidence limits , -65.5 , -20.2 g ) , captopril ( mean , -38.7 ; 95 % confidence limits , -61.0 , -16.4 g ) , and atenolol ( mean , -28.1 ; 95 % confidence limits , -50.9 , -5.3 g ) . These treatment effects differed from those of prazosin , diltiazem , or clonidine . CONCLUSIONS Antihypertensive drugs have disparate effects on LV mass independent of the magnitude of blood pressure reduction . Patients with adequate blood pressure control on captopril , hydrochlorothiazide , and atenolol show a reduction of LV mass after 1 year of treatment , whereas patients on diltiazem , clonidine , or prazosin do not",
"BACKGROUND There is a pressing clinical requirement for an early simple test of severity in acute pancreatitis . We investigated the use of an assay of trypsinogen activation peptide ( TAP ) . METHODS We undertook a multicentre study in 246 patients ( 172 with acute pancreatitis [ 35 with severe disease ] , 74 controls ) . We assessed the predictive value of urinary TAP concentrations measured by a vali date d competitive immunoassay . We compared the results with those for plasma C-reactive protein and three clinicobiochemical scoring systems . TAP and C-reactive protein concentrations were analysed at set times after symptom onset and compared with the clinicobiochemical systems scores at key times during hospital stay . FINDINGS At 24 h after symptom onset , the median urinary TAP concentration was 37 nmol/L ( IQR 17 - 110 ) for severe and 15 nmol/L ( 5 - 35 ) for mild disease ( p plasma C-reactive protein were 24 mg/L ( 3 - 34 ) and 25 mg/L ( 6 - 75 ; p=0.208 ) . The sensitivity , specificity , positive predictive , and negative predictive values of the test to show severe acute pancreatitis compared with mild acute pancreatitis at 24 h were : for TAP ( > 35 nmol/L ) , 58 % , 73 % , 39 % , and 86 % , respectively , and for C-reactive protein ( > 150 mg/L ) , 0 % , 90 % , 0 % , and 75 % . 48 h after admission the values for the clinicobiochemical scoring systems were : APACHE II ( > or = 8) , 56 % , 64 % , 30 % , and 85 % ; Ranson score ( > or = 3 ) , 89 % , 64 % , 38 % , and 96 % ; and Glasgow score ( > or = 3 ) , 77 % , 75 % , 44 % , and 93 % . At 48 h , the values for C-reactive protein were 86 % , 61 % , 37 % , and 94 % and for TAP were 83 % , 72 % , 44 % , and 94 % . Combined testing of C-reactive protein and TAP was not superior to TAP alone for accuracy . INTERPRETATION Urinary TAP provided accurate severity prediction 24 h after onset of symptoms . This single marker of severity in acute pancreatitis deserves routine clinical application",
"It is well established that hypertensive patients benefit from drug treatment of their disorder . In recent years three major out-come studies of antihypertensive treatment in elderly hypertensives have shown substantial benefits , i.e. a reduction in the risk of stroke and other cardiovascular mortality and morbidity . In all these studies beta-blockers and /or diuretics were used in comparison with placebo . Newer therapeutic alternatives have , however , at least theoretically , many advantages which could result in further improvements in prognosis . The initial Swedish Trial in Old Patients with Hypertension ( STOP-Hypertension 1 ) was conducted in men and women aged 70 - 84 years . STOP-Hypertension 2 will evaluate the therapy used in STOP-Hypertension 1 against therapy based on either ACE-inhibitors ( enalapril and lisinopril ) or on calcium antagonists ( isradipine and felodipine ) , using the PROBE design ( Prospect i ve , R and omised , Open , Blinded Endpoint evaluation ) . The primary aim will be to assess the effect on cardiovascular mortality . Statistical calculations indicate that 6,600 patients , followed for four years will be needed ( 2p or = 180/105 mmHg ( and /or ) . Recruitment of patients started in September 1992 and so far more than 100 patients /week have been included",
"OBJECTIVES We sought to determine the efficacy of isradipine in reducing left ventricular ( LV ) mass and wall thickness in hypertensive patients . BACKGROUND LV hypertrophy on the echocardiogram is a strong predictor of cardiovascular events . Reduction of LV mass may be a desirable goal of drug therapy for hypertension . However , although thiazide diuretic drugs have been advocated as first-line therapy for hypertension , their efficacy in reducing LV mass has been question ed . METHODS Patients with mild to moderate diastolic hypertension and LV mass in excess of 1 SD of normal values were r and omized to isradipine ( n = 89 ) or hydrochlorothiazide therapy ( n = 45 ) . Evaluations were obtained at baseline , after 3 and 6 months of treatment and 2 weeks after treatment was stopped . RESULTS At 6 months , LV mass decreased by 43 + /- 45 g ( mean + /- SD ) with hydrochlorothiazide ( p isradipine ( p = NS ; between-group comparison , p LV mass remained 24 + /- 41 g lower than that at baseline in the hydrochlorothiazide group ( p = 0.003 ) but only 7 + /- 50 g lower in the isradipine group ( p = NS ) . Septal and posterior wall thicknesses were significantly and equally reduced with both isradipine and hydrochlorothiazide . Greater LV mass reduction with hydrochlorothiazide was related to a 2.8 + /- 3.3-mm reduction of LV cavity size with hydrochlorothiazide but no reduction with isradipine . At 6 months of treatment , diastolic blood pressure ( BP ) by design was equally reduced in both treatment groups . At 3 months , systolic BP was reduced by 17 + /- 15 mm Hg with isradipine and by 26 + /- 15 and 25 + /- 17 mm Hg at 3 and 6 months , respectively , with hydrochlorothiazide ( p = 0.003 , between-group comparison ) . However , on stepwise multivariable regression analysis , treatment selection ( partial r2 = 0.082 , p = 0.001 ) , change in average 24-h systolic BP ( partial r2 = 0.032 , p = 0.029 ) and change in average sitting systolic BP ( partial r2 = 0.017 , p = 0.096 ) were predictive of LV mass reduction . CONCLUSIONS Despite an equivalent reduction of diastolic BP , 6 months of therapy with hydrochlorothiazide is associated with a substantial reduction of LV mass , greater than that with isradipine . The superior efficacy of hydrochlorothiazide for LV mass reduction is associated with a greater reduction of systolic BP as well as drug selection itself . These data may have important therapeutic implication",
"BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure",
"Essential hypertension is a major Public Health issue . Although the number of treated hypertensive patients has increased , only 25 % of treated patients have their blood pressure levels under control . The benefit of treating hypertension has been proven , but cardiovascular morbidity and mortality rates remain high . The ideal antihypertensive drug should not only normalize blood pressure levels , but also reduce the associated cardiovascular morbidity and mortality rates . The role of angiotensin II in systemic hypertension and its complications has been recently redefined . The potent trophic effects of angiotensin II on blood vessels and on cardiac cells have been well demonstrated , especially the role of angiotensin II in left ventricular hypertrophy , vascular hypertrophy , endothelial dysfunction , and congestive heart failure . Of all ongoing mortality and morbidity trials in systemic hypertension , VALUE ( Valsartan Antihypertensive Long-term Use Evaluation ) is the only one comparing an angiotensin II antagonist ( valsartan ) with a third-generation calcium channel blocker ( amlodipine ) . The main hypothesis of the VALUE trial is that , for an equivalent decrease in blood pressure , valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity . VALUE is a prospect i ve , multinational , multicentre , double-blind , r and omized , active-controlled , 2-arm parallel group comparison with a response-dependent dose titration scheme . VALUE involves 14,400 patients in over 30 countries , who will be followed for 4 years or until 1450 patients experience a primary endpoint . The population to be included in VALUE consists of hypertensive men and women , aged 50 years or older , and at a relatively high risk of sustaining a cardiovascular event . The high risk profile is defined taking into account age , gender , and a list of cardiovascular risk factors and disease factors . Risk factors are cigarette smoking , hypercholesterolaemia , diabetes mellitus , uncomplicated left ventricular hypertrophy , proteinuria , and high serum creatinine . Disease factors include documented history of myocardial infa rct ion , peripheral vascular disease , stroke or transient ischaemic attack , or the presence of left ventricular hypertrophy with strain on the ECG . A unique feature of VALUE is the assessment of the predictive power of this cardiovascular risk factor scale in a large population of treated hypertensive patients . The trial started on 10 September 1997",
"Objective : Our aim was to compare the effect of lacidipine and chlorthalidone on cardiovascular outcome as a primary parameter and blood pressure as a secondary in elderly patients with isolated systolic hypertension in a prospect i ve study with an open design . Methods : 1882 males and females out patients ≥60 years were r and omly assigned to the administration of chlorthalidone 12.5 mg o.d . or lacidipine 4 mg o.d . Patients were recruited if sitting systolic blood pressure was ≥160 mmHg with a diastolic blood pressure equal or lower than 95 mmHg . Primary endpoint was a composite of cardiovascular and cerebrovascular events . Results : At r and omization mean systolic blood pressure was 178.1 mmHg in the lacidipine and 178.2 mmHg in the chlorthalidone group , the corresponding mean diastolic values being 86.9 and 86.8 mmHg . In both lacidipine and chlorthalidone groups treatment caused a significant ( p and marked systolic blood pressure reduction which was maintained throughout the treatment period with a significant ( p in diastolic blood pressure as well . At the end of treatment period ( median 32 months ) , the reduction was 36.8/8.1 mmHg ( systolic/diastolic ) in the chlorthalidone and 38.4/7.9 mmHg in the lacidipine group , the final on treatment blood pressures being 142.0/79.2 and 143.2/79.5 mmHg , respectively . Treatments were similarly effective in males and females and in age groups between 60 and 69 years ( n = 763 ) , 70 and 79 years ( n = 744 ) and ≥80 years ( n = 375 ) . Similar reductions were obtained in a subgroup of patients ( n = 209 ) followed in double-blind fashion for 1 year . The overall incidence of the primary endpoints was 9.3 % with no significant between-group difference . Total mortality was also similar between groups . Conclusions : In elderly patients with isolated systolic hypertension , administration of lacidipine or chlorthalidone markedly reduced systolic blood pressure with no difference in the incidence of cardiovascular events and total mortality",
"BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications . Because this issue remains controversial , we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were r and omly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study . METHODS The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve , r and omized , blinded trial comparing the effects of moderate control of blood pressure ( target diastolic pressure , 80 to 89 mm Hg ) with those of intensive control of blood pressure ( diastolic pressure , 75 mm Hg ) on the incidence and progression of complications of diabetes . The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes . In the current study , we analyzed data on a secondary end point ( the incidence of myocardial infa rct ion ) in the subgroup of patients in the ABCD Trial who had hypertension . RESULTS Analysis of the 470 patients in the trial who had hypertension ( base-line diastolic blood pressure , > or = 90 mm Hg ) showed similar control of blood pressure , blood glucose and lipid concentrations , and smoking behavior in the nisoldipine group ( 237 patients ) and the enalapril group ( 233 patients ) throughout five years of follow-up . Using a multiple logistic-regression model with adjustment for cardiac risk factors , we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infa rct ions ( a total of 24 ) than enalapril ( total , 4 ) ( risk ratio , 9.5 ; 95 percent confidence interval , 2.7 to 33.8 ) . CONCLUSIONS In this population of patients with diabetes and hypertension , we found a significantly higher incidence of fatal and nonfatal myocardial infa rct ion among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril . Since our findings are based on a secondary end point , they will require confirmation",
"Objective : A case control study has reported a 60 % higher risk of myocardial infa rct ion in hypertensives treated with a calcium channel blocker ( CCB ) . We examined the Department of Health Hypertension Care Computing Project ( DHCCP ) data to see if we could confirm or refute this suggestion . Design : Two case control studies , matched and unmatched , plus two longitudinal studies from 1 year of presentation , one for all subjects given a CCB for more than 1 year compared with those not given this drug , and the second comparing survival on the different drugs initially given between 3 and 12 months of follow-up . Subjects : A total of 9328 subjects were included in the analyses and 2154 died . Of these , 6406 received one or more of the following index drugs : 26 % a calcium channel blocker ( CCB ) ; 84 % a diuretic ; 29 % alpha methyldopa ; 12 % a beta-blocker ( BB ) ; and 11 % an angiotensin-converting enzyme ( ACE ) inhibitor . The CCBs were nifedipine , diltiazem or verapamil . Results : In the case control studies a group given diuretics ± other treatments ( but not including one of the index drugs ) provided a reference group with a relative risk ( RR ) of 1.0 . In the matched case control study the adjusted RR for a CCB without a diuretic was 1.32 ( 95 % CI 0.64–2.70 ) for IHD mortality and 1.05 ( 95 % CI 0.60–1.84 ) for cardiovascular mortality . Similar results were observed for methyldopa , BBs and ACE inhibitors . The results in the unmatched case control analysis were also similar . The longitudinal study comparing all those treated for over 1 year with a CCB with all other treatments showed a RR for total mortality of 1.03 ( 95 % CI 0.85–1.25 ) . The longitudinal study of total mortality according to treatment initiated at 3–12 months found results of a similar magnitude for CCBs , methyldopa and BBs . Conclusions : The reference diuretic group had less severe cardiovascular disease than other groups . Treatment with a CCB , BB or methyldopa was associated with an excess mortality in comparison with this reference group . The excess was similar in the different drug groups",
"Context Previously published results of this r and omized , double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy . Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine . Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks . Caution s The trial had limited power to detect important differences between groups in mortality or strokes , and most patients received several antihypertensive agents . The Editors Patients with diabetes have an increased risk for cardiovascular complications and death ( 1 ) . Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes ( 2 - 5 ) or were done exclusively in patients with diabetes ( 6 - 8 ) . The meta- analysis of these studies ( 9 ) , the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation ( HOPE ) study ( 2 ) , and the Losartan Intervention for Endpoint Reduction in Hypertension ( LIFE ) trial ( 5 ) demonstrated that angiotensin-converting enzyme ( ACE ) inhibitors ( 2 , 9 ) and angiotensin-receptor blockers ( 5 ) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events . These studies r and omly assigned few patients with renal involvement and overt proteinuria . Overt proteinuria occurred in fewer than 20 % of the 470 patients in the Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial ( 6 ) , and only 11 % of the 1195 patients in the LIFE trial ( 5 ) . The Captopril Prevention Project ( CAPP ) ( 3 ) and the Swedish Trial in Old Patients with Hypertension-2 ( STOP Hypertension-2 ) ( 4 ) did not state the number of patients with diabetes and overt proteinuria . There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial ( FACET ) ( 7 ) , and patients with dipstick-positive albuminuria were excluded from the HOPE trial ( 2 ) . Since proteinuria is an independent risk factor for cardiovascular disease ( 10 , 11 ) , the data obtained in the aforementioned trials can not be extrapolated to patients with type 2 diabetes and overt nephropathy . Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy ( 12 , 13 ) without a change in all-cause mortality . Apart from studies in heart failure , few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers . We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) ( 12 ) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents . Methods Patients The IDNT was a r and omized , double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy . The protocol of this study has been published ( 12 , 14 ) . Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy , as evidence d by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater , serum creatinine level of 89 mol/L ( 1.0 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in women or of 106 mol/L ( 1.2 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in men , and baseline seated blood pressure greater than 135/85 mm Hg . The institutional review boards of each center approved the protocol . All patients gave written informed consent . Treatment and R and omization Patients were r and omly assigned central ly by computer to receive treatment with irbesartan , 300 mg/d ( Avapro , Bristol-Myers Squibb , Princeton , New Jersey ) ; amlodipine , 10 mg/d ( Norvasc , Pfizer , New York ) ; or matched placebo . To minimize any center effect , r and omization was blocked by center . All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors , angiotensin II receptor blocking agents , or calcium-channel blockers . For the analysis of cardiovascular end points , patients were followed to initiation of treatment for end-stage renal failure ( dialysis or renal transplantation ) , reaching a serum creatinine level of 530.4 mol/L ( 6.0 mg/dL ) or higher , death , or administrative censoring in December 2000 . Outcomes We prospect ively established cardiovascular outcomes , defined in the Appendix Table . Appendix Table . Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb , Princeton , New Jersey , by trained , blinded clinical research associates to identify potential cardiovascular events . Investigators used study forms to report and characterize all cardiovascular outcomes . For all potential events , records , including laboratory values , electrocardiograms , and radiographic reports were obtained for clarification . Since myocardial infa rct ions may go unrecognized , a central electrocardiogram reading center was established at Brigham and Women 's Hospital , Boston , Massachusetts , where two cardiologists review ed every electrocardiogram . Electrocardiography was performed at baseline , 6 months , 12 months , and annually thereafter . A total of 5698 electrocardiograms were review ed at the center . When a new Q-wave infa rct ion was found , the cardiologists asked whether a clinical myocardial infa rct ion was reported . Even when myocardial infa rct ions were not clinical ly reported , these Q-wave infa rct ions were adjudicated as myocardial infa rct ions . Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events , defined in the Appendix Table . The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee ( Appendix ) . If the committee member agreed with the judgment of the center investigator , their combined judgment was accepted . If the center investigator and the committee member differed , the case material was review ed by the membership of the committee , whose decision was accepted . Deaths were adjudicated by a Mortality Committee ( Appendix ) . Each death was review ed by two members of the committee and presented to the membership , whose decision was accepted as final . Statistical Analysis For graphical presentation ( Figure ) and overall testing for statistically significant differences among the three treatment groups , time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test ( 15 ) . We used proportional hazards modeling to determine hazard ratios . For the cardiovascular death outcome , which could occur only once , we used the st and ard proportional hazards model ( 16 ) , with treatment assignment as the only independent covariate . For other cardiovascular outcomes , which could occur more than once , we used the And ersonGill formulation of the proportional hazards model ( 17 ) , in which patients are considered at risk for the first event from r and omization to the first event , at risk for the second event from the day following the first event to the second event , and so forth , permitting use of all the data . In accordance with the method of Lee and colleagues ( 18 ) , we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient . We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event . Therefore , both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses . The time-dependent covariate was statistically significant in each case , confirming the above assumption . There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent events and inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significance s. Figure . Time to first cardiovascular composite event as a function of treatment assignment . P Data management and computations were done by using SAS software for Windows , version 8 ( SAS Institute , Inc. , Cary , North Carolina ) , or S-Plus for Windows , version 6.0 ( Insightful Corp. , Seattle , Washington ) . Statistical tests were two sided . A P value of 0.05 or less , unadjusted for the multiple comparisons , was considered statistically significant . Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to su bmi t the manuscript for publication . Results The baseline characteristics of the three groups are shown in Table 1 . A flow diagram of the study is shown in the Appendix Figure . Table 1 . Baseline Characteristics Appendix Figure . Flow diagram for the Irbesartan Diabetic Nephropathy Trial . Clinical Management During the study , the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group , 141/77 mm Hg in the amlodipine group , and 144/80 mm Hg in the placebo group . Blood pressure in the two active treatment groups did not differ ; values in both groups were statistically significantly lower than in the placebo group ( P = 0.001 ) . The distribution of non study drugs used to achieve the target blood pressure was similar",
"A multicenter , r and omized , controlled , double-blind U.S. trial is comparing the combined effects of diet treatment and 1 of 5 active drug regimens with diet treatment alone , for the long-term management of middle-aged adults with \" mild \" hypertension . Factors stimulating this trial are data documenting the high prevalence of mild hypertension in the adult population ; mild hypertension 's responsibility for a high proportion of morbidity and mortality attributable to hypertension overall ; data from long-term hypertension intervention trials showing reduced morbidity and mortality of people with mild hypertension with use of either diuretics or beta blockers as step-1 therapy , and other trials that failed to demonstrate beneficial impact on morbidity and mortality , possibly due to residual questions concerning aspects of benefit to risk ratios with these medications ; recent data from trials showing long-term control of mild hypertension and other risk factors by nutritional means ; lack of data from long-term trials on benefit to risk ratios with newer drugs such as selective alpha 1 inhibitors , angiotensin converting enzyme inhibitors and calcium channel blockers ; paucity of data from trials on long-term combined effects of diet and drug therapy , and of diet alone , for people with mild hypertension . During the next few years , phase 1 of the trial will study 6 groups of drugs . The step-1 drugs are angiotensin converting enzyme inhibitor ( enalapril ) , alpha 1 inhibitor ( doxazosin ) , beta blocker ( acebutolol ) , calcium channel blocker ( amlodipine ) , diuretic ( chlorthalidone ) and placebo . All participants are to receive vigorous sustained nutritional counseling to reduce obesity , moderate sodium intake and avoid heavy use of alcohol . Key endpoints for phase 1 of the study are the need for additional medication to control mild hypertension , side effects ( i.e. , clinical and biochemical ) and consequent need to discontinue drug and quality of life . Phase-1 data are to be used to complete the phase-2 design , with the ultimate aim to assess effects on morbidity and mortality",
"A single-center , prospect i ve double-blind r and omized trial was conducted to compare the efficacy and safety of the calcium channel blocker nisoldipine in a sustained release coat-core formulation ( CC ) , titrated from 10 mg to 40 mg daily , with the angiotensin converting enzyme inhibitor enalapril , titrated from 10 to 40 mg daily , in the treatment of black South African patients with severe hypertension ( sitting diastolic blood pressure [ DBP ] between 115 and 140 mm Hg , confirmed by 24-h ambulatory blood pressure monitoring ) . Treatment target was a sitting DBP nisoldipine CC 10 to 60 mg daily . Ninety-six patients had complete data at baseline , and at the end of the double-blind and open phases , and were included in this analysis . In both groups , all patients required titration up to the maximal dose of double-blind medication . Monotherapy with nisoldipine CC , but not enalapril , significantly reduced both sitting and 24-h ambulatory blood pressure ( BP ) . Twenty-four-hour BP in the nisoldipine CC group decreased from 179+/-14 / 118+/-7 to 144+/-16 / 94+/-10 mm Hg ( P enalapril group ( P = ns ) . The profound decrease in blood pressure achieved with nisoldipine CC was accompanied by a significant reduction in left ventricular [ LV ] mass index , observed after only 2 months of treatment ( from 146+/-40 to 129+/-35 g/m2 , P = .05 ) . In contrast , enalapril had no effect on LV mass ( from 139+/-36 to 142+/-50 g/m2 , P = NS ) . The antihypertensive effect of nisoldipine CC was further demonstrated in the open phase , during which 24-h BP decreased from 180+/-14 / 118+/-6 mm Hg ( at baseline ) to 142+/-16 / 92+/-10 mm Hg at the end of the 16-week open phase ( P trough-to-peak ratio of 74 % for systolic and 67 % for diastolic BP , with further regression in LV mass . Reduction in 24-h systolic BP to nisoldipine CC . The incidence of adverse events in both groups was low and both nisoldipine CC and enalapril were well tolerated . The incidence of significant ventricular arrhythmia was also low and did not change with treatment . In conclusion , our findings suggest that nisoldipine CC administered once daily could be considered as a suitable first-line antihypertensive agent in black patients with severe hypertension , based on its profound and sustained blood-pressure-lowering effect , associated with significant regression of left ventricular mass and its low side effect profile",
"To determine whether a dose of 5 mg of nifedipine would be useful in the treatment of hypertensive emergencies , we compared the acute hypotensive effects of two different doses of nifedipine , 5 mg and 10 mg , in patients with severe hypertension . In this prospect i ve , r and omized , double-blind study , 30 consecutive black patients with diastolic blood pressure that was equal to or greater than 115 mm Hg received either a 5 mg or 10 mg nifedipine capsule and a placebo capsule , which matched that of the alternative strength . Patients were asked to bite the capsules and swallow the contents . Blood pressure response over 4 hours and adverse effects were monitored . Mean systolic blood pressure was reduced from 191.7 mm Hg ( 95 % confidence interval 170.8 to 212.7 mm Hg ) to 157.9 mm Hg ( 137.0 to 178.9 mm Hg ) and 206.1 mm Hg ( 185.1 to 227.0 mm Hg ) to 153.7 mm Hg ( 132.8 to 174.7 mm Hg ) in patients who were given 5 mg and 10 mg doses of nifedipine , respectively . Mean diastolic blood pressure in the group of patients that received 5 mg doses of nifedipine decreased from 128.2 mm Hg ( 115.6 to 140.7 mm Hg ) to 105.2 mm Hg ( 92.7 to 117.7 mm Hg ) ; the corresponding values in the group that received 10 mg doses of nifedipine were 129.9 mm Hg ( 117.4 to 142.5 mm Hg ) and 97.5 mm Hg ( 85.0 to 110.1 mm Hg ) , respectively . The minimum mean systolic blood pressures occurred 20 and 25 minutes after administration of the 5 mg and 10 mg capsules , respectively ; the minimum diastolic blood pressures were reached after 20 and 30 minutes , respectively . ( ABSTRACT TRUNCATED AT 250 WORDS",
"Although clinical trials of the efficacy of antihypertensive treatment have demonstrated impressive reductions in the incidence of stroke , the reduction in coronary artery disease mortality has been less impressive . It may be that the antihypertensive drugs used in these trials induced metabolic disturbances , or produced inadequate regression of left ventricular hypertrophy , thus blunting the reduction in risk of coronary artery disease expected with blood pressure-lowering . Isradipine , a dihydropyridine calcium antagonist known to be an effective antihypertensive agent , has also displayed pronounced antiatherogenic effects in animals . Thus , a reasonable hypothesis could be that isradipine not only reduces the level of blood pressure , but also may have a positive effect on the evolution of atherosclerotic plaque in coronary and carotid arteries , thereby leading to prevention of clinical sequelae of atherosclerosis . On this basis , a 3-year clinical trial is being carried out in the United States – the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS)–to establish the efficacy of isradipine in inhibiting atherogenesis and retarding the progression of atherosclerosis in carotid arteries of hypertensive patients . The primary end point of the study is intima-media thickness and the extent of atherosclerotic plaque in the carotid arteries , as measured by B-mode ultrasonography",
"BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe . In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common",
"OBJECTIVE The primary objective of the ABCD ( Appropriate Blood Pressure Control in Diabetes ) Trial is to determine the efficacy of intensive versus moderate antihypertensive control on the outcome of type II diabetic end-organ complications in normotensive and hypertensive population s. The secondary objective is to determine whether any differential effect on end-organ complications exists between an angiotensin converting enzyme inhibitor ( enalapril ) and a calcium channel blocker ( nisoldipine ) . DESIGN The ABCD Trial is a prospect i ve , controlled , r and omized , double-blind trial , with a planned follow-up of 5 years . SETTING All patients are seen at the Colorado Prevention Center , site of the ABCD Trial , for follow-up visits . PATIENTS Patients are type II diabetic males and females between the ages of 40 and 74 years with entry diastolic blood pressures > or = 80 mmHg . Patients were recruited from University of Colorado-affiliated hospitals , several health maintenance organizations , and mailing lists from the Colorado affiliate of the American Diabetes Association . INTERVENTIONS Patients were r and omized to intensive antihypertensive drug therapy or moderate antihypertensive drug therapy . Patients were also r and omized to nisoldipine or enalapril , with open-label medications added if further blood pressure control was necessary . MAIN OUTCOME MEASURES The primary outcome measure is glomerular filtration rate as assessed by 24-hour creatinine clearance . Secondary outcome measures are microalbumin urinary excretion , left ventricular hypertrophy , retinopathy , and neuropathy . Cardiovascular morbidity and mortality will also be evaluated . CONCLUSION Given the data showing the impact of hypertension on diabetic complications , the ABCD Trial was design ed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of these complications . Results from the ABCD Trial are expected to lend interpretable and clinical ly relevant findings with regards to the treatment of hypertension in type II diabetes",
"BACKGROUND The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established . We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension . METHODS We did a prospect i ve , r and omised , double-blind trial in Europe and Israel in 6321 patients aged 55 - 80 years with hypertension ( blood pressure > or = 150/95 mm Hg , or > or = 160 mm Hg systolic ) . Patients had at least one additional cardiovascular risk factor . We r and omly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system ( GITS ) formulation ( n=3157 ) , or co-amilozide ( hydrochlorothiazide 25 mg [ corrected ] plus amiloride 2.5 mg ; n=3164 ) . Dose titration was by dose doubling , and addition of atenolol 25 - 50 mg or enalapril 5 - 10 mg . The primary outcome was cardiovascular death , myocardial infa rct ion , heart failure , or stroke . Analysis was done by intention to treat . FINDINGS Primary outcomes occurred in 200 ( 6.3 % ) patients in the nifedipine group and in 182 ( 5.8 % ) in the co-amilozide group ( 18.2 vs 16.5 events per 1000 patient-years ; relative risk 1.10 [ 95 % CI 0.91 - 1.34 ] , p=0.35 ) . Overall mean blood pressure fell from 173/99 mm Hg ( SD 14/8 ) to 138/82 mm Hg ( 12/7 ) . There was an 8 % excess of withdrawals from the nifedipine group because of peripheral oedema ( 725 vs 518 , p serious adverse events were more frequent in the co-amilozide group ( 880 vs 796 , p=0.02 ) . Deaths were mainly non-vascular ( nifedipine 176 vs co-amilozide 172 ; p=0.81 ) . 80 % of the primary events occurred in patients receiving r and omised treatment ( 157 nifedipine , 147 co-amilozide , difference 0.33 % [ -0.7 to 1.4 ] ) . INTERPRETATION Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications . The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy",
"A novel design for intervention studies is presented , the so called PROBE study ( Prospect i ve R and omized Open , Blinded End-point ) . This design is compared to the classical double-blind design . Among the advantages of the PROBE design are lower cost and greater similarity to st and ard clinical practice , which should make the results more easily applicable in routine medical care . Since end-points are evaluated by a blinded end-point committee it is obvious that there should be no difference between the two types of trials in this regard",
"BACKGROUND The apparent shortfall in prevention of coronary heart disease ( CHD ) noted in early hypertension trials has been attributed to disadvantages of the diuretics and beta blockers used . For a given reduction in blood pressure , some suggested that newer agents would confer advantages over diuretics and beta blockers . Our aim , therefore , was to compare the effect on non-fatal myocardial infa rct ion and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril . METHODS We did a multicentre , prospect i ve , r and omised controlled trial in 19 257 patients with hypertension who were aged 40 - 79 years and had at least three other cardiovascular risk factors . Patients were assigned either amlodipine 5 - 10 mg adding perindopril 4 - 8 mg as required ( amlodipine-based regimen ; n=9639 ) or atenolol 50 - 100 mg adding bendroflumethiazide 1.25 - 2.5 mg and potassium as required ( atenolol-based regimen ; n=9618 ) . Our primary endpoint was non-fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) and fatal CHD . Analysis was by intention to treat . FINDINGS The study was stopped prematurely after 5.5 years ' median follow-up and accumulated in total 106 153 patient-years of observation . Though not significant , compared with the atenolol-based regimen , fewer individuals on the amlodipine-based regimen had a primary endpoint ( 429 vs 474 ; unadjusted HR 0.90 , 95 % CI 0.79 - 1.02 , p=0.1052 ) , fatal and non-fatal stroke ( 327 vs 422 ; 0.77 , 0.66 - 0.89 , p=0.0003 ) , total cardiovascular events and procedures ( 1362 vs 1602 ; 0.84 , 0.78 - 0.90 , p all-cause mortality ( 738 vs 820 ; 0.89 , 0.81 - 0.99 , p=0.025 ) . The incidence of developing diabetes was less on the amlodipine-based regimen ( 567 vs 799 ; 0.70 , 0.63 - 0.78 , p amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen . On the basis of previous trial evidence , these effects might not be entirely explained by better control of blood pressure , and this issue is addressed in the accompanying article . Nevertheless , the results have implication s with respect to optimum combinations of antihypertensive agents ",
"BACKGROUND Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world . Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective in type I diabetes and are now the st and ard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria . The role of blockade of the renin-angiotensin system in type II diabetic patients is not defined . The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial ( IDNT ) , study ing the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension . Here we report the study design and baseline patient characteristics . METHODS To qualify , hypertensive type II patients , age 30 - 70 years , must have a 24 h urinary protein excretion of > 900 mg and a serum creatinine 90 - 265 micromol/l ( 1.0 - 3 . 0 mg/dl ) in women and 110 - 265 micromol/l ( 1.2 - 3.0 mg/dl ) in men . Three treatment arms include irbesartan , placebo and amlodipine , with every attempt made to achieve similar blood pressure levels in all treatment arms . A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide . The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine , end-stage renal disease or death . The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events . The average length of patient follow-up is expected to be approximately 36 months . RESULTS The baseline characteristics of the study subjects are : age 59+/-8 years , duration of diabetes 15+/-9 years , height 168+/-11 cm ( 5 ft 6 in ) , weight 87+/-19 kg ( 192 lb ) , body mass index 31+/-7 kg/m(2 ) , blood pressure 156+/-18 mmHg/85+/-11 mmHg , serum creatinine 150+/-53 micromol/l ( 1.7+/-0.6 mg/dl ) , creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day ",
"The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints ( CONVINCE ) Trial is a r and omized , prospect i ve , double-blind , parallel-group , two-arm , actively controlled , multicenter , international 5-year clinical trial involving 15,000 patients . CONVINCE will compare the incidence of fatal or nonfatal myocardial infa rct ion ( MI ) , fatal or nonfatal stroke , or cardiovascular-disease-related death in two antihypertensive treatment regimens . One treatment arm begins with controlled onset-extended release (COER)-verapamil , which has its major antihypertensive effect 6 - 12 hours after administration . The other arm ( st and ard of care ( SOC ) ) begins with either hydrochlorothiazide ( HCTZ ) or atenolol , one of which is preselected by the investigator for an individual patient prior to r and omization . Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint ( separately ) , death or hospitalization related to cardiovascular disease , efficacy in lowering blood pressure to goal , primary events occurring between 6 am and noon , all-cause mortality , withdrawals from blinded therapy , cancer , and hospitalizations due to bleeding . Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease . Initial medications include COER-verapamil ( 180 mg/d ) , HCTZ ( 12.5 mg/d ) , or atenolol ( 50 mg/d ) . Initial doses are doubled if blood pressure ( BP ) does not reach goal ( systolic BP BP is not controlled by the higher dose of the initial medication , HCTZ is added to COER-verapamil , or the SOC choice not initially selected is added in the SOC arm . An ACE-inhibitor is recommended ( although nearly any open-label medication is allowed ) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications . Patients take two sets of tablets daily , one in the morning and one in the evening . Although most patients switch from an established antihypertensive medication to r and omized treatment , untreated patients with stages I-III hypertension ( SBP between 140 and 190 or DBP between 90 and 110 mm Hg ) are eligible . Outcomes are monitored by an independent Data and Safety Monitoring Board . Enrollment began during the third quarter of 1996 , and follow-up is to be completed in the third quarter of 2002",
"CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy",
"Treatment of hypertension with ACE inhibitors in diabetic patients reduces proteinuria and slows progression of nephropathy compared with agents that do not maintain declines in proteinuria . Calcium channel blockers ( CCBs ) have variable effects on proteinuria ; their long-term effects on progression of diabetic nephropathy are not known . The current study examines the hypothesis that CCBs that maintain reductions in proteinuria slow progression of nephropathy associated with non-insulin dependent diabetes mellitus ( NIDDM ) by a degree comparable to ACE inhibitors , given similar levels of blood pressure control . To test this hypothesis we r and omized 52 patients with NIDDM associated nephropathy and hypertension , mean age of 63 + /- 8 years , to either the ACE inhibitor , lisinopril ( N = 18 ) , nondihydropyridine CCBs ( NDCCBs ) , verapamil SR ( N = 8) or diltiazem SR ( N = 10 ) , or the beta blocker , atenolol ( N = 16 ) . Goal blood pressure was 140/90 mm Hg . Patients were followed for a mean period of 63 + /- 7 months . The primary end point was change in creatinine clearance ( CCr ) slope in each group . There was no significant difference in mean arterial pressure reduction among the groups over the study period ( P = 0.14 ) . The mean rate of decline in CCr was greatest in the atenolol group ( -3.48 ml/min/year/1.73 m2 ; P CCr slopes between lisinopril and NDCCBs groups ( P = 0.36 ) . Proteinuria was reduced to a similar extent in the lisinopril and NDCCBs groups ( P > 0.99 ) . Therefore , in persons with renal insufficiency secondary to NIDDM , similar levels of blood pressure control with either lisinopril or NDCCBs slowed progression of renal disease to a greater extent than atenolol . Moreover , this enhanced slowing of renal disease progression correlated with sustained and significant reductions in proteinuria , findings not observed in the atenolol group",
"OBJECTIVE To assess the association between first myocardial infa rct ion and the use of antihypertensive agents . DESIGN AND SETTING We conducted a population -based case-control study among enrollees of the Group Health Cooperative of Puget Sound ( GHC ) . PATIENTS AND METHODS Cases were hypertensive patients who sustained a first fatal or nonfatal myocardial infa rct ion from 1986 through 1993 among women and from 1989 through 1993 among men . Controls were a stratified r and om sample of hypertensive GHC enrollees , frequency matched to the cases on age , sex , and calendar year . All 623 cases and 2032 controls had pharmacologically treated hypertension . Data collection included a review of the ambulatory medical record a brief telephone interview of consenting survivors . Antihypertensive therapy was assessed using the GHC 's computerized pharmacy data base . RESULTS The first analysis included only the 335 cases and 1395 controls initially free of cardiovascular disease . Compared with users of diuretics alone , the adjusted risk ratio of myocardial infa rct ion was increased by about 60 % among users of calcium channel blockers with or without diuretic ( risk ratio = 1.62 % ; 95 % confidence interval [ Cl ] , 1.11 to 2.34 ; P = .01 ) . The second analysis was restricted to 384 cases and 1108 controls who were taking either a calcium channel blocker or a beta-blocker . Among these subjects , the use of calcium channel blockers compared with beta-blockers was associated with about a 60 % increase in the adjusted risk of myocardial infa rct ion ( risk ratio = 1.57 ; 95 % Cl , 1.21 to 2.04 ; P risk of myocardial infa rct ion ( trend P = .04 ) , high doses of calcium channel blockers were associated with an increased risk ( trend P hypertensive patients , the use of short-acting calcium channel blockers , especially in high doses , was associated with an increased risk of myocardial infa rct ion . Ongoing large-scale clinical trials will assess the effect of various antihypertensive therapies , including calcium channel blockers , on several important cardiovascular end points . Until these results are available , the findings of this study support the current guidelines from the Joint National Committee on the Detection , Evaluation and Treatment of High Blood Pressure that recommend diuretics and beta-blockers as first-line agents unless contraindicated , unacceptable , or not tolerated",
"Objective To test the primary hypothesis that a newer antihypertensive treatment regimen ( calcium channel blocker ± an angiotensin converting enzyme inhibitor ) is more effective than an older regimen ( β-blocker ± a diuretic ) in the primary prevention of coronary heart disease ( CHD ) . To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol ⩽ 6.5 mmol/l . Design Prospect i ve , r and omized , open , blinded endpoint trial with a double-blinded 2 × 2 factorial component . Setting Patients were recruited mainly from general practice s. Patients Men and women aged 40–79 were eligible if their blood pressure was ⩾160 mmHg systolic or ⩾ 100 mmHg diastolic ( untreated ) or ⩾140 mmHg systolic or ⩾ 90 mmHg diastolic ( treated ) at r and omization . Interventions Patients received either amlodipine ( 5/10 mg ) ± perindopril ( 4/8 mg ) or atenolol ( 50/100 mg ) ± bendroflumethiazide ( 1.25/2.5 mg ) + K+ with further therapy as required to reach a blood pressure of ⩽140 mmHg systolic and 90 mmHg diastolic . Patients with a total cholesterol of ⩽ 6.5 mmol/l were further r and omized to receive either atorvastatin 10 mg or placebo daily . Main outcome measure Non-fatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) . Results 19 342 men and women were initially r and omized , of these 10 297 were also r and omized into the lipid-lowering limb . All patients had three or more additional cardiovascular risk factors . Conclusions The study has 80 % power ( at the 5 % level ) to detect a relative difference of 20 % in CHD endpoints between the calcium channel blocker-based regimen and the β-blocker-based regimen . The lipid-lowering limb of the study has 90 % power at the 1 % level to detect a relative difference of 30 % in CHD endpoints between groups",
"PREVALENCE OF HYPERTENSION IN ELDERLY JAPANESE PATIENTS : Data collected from post-mortem information at the Tokyo Metropolitan Geriatric Hospital showed that the overall prevalence of hypertension in Japanese patients aged over 60 years was 53 % ; one-third of these elderly hypertensives had isolated systolic hypertension . Isolated systolic and systolodiastolic hypertension were each associated with a similar degree of increased atherosclerosis and cardiovascular complications . In a placebo-controlled study antihypertensive treatment produced a reduction in withdrawal from treatment in elderly patients with mild hypertension . INTERIM TRIAL RESULTS : Some interim results have been obtained from a new trial which is currently under way in Japan , the National Intervention Cooperative Study for the Treatment of Elderly Hypertensives , a long-term study comparing the effects of a calcium antagonist ( nicardipine ) and a thiazide diuretic ( trichlormethiazide ) on cardiovascular complications in elderly patients with mild to moderate hypertension",
"Blood pressure ( BP ) control rates around the world are suboptimal . Part 2 of the National Health and Nutrition Educational Survey ( NHANES ) III indicates that only 27.4 % of hypertensive Americans aged 18 to 74 years have a BP of 140/90 mm Hg . We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints ( CONVINCE ) Study , an international clinical trial that compares outcomes in hypertensive patients r and omized to initial treatment with either controlled-onset extended-release verapamil or the investigator ’s choice of atenolol or hydrochlorothiazide . At r and omization , BP was only 20.3 % of the 16 602 subjects ( average±SD age 65.6±7.4 years ; 56 % women , 84 % white/7 % black/7 % Hispanic ) . The average BP at enrollment was 148/85 mm Hg for patients taking BP medications ( n=13 879 ) and 161/94 mm Hg for previously untreated patients ( n=2723 ) . After medication titration , with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg , 84.8 % of the subjects attained the goal BP . During 2 years of treatment , BP control was maintained in 67 % to 69 % of the subjects ( 69 % to 71 % for systolic BP of the control of systolic BP is more difficult than the control of diastolic BP . The US national goal of having 50 % of hypertensives with a BP of < 140/90 mm Hg may be achievable if a forced titration strategy is used . Interested investigators , free care and medications , and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population",
"Background It is unclear whether the carotid intima – media thickness can be influenced by antihypertensive treatment and whether some antihypertensive agents , such as calcium antagonists , may have a greater effect on this parameter than others , such as diuretics . The present paper reports the principal results of the ultrasound sub study of the r and omized , prospect i ve , controlled , Verapamil in Hypertension and Atherosclerosis Study ( VHAS ) . Design and methods In 498 hypertensive patients in eight Italian centres , r and omized to either verapamil ( 240 mg once a day ) or chlorthalidone ( 25 mg once a day ) , a B-mode ultrasound scan was performed according to a st and ardized procedure at baseline and after 3 , 12 , 24 , 36 and 48 months of treatment . The maximum intima – media thicknesses of the far walls of common , bifurcation and internal carotid arteries were measured bilaterally , and the following indices calculated : the mean thickness at the six measured sites , the mean thickness at the common and bifurcation sites and the single maximum thickness . The primary endpoint for treatment efficacy was the slope of the change over 4 years ( rate of change , mm/year ) , corrected by using the initial mean over the six sites ( baseline + 3 months ) as a covariate ( mm/year per mm ) . The patients were also classified into three strata according to their baseline single maximum thickness : those with normal carotid arteries ( single maximum ( 1 mm ) , those with thickened carotid arteries ( single maximum > 1 and ≤ 1.5 mm and those with carotid plaques ( single maximum > 1.5 mm ) . Results Among the 456 patients with satisfactory baseline ultrasound readings , 33 % were classified with normal carotid arteries , 27 % with thickened carotid arteries and 40 % with plaques . In the intention-to-treat population ( 377 patients with ultrasound measurements taken on at least three different occasions over a period of at least 2 years ) , the rate of change in the mean thickness at the six sites measured was rather small ( 0.015 mm/year ) , but significantly ( P the rate of change in the mean thickness at the six sites had a negative slope ( −0.059 mm/year per mm , P in the carotid intima – media thickness in unstratified patients were not different in those treated with verapamil or with chlorthalidone , when changes in the mean thickness of six sites were related to the initial value , the slope of this relationship was significantly different in the two treatment groups ( verapamil −0.082 versus chlorthalidone −0.037 mm/year per mm , P The blood pressure-lowering effect of the two r and omized treatments was similar . Taking fatal and nonfatal , major and minor cardiovascular events together , there were 19 events in the verapamil group and 35 in the chlorthalidone group , with a significantly ( P chlorthalidone ( P verapamil was more effective than the diuretic chlorthalidone in promoting regression of thicker carotid lesions . Changes in the carotid intima – media thickness were small in both groups , and the differences between the changes under the two treatments were consequently small , but the observation that these small differences in carotid wall changes were paralleled by differences in the incidence of cardiovascular events ( better intima – media thickness regression with verapamil paralleled by a lower cardiovascular event rate ) suggests that even small effects on carotid plaques may have clinical and prognostic relevance",
"OBJECTIVE The Swedish Trial in Old Patients with Hypertension-2 ( STOP-Hypertension-2 ) was design ed by a project group of the Swedish Hypertension Society to test whether the \" newer \" treatment alternatives ( ACE inhibitors and calcium antagonists ) are as good as , better or less good than , the \" older \" ones ( beta-blockers and diuretics ) in terms of preventing cardiovascular morbidity and mortality in elderly hypertensives . The aim of the present paper is to report on the progress of the study . DESIGN Prospect i ve , open trial with blinded end-point committee and central ized r and omization ( PROBE design ) . STOP-Hypertension-2 may be regarded as a scientific follow-up of the previously published Swedish Trial in Old Patients with Hypertension ( STOP-Hypertensioon-1 ) ( 6 ) using the same study organization . SUBJECTS By the end of 1994 when recruitment was stopped , 6628 hypertensive men ( 34 % ) and women ( 66 % ) aged 70 - 84 ( mean age 76 ) had been included at 312 Swedish health centres ( out of approximately 850 ) . In the whole cohort 11 % are diabetics and 9 % smokers . The mean total cholesterol value is 6.5 mmol/L. RESULTS In the whole study cohort , blood pressure was lowered from 194/98 mmHg to 167/85 mmHg after one year . At the end of 1995 , 319 fatal events ( all-cause mortality ) had been reported , corresponding to a mortality rate of 21.3 per 1000 person-years . CONCLUSION In STOP-Hypertension-2 , 6628 elderly hypertensive have been r and omized to three different treatment regimes : beta-blocker+diuretics ( the active treatment arm in STOP-Hypertension-1 ) , ACE inhibitors , or calcium antagonists . Their average lowering of blood pressure was 27/13 mmHg and end-points have occurred at the expected rate . Thus , it should be possible to terminate STOP-Hypertension-2 within two to three years",
"BACKGROUND Patients with chronic kidney disease are at increased risk for cardiovascular ( CV ) events . METHODS We r and omly assigned 1,094 African Americans with hypertensive nephrosclerosis ( glomerular filtration rate [ GFR ] , 20 to 65 mL/min/1.73 m(2 ) [ 0.33 to 1.08 mL/s ] ) to initial antihypertensive treatment with either : ( 1 ) a beta-blocker , metoprolol ; ( 2 ) an angiotensin-converting enzyme inhibitor , ramipril ; or ( 3 ) a dihydropyridine calcium channel blocker , amlodipine , and either a usual-blood pressure ( BP ) or low-BP treatment goal . Using a design powered to detect renal outcome differences , we compared the effect of treatment on the CV event rate ( cardiac death , myocardial infa rct ion , stroke , and heart failure ) during a mean follow-up period of 4.1 years and determined baseline factors that predict CV outcomes . RESULTS Thirty-one patients died of CV disease ( 0.7%/patient-year ) , and 149 patients experienced at least 1 CV outcome ( 3.3%/patient-year ) . Overall , 202 CV events ( 4.5%/patient-year ) occurred . The CV outcome rate was not related significantly to r and omized interventions . In multivariable analyses , 7 baseline risk factors remained independently associated with increased risk for the CV composite outcome after controlling for age , sex , baseline GFR , and baseline proteinuria group : pulse pressure , duration of hypertension , abnormal electrocardiogram result , non-high-density lipoprotein cholesterol level , serum urea nitrogen level , urine protein-creatinine ratio , urine sodium-potassium ratio , and annual income less than 15,000 dollars . CONCLUSION Neither r and omized class of antihypertensive therapy nor BP level had a significant effect on the occurrence of CV events , possibly because of limited power . However , this analysis identifies unique and potentially modifiable CV risk factors in this high-risk cohort",
"CONTEXT Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease ( CHD ) reduce CHD events . However , many of these studies were too small to assess all-cause mortality or outcomes in important subgroups . OBJECTIVE To determine whether pravastatin compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic , hypertensive participants with at least 1 additional CHD risk factor . DESIGN AND SETTING Multicenter ( 513 primarily community-based North American clinical centers ) , r and omized , nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) . PARTICIPANTS Ambulatory persons ( n = 10 355 ) , aged 55 years or older , with low-density lipoprotein cholesterol ( LDL-C ) of 120 to 189 mg/dL ( 100 to 129 mg/dL if known CHD ) and triglycerides lower than 350 mg/dL , were r and omized to pravastatin ( n = 5170 ) or to usual care ( n = 5185 ) . Baseline mean total cholesterol was 224 mg/dL ; LDL-C , 146 mg/dL ; high-density lipoprotein cholesterol , 48 mg/dL ; and triglycerides , 152 mg/dL. Mean age was 66 years , 49 % were women , 38 % black and 23 % Hispanic , 14 % had a history of CHD , and 35 % had type 2 diabetes . INTERVENTION Pravastatin , 40 mg/d , vs usual care . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality , with follow-up for up to 8 years . Secondary outcomes included nonfatal myocardial infa rct ion or fatal CHD ( CHD events ) combined , cause-specific mortality , and cancer . RESULTS Mean follow-up was 4.8 years . During the trial , 32 % of usual care participants with and 29 % without CHD started taking lipid-lowering drugs . At year 4 , total cholesterol levels were reduced by 17 % with pravastatin vs 8 % with usual care ; among the r and om sample who had LDL-C levels assessed , levels were reduced by 28 % with pravastatin vs 11 % with usual care . All-cause mortality was similar for the 2 groups ( relative risk [ RR ] , 0.99 ; 95 % confidence interval [ CI ] , 0.89 - 1.11 ; P = .88 ) , with 6-year mortality rates of 14.9 % for pravastatin vs 15.3 % with usual care . CHD event rates were not significantly different between the groups ( RR , 0.91 ; 95 % CI , 0.79 - 1.04 ; P = .16 ) , with 6-year CHD event rates of 9.3 % for pravastatin and 10.4 % for usual care . CONCLUSIONS Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol ( 9.6 % ) and LDL-C ( 16.7 % ) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention",
"OBJECTIVE To determine whether older persons with hypertension who use specific calcium antagonists and ACE inhibitors have a different risk of mortality than those using beta-blockers . DESIGN A prospect i ve cohort study continuing from 1988 through 1992 . SETTING Three communities of the Established Population s for Epidemiologic Studies of the Elderly . PARTICIPANTS Hypertensive participants aged > or = 71 years ( n = 906 ) who had no evidence of congestive heart failure and who were using either beta-blockers ( n = 515 ) , verapamil ( n = 77 ) , diltiazem ( n = 92 ) , nifedipine ( n = 74 ) , or ACE inhibitors ( n = 148 ) . Nifedipine was of the short acting variety . MEASUREMENTS The main outcome measure was all-cause mortality . Age , gender , smoking , HDL-cholesterol , blood pressure , intake of digoxin and diuretics , physical disability , self-perceived health , and comorbid conditions were examined as confounders . RESULTS During 3538 person-years of follow-up , 188 participants died ( 53 deaths per 1000 person-years ) . Compared with beta-blockers , after adjusting for age , gender , comorbid conditions and other health-related factors , the relative risks ( 95 % confidence interval ) for mortality associated with use of verapamil , diltiazem , nifedipine , and ACE inhibitors were 0.8 ( 0.4 - 1.4 ) , 1.3 ( 0.8 - 2.1 ) , 1.7 ( 1.1 - 2.7 ) , and 0.9 ( 0.6 - 1.4 ) , respectively . The results were unchanged after excluding participants with other potential contraindications to beta-blockers and after stratifying on coronary heart disease and use of diuretics . Higher doses of nifedipine were associated with higher mortality . CONCLUSION Compared with beta-blockers , use of short acting nifedipine was associated with decreased survival in older hypertensive persons . However , selective factors influencing the use of specific drugs in higher risk patients could not be completely discounted , and final conclusions will depend on clinical trials",
"OBJECTIVE To compare the rate of progression of mean maximum intimal-medial thickness ( IMT ) in carotid arteries , using quantitative B-mode ultrasound imaging , during antihypertensive therapy with isradipine vs hydrochlorothiazide . DESIGN R and omized , double-blind , positive-controlled trial . SETTING Nine medical center clinics . POPULATION A total of 883 patients with baseline mean + /- SD systolic and diastolic blood pressure ( SBP and DBP , respectively ) of 149.7 + /- 16.6 and 96.5 + /- 5.1 mm Hg , age of 58.5 + /- 8.5 years , and maximum IMT of 1.17 + /- 0.20 mm . INTERVENTIONS Twice daily doses of isradipine ( 2.5 - 5.0 mg ) or hydrochlorothiazide ( 12.5 - 25 mg ) . MAIN OUTCOME MEASURE ( PRIMARY END POINT ) : Rate of progression of mean maximum IMT in 12 carotid focal points over 3 years . RESULTS There was no difference in the rate of progression of mean maximum IMT between isradipine and hydrochlorothiazide over 3 years ( P=.68 ) . There was a higher incidence of major vascular events ( eg , myocardial infa rct ion , stroke , congestive heart failure , angina , and sudden death ) in isradipine ( n=25 ; 5.65 % ) vs hydrochlorothiazide ( n=14 ; 3.17 % ) ( P=.07 ) , and a significant increase in nonmajor vascular events and procedures ( eg , transient ischemic attack , dysrhythmia , aortic valve replacement , and femoral popliteal bypass graft ) in isradipine ( n=40 ; 9.05 % ) vs hydrochlorothiazide ( n=23 ; 5.22 % ) ( P=.02 ) . At 6 months , mean DBP decreased by 13.0 mm Hg in both groups , and mean SBP decreased by 19.5 mm Hg in hydrochlorothiazide and 16.0 mm Hg in isradipine ( P=.002 ) ; the difference in SBP between the 2 groups persisted throughout the study but did not explain the increased incidence of vascular events in patients treated with isradipine . CONCLUSION The rate of progression of mean maximum IMT in carotid arteries , the surrogate end point in this study , did not differ between the 2 treatment groups . The increased incidence of vascular events in patients receiving isradipine compared with hydrochlorothiazide is of concern and should be studied further",
"Background Isolated systolic hyprtension occurs in around 8 % of Chinese people aged 60 years or older . In 1988 , the Systolic Hypertension in China ( Syst-China ) Collaborative Group started to investigate whether active treatment could reduce the incidence of stroke and other cardiovascular complications in older patients with isolated systolic hypertension . Methods All patients were initially started on masked placebo . After stratification for centre , sex and previous cardiovascular complications , alternate patients ( n = 1253 ) were assigned nitrendipine at 10–40 mg daily , with the addition of captopril at 12.5–50.0 mg daily or hydrochlorothiazide at 12.5–50.0 mg daily , or both , if a sufficient blood pressure fall was not obtained . In the remaining 1141 control patients , matching placebos were administered similarly . Results At entry , sitting blood pressure averaged 170.5 mmHg systolic and 86.0 mmHg diastolic , age averaged 66.5 years and total serum cholesterol was 5.1 mmol/l . After 2 years of follow-up , sitting systolic and diastolic blood pressures had fallen by 10.9 mmHg and 1.9 mmHg in the placebo group and by 20.0 mmHg and 5.0 mmHg in the active treatment group . The intergroup differences were 9.1 mmHg systolic ( 95 % confidence interval 7.6–10.7 mmHg ) and 3.2 mmHg diastolic ( 95 % confidence interval 2.4–4.0 ) . Active treatment reduced total strokes by 38 % ( from 20.8 to 13.0 endpoints per 1000 patient-years , P = 0.01 ) , all-cause mortality by 39 % ( from 28.4 to 17.4 endpoints per 1000 patient-years , P = 0.003 ) , cardiovascular mortality by 39 % ( from 15.2 to 9.4 endpoints per 1000 patient-years , P = 0.03 ) , stroke mortality by 58 % ( from 6.9 to 2.9 endpoints per 1000 patient-years , P = 0.02 ) , and all fatal and nonfatal cardiovascular endpoints by 37 % ( from 33.3 to 21.4 endpoints per 1000 patient-years , P = 0.004 ) . Conclusions Antihypertensive treatment prevents stroke and other cardiovascular complications in older Chinese patients with isolated systolic hypertension . Treatment of 1000 Chinese patients for 5 years could prevent 55 deaths , 39 strokes or 59 major cardiovascular endpoints ",
"The Treatment of Mild Hypertension Study ( TOMHS ) is a r and omized , double-blind clinical trial currently being conducted to compare the effects of nonpharmacologic therapy alone with those of 1 of 5 active drug regimens combined with nonpharmacologic therapy , for long-term management of patients with mild hypertension . Six classes of drugs were studied : ( 1 ) acebutolol ( beta blocker ) , ( 2 ) amlodipine ( calcium antagonist ) , ( 3 ) chlorthalidone ( diuretic ) , ( 4 ) doxazosin ( alpha 1 antagonist ) , ( 5 ) enalapril ( angiotensin-converting enzyme inhibitor ) and ( 6 ) placebo . All participants received nutritional-hygienic advice to reduce weight and sodium and alcohol intakes and to increase physical activity . End points include blood pressure change , side effects and quality -of-life indices ; incidence of electrocardiographic and echocardiographic abnormalities ; and incidence of cardiovascular clinical events , including death , among participants receiving drugs as first-step treatment as well as nonpharmacologic treatment compared with incidence among those participants r and omized to nonpharmacologic treatment only as the initial step"
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4117c094-06ff-11f0-808a-c43d1ab1c353
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CONTEXT Observational studies have suggested a relationship between vitamin D status and asthma-related respiratory outcomes . The benefit of vitamin D supplementation for pulmonary function , symptoms and exacerbations is not well established . OBJECTIVE To systematic ally review paediatric clinical trials investigating the role of vitamin D on asthma-related respiratory outcomes . DATA SOURCES MEDLINE , EMBASE and CENTRAL were search ed until January 2014 . No date or language restrictions . STUDY SELECTION Clinical trials reporting asthma-related respiratory outcomes following vitamin D administration at a dose equal or greater than 500 IU per day were included and review ed independently by two authors for full systematic review eligibility . DATA EXTRACTION Two review ers independently extracted and verified pre-defined data fields . RESULTS We identified five studies that met study eligibility and assessed final data synthesis . The median trial size was 48 participants ( range 17 - 430 ) and the average daily dose of cholecalciferol ranged from 500 to 2000 IU/day . Overall study method ological quality was high , but some heterogeneity in population and vitamin D dosing regimen was evident . Meta- analysis suggested a statistically significant reduction ( RR 0.41 , CI 0.27 - 0.63 ) in asthma exacerbation with vitamin D therapy . LIMITATIONS Due to variability in outcome selection and missing data , it was not possible to perform meta- analysis for pulmonary function testing and asthma symptom scores . Vitamin D-related adverse events were not considered in four of five papers . CONCLUSIONS Available evidence from this systematic review suggests that high dose vitamin D may prevent asthma exacerbation . This should be confirmed through larger well- design ed r and omised controlled trials
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"This study deals with the relationship between the occurrence of hypercalcemia and the administration of prophylactic doses of vitamin D in children with hypothyroidism , before and during L-thyroxine ( LT4 ) treatment . The goal of the study was to determine the dosage of vitamin D necessary to prevent rickets without inducing hypercalcemia . There was a 23 % prevalence of hypercalcemia at the time of the diagnosis of hypothyroidism by screening whereas it was 21 % in the children who were not given vitamin D during the first 3 months of LT4 treatment . This figure was significantly higher in those who were given vitamin D during the first 3 months of treatment and reached 70 % . However , one of the 19 children not given vitamin D presented with biological signs evoking vitamin D deficiency . In conclusion , in hypothyroid infants , vitamin D should be administered carefully during the first 6 months of treatment and restricted to children at risk for developing vitamin D deficiency",
"BACKGROUND To our knowledge , no rigorously design ed clinical trials have evaluated the relation between vitamin D and physician-diagnosed seasonal influenza . OBJECTIVE We investigated the effect of vitamin D supplements on the incidence of seasonal influenza A in schoolchildren . DESIGN From December 2008 through March 2009 , we conducted a r and omized , double-blind , placebo-controlled trial comparing vitamin D(3 ) supplements ( 1200 IU/d ) with placebo in schoolchildren . The primary outcome was the incidence of influenza A , diagnosed with influenza antigen testing with a nasopharyngeal swab specimen . RESULTS Influenza A occurred in 18 of 167 ( 10.8 % ) children in the vitamin D(3 ) group compared with 31 of 167 ( 18.6 % ) children in the placebo group [ relative risk ( RR ) , 0.58 ; 95 % CI : 0.34 , 0.99 ; P = 0.04 ] . The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements ( RR : 0.36 ; 95 % CI : 0.17 , 0.79 ; P = 0.006 ) and who started nursery school after age 3 y ( RR : 0.36 ; 95 % CI : 0.17 , 0.78 ; P = 0.005 ) . In children with a previous diagnosis of asthma , asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D(3 ) compared with 12 children receiving placebo ( RR : 0.17 ; 95 % CI : 0.04 , 0.73 ; P = 0.006 ) . CONCLUSION This study suggests that vitamin D(3 ) supplementation during the winter may reduce the incidence of influenza A , especially in specific subgroups of schoolchildren . This trial was registered at https://center.umin.ac.jp as UMIN000001373",
"Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover . We utilized a r and omized , double-blind , two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration . The setting was an Outpatient clinic in a secondary referral center . Subjects included 14 boys and 3 girls with a mean age of 11.7 ( range , 6.1 - 14.4 ) years . Interventions included 15 microg ( 600 IU ) 25-OH-vitamin D ( cholecalciferol ) in one tablet ABCDin(R ) once daily in the morning . Primary outcome measures were : lower leg growth rate , serum osteocalcin , and serum markers of type I collagen turnover , i.e. , the amino terminal propeptide of type I procollagen ( PINP ) , the carboxy terminal propeptide of type I procollagen ( PICP ) ( formation markers ) , and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen ( ICTP ) ( degradation markers ) . Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment ( NS ) . Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment , respectively , PINP 574 and 565 microg/l , PICP 381 and 382 microg/l , and ICTP 11.5 and 11.1 microg/l , respectively ( NS ) . Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l , respectively ( P measures of pulmonary function . In conclusion , administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily",
"Objective To define the therapeutic role of vitamin D in children with moderate to severe bronchial asthma as an adjunct to st and ard treatment . Methods Hundred asthmatic children of either sex , attending the respiratory and asthma clinic were enroled in the study . Diagnosis was made on the basis of history and clinical examination . R and omization was done using sealed opaque envelop method . In addition to the treatment as per GINA guidelines , one group received oral vitamin D3 ( Cholecalciferol ) 60,000 IU per month for 6 mo and the other group received placebo powder in the form of glucose sachet with a double blinded design . Monthly follow up of every patient was done and during every visit change in severity , level of control , Peak expiratory flow rate ( PEFR ) , steroid dosage , number of exacerbations and number of emergency visits were assessed . Results Monthly doses of 60,000 IU vitamin D significantly reduced the number of exacerbations as compared to placebo ( p = 0.011 ) . PEFR significantly increased in the treatment group ( p = 0.000 ) . Monthly doses of vitamin D significantly reduced the requirement of steroids ( p = 0.013 ) and emergency visits ( p = 0.015 ) . Control of asthma was achieved earlier in patients who received monthly vitamin D. Vitamin D significantly reduced the level of severity of asthma patients over 6 mo of treatment ( p = 0.016 ) . Conclusions Vitamin D has a definite role in the management of moderate to severe persistent bronchial asthma as an adjunct to st and ard treatment",
"The effect of daily administration of 1200 IU vitamin D3 was compared with the response to a single oral dose of 200,000 IU in 21 young infants by determination of the plasma 25-OHCC levels . After about one week the mean value recorded in group 1 was 27 + /- 13 ng/ml ; the corresponding value in group 2 was 127 + /- 78.4 ng/ml . At the second control examination about one month subsequently , the mean values were 61 + /- 26.2 ng/ml and 104 + /- 69.0 ng/ml respectively . The wide range of values found in the single-dose group clearly demonstrates the advantage of daily vitamin D administration for routine prophylaxis against rickets in infancy",
"OBJECTIVES A fixed combination of long-acting beta(2)-agonists ( LABA ) plus inhaled corticosteroids ( ICS ) has never been proven to reduce asthma exacerbations vs ICS alone in children . This 12-month , double-blind , r and omized study in 341 children ( age range , 4 to 11 years ) with asthma uncontrolled on ICS investigated whether a novel regimen using budesonide/formoterol for maintenance and reliever therapy ( Symbicort maintenance and relief therapy [ SMART ] ) [ Symbicort ; AstraZeneca R&D , Lund , Sweden ] could reduce exacerbations . METHODS Patients received SMART ( budesonide/formoterol 80/4.5 microg qd maintenance plus additional inhalations for symptom relief ) , budesonide/formoterol 80/4.5 microg qd for maintenance ( fixed combination ) , or higher-dose budesonide 320 microg qd ( fixed-dose budesonide ) . Blinded as-needed medication ( terbutaline 0.4 microg ) was provided in both fixed-dose groups . RESULTS SMART prolonged the time to first exacerbation vs fixed-dose budesonide ( p = 0.02 ) and fixed-dose combination ( p Rates of exacerbation requiring medical intervention were reduced by 70 to 79 % with SMART vs fixed-dose budesonide and fixed-dose combination ( 0.08/patient vs 0.28/patient and 0.40/patient , respectively ; both p Mild exacerbation days and awakenings were significantly lower with SMART ; yearly growth improved by 1.0 cm vs fixed-dose budesonide ( p budesonide/formoterol for both maintenance and as-needed symptom relief reduces the exacerbation rate compared with both fixed-dose combination and higher fixed-dose ICS alone in children with asthma",
"RATIONALE Patients with asthma exhibit variable response to inhaled corticosteroids ( ICS ) . Vitamin D is hypothesized to exert effects on phenotype and glucocorticoid ( GC ) response in asthma . OBJECTIVES To determine the effect of vitamin D levels on phenotype and GC response in asthma . METHODS Nonsmoking adults with asthma were enrolled in a study assessing the relationship between serum 25(OH)D ( vitamin D ) concentrations and lung function , airway hyperresponsiveness ( AHR ) , and GC response , as measured by dexamethasone-induced expression of mitogen-activated protein kinase phosphatase (MKP)-1 by peripheral blood mononuclear cells . MEASUREMENTS AND MAIN RESULTS A total of 54 adults with asthma ( FEV(1 ) , 82.9 + /- 15.7 % predicted [ mean + /- SD ] , serum vitamin D levels of 28.1 + /- 10.2 ng/ml ) were enrolled . Higher vitamin D levels were associated with greater lung function , with a 22.7 ( + /-9.3 ) ml ( mean + /- SE ) increase in FEV(1 ) for each nanogram per milliliter increase in vitamin D ( P = 0.02 ) . Participants with vitamin D insufficiency ( AHR , with a provocative concentration of methacholine inducing a 20 % fall in FEV(1 ) of 1.03 ( + /-0.2 ) mg/ml versus 1.92 ( + /-0.2 ) mg/ml in those with vitamin D of 30 ng/ml or higher ( P = 0.01 ) . In ICS-untreated participants , dexamethasone-induced MKP-1 expression increased with higher vitamin D levels , with a 0.05 (+/-0.02)-fold increase ( P = 0.02 ) in MKP-1 expression observed for each nanogram per milliliter increase in vitamin D , a finding that occurred in the absence of a significant increase in IL-10 expression . CONCLUSIONS In asthma , reduced vitamin D levels are associated with impaired lung function , increased AHR , and reduced GC response , suggesting that supplementation of vitamin D levels in patients with asthma may improve multiple parameters of asthma severity and treatment response . Clinical trials registered with www . clinical trials.gov ( NCT00495157 , NCT00565266 , and NCT00557180 )"
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4117c0d0-06ff-11f0-808a-c43d1ab1c353
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Background : To assess the effects of patient education on mortality , morbidity , health-related quality of life ( HRQoL ) , and healthcare costs in people with coronary heart disease ( CHD ) . Design : Systematic review and meta- analysis . Methods : Data sources were Cochrane Library , Medline , Embase , PsycINFO , CINAHL , and ongoing trial registries until August 2010 . We also checked study references . The study selection was based on design ( r and omized controlled trials with follow up of at least 6 months , published from 1990 onwards ) , population ( adults with CHD ) , intervention ( patient education stated to be the primary intervention ) , and comparators ( usual care or no educational intervention ) . Results : Thirteen studies ( 68,556 people with CHD ) were included . Educational interventions ranged from two visits to a 4-week residential stay with 11 months of reinforcement sessions . Compared to no educational intervention , there was weak evidence that education reduced all-cause mortality ( pooled relative risk ( RR ) 0.79 , 95 % CI 0.55 to 1.13 ) and cardiac morbidity outcomes : myocardial infa rct ion ( pooled RR 0.63 , 95 % CI 0.26 to 1.48 ) , revascularization ( pooled RR 0.58 , 95 % CI 0.19 to 1.71 ) , and hospitalization ( pooled RR 0.83 , 95 % CI 0.65 to 1.07 ) at median 18-months follow up . There was evidence to suggest that education can improve HRQoL and decrease healthcare costs by reductions in downstream healthcare utilization . Conclusions : Our review had insufficient power to exclude clinical ly important effects of education on mortality and morbidity . Nevertheless it supports the practice of CHD secondary prevention and rehabilitation programmes including education as an intervention . Further research is needed to determine the most effective and cost-effective format , duration , timing , and methods of education delivery
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"Objective The aim of this study was to evaluate the impact of a home based intervention program ( HBIP ) on health related quality of life ( HRQoL ) after coronary artery bypass grafting ( CABG ) . To strengthen the clinical interpretation , HRQoL data were compared to the general population . Methods In a r and omised controlled trial ( RCT ) , a total of 185 CABG patients ( 93 vs 92 ) completed the study . The intervention group received a HBIP 2 and 4 weeks after surgery . HRQoL was measured by the Seattle Angina Question naire ( SAQ ) and the Short Form 36 ( SF-36 ) in both patient groups before surgery , at 6 weeks and 6 months after surgery . Results Significant improvements were found in both groups for the majority of subscales of HRQoL at 6-week and 6-month follow-up . However , these improvements did not differ significantly between the groups . Compared to the general population , significant differences ( P SF-36 subscales : role physical , role emotional and bodily pain . Conclusions HRQoL after CABG improved markedly over time , but no significant or clinical ly important differences were found when compared with controls . Thus , work to further develop and test the effect of a HBIP on HRQoL in patients undergoing rehabilitation following CABG is warranted",
"Findings of systematic review s incorporating meta analysis are by nature hypothesis generating and should be carefully and judiciously interpreted . This need is epitomized by two of the largest review s of interventions to support risk factor reduction after a diagnosis of coronary heart disease ( Table 1 ) . These review s both included r and omized trials published in a similar timeframe ( up to 2003 or 2004 ) that compared the effects of various risk factor reduction programmes for patients with confirmed coronary heart disease to usual care . In 2004 , a Cochrane review found that supervised and unsupervised exercise-based cardiac rehabilitation provided to patients with different forms of coronary heart disease lowered all cause total mortality by 20 % and cardiac mortality by 26 % in 48 trials of 8940 patients . The review ers concluded that there was ‘ no difference in mortality effect between exercise-only cardiac rehabilitation and comprehensive cardiac rehabilitation , or by exercise dose or duration of followup ’ . Also , the exercise-based programmes did not reduce recurrent myocardial infa rct ion and the need for repeat coronary revascularization to statistically significant levels . Around the same time , a second review of 63 trials involving 21,295 patients who had undergone secondary cardiac prevention programmes found reductions of total mortality of 15 % and of acute myocardial infa rct ion of 17 % . However , in contrast to the previous review , the secondary prevention programmes significantly reduced the rate of recurrent heart attacks . Also , benefits did not differ between programmes ‘ that incorporated education and counselling about coronary risk factors with a supervised exercise programme , those that included risk factor education or counselling but no exercise component , and those that consisted of only a structured exercise programme ’ . On first reading , these review s appear to offer different conclusions on effects on cardiovascular morbidity and regarding the benefits of supervised exercise . Either could be cited selectively to support or refute the benefits of exercise programmes for morbidity or to support or refute the incorporation of supervised exercise into services . Why might these different conclusions have come about and how should they be interpreted ? Firstly , it is unlikely that the different conclusions arise from differences in quality as both review s were of high quality as defined by PRISMA criteria and included many of the same trials : 37 of the 48 ( 77 % ) exercise-based trials were included in the 63 ( 59 % ) secondary prevention trials . Rather , issues of statistical power can explain the differences noted in morbidity . The forest plot analyses showed that , although exercise-based programmes in the Cochrane review did not reach statistically significant headline ‘ effect sizes ’ , there was a tendency towards reduced recurrent myocardial infa rct ion and the need for repeat coronary revascularization . The larger review of secondary prevention programmes considered over twice the number of events in the analysis of recurrent myocardial infa rct ion and found that secondary prevention programmes significantly reduced the rate of recurrent heart attacks . Hence , focusing only on the presence or absence of",
" Medicare beneficiaries in fee-for-service ( FFS ) who had chronic illnesses and volunteered to participate in 15 care coordination programs were r and omized to treatment or control status . Nurses provided patient education ( mostly by telephone ) to improve adherence and ability to communicate with physicians . Patients were contacted an average of two times per month . The findings after 2 years are not encouraging . Few programs improved patient behaviors , health , or quality of care . The treatment group had significantly fewer hospitalizations in only one program ; no program reduced gross or net expenditures . However , effects may be observed when 4 years of followup are available and sample sizes increase",
"AIMS In a multifactorial lifestyle behaviour programme , of 2 years duration , to study the maintenance of achieved behaviour and risk factor-related changes . METHODS AND RESULTS Out of a consecutive population of 151 patients treated with percutaneous transluminal angioplasty under 65 years of age , 87 were r and omly allocated to an intervention group ( n=46 ) or to a control group ( n=41 ) . The programme started with a 4 week residential stay , which was focused on health education and the achievement of behaviour change . During the first year of follow-up , a maintenance programme included regular contacts with a nurse , while no further rehabilitative efforts were offered during the second year . One patient died ( control ) . During the second year the proportion of hospitalized patients was lower in the intervention group ( 4 % vs 20%;P lifestyle dependent behaviours : diet ( index at 0 , 12 and 24 months ) : 10.5+/-3 . 4 , 12.9+/-2.5 and 12.4+/-2.6 in the intervention group ( I ) vs 10 . 1+/-3.2 , 10.7+/-3.0 and 11.8+/-3.2 in the control group (C);P exercise sessions per week : 2.5+/-2.3 , 4.5+/-1.9 and 4.4+/-2.1 ( I ) vs 3.1+/-2.2 , 3.5+/-2.3 and 3.7+/-2.7 (C);P smoking ; 18 % , 6 % and 9 % ( I ) vs 12 % , 21 % and 18 % (C);P exercise capacity ( 0 , 12 and 24 months ) : 156+/-42 , 174+/-49 and 165+/-47 W ( I ) vs 164+/-40 , 163+/-49 and 156+/-48 watts (C);P serum cholesterol levels at 0 and 24 months : 5 . 4+/-0.8 and 5.2+/-0.9 mmol . l(-1)(I ) vs 5.4+/-1.0 and 4.9+/-0.9 mmol . l(-1)(C ) ; ns , low density lipoprotein cholesterol level : 3.6+/-0.8 and 3.4+/-0.8 mmol . l(-1)(I ) vs 3.7+/-0.9 and 3.3+/-0.7 mmol . l(-1)(C ) ; ns , triglyceride level : 2.2+/-1.6 and 1.8+/-1.3 mmol . l(-1)(I ) vs 2.2+/-1.4 and 1.6+/-0.6 mmol . l(-1)(C ) ; ns , body mass index ( 0 , 12 and 24 months ) : 27.5+/-4.5 , 27.0+/-4.3 and 27.4+/- 4.5 kg . m(-2)(I ) vs 26.8+/-2.8 , 26.9+/-2.7 and 26.9+/- 3.2 kg . m(-2)(C ) ; ns , waist/hip ratio or blood pressure . The two groups did not differ in quality of life , or psychological factors . Return to work after 12 and 24 months was 74 % and 78 % ( I ) vs 68 % and 61 % ( C ) ; ns . CONCLUSION This rehabilitation programme influenced important lifestyle behaviour and reduced some , but not all , important risk",
"The LifeMasters Supported SelfCare demonstration program provides disease management ( DM ) services to Florida Medicare beneficiaries who are also enrolled in Medicaid and have congestive heart failure ( CHF ) , diabetes , or coronary artery disease ( CAD ) . The population -based program provides primarily telephonic patient education and monitoring services . Findings from the r and omized , intent-to-treat design over the first 18 months of operations show virtually no overall impacts on hospital or emergency room ( ER ) use , Medicare expenditures , quality of care , or prescription drug use for the 33,000 enrollees . However , for beneficiaries with CHF who resided in high-cost South Florida counties , the program reduced Medicare expenditures by 9.6 percent",
"OBJECTIVES This study involving 570 women aged 60 years or older with heart disease , assessed the effects of a disease management program on physical functioning , symptom experience , and psychosocial status . METHODS Women were r and omly assigned to control or program groups . Six to eight women met weekly with a health educator and peer leader over 4 weeks to learn self-regulation skills with physical activity as the focus . Evaluative data were collected through telephone interviews , physical assessment s , and medical records at baseline and 4 and 12 months post baseline . RESULTS At 12 months , compared with controls , program women were less symptomatic ( p dimension of the Sickness Impact Profile ( SIP ; p improved ambulation as measured by the 6-minute walk ( p lost more body weight ( p psychosocial factors as measured by the SIP were noted . CONCLUSION A self-regulation-based program that was provided to older women with heart disease and that focused on physical activity and disease management problems salient to them , improved their physical functioning and symptom experience . Psychosocial benefit was not evident and may be a result of measurement error or due to insufficient program time spent on psychosocial aspects of functioning",
"Abstract Objective : To assess the value of health education for patients with angina in reducing risk factors for cardiovascular disease and lessening the effect of angina on everyday activities . Design : R and omised controlled trial of personal health education given every four months . Setting : 18 general practice s in the greater Belfast area . Subjects : 688 patients aged less than 75 years and known to have had angina for at least six months ; 342 r and omised to receive education and 346 to no education . Main outcome measures : Restriction of everyday activities , dietary habit , smoking habit , frequency of physical exercise ; blood pressure , body mass index , and serum total cholesterol concentration at entry to trial and after two years . Results : 317 in the intervention group and 300 in the control group completed the trial . At the two year review more of the intervention group ( 140 , 44 % ) reported taking daily physical exercise than the control group ( 70 , 24 % ) . The intervention group also reported eating a healthier diet than the control group and less restriction by angina in any everyday activity . No significant differences were found between the groups in smoking habit , systolic or diastolic blood pressure , cholesterol concentration , or body mass index . Conclusion : Despite having no significant effect on objective cardiovascular risk factors , personal health education of patients with angina seems to increase exercise and improve dietary habits and is effective in lessening the restriction of everyday activities",
"Background Providing information is an important part of st and ard care and treatment for acute myocardial infa rct ion in patients . Evidence exists indicating that acute myocardial infa rct ion patients experience an information gap in the period immediately after discharge from the hospital . The aim of this study was to assess the short-term effects of a nurse-led telephone follow-up intervention to provide information and support to patients with acute myocardial infa rct ion after their discharge from hospital . Design and method A prospect i ve r and omized , controlled trial with a 6-month follow-up was conducted . A total of 288 patients were allocated to either an intervention group ( n = 156 ) or a control group ( n = 132 ) . The latter received routine post-discharge care . The primary endpoint measured at 3 and 6 months after discharge was the health-related quality of life using the 36-item Short Form Health Survey . Secondary endpoints included smoking and exercise habits . Results In both groups , health-related quality of life improved significantly over time on most subscales . A statistically significant difference in favour of the intervention group was found on the 36-item Short Form Health Survey Physical Health Component Summary Scale ( P=0.034 ) after 6 months . No difference was found between the groups on the Mental Health Component Summary Scale . We found a significant difference with respect to frequency of physical activity in favour of the intervention group after 6 months ( P=0.004 ) . More participants in the intervention group than the control group had ceased smoking at the 6-month follow-up ( P=0.055 ) . Conclusion A nurse-led systematic telephone follow-up intervention significantly improved the physical dimension of health-related quality of life in patients in the intervention group compared with usual care patients . Participation in this intervention also seemed to promote health behaviour change in patients after acute myocardial infa rct ion",
"This study evaluated the effects of a behaviorally oriented cardiac rehabilitation and secondary prevention program on lifestyle changes and on coronary recurrence rates . Patients recently treated with percutaneous coronary intervention ( PCI ) were r and omized to an intervention with an aggressive focus on lifestyle changes ( smoking , diet , exercise , and stress ; n=46 ) or to a st and ard-care control group ( n=42 ) . Results showed that the intervention group had significantly larger overall lifestyle changes than the control group after 12 , 24 , 36 , and 60 months . The intervention group had significantly lower rates of all coronary events ( acute myocardial infa rct ion , coronary artery bypass graft , PCI , cardiac death ; 30.4 % vs. 53.7 % ) , and of cardiovascular mortality ( 2.2 % vs. 14.6 % ) . The need for future large-scale and long-term evaluations of lifestyle-oriented secondary prevention interventions of this kind is emphasized",
"A group of 93 coronary patients recently treated with percutaneous transluminal coronary angioplasty ( PTCA ) were r and omly assigned to either an intervention or a control group . Subjects in the intervention group participated in a comprehensive behaviorally oriented program aim ed at achieving significant long-term changes in risk factor-related lifestyle behavior . Assessment s of lifestyle behaviors , psychological factors , biological risk factors , and rehabilitation as well as secondary prevention endpoints were carried out , at inclusion and after 12 months . Results showed that the intervention patients , as compared with controls , improved significantly on measures assessing smoking , exercise , and diet habits . These self-rated changes were confirmed by weight reductions and improved exercise capacity , as well as by between-group differences in sub clinical chest pain during an exercise test . However , few effects were found on the different psychological variables , as well as on morbidity or return to work",
"Background . There is increasing interest in the potential for chronic disease self-management interventions to provide health benefits while reducing health care costs . Objectives . To assess the impact of a heart disease management program on use of hospital services ; to estimate associated hospital cost savings ; and to compare potential cost savings with the cost of delivering the program . Research Design . R and omized , controlled study design . Data were collected from hospital billing records during a 36 month period . Multivariate models were used to compare health care use with cost between treatment and control groups . Estimated differences were then compared with the program costs to determine cost-effectiveness . Subjects . Participants were recruited from 6 hospital sites . Screening criteria included : female , 60 years or older , diagnosed cardiac disease , and seen by a physician approximately every 6 months . The study included 233 women in the intervention group and 219 in the control group . The “ Women Take PRIDE ” program utilizes a self-regulation process for addressing a problematic area of the heart regimen recommended by each woman ’s physician . It is tailored to the unique needs of older women . Measures . Hospital admissions , in-patient days , emergency department visits . Results . Program participants experienced 46 % fewer in-patient days ( P in-patient costs ( P the control group . No significant differences in emergency department utilization were found . Hospital cost savings exceeded program costs by a ratio of nearly 5-to-1 . Conclusions . A heart disease self-management program can reduce health care utilization and potentially yield monetary benefits to a health plan",
"AIMS An earlier combined proactive and reactive telephone follow-up intervention for acute myocardial infa rct ion patients after discharge from hospital showed positive effects after six months . The aim of the present study was to assess whether the intervention has long-term effects up to 18 months after discharge . DESIGN A prospect i ve r and omised controlled trial with 18 months follow-up . METHOD The trial was conducted with 288 patients allocated to a telephone follow-up intervention group ( n = 156 ) or control group ( n = 132 ) . The primary endpoint was health-related quality of life using the SF-36 . Secondary endpoints included smoking and exercise habits , return to work and rehospitalisation due to chest pain . RESULTS There were significant improvements over time on most dimensions of health-related quality of life in both the intervention and control group to US norm population levels on most SF-36 dimensions and summary scores . The intervention group showed no overall significant improvement beyond six months in the physical or mental summary scores , but there was a significant effect for those aged 70 or above . Although there was a promising effect for rehospitalisation due to chest pain , no significant differences were found between the groups on the secondary endpoints after six months . CONCLUSION This study demonstrated that despite positive short-term effects at six months , the telephone follow-up intervention had no long-term effects on health-related quality of life or secondary endpoints . However , the potential for improvement beyond six months was less than anticipated reflecting a reduced morbidity among acute myocardial infa rct ion patients . RELEVANCE TO CLINICAL PRACTICE Telephone follow-up after discharge from hospital is an easy implementable follow-up intervention enabling individualised provision of information and support in a time often experienced as stressful by patients . Our study indicates that six months is an adequate support period . Despite positive results six months after discharge no significant added long-term effects of telephone follow-up , compared to usual care were found in this study",
"Background : The aim of cardiac rehabilitation ( CR ) is not only physical improvement but also increased quality of life ( QoL ) . A CR programme based upon problem based learning ( PBL ) philosophy was developed , to achieve and apply new knowledge related to coronary artery disease ( CAD ) . The aim of this paper was to evaluate the impact of the PBL programme on QoL. Methods : 207 consecutive patients to a PBL group ( n = 104 ) or a control group ( n = 103 ) . In addition to st and ard treatment , the PBL patients participated in 13 group sessions during 1 year , where individual learning needs and behavioural changes were focused upon . QoL was measured by the Ladder of Life , Self-Rated Health ( SRH ) , SF 36 , and Cardiac Health Profile ( CHP ) . Results : Significant differences between the groups , favouring the PBL patients , were found by global instruments : more optimistic expectations of the future QoL and a better general condition . No differences were found by SRH , SF 36 or subscales of CHP , but QoL increased in both groups during the year . Conclusions : The main outcome was that QoL improved in both groups with some effects favouring the PBL programme",
"Health promotion programmes for patients with coronary heart disease are valuable,1 2 but there is little evidence on their lasting effect.3 A r and omised controlled trial in which patients who received personalised health promotion for two years showed significant benefits in lifestyle and quality of life.2 4 We investigated whether the differences in lifestyle , quality of life , and risk factors persisted between the two groups five years after enrolment . Patients aged under 75 who had had angina ( all grade s included ) for at least six months and no other concurrent serious illness were identified by 18 general practice s in Belfast . Their diagnosis was confirmed at interview , and they were r and omly allocated to receive either usual NHS care and personal health promotion from a trained nurse every four months for two years or usual NHS care alone . Sealed envelopes opened at interview showed group allocations . Both groups were review ed",
"PURPOSE Despite demonstrated benefits of cardiac rehabilitation and risk factor reduction , only 11 % to 38 % of eligible patients with cardiovascular disease ( CVD ) participate in cardiac rehabilitation programs . Women and older adults are particularly less likely to participate in cardiac rehabilitation . In an effort to broaden access to cardiac rehabilitation , the authors developed an alternative Internet-based program that allows nurse case managers to provide risk factor management training , risk factor education , and monitoring services to patients with CVD . METHODS The evaluation consisted of a r and omized , clinical trial involving 104 patients with CVD , 53 of whom used the program as a special intervention ( SI ) for 6 months and 51 of whom received usual care ( UC ) . RESULTS The results indicate that fewer cardiovascular events occurred among the SI subjects ( 15.7 % ) than among the UC subjects ( 4.1 % ) ( P = .053 ) , result ing in a gross cost savings of $ 1418 US dollars per patient . With a projected program cost of $ 453 USD per patient , the return on investment is estimated at 213 % . More weight loss occurred in the SI group ( -3.68 pounds ) than in the UC group ( + .47 pounds ) ( P = .003 ) . The differences between the two groups in terms of blood pressure , lipid levels , depression scores , minutes of exercise , and dietary habits were not statistically significant . CONCLUSION An Internet-based case management system could be used as a cost-effective intervention for patients with CVD , either independently or in conjunction with traditional cardiac rehabilitation",
"A r and omized controlled trial of two formats of a program ( Women Take PRIDE ) to enhance management of heart disease by patients was conducted . Older women ( N = 575 ) were r and omly assigned to a group or self-directed format or to a control group . Data regarding symptoms , functional health status , and weight were collected at baseline and at 4 , 12 , and 18 months . The formats produced different outcomes . At 18 months , the self-directed format was better than the control in reducing the number ( p ≤ .02 ) , frequency ( p ≤ .03 ) , and bothersomeness ( p ≤ .02 ) of cardiac symptoms . The self-directed format was also better than the group format in reducing symptom frequency of all types ( p ≤ .04 ) . The group format improved ambulation at 12 months ( p ≤ .04 ) and weight loss at 18 months ( p ≤ .03 ) , and group participants were more likely to complete the program ( p ≤ .05 ) . The availability of different learning formats could enhance management of cardiovascular disease by patients",
"STUDY OBJECTIVE : To investigate the cost effectiveness of personal health education for angina patients being treated in general practice . DESIGN : A r and omised controlled trial in which people were r and omised to intervention and control groups . All were assessed at the start and end of the study , with details recorded of disease status , coronary heart disease risk factors , and self assessed quality of life . A note was taken of their current use of drugs and over the course of the study their use of all health services . Those in the intervention group had three visits per year from a health visitor , whose brief was discuss ways of living more easily with their disease and in which risks of further events might be reduced . PATIENTS : Altogether 688 patents in the Greater Belfast area aged less than 75 years and known to have angina for at least six months . MAIN RESULTS : Significant improvements in survival and self assessed quality of life were found between the study and control groups . The intervention was associated with a reduction in drug usage and there was no significant difference between the intervention and control groups in terms of their use of other health services . CONCLUSION : Given the improvement in survival and self assessed quality of life and no significant differences in costs to the health service between the two groups , the intervention was deemed to be cost effective ",
"This paper presents findings from the evaluation of a self-management education program based on self-regulation principles . Older men and women ( N = 324 ) were r and omly assigned to program and control groups . Outcomes were measured using the Sickness Impact Profile . Twelve months following baseline data collection , psychosocial functioning of program participants was significantly better than that of controls . Different program effects were noted when results were analyzed by participant gender",
"Aim of the study was to assess efficacy of educational technology -- School for patients with stable angina -- in conditions of practical health care . We r and omized 100 patients with ischemic heart disease ( IHD ) and stable FC I-III angina into 2 groups one of which went through learning in a School for patients with IHD ( 6 90 min sessions 2 times a week ) . Patients of both main and control groups were followed up for 12 months . During the whole term of the investigation in both groups observation and treatment of patients was conducted by physicians of city polyclinic in accordance with generally accepted method of care of patients with diagnosis \" IHD , stable angina pectoris \" . Results of the investigation evidence that study ing in the School for patients with stable angina significantly elevates level of medical information adopted by patients , ensures positive dynamics of the whole row of clinical and psychological parameters as well as integral parameters of quality of life of patients with IHD",
"CONTEXT Medicare expenditures of patients with chronic illnesses might be reduced through improvements in care , patient adherence , and communication . OBJECTIVE To determine whether care coordination programs reduced hospitalizations and Medicare expenditures and improved quality of care for chronically ill Medicare beneficiaries . DESIGN , SETTING , AND PATIENTS Eligible fee-for-service Medicare patients ( primarily with congestive heart failure , coronary artery disease , and diabetes ) who volunteered to participate between April 2002 and June 2005 in 15 care coordination programs ( each received a negotiated monthly fee per patient from Medicare ) were r and omly assigned to treatment or control ( usual care ) status . Hospitalizations , costs , and some quality -of-care outcomes were measured with cl aims data for 18 309 patients ( n = 178 to 2657 per program ) from patients ' enrollment through June 2006 . A patient survey 7 to 12 months after enrollment provided additional quality -of-care measures . INTERVENTIONS Nurses provided patient education and monitoring ( mostly via telephone ) to improve adherence and ability to communicate with physicians . Patients were contacted twice per month on average ; frequency varied widely . MAIN OUTCOME MEASURES Hospitalizations , monthly Medicare expenditures , patient-reported and care process indicators . RESULTS Thirteen of the 15 programs showed no significant ( P hospitalizations ; however , Mercy had 0.168 fewer hospitalizations per person per year ( 90 % confidence interval [ CI ] , -0.283 to -0.054 ; 17 % less than the control group mean , P=.02 ) and Charlestown had 0.118 more hospitalizations per person per year ( 90 % CI , 0.025 - 0.210 ; 19 % more than the control group mean , P=.04 ) . None of the 15 programs generated net savings . Treatment group members in 3 programs ( Health Quality Partners [ HQP ] , Georgetown , Mercy ) had monthly Medicare expenditures less than the control group by 9 % to 14 % ( -$84 ; 90 % CI , -$171 to $ 4 ; P=.12 ; -$358 ; 90 % CI , -$934 to $ 218 ; P=.31 ; and -$112 ; 90 % CI , -$231 to $ 8 ; P=.12 ; respectively ) . Savings offset fees for HQP and Georgetown but not for Mercy ; Georgetown was too small to be sustainable . These programs had favorable effects on none of the adherence measures and only a few of many quality of care indicators examined . CONCLUSIONS Viable care coordination programs without a strong transitional care component are unlikely to yield net Medicare savings . Programs with substantial in-person contact that target moderate to severe patients can be cost-neutral and improve some aspects of care . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00627029"
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Background / Objectives Optimal doses of vitamin D ( VitD ) supplement in different population s are unclear . We aim to evaluate the relationship between VitD supplementation and post-intervention serum 25-hydroxyvitamin D [ 25(OH)D ] concentration , to provide a recommended dosage of VitD for achieving an optimal 25(OH)D concentration for different population s . Subjects/ Methods Literature search was conducted in Embase , etc . R and omized controlled trials about VitD supplemental intakes and their effect on 25(OH)D concentration were enrolled . The effect on 25(OH)D concentration between different supplementation doses in each population group was compared by meta- analysis . Multivariate meta-regression model is utilized to establish reference intake dosage of VitD. Results A total of 136 articles were included about children ( 3–17 years ) , adults ( 18–64 years ) , postmenopausal women , the elderly ( > 64 years ) , pregnant , or lactating women . Overall , intervention groups obtained higher 25(OH)D concentration than controls and there was obvious dose – response effect between intake dose and 25(OH)D concentration . Baseline 25(OH)D concentration and age were significant indicators for 25(OH)D concentration . To reach sufficient 25(OH)D concentration ( 75 nmol/L ) , the recommended VitD supplemental intakes was 1340 and 2250 IU/day for children and pregnant women , 2519 and 797 IU/day for European adults aged 18–64 and 65–85 years , 729 , 2026 , and 1229 IU/day for adults in North America , Asia and Middle East and Africa , respectively . Conclusions Regional- and age-specific recommended dosages of VitD supplements for population to achieve optimal 25(OH)D concentrations have been suggested
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"Vitamin D insufficiency is commonly associated with hip fracture . However , the equipotency of ergocalciferol and cholecalciferol supplementation in this patient group has not been studied in a r and omized trial using high-performance liquid chromatography ( HPLC ) measurement of serum 25-hydroxyvitamin D ( 25OHD ) . The objective of this study was to determine if ergocalciferol and cholecalciferol are equipotent therapies in vitamin D-insufficient hip fracture patients . Ninety five hip fracture in patients with vitamin D insufficiency ( 25OHD were r and omized , double-blind , to treatment with ergocalciferol 1000 IU/day ( n=48 ) or cholecalciferol 1000 IU/day ( n=47 ) for three months . All participants were also given a placebo matching the alternative treatment to maintain blinding of treatment allocation . The primary endpoint was total serum 25OHD measured by HPLC . Secondary endpoints included 25OHD measured by radioimmunoassay ( RIA ) , intact parathyroid hormone ( iPTH ) , and bioactive ( 1 - 84 ) whole PTH ( wPTH ) . Seventy patients ( 74 % ) completed the study with paired sample s for analysis . Cholecalciferol supplementation result ed in a 31 % greater increase in total HPLC-measured 25OHD ( p=0.010 ) and 52 % greater rise in RIA-measured 25OHD ( p ergocalciferol . Changes in iPTH and wPTH were not significantly different between calciferol treatments ( p>0.05 ) . In vitamin D-insufficient hip fracture patients , supplementation with cholecalciferol 1000 IU/day for three months was more effective in increasing serum 25OHD than an equivalent dose of ergocalciferol . However , the lack of difference in PTH lowering between calciferol treatments raises questions about the biological importance of this observation",
" Summary Vitamin D deficiency is very common in non-western immigrants . In this r and omized clinical trial , vitamin D 800 IU/day or 100,000 IU/3 months were compared with advised sunlight exposure . Vitamin D supplementation was more effective than advised sunlight exposure in improving vitamin D status and lowering parathyroid hormone levels . Introduction Vitamin D deficiency ( 25-hydroxyvitamin D [ 25(OH)D ] vitamin D supplementation or sunlight exposure . Methods To determine whether the effect of vitamin D3 supplementation ( daily 800 IU or 100,000 IU/3 months ) or sunlight exposure advice is similar with regard to serum 25(OH)D and parathyroid hormone ( PTH ) concentrations . R and omized clinical trial in 11 general practice s in The Netherl and s. Non-western immigrants , aged 18–65 years ( n = 232 ) and serum 25(OH)D were r and omly assigned to supplementation ( daily 800 IU or 100,000 IU/3 months ) or advice for sunlight exposure for 6 months ( March – September ) . Blood sample s were collected at baseline , during treatment ( 3 months , 6 months ) , and at follow-up ( 12 months ) . Statistical analysis was performed with multilevel regression modelling . Results The intention-to-treat analysis included 211 persons . Baseline serum 25(OH)D was 22.5 ± 11.1 nmol/l . After 6 months , mean serum 25(OH)D increased to 53 nmol/l with 800 IU/day , to 50.5 nmol/l with 100,000 IU/3 months , and to 29.1 nmol/l with advised sunlight exposure ( supplementation vs sunshine p PTH decreased significantly in all groups after 3 months , more in the supplementation groups than in the advised sunlight group ( p limitations . Conclusion Vitamin D supplementation is more effective than advised sunlight exposure for treating vitamin D deficiency in non-western immigrants",
"Objectives To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity , insulin secretion , β-cell function , inflammation and metabolic markers . Design 6-month r and omized , placebo-controlled trial . Participants Ninety-five adults with serum 25-hydroxyvitamin D [ 25(OH)D ] ≤55 nmol/L at risk of type 2 diabetes ( with prediabetes or an AUSDRISK score ≥15 ) were r and omized . Analyses included participants who completed the baseline and final visits ( treatment n = 35 ; placebo n = 45 ) . Intervention Daily calcium carbonate ( 1,200 mg ) and cholecalciferol [ 2,000–6,000 IU to target 25(OH)D > 75 nmol/L ] or matching placebos for 6 months . Measurements Insulin sensitivity ( HOMA2%S , Matsuda index ) , insulin secretion ( insulinogenic index , area under the curve ( AUC ) for C-peptide ) and β-cell function ( Matsuda index x AUC for C-peptide ) derived from a 75 g 2-h OGTT ; anthropometry ; blood pressure ; lipid profile ; hs-CRP ; TNF-α ; IL-6 ; adiponectin ; total and undercarboxylated osteocalcin . Results Participants were middle-aged adults ( mean age 54 years ; 69 % Europid ) at risk of type 2 diabetes ( 48 % with prediabetes ) . Compliance was > 80 % for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group ( 91 % achieved > 75 nmol/L ) , but remained unchanged in controls . There were no significant changes in insulin sensitivity , insulin secretion and β-cell function , or in inflammatory and metabolic markers between or within the groups , before or after adjustment for potential confounders including waist circumference and season of recruitment . In a post hoc analysis restricted to participants with prediabetes , a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity ( HOMA%S and Matsuda ) was observed . Conclusions Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity , insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes . However , in participants with prediabetes , supplementation with vitamin D and calcium may improve insulin sensitivity . Trial Registration Australian New Zeal and Clinical Trials Registry",
"Background Calcium ( Ca2 + ) and vitamin D ( VitD ) play an important role in child health . We evaluated the daily intake of Ca2 + and VitD in healthy children . Moreover , we demonstrate the efficacy of Ca2 + and VitD supplementation . Methods Daily Ca2 + and VitD intake was evaluated in consecutive healthy children through a vali date d question naire . Subjects with Ca2 + and VitD were invited to participate in a prospect i ve r and omized trial with 2 groups of nutritional intervention : Group 1 , dietary counseling aim ing to optimize daily Ca2 + and VitD intake plus administration of a commercially available Ca2 + and VitD supplementation product ; Group 2 , dietary counseling alone . At the enrollment ( T0 ) and after 4 months ( T1 ) serum 25(OH ) Vitamin D levels were assessed . Results We evaluated 150 healthy children ( male 50 % , mean age 10 years ) ; at baseline a low VitD intake was observed in all subjects ( median 0.79 μg/die , IQR 1.78 ; range 0.01 - 5.02 ) ; this condition was associated with Ca2 + intake baseline serum 25(OH)D levels were low ( of serum 25(OH)D levels ( ≥30 ng/ml ) was observed in all children in Group 1 and in only one subject in Group 2 [ Group 1 : T1 33.8 ng/ml ( IQR 2.5 ) vs Group 2 : T1 24.5 ng/ml ( IQR 5.2 ) , p Ca2 + and VitD intakes are difficult to obtain through dietary counseling alone in pediatric subjects . Oral supplementation with of Ca2 + and VitD is a reliable strategy to prevent this condition . Trial registration The study was registered in Clinical Trials Protocol Registration System ( ID number : NCT01638494 )",
"Low serum 25-hydroxyvitamin D ( 25(OH)D ) has been shown to correlate with increased risk of type 2 diabetes . Small , observational studies suggest an action for vitamin D in improving insulin sensitivity and /or insulin secretion . The objective of the present study was to investigate the effect of improved vitamin D status on insulin resistance ( IR ) , utilising r and omised , controlled , double-blind intervention administering 100 microg ( 4000 IU ) vitamin D(3 ) ( n 42 ) or placebo ( n 39 ) daily for 6 months to South Asian women , aged 23 - 68 years , living in Auckl and , New Zeal and . Subjects were insulin resistant - homeostasis model assessment 1 (HOMA1)>1.93 and had serum 25(OH)D concentration vitamin D supplementation > 25 microg ( 1000 IU)/d . The HOMA2 computer model was used to calculate outcomes . Median ( 25th , 75th percentiles ) serum 25(OH)D(3 ) increased significantly from 21 ( 11 , 40 ) to 75 ( 55 , 84 ) nmol/l with supplementation . Significant improvements were seen in insulin sensitivity and IR ( P = 0.003 and 0.02 , respectively ) , and fasting insulin decreased ( P = 0.02 ) with supplementation compared with placebo . There was no change in C-peptide with supplementation . IR was most improved when endpoint serum 25(OH)D reached > or = 80 nmol/l . Secondary outcome variables ( lipid profile and high sensitivity C-reactive protein ) were not affected by supplementation . In conclusion , improving vitamin D status in insulin resistant women result ed in improved IR and sensitivity , but no change in insulin secretion . Optimal vitamin D concentrations for reducing IR were shown to be 80 - 119 nmol/l , providing further evidence for an increase in the recommended adequate levels . Registered Trial No. ACTRN12607000642482",
"BACKGROUND The effects of vitamin D supplementation in healthy prepubertal children on physiologic outcomes have not been investigated . OBJECTIVE The objective was to evaluate the effects of supplementation with 1000 IU vitamin D(3)/d on calcium absorption . DESIGN In a double-blind , placebo-controlled trial , we r and omly assigned 64 children to 1000 IU vitamin D(3)/d ( n = 32 ) or placebo ( n = 32 ) for 8 wk . Stable isotopes were used to assess calcium absorption . The main outcome measure was calcium absorption before and after supplementation . RESULTS All of the data are shown as means ± SDs . At baseline , vitamin D intake was 221 ± 79 IU/d and calcium intake was 830 ± 197 mg/d . Baseline serum 25-hydroxyvitamin D [ 25(OH)D ] was not significantly correlated with fractional or total calcium absorption . After 8 wk , with baseline values used as a covariate , no differences were seen in fractional or total calcium absorption based on supplementation group ( P = 0.75 and 0.36 , respectively ) . Supplemented children had a significant increase in 25(OH)D concentrations ( from 27.7 ± 7.4 to 36.0 ± 10.3 ng/mL ; P decrease in parathyroid hormone ( from 21.4 ± 10.4 to 12.9 ± 7.1 pg/mL ; P . No adverse side effects were noted in either group . CONCLUSIONS Vitamin D(3 ) supplementation at 1000 IU/d increases 25(OH)D and decreases parathyroid hormone in children with average vitamin D intakes below the dietary recommendations of the Institute of Medicine . However , no significant effects of this change on calcium absorption occurred . This trial was registered at clinical trials.gov as NCT 00868738",
"INTRODUCTION A high peak bone mass may be essential for reducing the risk of osteoporosis later in life and a sufficient vitamin D level during puberty may be necessary for optimal bone accretion and obtaining a high peak bone mass . Dietary intake and synthesis during winter of vitamin D might be limited but the effect of vitamin D supplementation in adolescence on bone mass is not well established . OBJECTIVE To investigate the effect of supplementation with 5 and 10 microg/day vitamin D(3 ) for 12 months in 11- to 12-year-old girls on bone mass and bone turnover as well as the possible influence of VDR and ER genotype on the effect of the supplementation . METHODS The girls ( n=221 ) were r and omized to receive either 5 microg or 10 microg vitamin D(3 ) supplementation per day or placebo for 12 months . Whole body and lumbar spine bone mass measured by DXA and pubertal status were determined at baseline and after 12 months whereas physical activity and dietary intake of calcium and vitamin D were assessed at baseline . Serum ( S ) 25-hydroxyvitamin D ( 25OHD ) , S-osteocalcin , S-parathyroid hormone , S-calcium , S-inorganic phosphate , urinary ( U ) pyridinoline ( Pyr ) and deoxpyridinoline ( Dpyr ) were measured at baseline and after 6 and 12 months . RESULTS The S-25OHD concentration increased ( p vitamin D-supplementation on biomarkers for bone turnover or on whole body or spine bone mineral augmentation . However , vitamin D supplementation increased whole body bone mineral density ( BMD ) ( p=0.007 ) and bone mineral content ( BMC ) ( p=0.048 ) in the FF VDR genotype but not in the Ff or ff VDR genotypes . CONCLUSION Supplementation with vitamin D ( 5 or 10 microg/day ) over 12 months increased the S-25OHD concentration but there was no effect on indices of bone health in the entire group of girls . However , there was an effect on BMD for a subgroup with the FF VDR genotype indicating an influence of genotype",
"OBJECTIVE : To determine the vitamin D dose necessary to achieve serum 25-hydroxyvitamin D ( 25(OH)D ) concentration ≥20 ng/mL during infancy . METHODS : A r and omized , double-blind , placebo-controlled trial in New Zeal and . Pregnant mothers , from 27 weeks ’ gestation to birth , and then their infants , from birth to age 6 months , were r and omly assigned to 1 of 3 mother/infant groups : placebo/placebo , vitamin D3 1000/400 IU , or vitamin D3 2000/800 IU . Serum 25(OH)D and calcium concentrations were measured at enrollment , 36 weeks ’ gestation , in cord blood , and in infants at 2 , 4 , and 6 months of age . RESULTS : Two-hundred- and -sixty pregnant women were r and omized . At enrollment , the proportions with serum 25(OH)D ≥20 ng/mL for placebo , lower-dose , and higher-dose groups were 54 % , 64 % , and 55 % , respectively . The proportion with 25(OH)D ≥20 ng/mL was larger in both intervention groups at 36 weeks ’ gestation ( 50 % , 91 % , 89 % , P the proportion of infants with 25(OH)D ≥20 ng/mL was larger in both intervention groups to age 4 months : cord blood ( 22 % , 72 % , 71 % , P CONCLUSIONS : Daily vitamin D supplementation during pregnancy and then infancy with 1000/400 IU or 2000/800 IU increases the proportion of infants with 25(OH)D ≥20 ng/mL , with the higher dose sustaining this increase for longer",
"We assessed the effect of vitamin D supplementation on related biochemistry , infection and dentition of the infant . In a double-blind , placebo-controlled trial conducted in Lucknow , India ( latitude 26 ° N ) , 230 mother -newborn pairs were r and omised to receive , for 9 months , 3000µg/month oral vitamin D3 by the mother ( group A ) or 10µg/d by the infant ( group B ) or double placebo ( group C ) . All babies received 15 min of sun exposure ( unclothed ) during massage . Infants ' median 25-hydroxyvitamin D ( 25(OH)D ) was lower in group C ( median 45·3 ; interquartile range ( IQR ) 22 - 59·5 nmol/l ) than in groups A ( median 60·8 ; IQR 41·3 - 80·5 nmol/l ( P7.5µkat/l ) was significantly more frequent in group C babies ( 16 % ) than in group A ( 4 % ) or group B ( 0 % ) babies . The number of days with respiratory or diarrhoeal infection by 9 months of age was higher in group C ( median 46·5 ; IQR 14·8 - 73·3 d ) than in group A ( median 18·5 ; IQR 8·8 - 31·0 d ( P with vitamin D along with sun exposure is superior to sun exposure alone in maintaining normal infant 25(OH)D at 3·5 months , and provide protection from elevated alkaline phosphatase and infectious morbidity",
"Objective : Assessment of the effectiveness and safety of high daily 125 μg ( 5000 IU ) or 250 μg ( 10 000IU ) doses of vitamin D2 during 3 months , in rapidly obtaining adequate 25 hydroxyvitamin D ( 25OHD ) levels . Design : Longitudinal study .Subjects : Postmenopausal osteopenic/osteoporotic women ( n=38 ) were studied during winter and spring . Median age ( 25–75th percentile ) was 61.5 ( 57.00–66.25 ) years , and mean bone mineral density ( BMD ) was 0.902 (0.800–1.042)g/cm2 . Subjects were r and omly divided into three groups : control group ( n=13 ) : no vitamin D2 , 125 μg/day ( n=13 ) and 250 μg/day ( n=12 ) of vitamin D2 groups , all receiving 500 mg calcium/day . Serum calcium , phosphate , bone alkaline phosphatase ( BAP ) , C-telopeptide ( CTX ) , 25OHD , mid-molecule parathyroid hormone ( mmPTH ) , daily urinary calcium and creatinine excretion were determined at baseline and monthly . Results : For all subjects ( n=38 ) , the median baseline 25 hydroxyvitamin D ( 25OHD ) level was 36.25 ( 27.5–48.12 ) nmol/l . After 3 months , 8 % of the patients in the control group , 50 % in the 125 μg/day group and 75 % in the 250 μg/day group had 25OHD values above 85 nmol/l ( 34 ng/ml ) . Considering both vitamin D2 groups together , mmPTH and BAP levels diminished significantly after 3 months ( P CTX . Serum calcium remained within normal range during the follow-up . Conclusions : The oral dose of vitamin D2 required to rapidly achieve adequate levels of 25OHD is seemingly much higher than the usual recommended vitamin D3 dose ( 20 μg/day ) . During 3 months , 250 μg/day of vitamin D2 most effectively raised 25OHD levels to 85 nmol/l in 75 % of the postmenopausal osteopenic/osteoporotic women treated",
"Epidemiological evidence suggests that circulating 25-hydroxyvitamin D ( 25OHD ) levels are inversely associated with hemoglobin ( Hb ) levels and anemia risk . We evaluated whether vitamin D supplementation improves Hb levels and reduces anemia risk in hypertensive patients . Two hundred patients with 25OHD levels Patients r and omly received 2800 IU vitamin D3 daily or a matching placebo for eight weeks . Initially , the prevalence of anemic status ( Hb levels deficient 25OHD levels ( had 25OHD levels > 50 nmol/L. The mean ( 95 % confidence interval ) vitamin D effect on Hb levels was 0.04 ( −0.14 to 0.22 ) g/dL ( P = 0.661 ) . Moreover , vitamin D treatment did not influence anemic status significantly ( P > 0.999 ) . Likewise , vitamin D had no significant effect on Hb levels in the subgroups of anemic patients or in patients with initial 25OHD levels daily vitamin D supplement of 2800 IU for eight weeks did not improve Hb levels or anemic status in hypertensive patients . Future trials should focus on anemic patients with deficient 25OHD levels ( e.g. , < 30 nmol/L ) . This trial is registered with clinical trials.gov [ NCT02136771 ]",
"Objective : To assess the vitamin D status of healthy young people living in Northern Irel and and the effect of vitamin D supplementation on vitamin D status and bone turnover . Design : Double-blinded r and omised controlled intervention study . Setting : University of Ulster , Coleraine , Northern Irel and .Subjects : In total , 30 apparently healthy students ( 15 male and 15 female subjects ) , aged 18–27 years , were recruited from the university , with 27 completing the intervention . Interventions : Subjects were r and omly assigned , to receive either 15 μg ( 600 IU ) vitamin D3 and 1500 mg calcium/day ( vitamin D group ) , or 1500 mg calcium/day ( control group ) for 8 weeks between January and March . Vitamin D status , bone turnover markers , serum calcium and parathyroid hormone concentrations were measured at baseline and post intervention . Results : At baseline , vitamin D status was low in both the vitamin D group ( 47.9 ( s.d . 16.0 ) ) and the control group ( 55.5 ( s.d . 18.6 ) nmol/l 25(OH)D ) . Post intervention vitamin D status was significantly higher in the vitamin D-treated group ( 86.5 ( s.d . 24.5 ) ) compared to the control group ( 48.3 ( s.d . 16.8 ) nmol/l ) ( P supplementation on bone turnover markers or PTH concentrations . Conclusions : This study suggests that young adults in Northern Irel and do not consume an adequate daily dietary intake of vitamin D to maintain plasma vitamin D concentrations in the wintertime . A daily supplement of 15 μg vitamin D3 significantly increased vitamin D status in these individuals to levels of sufficiency . Achievement of an optimum vitamin D status among young adults may have future positive health implication",
"Aim / Background : Vitamin D supplementation during pregnancy is a well-accepted recommendation worldwide ; however , the debate about the correct dose is ongoing . We aim ed to compare daily doses of 600 , 1,200 , and 2,000 IU in this r and omized , controlled study . Methods : The study group consisted of 91 pregnant women aged 16 - 42 years admitted to Kocaeli Maternity and Children Hospital between April 2011 and April 2012 . The participants were r and omly divided into 3 groups . 600 , 1,200 , and 2,000 IU/day of vitamin D was supplemented to group 1 ( control group , n = 31 ) , group 2 ( n = 31 ) , and group 3 ( n = 32 ) , respectively . Serum calcium , 25-hydroxyvitamin D ( 25OHD ) , and the calcium/creatinine ratio in spot urine sample s were measured in the follow-up period . The serum calcium and 25OHD levels of the mothers ' infants were measured as well . Results : The frequency of vitamin D sufficiency after supplementation was 80 % in group 3 and it was significantly higher than in groups 1 ( 42 % ) and 2 ( 39 % ) ( p = 0.03 ) . The frequency of vitamin D sufficiency in the infants of the participants was 91 % in group 3 and it was significantly higher than in groups 1 ( 36 % ) and 2 ( 52 % ) ( p = 0.006 ) . Conclusions : At least 2,000 IU/day of vitamin D is needed to ensure adequate vitamin D status in pregnancy and early infancy",
"Abstract Purpose To determine the dose – response of vitamin D3 supplementation on serum 25-hydroxyvitamin D [ 25(OH)D ] among Chinese adults . Methods In this 5-arm , r and omized , double-blinded controlled trial , 76 healthy participants were assigned to orally administrate 0 , 400 , 800 , 1200 or 2000 IU/d of vitamin D3 for 16 weeks . Serum 25(OH)D , parathyroid hormone , calcium , biomarkers of liver and renal function were measured at multiple time points . Results The mean ( SD ) serum 25(OH)D at baseline was 31.6 ( 8.7 ) nmol/L , and the dose – response relationship was curvilinear with a plateau around 6 weeks for all doses . At week 16 , 25(OH)D was increased by 6.0 ( 6.5 ) , 21.7 ( 15.8 ) , 26.3 ( 12.6 ) , 32.0 ( 12.8 ) and 36.3 ( 26.0 ) nmol/L for 0 , 400 , 800 , 1200 and 2000 IU/d ( all P ≤ 0.002 ) , corresponding to approximately 19 , 53 , 67 , 77 and 80 % of reversion of vitamin D deficiency , respectively . Daily intake of 800 IU vitamin D3 reached a targeted 25(OH)D ≥ 30 nmol/L in at least 97.5 % of Chinese , but not a targeted 25(OH)D ≥ 50 nmol/L even with 2000 IU/d . Change of 25(OH)D was inversely associated with change of PTH concentration ( r = −0.39 , P the change in serum calcium , alanine transaminase , aspartate aminotransferase , gamma-glutamyltransferase and creatinine ( P ≥ 0.22 ) . Conclusions Supplementation with 400 , 800 , 1200 or 2000 IU/d vitamin D could improve the vitamin D deficiency with various degrees . Whether 2000 IU/d vitamin D3 would generate a better result without side effect requires more studies with larger sample s in future",
"BACKGROUND Pregnancy and lactation in adolescents with habitually low calcium intake may adversely affect maternal bone mass . OBJECTIVE We investigated the effect of calcium plus vitamin D supplementation during pregnancy on bone mass during lactation in Brazilian adolescent mothers with low-calcium diets ( ∼600 mg/d ) . DESIGN Pregnant adolescents ( 14 - 19 y ) r and omly received daily calcium ( 600 mg ) plus vitamin D3 ( 200 IU ) ( n = 30 ) or a placebo ( n = 26 ) from 26 wk of pregnancy ( baseline ) until parturition . The bone mineral content ( BMC ) , bone area ( BA ) , and bone mineral density ( BMD ) at the total body , lumbar spine , and hip ( total and femoral neck ) were evaluated by using dual-energy X-ray absorptiometry at 5 and 20 wk postpartum . Serum hormones and 25-hydroxyvitamin D [ 25(OH)D ] were measured . Group comparisons were adjusted for significant covariates . RESULTS The mean serum 25(OH)D concentration was 59 nmol/L at baseline . In comparison with the placebo , 25(OH)D tended to be 14 - 15 nmol/L higher postpartum in the supplemented group ( P = 0.08 ) . Total body and hip BMC and BMD decreased over time ( P ≤ 0.005 ) in both groups with a group × time interaction at the femoral neck ( P higher lumbar spine BA ( 6.7 % ; P = 0.002 ) and lumbar spine BMC ( 7.9 % , P = 0.08 ) than did mothers who consumed the placebo at 5 wk postpartum . At 20 wk postpartum , differences between groups were more evident , with higher lumbar spine BMC ( 13.9 % ) , lumbar spine BA ( 6.2 % ) , and lumbar spine BMD ( 10.6 % ) in the supplemented group ( P ≤ 0.008 ) . CONCLUSIONS Calcium plus vitamin D supplementation during pregnancy of adolescents with low calcium intake results in higher lumbar spine bone mass and a reduced rate of femoral neck bone loss during lactation . Additional studies are required to determine whether bone effects are temporary or long-lasting . This trial was registered at clinical trials.gov as NCT01732328",
"Introduction Fibroblast growth factor-23 plays an important role in regulating systemic phosphate homeostasis , and vitamin D metabolism . However , the effect of Cholecalciferol therapy on FGF23 serum level in patients with vitamin D deficiency has not been studied , yet . Material s and methods This is a double-blind , r and omized clinical trial on 119 vitamin D deficient patients in 2016 . Biochemical variables of treatment and placebo groups were analyzed after 12 weeks of 50,000 IU of Cholecalciferol vs. placebo therapy once a week , by SPSS18 . Results After Cholecalciferol therapy , delta of serum PTH in treatment group was less than the controls ( P , delta values of serum 25(OH)D3 , 1,25(OH)2D3 and FGF23 in vitamin D treated group were more than the placebo-treated ones ( P Moreover , FGF23 serum level in treatment group was associated with serum calcium ( P = 0.005 , r = −0.256 ) , and serum 1,25(OH)2D3 ( P with serum FGF23 , and hypostasized that serum calcium might be a down regulator of serum FGF23",
"Importance Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections . However , whether winter supplementation of vitamin D reduces the risk among children is unknown . Objective To determine whether high-dose vs st and ard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children . Design , Setting , and Participants A r and omized clinical trial was conducted during the winter months between September 13 , 2011 , and June 30 , 2015 , among children aged 1 through 5 years enrolled in TARGet Kids ! , a multisite primary care practice –based research network in Toronto , Ontario , Canada . Interventions Three hundred forty-nine participants were r and omized to receive 2000 IU/d of vitamin D oral supplementation ( high-dose group ) vs 354 participants who were r and omized to receive 400 IU/d ( st and ard-dose group ) for a minimum of 4 months between September and May. Main Outcome Measures The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months . Secondary outcomes included the number of influenza infections , noninfluenza infections , parent-reported upper respiratory tract illnesses , time to first upper respiratory tract infection , and serum 25-hydroxyvitamin D levels at study termination . Results Among 703 participants who were r and omized ( mean age , 2.7 years , 57.7 % boys ) , 699 ( 99.4 % ) completed the trial . The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 ( 95 % CI , 0.91 - 1.19 ) for the high-dose group and 1.03 ( 95 % CI , 0.90 - 1.16 ) for the st and ard-dose group , for a between-group difference of 0.02 ( 95 % CI , −0.17 to 0.21 ) per child . There was no statistically significant difference in number of laboratory-confirmed infections between groups ( incidence rate ratio [ RR ] , 0.97 ; 95 % CI , 0.80 - 1.16 ) . There was also no significant difference in the median time to the first laboratory-confirmed infection : 3.95 months ( 95 % CI , 3.02 - 5.95 months ) for the high-dose group vs 3.29 months ( 95 % CI , 2.66 - 4.14 months ) for the st and ard-dose group , or number of parent-reported upper respiratory tract illnesses between groups ( 625 for high-dose vs 600 for st and ard-dose groups , incidence RR , 1.01 ; 95 % CI , 0.88 - 1.16 ) . At study termination , serum 25-hydroxyvitamin D levels were 48.7 ng/mL ( 95 % CI , 46.9 - 50.5 ng/mL ) in the high-dose group and 36.8 ng/mL ( 95 % CI , 35.4 - 38.2 ng/mL ) in the st and ard-dose group . Conclusions and Relevance Among healthy children aged 1 to 5 years , daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections . These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections . Trial Registration clinical trials.gov Identifier :",
"Objective The aim was to investigate whether vitamin D supplementation , combined with a hypocaloric diet , could have an independent effect on insulin sensitivity in subjects with both overweight and hypovitaminosis D. Changes from baseline in anthropometric parameters , body composition , glucose tolerance , and insulin secretion were considered as secondary outcomes . Methods Eighteen volunteers who were nondiabetic and vitamin D deficient and had BMI > 25 kg/m2 were r and omized ( 1:1 ) in a double‐blind manner to a hypocaloric diet + either oral cholecalciferol at 25,000 IU/wk or placebo for 3 months . Hyperinsulinemic‐euglycemic clamp to measure insulin sensitivity was performed at baseline and after intervention . Results Body weight in both groups decreased significantly ( −7.5 % in the vitamin D group and −10 % in the placebo group ; P differences . Serum 25‐hydroxyvitamin D levels in the vitamin D group increased considerably ( from 36.7 ± 13.2 nmol/L to 74.8 ± 18.7 nmol/L ; P 0.001 ) . Insulin sensitivity in the vitamin D group improved ( from 4.6 ± 2.0 to 6.9 ± 3.3 mg·kg−1·min−1 ; P 0.84 ) . Conclusions Cholecalciferol supplementation , combined with a weight loss program , significantly improves insulin sensitivity in healthy subjects with obesity and might represent a personalized approach for insulin‐resistant subjects with obesity ",
"Context : Available evidence shows an association of vitamin D with and rogen levels in men . However , results from preliminary r and omized controlled trials ( RCTs ) are conflicting . Objective : To evaluate whether vitamin D supplementation increases total testosterone ( TT ) levels in healthy men . Design : The Graz Vitamin D&TT‐ RCT is a single‐center , double‐blind , r and omized , placebo‐controlled trial conducted between December 2012 and January 2017 . Setting : Endocrine outpatient clinic at the Medical University of Graz , Austria . Participants : Ninety‐eight healthy men with TT levels ≥10.4 nmol/L and 25‐hydroxyvitamin D [ 25(OH)D ] levels Intervention : Subjects were r and omly assigned to receive 20,000 IU/wk of vitamin D3 ( n = 50 ) or placebo ( n = 50 ) for 12 weeks . Main Outcome Measures : Primary outcome was TT measured using mass spectrometry . Secondary outcomes were free testosterone , sex hormone‐binding globulin , estradiol , follicle‐stimulating hormone , and luteinizing hormone levels ; free and rogen index ; metabolic characteristics ; and body composition . Results : In healthy men [ mean values ± st and ard deviation : age , 39 years ( ±13 years ) ; 25(OH)D level , 53.3 nmol/L ( ±18.3 nmol/L ) ; TT , 19.1 nmol/L ( ±5.6 nmol/l ) ] , no significant treatment effect on TT was found ; however , there were significant effects on quantitative insulin sensitivity check index ( QUICKI ) and a trend toward decreased Matsuda index . In the treatment group , median ( interquartile range ) changes for TT , QUICKI , and Matsuda index were 0.5 nmol/L ( −0.63 to 0.63 nmol/L ; P = 0.497 ) , −0.02 ( −0.04 to 0.01 ; P = 0.034 ) , and −0.9 ( −3.2 to 0.8 ; P = 0.051 ) , respectively . Conclusion : Vitamin D treatment had no effect on TT levels in middle‐aged healthy men with normal baseline TT , but it significantly decreased QUICKI . Additional studies investigating vitamin D effects on TT and insulin sensitivity in healthy men are required",
"Objective We investigated the daily dose of vitamin D needed to achieve serum 25-hydroxyvitamin D [ 25(OH)D ] sufficiency among schoolchildren at risk for deficiency . Study Design The Daily D Health Study was a r and omized double-blind vitamin D supplementation trial among racially/ethnically diverse schoolchildren ( n = 685 ) in the northeastern United States . Children were supplemented with vitamin D3 at 600 , 1000 , or 2000 IU/d for 6 months . Measurements included serum 25(OH)D at baseline ( October to December ) , 3 months ( January to March ) , 6 months ( April to June ) , and 12 months ( 6 months after supplementation ) . Results At baseline , mean ± st and ard deviation serum 25(OH)D level was 22.0 ± 6.8 ng/mL , with 5.5 % severely vitamin D deficient ( levels of serum 25(OH)D were found among black ( 17.9 ± 6.7 ng/mL ) and Asian children ( 18.9 ± 4.8 ng/mL ) , with no baseline differences by weight status . Serum 25(OH)D increased over 6 months in all three dose groups . The 2000 IU/d group achieved a higher mean serum 25(OH)D level than the other two dose groups ( 33.1 vs 26.3 and 27.5 ng/mL ; P in 25(OH)D at 12 months . Conclusions Children at risk for vitamin D deficiency benefited from daily sustained supplementation of 2000 IU/d compared with lower doses closer to the current recommended daily allowance for vitamin D intake . This benefit occurred over the winter months , when serum 25(OH)D level tend to fall",
"Context Results of animal models and cross-sectional cohort studies have suggested a beneficial role for vitamin D in male reproduction . Objective Determine the effect of vitamin D and calcium supplementation on semen quality in infertile men with serum 25-hydroxyvitamin-D ( 25OHD ) levels ≤50 nmol/L. Design A single-center , triple-blinded , r and omized clinical trial . Participants A total of 1427 infertile men were screened to include 330 ; 1002 men did not meet inclusion criteria and 95 did not wish to participate . Intervention The active group received cholecalciferol 300,000 IU initially , then 1400 IU cholecalciferol and 500 mg of calcium daily for 150 days ; the other group received placebo . Results Serum concentrations of 25OHD and 1,25-dihydroxyvitamin D3 were significantly higher in men in the treatment group compared with the placebo group . Vitamin D supplementation was not associated with changes in semen parameters , although spontaneous pregnancies tended to be higher in couples in which the man was in the treatment group [ 7.3 % vs 2.4 % , Δ5.0 % ( -0.6 % ; 10.5 % ) ] . Vitamin D treatment in a subgroup of oligozoospermic men increased the chance for a live birth compared with placebo [ 35.6 % vs 18.3 % , Δ17.3 % ( 1.6 % ; 32.9 % ) ] . Moreover , serum inhibin B levels were higher in men deficient in vitamin D who were r and omly assigned to receive high-dose vitamin D [ 193 pg/mL vs 143 pg/mL , Δ49 pg/mL ( 8 ; 91 pg/mL ) ] ; however , the increase in sperm concentration was not significantly higher than in the placebo group ( P = 0.07 ) . Conclusion High-dose vitamin D supplementation did not improve semen quality in vitamin D-insufficient infertile men . The positive impact of vitamin D supplementation on live birth rate and serum inhibin B in oligozoospermic and vitamin D-deficient men may be of clinical importance and warrant verification by others",
"Objective : Our study aim ed to investigate the nutritional vitamin D status of school children aged 9–15 years and white-collar workers in Zhejiang province , and evaluate the efficacy of low-dose-oral vitamin D supplementation in both population s. Methods : We conducted a prospect i ve controlled trial during March 2014 to November 2015 , comparing the efficacy of vitamin D supplements ( 400 IU/day ) with non-intervention for 18 months in school children aged 9–15 years . Meanwhile , a before-after study was conducted among white-collar workers for 1 year . Serum 25(OH)D concentration was measured at baseline and after vitamin D supplementation , respectively . Results : At the baseline , 95 % of school children and 84 % of adult participants had vitamin D deficiency ( regard to anthropometric data . Serum 25(OH)D concentrations of the school children intervention group , school children control group and white-collar workers were 12.77 ± 3.01 ng/mL , 14.17 ± 3.59 ng/mL and 16.58 ± 3.66 ng/mL at baseline and increased to 17.34 ± 3.78 ng/mL , 18.04 ± 4.01 ng/mL and 17.75 ± 5.36 ng/mL after vitamin D supplementation , respectively . Although , after adjusting for potential confounders , the 400 IU oral vitamin D supplementation increased serum 25(OH)D concentration in school children ( β = 0.81 , p = 0.0426 ) as well as in white-collar workers ( p = 0.0839 ) , the prevalence of vitamin D deficiency was still very high among school children ( 79.23 % in intervention group and 72.38 % in control group ) and white-collar workers ( 76.00 % ) . Conclusions : High prevalence of vitamin D deficiency was common in these two study population s. Daily doses of 400 IU oral vitamin D supplementation was not able to adequately increase serum 25(OH)D concentrations . A suitable recommendation regarding the level of vitamin D supplementation is required for this Chinese population",
"Context Little is known about how genetic and nongenetic factors modify responses of vitamin D supplementation in nonwhite population s. Objective To investigate factors modifying 25-hydroxyvitamin D [ 25(OH)D ] and bioavailable 25(OH)D [ 25(OH)DBio ] responses after vitamin D3 supplementation . Design , Setting , Participants , and Intervention In this 20-week , r and omized , double-blinded , placebo-controlled trial , 448 Chinese with vitamin D deficiency received 2000 IU/d vitamin D3 or placebo . Main Outcome Measures Serum 25(OH)D , vitamin D-binding protein ( VDBP ) , parathyroid hormone ( PTH ) and calcium were measured , and 25(OH)DBio was calculated based on VDBP levels . Six common polymorphisms in vitamin D metabolism genes were genotyped . Results Between-arm net changes were + 30.6 ± 1.7 nmol/L for 25(OH)D , + 2.7 ± 0.2 nmol/L for 25(OH)DBio , and -5.2 ± 1.2 pg/mL for PTH , corresponding to 70 % [ 95 % confidence interval ( CI ) , 62.8 % to 77.2 % ] net reversion rate for vitamin D deficiency at week 20 ( P Only 25(OH)DBio change was positively associated with calcium change ( P on 25(OH)D or 25(OH)DBio responses than nongenetic factors , including baseline value , body mass index , and sex . An inverse association of PTH-25(OH)D was demonstrated only at 25(OH)D of IU/d vitamin D3 raised 25(OH)D and 25(OH)DBio but was unable to correct deficiency in 25 % of Chinese participants , which might be partially attributed to the effect of genetic modification . More studies are needed to eluci date appropriate vitamin D recommendations for Asians and the potential clinical implication s of 25(OH)DBio",
"Vitamin D deficiency is highly prevalent in newly settled refugees in Western Australia ( WA ) . If adherence to daily vitamin D therapy is problematic , depot therapy is a therapeutic alternative . The aim of this study was to compare daily versus depot treatment and factors influencing the therapeutic outcome . Newly settled refugees ( n = 151 ) with 25(OH)D levels less than 78 nmol/L were r and omised to receive daily or depot vitamin D therapy with eight weekly interval follow up to 40 weeks . Biochemical and clinical parameters were collected at each visit . Generalized Linear Mixed Models ( GLMM ) examined the longitudinal changes over time controlling for confounders including age , gender , treatment arm , season , country of refuge/origin and sun exposure score . Participants were aged 5.5 months to 16.0 years ( 75 males , 83 females ) . Both treatment groups achieved vitamin D sufficiency . The daily treatment group had significantly higher 25(OH)D levels at each visit post baseline and a higher proportion of participants with levels above 50 nmol/L at all time points . Time , treatment group , calcium and sun exposure score were significant predictors of 25(OH)D serum levels . Depot vitamin D therapy is an alternative to daily treatment in this at-risk group of children and adolescents in whom treatment adherence is problematic",
"Higher circulating 25-hydroxyvitamin D ( 25[OH]D ) concentration has been linked to a lower prevalence of insulin resistance and type 2 diabetes mellitus . However , r and omized controlled trials have not clarified the effect of vitamin D supplementation on insulin resistance in healthy adults . The objective of this study was to assess the effect of vitamin D supplementation for 1 year on insulin resistance ; the study was a secondary analysis of a clinical trial . We hypothesized that increased 25(OH)D concentration after vitamin D supplementation for 1 year would significantly improve insulin resistance . Ninety-six healthy adults participated in this study , of whom 81 completed the study . The participants r and omly received daily either 420 IU vitamin D3 or placebo in a double-blind manner for 1 year . The levels of fasting insulin , glucose , and other parameters were assessed at baseline and after 1 year of intervention . Homeostasis model assessment of insulin resistance index was calculated from insulin and glucose levels . Visceral fat area and physical activity were also investigated . Serum 25(OH)D and 1,25-dihydroxyvitamin D concentrations were significantly increased by approximately 29.5 nmol/L and 7.0 pg/mL , respectively , after 1-year vitamin D supplementation . After vitamin D supplementation , fasting glucose levels and values of homeostasis model assessment of insulin resistance index significantly decreased from 88.3 to 85.3 mg/dL ( P vitamin D supplementation for 1 year effectively improves fasting glucose level and insulin resistance in healthy Japanese adults",
"BACKGROUND Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers . However , interventional studies to test this effect are lacking . OBJECTIVE The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types . DESIGN This was a 4-y , population -based , double-blind , r and omized placebo-controlled trial . The primary outcome was fracture incidence , and the principal secondary outcome was cancer incidence . The subjects were 1179 community-dwelling women r and omly selected from the population of healthy postmenopausal women aged > 55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were r and omly assigned to receive 1400 - 1500 mg supplemental calcium/d alone ( Ca-only ) , supplemental calcium plus 1100 IU vitamin D3/d ( Ca + D ) , or placebo . RESULTS When analyzed by intention to treat , cancer incidence was lower in the Ca + D women than in the placebo control subjects ( P unadjusted relative risks ( RR ) of incident cancer in the Ca + D and Ca-only groups were 0.402 ( P = 0.01 ) and 0.532 ( P = 0.06 ) , respectively . When analysis was confined to cancers diagnosed after the first 12 mo , RR for the Ca + D group fell to 0.232 ( CI : 0.09 , 0.60 ; P treatment and serum 25-hydroxyvitamin D concentrations were significant , independent predictors of cancer risk . CONCLUSIONS Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women . This trial was registered at clinical trials.gov as NCT00352170",
"BACKGROUND Indirect evidence suggests that optimal vitamin D status is achieved with a serum 25-hydroxyvitamin D [ 25(OH)D ] concentration > 75 nmol/L. OBJECTIVE We aim ed to determine the intake of vitamin D(3 ) needed to raise serum 25(OH)D to > 75 nmol/L. DESIGN The design was a 6-mo , prospect i ve , r and omized , double-blinded , double-dummy , placebo-controlled study of vitamin D(3 ) supplementation . Serum 25(OH)D was measured by radioimmunoassay . Vitamin D(3 ) intake was adjusted every 2 mo by use of an algorithm based on serum 25(OH)D concentration . RESULTS A total of 138 subjects entered the study . After 2 dose adjustments , almost all active subjects attained concentrations of 25(OH)D > 75 nmol/L , and no subjects exceeded 220 nmol/L. The mean ( + /-SD ) slope at 9 wk [ defined as 25(OH)D change/baseline dose ] was 0.66 + /- 0.35 (nmol/L)/(microg/d ) and did not differ statistically between blacks and whites . The mean daily dose was 86 microg ( 3440 IU ) . The use of computer simulations to obtain the most participants within the range of 75 - 220 nmol/L predicted an optimal daily dose of 115 microg/d ( 4600 IU ) . No hypercalcemia or hypercalciuria was observed . CONCLUSIONS Determination of the intake required to attain serum 25(OH)D concentrations > 75 nmol/L must consider the wide variability in the dose-response curve and basal 25(OH)D concentrations . Projection of the dose-response curves observed in this convenience sample onto the population of the third National Health and Nutrition Examination Survey suggests a dose of 95 microg/d ( 3800 IU ) for those above a 25(OH)D threshold of 55 nmol/L and a dose of 125 microg/d ( 5000 IU ) for those below that threshold",
"BACKGROUND We previously found a high prevalence of vitamin D deficiency and low medication regimen compliance in Arab and East Indian women residing in the United Arab Emirates ( UAE ) . The appropriate dosing regimen for improving vitamin D status in this population is not known . OBJECTIVE We aim ed to determine the efficacy of daily and monthly supplementation with vitamin D2 , the only high-dose calciferol available in the UAE , in lactating and Noneiparous women . DESIGN Healthy lactating ( n = 90 ) and Noneiparous ( n = 88 ) women were r and omly assigned to consume 2000 IU vitamin D2/d or 60,000 IU vitamin D2/mo for 3 mo . Serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations were measured by radioimmunoassay at baseline and every month . RESULTS Most women had vitamin D deficiency [ ie , 25(OH)D study entry . Mean + /- SD 25(OH)D concentrations at 3 mo were significantly higher than baseline in both lactating ( 39.8 + /- 12.4 and 25.2 + /- 10.7 nmol/L , respectively ) and Noneiparous ( 40.4 + /- 23.4 and 19.3 + /- 12.2 nmol/L , respectively ) women ( P vitamin D supplementation was effective in achieving serum 25(OH)D concentrations of > or=50 nmol/L in 21 ( 30 % ) of 71 women at endpoint . CONCLUSIONS Oral vitamin D2 supplementation with 2000 IU/d or 60,000 IU/mo for 3 mo was safe , and it increased serum 25(OH)D concentrations significantly ; however , only a small proportion of the women studied achieved concentrations of > or=50 nmol/L. This suggests that , when sunlight exposure is limited , doses of vitamin D2 higher than those currently studied may be needed . Monthly dosing appears to be a safe and effective alternative to daily dosing",
"AIMS The aim of this study was to investigate effect of vitamin D supplementation on anthropometric indices among women with overweight and obesity . METHODS This double blind r and omize clinical trial was conducted on 66 overweight and obese women . Those in intervention group received oral supplement of vitamin D 50,000 IU ( 1250 mcg ) per 25 day and in control group participants received placebo for 3 months . Anthropometric indices were measured before and after 3 months intervention . Before the intervention a 24-h dietary recall ( 3 days ) were used to assess dietary intake of individuals . Independent t test and multivariate repeated measure were used to data analysis . RESULTS The mean difference of anthropometric indices , serum calcium , 25 ( OH ) D3 and serum PTH between the intervention and control groups were significant ( P in serum phosphorus between the intervention and control groups were seen . CONCLUSION Supplementation with vitamin D 50 μg for each day for 3 months result ed in a significant reduction in anthropometric indices in women with obesity and overweight with normal primary 25(OH ) D3 serum levels",
"BACKGROUND Knowledge gaps have contributed to considerable variation ( between 0 and 15 μg/d ) in international dietary recommendations for vitamin D in adolescents . OBJECTIVE We aim ed to establish the distribution of dietary vitamin D required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above several proposed cutoffs ( 25 , 37.5 , 40 , and 50 nmol/L ) during wintertime in adolescent white girls . DESIGN Data ( baseline and 6 mo ) from 2 r and omized , placebo-controlled , double-blind , 12-mo intervention studies in Danish ( 55 ° N ) and Finnish ( 60 ° N ) girls ( n = 144 ; mean age : 11.3 y ; mean vitamin D intake : 3.7 μg/d ) at vitamin D(3 ) supplementation amounts of 0 , 5 , and 10 μg/d were used . Serum 25(OH)D was measured with an HPLC assay in a central ized laboratory . RESULTS Clear dose-related increments ( P serum 25(OH)D with increasing supplemental vitamin D(3 ) were observed . The slope of the relation between vitamin D intake and serum 25(OH)D at the end of winter was 2.43 nmol ⋅ L(-1 ) ⋅ μg intake(-1 ) , and no difference in the slopes between Finnish and Danish girls was observed . The vitamin D intakes that maintained serum 25(OH)D concentrations at > 25 , > 37.5 , and > 50 nmol/L in 97.5 % of the sample were 8.3 , 13.5 , and 18.6 μg/d , respectively , whereas an intake of 6.3 μg/d maintained a serum 25(OH)D concentration > 40 nmol/L in 50 % of the sample . CONCLUSION The vitamin D intakes required to ensure that adequate vitamin D status [ defined variably as serum 25(OH)D > 25 and > 50 nmol/L ] is maintained during winter in the vast majority ( > 97.5 % ) of adolescent girls ( mean age : 11.3 y ) at northern latitudes ( > 55 ° N ) are 8.3 and 18.6 μg/d , respectively . This trial was registered at clinical trials.gov as NCT00267540",
"Summary In a r and omised controlled trial of vitamin D during pregnancy , we demonstrated that women with lower self-efficacy were more likely to experience practical problems with taking the trial medication and that this was associated with lower compliance and achieved 25(OH)-vitamin D concentrations . Introduction The relationship between self-efficacy ( the belief that one can carry out a behaviour ) , compliance with study protocol and outcome was explored within a r and omised , double-blind , placebo-controlled trial of vitamin D supplementation in pregnancy . Methods In the Maternal Vitamin D Osteoporosis Study ( MAVIDOS ) trial , women with circulating plasma 25(OH)-vitamin D of 25–100 nmol/l in early pregnancy were r and omised to either 1000 IU cholecalciferol/day or matched placebo from 14 weeks until delivery . Circulating 25(OH)-vitamin D concentrations were assessed at 14 and 34 weeks ’ gestation . A sequential sub- sample completed Schwarzer ’s General Self-Efficacy Scale at 14 and 34 weeks and the Problematic Experiences of Therapy Scale at 34 weeks . Women were interviewed about their experiences of the trial and interview transcripts analysed thematically . Results In 203 women , those with higher self-efficacy were less likely to experience practical problems taking the study medication ( odds ratio ( OR ) 0.81 ( 95 % confidence interval ( CI ) 0.69–0.95 ) , p = 0.01 ) . Over half reported practical problems associated with poorer compliance with the protocol requiring women to take the medication daily . Compliance in women who experienced practical problems was 94 % compared with 98 % for those with no problems ( p Poorer compliance was also associated with lower concentrations of 25(OH)-D in late pregnancy in the treatment group ( β = 0.54 nmol/l ( 95 % CI 0.18–0.89 ) , p = 0.003 ) . Thematic analysis suggested common difficulties were remembering to take the medication every day and swallowing the large capsules . Conclusions These findings suggest that differences in self-efficacy influence trial outcomes . Such information may help clinicians anticipate responses to routine vitamin D supplementation in pregnancy and identify those who may need more support to comply . Trial registration IS RCT N82927713 , registered 11/04/2008",
"We studied bone mineral content ( BMC ) , bone mineral density ( BMD ) , and body composition in offspring of women supplemented with vitamin D during pregnancy . Pregnant women were r and omized to receive oral cholecalciferol 60,000 units 4 weekly ( group 1 ) , 8 weekly ( group 2 ) , or placebo ( group 3 ) . All received 1 g calcium daily ( groups 1 and 2 without , and group 3 with 400 units vitamin D ) . Offspring at 12–16 months underwent dual-energy X-ray absorptiometry . Maternal hypovitaminosis D at recruitment was common ( serum 25OHD 50 nmol/L in 88 % ) and severe ( 25OHD in 46 % ) . Groups 1 and 2 ( n = 23 and 13 , median age 14 months ) had higher cord blood 25OHD ( 47.8 ± 13.8 and 31.0 ± 14.0 nmol/L ) versus group 3 ( n = 16 , median age 16 months , 17.8 ± 13.5 nmol/L , p higher whole-body BMC ( 250.8 ± 42.5 gm ) and BMD ( 0.335 ± 0.033 gm/cm2 ) compared to group 1 ( 213.1 ± 46.2 gm and 0.295 ± 0.041 gm/cm2 ) and group 2 ( 202.9 ± 29.9 gm and 0.287 ± 0.023 gm/cm2 ) ( p = 0.006 and 0.001 , respectively ) . In multivariate analysis , age , weight z score , and lean body mass remained significant contributors to BMC . Parameters of body composition were comparable among the groups . Vitamin D supplementation to pregnant women with severe deficiency in doses that improved cord blood 25OHD did not result in improved bone health or body composition in offspring at 12–16 months , compared to a dose too small to improve 25OHD levels",
"Summary This trial compared the effects of daily treatment with vitamin D or placebo for 1 year on blood tests of vitamin D status . The results demonstrated that daily 4000 IU vitamin D3 is required to achieve blood levels associated with lowest disease risks , and this dose should be tested in future trials for fracture prevention . Introduction The aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000 IU ( 100 μg ) , 2000 IU ( 50 μg ) or placebo for 1 year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes . Methods This is a r and omized placebo-controlled trial in 305 community-dwelling people aged 65 years or older in Oxfordshire , UK . Outcomes included biochemical markers of vitamin D status ( plasma 25-hydroxy-vitamin D [ 25[OH]D ] , parathyroid hormone [ PTH ] , calcium and alkaline phosphatase ) , cardiovascular risk factors and tests of physical function . Results Mean ( SD ) plasma 25(OH)D levels were 50 ( 18 ) nmol/L at baseline and increased to 137 ( 39 ) , 102 ( 25 ) and 53 ( 16 ) nmol/L after 12 months in those allocated 4000 IU , 2000 IU or placebo , respectively ( with 88 % , 70 % and 1 % of these groups achieving the pre-specified level of > 90 nmol/L ) . Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium . The additional effect on 25(OH)D levels of 4000 versus 2000 IU was similar in all subgroups except for body mass index , for which the further increase was smaller in overweight and obese participants compared with normal-weight participants . Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function . Conclusions After accounting for average 70 % compliance in long-term trials , doses of 4000 IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies",
"Purpose Vitamin D inadequacy is a global health concern in athletes as well as the general population . Whilst the role of vitamin D in skeletal health is well defined , there remains uncertainty over whether vitamin D supplementation has an added benefit beyond bone health . Methods This r and omised placebo-controlled trial in healthy male and female Gaelic footballers ( n = 42 ) investigated the effect of vitamin D3 supplementation [ 3000 IU ( 75 µg ) daily for 12 weeks , via an oral spray solution ] on VO2 max which was the primary outcome measure . Secondary outcomes included skeletal muscle and lung function . Results Supplementation significantly increased total 25-hydroxyvitamin D concentrations compared to the placebo group ( mean ± SD change from baseline , 36.31 ± 32.34 vs. 6.11 ± 23.93 nmol/L , respectively ; P = 0.006 ) . At baseline , 50 and 22 % of footballers presented with vitamin D insufficiency ( 31–49 nmol/L ) and deficiency ( respectively . Total 25-hydroxyvitamin D concentration did not significantly correlate with any measure of physical performance . Analysis of covariance ( ANCOVA ) models demonstrated that vitamin D supplementation over 12 weeks had no significant effect on VO2 max ( P = 0.375 ) , vertical jump height ( P = 0.797 ) , left and right h and grip strength ( P = 0.146 and P = 0.266 , respectively ) , forced vital capacity ( P = 0.573 ) or forced expiratory volume at 1 s ( P = 0.665 ) , after adjusting for confounders . The high prevalence of vitamin D inadequacy observed in this cohort of collegiate Gaelic footballers supports the need for vitamin D supplementation during wintertime to avoid being at risk of poor bone health . Conclusions Twelve-week daily supplementation with 3000 IU ( 75 µg ) vitamin D3 successfully resolved deficiency but did not have any significant effect on VO2 max , skeletal muscle or lung function ",
"Background : This double-blind , placebo-controlled parallel group trial assessed whether oral supplementation with 1,000 , 2,000 , or 3,000 IU/day vitamin D3 over one year reduces percent mammographic breast density in premenopausal women . Methods : The trial was conducted between October 2012 and June 2015 , among premenopausal female volunteers from Quebec City ( Quebec , Canada ) . Women were r and omized with ratio 1:1:1:1 to one of four study arms ( 1,000 , 2,000 , or 3,000 IU/day vitamin D3 or placebo ) . The primary outcome was mean change in percent mammographic breast density . Participants and research team were blinded to study arm assignment . Results : Participants ( n = 405 ) were r and omized to receive 1,000 ( n = 101 ) , 2,000 ( n = 104 ) , or 3,000 IU/day ( n = 101 ) vitamin D3 , or a placebo ( n = 99 ) . The primary analysis included 391 participants ( 96 , 99 , 100 , and 96 , respectively ) . After the one-year intervention , mean ± SE change in percent breast density in the arms 1,000 IU/day ( –5.5 % ± 0.5 % ) and 2,000 IU/day ( –5.9 % ± 0.5 % ) vitamin D3 was similar to that in the placebo arm ( −5.7 % ± 0.5 % ) ( P values = 1.0 ) . In the 3,000 IU/day vitamin D3 arm , percent breast density also declined but slightly less ( –3.8 % ± 0.5 % ) compared with placebo arm ( P = 0.03 ) . Adherence to intervention was excellent ( 92.8 % ) , and reporting of health problems was comparable among study arms ( P ≥ 0.95 ) . All participants had normal serum calcium . Conclusions : In premenopausal women , one-year supplementation with 1,000 , 2,000 , or 3,000 IU/day vitamin D3 result ed in a reduction of percent breast density no greater than that seen with the placebo . Impact : At doses of 1,000–3,000 IU/day , vitamin D supplementation will not reduce breast cancer risk through changes in breast density . Cancer Epidemiol Biomarkers Prev ; 26(8 ) ; 1233–41 . © 2017 AACR",
"Rhododendrol ( RD ) , 4-(4-hydroxyphenyl)-2-butanol , inhibits melanin synthesis and has been used for skin-whitening cosmetic products . RD has been very effective in lightening skin pigmentation , but some persons have developed so-called RD vitiligo , in which vitiligo starts on the face , neck and h and s where topical RD has been applied and even extended over skin areas where RD has not been applied . RD vitiligo lesions in some patients have lasted for years and have been resistant to conventional vitiligo treatments . We examined the effects of cholecalciferol on RD vitiligo in a blinded r and omized clinical trial . Forty-eight female RD vitiligo patients were recruited for the trial and were r and omized into two groups : the vitamin D (VD)-intervention group that received daily 5000 IU cholecalciferol for 5 months and the control group . Three blinded investigators scored vitiligo improvement by comparing photographic images of baseline and at 5-month observation . Serum 25(OH)D3 of RD vitiligo patients was not significantly different from age-matched healthy volunteers . Twenty-two in the VD-intervention group and 23 in the control group completed the 5-month observation . Serum 25(OH)D3 levels were significantly increased after the 5-month VD intervention , while the control group did not change . The improvement scores were significantly higher in the VD-intervention group than the control group . The improvement scores were positively correlated with the serum 25(OH)D3 levels after the 5-month intervention period but not before the treatment . This blinded r and omized clinical trial showed favor in administrating 5000 IU cholecalciferol daily to RD vitiligo patients",
"BACKGROUND Association studies have suggested that lower circulating 25-hydroxyvitamin D [ 25(OH)D ] in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this population . Nonetheless , the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined . OBJECTIVE Our primary objective was to determine the dose-response relation between vitamin D and plasma 25(OH)D. DESIGN A total of 328 African Americans in Boston , MA , were enrolled over 3 winters from 2007 to 2010 and r and omly assigned to receive a placebo or 1000 , 2000 , or 4000 IU vitamin D₃/d for 3 mo . Subjects completed sociodemographic and dietary question naires , and plasma sample s were drawn at baseline and 3 and 6 mo . RESULTS Median plasma 25(OH)D concentrations at baseline were 15.1 , 16.2 , 13.9 , and 15.7 ng/mL for subjects r and omly assigned to receive the placebo or 1000 , 2000 , or 4000 IU/d , respectively ( P = 0.63 ) . The median plasma 25(OH)D concentration at 3 mo differed significantly between supplementation arms at 13.7 , 29.7 , 34.8 , and 45.9 ng/mL , respectively ( P raise the plasma 25(OH)D concentration to ≥ 20 ng/mL in ≥ 97.5 % of participants , whereas a dose of 4000 IU/d was needed to achieve concentrations ≥ 33 ng/mL in ≥ 80 % of subjects . No significant hypercalcemia was seen in a subset of participants . CONCLUSIONS Within African Americans , an estimated 1640 IU vitamin D₃/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine , whereas 4000 IU/d was needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospect i ve observational studies . These results may be helpful for informing future trials of disease prevention",
"Summary Vitamin D supplementation for 16 weeks did not reduce musculoskeletal pain or headache in this r and omized , double‐blind , placebo‐controlled study among ethnic minorities living in Norway . ABSTRACT Immigrants from South Asia , the Middle East , and Africa living in Northern Europe frequently have low vitamin D levels and more pain compared to the native Western population . The aim of this study was to examine whether daily vitamin D3 ( 25 & mgr;g/d or 10 & mgr;g/d ) supplementation for 16 weeks would improve musculoskeletal pain or headache compared to placebo . This r and omized , double‐blind , placebo‐controlled , parallel‐group trial recruited 251 participants aged 18 to 50 years , and 215 ( 86 % ) attended the follow‐up visit . The pain measures were occurrence , anatomical localization , and degree of musculoskeletal pain , as measured by visual analogue scale ( VAS ) score during the past 2 weeks . Headache was measured with VAS and the Headache Impact Test ( HIT‐6 ) question naire . At baseline , females reported more pain sites ( 4.7 ) than males ( 3.4 ) , and only 7 % reported no pain in the past 2 weeks . During the past 4 weeks , 63 % reported headache with a high mean HIT‐6 score of 60 ( SD 7 ) . At follow‐up , vitamin D level , measured as serum 25(OH)D3 , increased from 27 nmol/L to 52 nmol/L and from 27 nmol/L to 43 nmol/L in the 25‐&mgr;g and 10‐&mgr;g supplementation groups , respectively , whereas serum 25(OH)D3 did not change in the placebo group . Pain scores and headache scores were improved at follow‐up compared with baseline . The use of vitamin D supplements , however , showed no significant effect on the occurrence , anatomical localization , and degree of pain or headache compared to placebo",
"OBJECTIVES Low vitamin D status has been shown to be associated with hypertension . We planned to research the effect of vitamin D and nifedipine in the treatment of patients with essential hypertension . METHODS Patients with grade s I-II essential hypertension were enrolled in this single-center , double-blind , placebo-controlled trial in Beijing . All patients received a conventional antihypertensive drug ( nifedipine , 30 mg/d ) . One hundred and twenty-six patients were r and omly assigned to receive vitamin D ( n=63 , 2000 IU/d ) or a placebo ( n=63 ) as an add-on to nifedipine , by the method of permutated block r and omization . Ambulatory blood pressure monitoring was performed at baseline ( month 0 ) , at month 3 and at month 6 . RESULTS In vitamin D supplementation group , there was a significant increase in mean 25-hydroxyvitamin D levels from baseline ( 19.4 ± 11.6 ng/ml ) to 6 months ( 34.1 ± 12.2 ng/ml ; p the fall of 24-h mean blood pressure , between the groups was -6.2 mmHg ( 95 % CI -11.2 ; -1.1 ) for systolic blood pressure ( p for diastolic blood pressure ( p patients with vitamin D baseline ( n=113 ) , 24-h mean blood pressure decreased by 7.1/5.7 mmHg ( p were similar among the two groups . CONCLUSIONS Vitamin D supplementation can reduce blood pressure in patients with hypertension , it can be an adjuvant therapy for patients with grade s I-II essential hypertension . CLINICAL TRIAL REGISTRATION This study was registered in the Chinese Clinical Trial Registry , it is available in Website : http://www.chictr.org/cn/ ; REGISTRATION NUMBER ChiCTR-ONC-13003840",
"Background / Objectives : Controversies surround the actual requirements of vitamin D in adolescents . We aim ed to assess the efficacy and safety of different doses of vitamin D in high schoolchildren of Taleghan ( latitude 36.5 ° N ) near Tehran . Subjects/ Methods : In a r and omized double-blind , placebo-controlled trial , 210 subjects , aged 14–20 years , 105 boys and 105 girls were assigned to three groups ; group A ( n=70 ) received 50 000 U oral cholecalciferol monthly ( equal to 1600 U per day ) , group B ( n=70 ) , 50 000 U bimonthly ( equal to 800 U/day ) and group C ( n=70 ) , placebo . The study began in November 2007 and continued until April 2008 . Serum 25(OH)D , parathyroid hormone ( PTH ) , calcium ( Ca ) and bone markers were measured . Results : At baseline , girls had significantly lower concentrations of 25(OH)D than boys ( 19.25±16 vs 40.5±14 nmol/l ) . Mean 25(OH)D increased from 32±22 to 60±27.5 and 28.25±14.5 to 45.75±24 in groups A and B , respectively ( P vs 29±17.5 ) . Increment of mean 25(OH)D was higher in group A than in group B ( P girls had lower concentrations of 25(OH)D than boys ( P ) . Serum Ca increased and PTH decreased in groups A and B ( P A , osteocalcin ( OC ) and bone-specific alkaline phosphatase increased ( P B only OC increased ( P did not change in all three groups ; no case of hypercalcemia was observed . Conclusions : Although monthly administration of 50 000 U vitamin D3 increased serum 25(OH)D significantly , it was apparently not enough to correct vitamin D deficiency especially in girls",
"The need , safety , and effectiveness of vitamin D supplementation during pregnancy remain controversial . In this r and omized , controlled trial , women with a singleton pregnancy at 12 to 16 weeks ' gestation received 400 , 2000 , or 4000 IU of vitamin D(3 ) per day until delivery . The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [ 25(OH)D ] concentration at delivery , with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3 ) [ 1,25(OH)(2)D(3 ) ] production . Of the 494 women enrolled , 350 women continued until delivery : Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different ( p relative risk ( RR ) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups ( RR = 1.52 , 95 % CI 1.24 - 1.86 ) , the 4000- and the 400-IU groups ( RR = 1.60 , 95 % CI 1.32 - 1.95 ) but not between the 4000- and . 2000-IU groups ( RR = 1.06 , 95 % CI 0.93 - 1.19 ) . Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3 ) concentrations throughout pregnancy ( p safety measure . Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels . It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race , whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations , especially in African Americans",
"Objective : We aim ed to investigate whether vitamin D supplementation modulates peripheral blood mononuclear cell ( P BMC ) telomerase activity in overweight African Americans . Design : A double blind , r and omized and placebo-controlled clinical trial ( # NCT01141192 ) was recently conducted . Subjects And Methods : African-American adults were r and omly assigned to either the placebo , or the vitamin D group ( 60 000 IU per month ( equivalent to ∼2000 IU per day ) oral vitamin D3 supplementation ) . Fresh P BMC s were collected from 37 subjects ( 18 in the placebo group and 19 in the vitamin D group ) , both at baseline and 16 weeks . P BMC telomerase activity was measured by the telomeric repeat amplification protocol . Results : Serum 25 hydroxyvitamin D levels increased from 40.7±15.7 at baseline to 48.1±17.5 nmol l–1 at posttest ( P=0.004 ) in the placebo group , and from 35.4±11.3 at baseline to 103.7±31.5 nmol l–1 at posttests ( P the vitamin D group , P BMC telomerase activity increased by 19.2 % from baseline ( 1.56±0.29 absorbance reading unit ( AU ) ) to posttest ( 1.86±0.42 AU , P ) . P BMC telomerase activity in the placebo group did not change from baseline ( 1.43±0.26 AU ) to posttest ( 1.46±0.27 AU , P=0.157 ) . Conclusion : Vitamin D supplementation significantly increased P BMC telomerase activity in overweight African Americans . Our data suggest that vitamin D may improve telomere maintenance and prevent cell senescence and counteract obesity-induced acceleration of cellular aging ",
"Many people worldwide are vitamin D ( VTD ) deficient or insufficient , and there is still no consensus on the dose of VTD that should be administered to achieve a 25(OH)D concentration of 20 or 30 ng/mL. In this study , we aim ed to determine an adapted supplementation of VTD able to quickly and safely increase the vitamin D status of healthy adults with low 25(OH)D. One hundred and fifty ( 150 ) subjects were r and omized into three groups , each to receive , orally , a loading dose of 50,000 , 100,000 or 200,000 IU of VTD3 at Week 0 , followed by 25,000 , 50,000 or 100,000 IU at Week 4 and Week 8 . Whereas 25(OH)D baseline values were not different between groups ( p = 0.42 ) , a significant increase was observed at Week 12 ( p weeks . No related adverse event was recorded . This study demonstrated a linear dose-response relationship with an increase in 25(OH)D levels proportional to the dose administered . In conclusion , a loading dose of 200,000 IU VTD3 followed by a monthly dose of 100,000 IU is the best dosing schedule to quickly and safely correct the VTD status",
"Summary Treatment of vitamin D deficiency for 3 months with oral cholecalciferol 5,000 IU daily was more effective than 2,000 IU daily in achieving optimal serum 25-hydroxyvitamin D ( 25OHD ) concentrations . Optimal 25OHD serum level calculated to be 63.8 nmol/L. All parameters of muscle strength improved following administration of cholecalciferol for 3 months . Introduction The aim of this study was to determine the optimal dose of cholecalciferol required to achieve target serum 25OHD level ≥75 nmol/L and its relationship to both bone turnover and muscle strength . Methods Thirty deficient patients ( serum 25OHD ≤50 nmol/L ) were r and omly assigned into two groups — i.e . 2,000 and 5,000 IU/day . Data were collected at baseline , at 2 and 3 months post-therapy : ( a ) clinical demographics , ( b ) dietary calcium recall , ( c ) physical tests of muscle function and ( d ) biochemistry . Statistical analysis used paired student t test and analysis of variance . Regression analysis was used to determine relationship between serum 25OHD and parathyroid hormone ( PTH ) . Results Twenty-six ( 87 % ) patients completed 3 months of therapy . The percent increase in serum 25OHD ( compared to baseline ) was 82.7 % in 2,000-IU group and 219.5 % in 5,000-IU group . All participants ( 100 % ) achieved a serum 25OHD concentration > 50 nmol/L ; only 5 subjects ( 45.4 % ) in 2,000-IU group compared to 14 subjects ( 93.3 % ) in 5,000-IU group achieved final 25OHD concentration ≥75 nmol/L ( p the PTH level increased above the normal range was calculated to be 63.8 nmol/L 25OHD . All parameters of muscle strength showed trends in improvements following the administration of both the 2,000 and 5,000 IU doses . No patient reported untoward side effects and no patient developed hypercalcaemia . Conclusion Treatment for 3 months with oral cholecalciferol 5,000 IU daily may be more effective than 2,000 IU daily in achieving optimal serum 25OHD concentrations in vitamin D-deficient patients",
"ABSTRACT . Fifty‐one healthy prepubertal schoolchildren were followed for 13 months in a double blind study . Twenty‐four of them were supplemented with 400 IU of vitamin D2 5–7 times weekly , while 27 received a placebo . The children were examined in winter both at the beginning and at the end of the study , and in the middle of the study in autumn . Mean 25‐hydroxyvitamin D levels in the supplemented group were significantly higher than those in the placebo group both in autumn and in winter , when the study ended . The vitamin D supplementation did not , however , affect other vitamin D metabolites , serum calcium , albumin , inorganic phosphorus , parathyroid hormone concentrations or alkaline phosphatase activity . Moreover , the supplementation caused no alterations in the weight or height gain or bone mineral content of the distal radius of the children , and thus sub clinical rickets could not be shown",
"BACKGROUND Children in northern latitudes are at high risk of vitamin D deficiency during winter because of negligible dermal vitamin D3 production . However , to our knowledge , the dietary requirement for maintaining the nutritional adequacy of vitamin D in young children has not been investigated . OBJECTIVE We aim ed to establish the distribution of vitamin D intakes required to maintain winter serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above the proposed cutoffs ( 25 , 30 , 40 , and 50 nmol/L ) in white Danish children aged 4 - 8 y living at 55 ° N. DESIGN In a double-blind , r and omized , controlled trial 119 children ( mean age : 6.7 y ) were assigned to 0 ( placebo ) , 10 , or 20 μg vitamin D3/d supplementation for 20 wk . We measured anthropometry , dietary vitamin D , and serum 25(OH)D with liquid chromatography-t and em mass spectrometry at baseline and endpoint . RESULTS The mean ± SD baseline serum 25(OH)D was 56.7 ± 12.3 nmol/L ( range : 28.7 - 101.4 nmol/L ) . Serum 25(OH)D increased by a mean ± SE of 4.9 ± 1.3 and 17.7 ± 1.8 nmol/L in the groups receiving 10 and 20 μg vitamin D3/d , respectively , and decreased by 24.1 ± 1.2 nmol/L in the placebo group ( P model of serum 25(OH)D as a function of total vitamin D intake ( diet and supplements ) was fit to the data . The estimated vitamin D intakes required to maintain winter serum 25(OH)D > 30 ( avoiding deficiency ) and > 50 nmol/L ( ensuring adequacy ) in 97.5 % of participants were 8.3 and 19.5 μg/d , respectively , and 4.4 μg/d was required to maintain serum 25(OH)D > 40 nmol/L in 50 % of participants . CONCLUSIONS Vitamin D intakes between 8 and 20 μg/d are required by white 4- to 8-y-olds during winter in northern latitudes to maintain serum 25(OH)D > 30 - 50 nmol/L depending on chosen serum 25(OH)D threshold . This trial was registered at clinical trials.gov as NCT02145195",
"Public health recommendations do not distinguish between vitamin D2 and vitamin D3 , yet disagreement exists on whether these two forms should be considered equivalent . The objective of the present study was to evaluate the effect of a daily physiological dose of vitamin D2 or vitamin D3 on 25-hydroxyvitamin D ( 25(OH)D ) status over the winter months in healthy adults living in Dunedin , New Zeal and ( latitude 46 ° S ) . Participants aged 18 - 50 years were r and omly assigned to 25 μg ( 1000 IU ) vitamin D3 ( n 32 ) , 25 μg ( 1000 IU ) vitamin D2 ( n 31 ) or placebo ( n 32 ) daily for 25 weeks beginning at the end of summer . A per- protocol approach , which included ≥ 90 % supplement compliance , was used for all analyses . Serum 25-hydroxyvitamin D3 ( 25(OH)D3 ) , 25-hydroxyvitamin D2 ( 25(OH)D2 ) and parathyroid hormone ( PTH ) were measured at baseline and at 4 , 8 , 13 and 25 weeks . Geometric mean total serum 25(OH)D concentrations ( sum of 25(OH)D2 and 25(OH)D3 ) at baseline was 80 nmol/l . After 25 weeks , participants r and omised to D2 and placebo had a significant reduction in serum 25(OH)D3 concentrations over the winter months compared with vitamin D3-supplemented participants ( both P Supplementation with vitamin D2 increased serum 25(OH)D2 but produced a 9 ( 95 % CI 1 , 17 ) nmol/l greater decline in the 25(OH)D3 metabolite compared with placebo ( P 0.036 ) . Overall , total serum 25(OH)D concentrations were 21 ( 95 % CI 14 , 30 ) nmol/l lower in participants receiving vitamin D2 compared with those receiving D3 ( P whom total serum 25(OH)D concentrations remained unchanged . No intervention-related changes in PTH were observed . Daily supplementation of vitamin D3 was more effective than D2 ; however , the functional consequence of the differing metabolic response warrants further investigation",
"Low levels of 25-hydroxyvitamin D ( 25OHD ) are associated with increased bone turnover and risk of fractures . Plasma 25OHD is inversely related to body mass index , and vitamin D deficiency is common in obesity . We aim ed to determine whether vitamin D supplementation affects bone turnover and bone mineral density ( BMD ) in obese subjects . Fifty-two healthy obese men and women aged 18–50 years with plasma 25OHD levels below 50 nmol/L were r and omized to 7,000 IU of cholecalciferol daily or placebo for 26 weeks . We measured plasma levels of 25OHD , parathyroid hormone ( PTH ) , and markers of bone turnover , as well as BMD at the hip , spine , forearm , and whole body . Compared with placebo , treatment with cholecalciferol increased mean plasma 25OHD from 35 to 110 nmol/L ( p significantly decreased PTH ( p 0.05 ) . BMD increased significantly at the forearm by 1.6 ± 0.7 % ( p = 0.03 ) . The bone resorption marker C-terminal telopetide of type 1 collagen ( CTX ) decreased borderline significantly in the cholecalciferol group compared with the placebo group ( p = 0.07 ) . Changes in plasma 25OHD correlated inversely with changes in plasma levels of bone-specific alkaline phosphatase ( r = −0.38 , p = 0.01 ) and CTX ( r = −0.33 , p = 0.03 ) . Changes in CTX correlated inversely with changes in spine BMD ( r = −0.45 , p = 0.04 ) . Increasing circulating 25OHD levels by cholecalciferol treatment is of importance to bone health in young obese subjects as increased levels of 25OHD are associated with a decrease in both PTH and bone turnover and with an increase in BMD at the forearm",
"Background : Although vitamin D deficiency has been linked to potential complications in reproductive women , the recommended intake dosage of this vitamin in population s with high incidence of deficiency in preconception period has not been defined . Objectives : The study investigated the effect of consuming a dosage of 2000 IU/day oral vitamin D for 105 days , on serum levels of this vitamin in reproductive women . Material s and Methods : 229 women with 18 - 35 years old , who were confirmed to be vitamin D deficient ( vitamin D , were r and omized into the intervention and control groups and after 15 weeks consumption of the supplement and placebo , their serum sample s were obtained . Results : At baseline the mean serum levels of vitamin D in the control group was 23.34 ± 15.87 nmol/L and in intervention group was 25.13 ± 18.46 nmol/L , that these values did n’t have any significant difference ( P = 0.43 ) , while after intervention , significant differences between the two groups was noticed ( P oral vitamin D on the serum level elevation of this vitamin in reproductive women",
"BACKGROUND Autism spectrum disorder ( ASD ) is a frequent developmental disorder characterized by pervasive deficits in social interaction , impairment in verbal and nonverbal communication , and stereotyped patterns of interests and activities . It has been previously reported that there is vitamin D deficiency in autistic children ; however , there is a lack of r and omized controlled trials of vitamin D supplementation in ASD children . METHODS This study is a double-blinded , r and omized clinical trial ( RCT ) that was conducted on 109 children with ASD ( 85 boys and 24 girls ; aged 3 - 10 years ) . The aim of this study was to assess the effects of vitamin D supplementation on the core symptoms of autism in children . ASD patients were r and omized to receive vitamin D3 or placebo for 4 months . The serum levels of 25-hydroxycholecalciferol ( 25 (OH)D ) were measured at the beginning and at the end of the study . The autism severity and social maturity of the children were assessed by the Childhood Autism Rating Scale ( CARS ) , Aberrant Behavior Checklist ( ABC ) , Social Responsiveness Scale ( SRS ) , and the Autism Treatment Evaluation Checklist ( ATEC ) . TRIAL REGISTRATION NUMBER UMIN-CTR Study Design : trial number : UMIN000020281 . RESULTS Supplementation of vitamin D was well tolerated by the ASD children . The daily doses used in the therapy group was 300 IU vitamin D3/kg/day , not to exceed 5,000 IU/day . The autism symptoms of the children improved significantly , following 4-month vitamin D3 supplementation , but not in the placebo group . This study demonstrates the efficacy and tolerability of high doses of vitamin D3 in children with ASD . CONCLUSIONS This study is the first double-blinded RCT proving the efficacy of vitamin D3 in ASD patients . Depending on the parameters measured in the study , oral vitamin D supplementation may safely improve signs and symptoms of ASD and could be recommended for children with ASD . At this stage , this study is a single RCT with a small number of patients , and a great deal of additional wide-scale studies are needed to critically vali date the efficacy of vitamin D in ASD",
"BACKGROUND Persons with limited exposure to ultraviolet B light , including space travelers , may not receive enough vitamin D. Recent studies indicate that optimal serum 25-hydroxyvitamin D [ 25(OH)D ] should be > or = 80 nmol/L. OBJECTIVE This study was design ed to evaluate the effectiveness of 3 doses of vitamin D to raise and maintain 25(OH)D to a concentration > 80 nmol/L in persons with limited ultraviolet B light exposure . DESIGN This was a 5-mo , prospect i ve , r and omized , double-blind study of vitamin D supplementation . It was conducted during winter in Anta rct ica at the McMurdo Station , when ultraviolet B radiation levels are essentially zero . The 55 subjects were r and omly divided into 3 groups for vitamin D supplementation : 2000 IU/d ( n = 18 ) , 1000 IU/d ( n = 19 ) , and 400 IU/d ( n = 18 ) . An additional 7 subjects did not take supplements or took supplements of their own choosing . Blood sample s were collected about every 2 mo during the winter . RESULTS About 5 mo after supplementation started , 25(OH)D increased to 71 + /- 23 nmol/L in the 2000-IU/d group , 63 + /- 25 nmol/L in the 1000-IU/d group , and 57 + /- 15 nmol/L in the 400-IU/d group and decreased to 34 + /- 12 nmol/L in the group not taking supplements . CONCLUSIONS These data will enable us to provide space crews with evidence -based recommendations for vitamin D supplementation . The findings also have implication s for other persons with limited ultraviolet light exposure , including polar workers and the elderly",
"The aim was to assess the effects of resistance training and vitamin D supplementation on physical performance of healthy elderly subjects . Ninety-six subjects , aged 70 years or more with 25 OH vitamin D levels of 16 ng/ml or less , were r and omized to a resistance training or control group . Trained and control groups were further r and omized to receive in a double blind fashion , vitamin D 400 IU plus 800 mg of calcium per day or calcium alone . Subjects were followed for nine months . Serum 25 OH vitamin D increased from 12.4+/-2.2 to 25.8+/-6.5 ng/ml among subjects supplemented with vitamin D. Trained subjects had significant improvements in quadriceps muscle strength , the short physical performance test and timed up and go . The latter improved more in trained subjects supplemented with vitamin D. At the end of the follow up , gait speed was higher among subjects supplemented with vitamin ( whether trained or not ) than in non-supplemented subjects ( 838+/-147 and 768+/-127 m/12 min , respectively , p=0.02 ) . Romberg ratio was lower among supplemented controls than non-supplemented trained subjects ( 128+/-40 % and 144+/-37 % , respectively , p=0.05 ) . In conclusion , vitamin D supplementation improved gait speed and body sway , and training improved muscle strength",
"OBJECTIVE Epidemiological data suggest low serum 25-hydroxyvitamin D3 ( 25-OH-D3 ) levels are associated with radiological progression of knee osteoarthritis ( OA ) . This study aim ed to assess whether vitamin D supplementation can slow the rate of progression . METHOD A 3-year , double-blind , r and omised , placebo-controlled trial of 474 patients aged over 50 with radiographically evident knee OA comparing 800 IU cholecalciferol daily with placebo . Primary outcome was difference in rate of medial joint space narrowing ( JSN ) . Secondary outcomes included lateral JSN , Kellgren & Lawrence grade , Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) pain , function , stiffness and the Get up and Go test . RESULTS Vitamin D supplementation increased 25-OH-D3 from an average of 20.7 ( st and ard deviation ( SD ) 8.9 ) μg/L to 30.4 ( SD 7.7 ) μg/L , compared to 20.7 ( SD 8.1 ) μg/L and 20.3 ( SD 8.1 ) μg/L in the placebo group . There was no significant difference in the rate of JSN over 3 years in the medial compartment of the index knee between the treatment group ( average -0.01 mm/year ) and placebo group ( -0.08 mm/year ) , average difference 0.08 mm/year ( 95 % confidence interval ( CI ) [ -0.14 - 0.29 ] , P = 0.49 ) . No significant interaction was found between baseline vitamin D levels and treatment effect . There were no significant differences for any of the secondary outcome measures . CONCLUSION Vitamin D supplementation did not slow the rate of JSN or lead to reduced pain , stiffness or functional loss over a 3-year period . On the basis of these findings we consider that vitamin D supplementation has no role in the management of knee OA",
"CONTEXT Effects of long-term calcium , with or without vitamin D , on hip bone mineral density ( BMD ) and bone turnover in sunny climates have not been reported . OBJECTIVE The aim was to evaluate the effect of vitamin D added to calcium supplementation on hip dual-energy x-ray absorptiometry BMD and calcium-related analytes . DESIGN , SETTING , AND PARTICIPANTS The study was a 5-yr r and omized , controlled , double-blind trial of 120 community-dwelling women aged 70 - 80 yr . INTERVENTIONS The interventions were 1200 mg/d calcium with placebo vitamin D ( Ca group ) or with 1000 IU/d vitamin D2 ( CaD group ) , or double placebo ( control ) . MAIN OUTCOME MEASURES Hip BMD , plasma 25-hydroxyvitamin D , biomarkers of bone turnover , PTH , and intestinal calcium absorption were measured . RESULTS Hip BMD was preserved in CaD ( -0.17 % ) and Ca ( 0.19 % ) groups but not controls ( -1.27 % ) at yr 1 and maintained in the CaD group only at yr 3 and 5 . The beneficial effects were mainly in those with baseline 25-hydroxyvitamin D levels below the median ( 68 nmol/liter ) . At yr 1 , compared with controls , the Ca and CaD groups had 6.8 and 11.3 % lower plasma alkaline phosphatase , respectively ( P urinary deoxypyridinoline to creatinine ratio , respectively ( P PTH at 3 and 5 yr cf . controls ( 27.8 and 31.3 % , P PTH levels above the median ( 3.6 pmol/liter ) . Therapy did not affect intestinal calcium absorption at high carrier loads . CONCLUSIONS Addition of vitamin D to calcium has long-term beneficial effects on bone density in elderly women living in a sunny climate , probably mediated by a long-term reduction in bone turnover rate",
"Severe vitamin D deficiency is common among Muslim immigrants . The dose necessary to correct the deficiency and its consequence for bone health are not known for immigrants . The aim was to assess the effect of relatively low dosages of supplemental vitamin D on vitamin D and bone status in Pakistani immigrants . This 1-year-long r and omised double-blinded placebo-controlled intervention with vitamin D3 ( 10 and 20 microg/d ) included girls ( 10.1 - 14.7 years ) , women ( 18.1 - 52.7 years ) and men ( 17.9 - 63.5 years ) of Pakistani origin living in Denmark . The main endpoints were serum 25-hydroxyvitamin D ( S-25OHD ) , parathyroid hormone , bone turnover markers and bone mass . The study showed that supplementation with 10 and 20 microg vitamin D3 per d increased S-25OHD concentrations similarly in vitamin D-deficient Pakistani women ( 4-fold ) , and that 10 microg increased S-25OHD concentrations 2-fold and 20 microg 3-fold in Pakistani men . S-25OHD concentrations increased at 6 months and were stable thereafter . Baseline S-25OHD concentrations tended to be lower in girls and women than in men ; females achieved about 46 nmol/l and men 55 nmol/l after supplementation . Serum intact parathyroid hormone concentrations decreased at 6 months , but there was no significant effect of the intervention on bone turnover markers and dual-energy X-ray absorptiometry measurements of the whole body and lumbar spine",
"Context : Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D ( 25(OH)D ) response . Objective : We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol . Design : Within-r and omization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy . Setting : Hospital antenatal clinics . Participants : A total of 829 pregnant women ( 422 placebo , 407 cholecalciferol ) . At 14 and 34 weeks of gestation , maternal anthropometry , health , and lifestyle were assessed and 25(OH)D measured . Compliance was determined using pill counts at 19 and 34 weeks . Interventions : 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery . Main Outcome Measure : 25(OH)D at 34 weeks , measured in a single batch ( Diasorin Liaison ) . Results : 25(OH)D at 34 weeks of gestation was higher in the women r and omized to vitamin D ( mean [ SD ] , 67.7 [ 21.3 ] nmol/L ) compared with placebo ( 43.1 [ 22.5 ] nmol/L ; P cholecalciferol , higher pregnancy weight gain from 14 to 34 weeks of gestation ( kg ) ( β = −0.81 [ 95 % confidence interval −1.39 , −0.22 ] ) , lower compliance with study medication ( % ) ( β = −0.28 [ −0.072 , −0.48 ] ) , lower early pregnancy 25(OH)D ( nmol/L ) ( β = 0.28 [ 0.16 , 0.40 ] ) , and delivery in the winter vs the summer ( β = −10.5 [ −6.4 , −14.6 ] ) were independently associated with lower 25(OH)D at 34 weeks of gestation . Conclusions : Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol . Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy",
"Background and Objective : The purpose of the present study is to explore the assessment if the transdermal delivery of vitamin D is feasible . Methods : In 50 female Medical students , this study was conducted . Age , weight and height was taken , a detailed history and clinical examination was performed . Blood was drawn for 25 Hydroxy Vitamin D3 ( 25OHD ) level . Two women had > 30 ng/mL of 25OHD and was excluded from the study . The participants were divided into two groups of 24 in each arm . All participants equivocally agreed not to change their dietary habits and life style till the study was over . The study group of women were asked to apply ; Top-D ( Aloe Vera based- Vitamin D3 ) ( Patency Pending ) was developed at King Fahd Hospital of the University , AlKhobar with each gram of the Top-D cream delivering 5000 IU of vitamin D3 . The second group used 1 gram of Aloe vera gel . The participants had no knowledge to which group they belong . A second blood sample was taken at the end of 3 months and the data was analyzed . Results : The data of 48 women was available for analysis . The average age was 22.58 ± 1.95 years . The mean pre-treatment 25OHD in the study group was 12.05 ng/Ml ± 6.54 and post-treatment was 37.95 ng/mL ± 6.43 ( P=0.001 , CI group pre-treatment 25OHD was 11.4 ng/mL ± 3.97 and post-treatment was 10.58ng/mL ± 3.03 . Conclusions : This r and omized control study shows that vitamin D3 can safely be delivered through the dermal route . This route could be exploited in treating vitamin D deficiency",
"Background Symptomatic vitamin D deficiency is associated with slowed growth in children . It is unknown whether vitamin D repletion in children with asymptomatic serum vitamin D deficiency can restore normal growth . Objective We tested the impact of vitamin D-supplementation on serum concentrations of 25-hydroxyvitamin D [ 25(OH)D ] and short-term growth in Mongol children , with very low serum vitamin D levels in winter . Design We conducted two r and omized , double-blind , placebo-controlled trials in urban school age children without clinical signs of rickets . The Supplementation Study was a 6-month intervention with an 800 IU vitamin D3 supplement daily , compared with placebo , in 113 children aged 12–15 years . A second study , the Fortification Study , was a 7-week intervention with 710 ml of whole milk fortified with 300 IU vitamin D3 daily , compared with unfortified milk , in 235 children aged 9–11 years . Results At winter baseline , children had low vitamin D levels , with a mean ( ±SD ) serum 25-hydroxyvitamin D [ 25(OH)D ] concentration of 7.3 ( ±3.9 ) ng/ml in the Supplementation Study and 7.5 ( ±3.8 ) ng/ml in the Fortification Study . The serum levels increased in both vitamin D groups — by 19.8 ( ±5.1 ) ng/ml in the Supplementation Study , and 19.7 ( ±6.1 ) ng/ml in the Fortification Study . Multivariable analysis showed a 0.9 ( ±0.3 SE ) cm greater increase in height in the vitamin-D treated children , compared to placebo treated children , in the 6-month Supplementation Study ( p = 0.003 ) . Although the children in the 7-week Fortification Study intervention arm grew 0.2 ( ±0.1 ) cm more , on average , than placebo children this difference was not statistically significant ( p = 0.2 ) . There were no significant effects of vitamin D supplements on differences in changes in weight or body mass index in either trial . For the Fortification Study , girls gained more weight than boys while taking vitamin D 3 ( p-value for interaction = 0.03 ) , but sex was not an effect modifier of the relationship between vitamin D3 and change in either height or BMI in either trial . Conclusions Correcting vitamin D deficiency in children with very low serum vitamin D levels using 800 IU of vitamin D3 daily for six months increased growth , at least in the short-term , whereas , in a shorter trial of 300 IU of D fortified milk daily for 7 weeks did not",
"Summary The effects of higher than recommended vitamin D doses on bone mineral density ( BMD ) and quality are not known . In this study , higher intakes , in postmenopausal women undergoing weight control over 1 year , had no effect on areal or volumetric BMD but prevented the deterioration in cortical bone geometry . Introduction Studies examining how bone responds to a st and ard dose of vitamin D supplementation have been inconsistent . In addition , the effects of higher doses on BMD and quality are not known . Postmenopausal women undergoing weight control to improve health outcomes are particularly at risk for bone loss and might benefit from supplemental vitamin D intake above the recommended allowance . Methods This 1-year-long , r and omized , double-blind controlled study addresses whether vitamin D supplementation , in healthy overweight/obese older women , affects BMD and bone structural parameters . In addition , bone turnover and serum total , free , and bioavailable 25-hydroxyvitamin D ( 25OHD ) responses to one of three daily levels of vitamin D3 ( 600 , 2000 , 4000 IU ) with 1.2 Ca g/day during weight control were examined . Results Fifty-eight women ( age , 58 ± 6 years ; body mass index , 30.2 ± 3.8 kg/m2 , serum 25OHD , 27.3 ± 4.4 ng/mL ) were r and omized to treatment . After 1 year , serum 25OHD concentrations increased to 26.5 ± 4.4 , 35.9 ± 4.5 , and 41.5 ± 6.9 ng/mL , in groups 600 , 2000 , and 4000 IU , respectively , and differed between groups ( p ± 4.1 % ) . Cortical ( Ct ) thickness of the tibia changed by −1.5 ± 5.1 % , + 0.6 ± 3.2 % , and + 2.0 ± 4.5 % in groups 600 , 2000 , and 4000 IU , respectively , and each group was significantly different from each other ( p decline in Ct thickness was prevented with higher vitamin D3 supplementation , but there were no other significant changes due to treatment over 1 year . Whether these findings translate to changes in biomechanical properties leading to reduced fracture risk should be addressed in future studies",
"Summary Daily dosing with vitamin D often fails to achieve optimal outcomes , and it is uncertain what the target level of 25-hydroxyvitamin D should be . This study found that large loading doses of vitamin D3 rapidly and safely normalize 25OHD levels , and that monthly dosing is similarly effective after 3–5 months . With baseline 25OHD > 50 nmol/L , vitamin D supplementation does not reduce PTH levels . Introduction There is concern that vitamin D supplementation doses are frequently inadequate , and that compliance with daily medication is likely to be suboptimal . Methods This r and omized double-blind trial compares responses to three high-dose vitamin D3 regimens and estimates optimal 25-hydroxyvitamin D ( 25OHD ) levels , from changes in parathyroid hormone ( PTH ) , and procollagen type I amino-terminal propeptide ( P1NP ) in relation to baseline 25OHD . Sixty-three elderly participants were r and omized to three regimens of vitamin D supplementation : a 500,000-IU loading dose ; the loading dose plus 50,000 IU/month ; or 50,000 IU/month . Results The Loading and Loading + Monthly groups showed increases in 25OHD of 58 ± 28 nmol/L from baseline to 1 month . Thereafter , levels gradually declined to plateaus of 69 ± 5 nmol/L and 91 ± 4 nmol/l , respectively . In the Monthly group , 25OHD reached a plateau of ~80 ± 20 nmol/L at 3–5 months . There were no changes in serum calcium concentrations . PTH and P1NP were only suppressed by vitamin D treatment in those with baseline 25OHD levels of vitamin D3 rapidly and safely normalize 25OHD levels in the frail elderly . Monthly dosing is similarly effective and safe , but takes 3–5 months for plateau 25OHD levels to be reached",
"In this double blind , unicentre , r and omized , placebo controlled study , we evaluated the changes in 25-hydroxyvitamin D ( 25(OH)D ) serum levels in 150 young Belgian adults ( 18–30 years ) , monthly supplemented with 50,000 IU of vitamin D ( VTD ) or placebo for 6 months , from November 2010 to May 2011 . At T0 , 30 % of the population presented 25(OH)D serum levels below 20 ng/mL. In the VTD-treated group , mean serum levels increased from 21.2 ± 8.2 to 30.6 ± 8.8 ng/mL ( P no changes in serum levels were , however , observed in 10 % of the treated group . In the placebo group , mean 25(OH)D serum levels decreased from 22.8 ± 8.5 to 14.0 ± 6.9 ng/mL at T3mo ( P . No difference between serum calcium levels was observed between the groups throughout the study . In conclusion , monthly supplementation with 50,000 UI of VTD in winter can warrant serum 25(OH)D levels above 20 ng/mL in 96.2 % of those healthy young adults without inducing unacceptably high 25(OH)D concentration . This supplementation is safe and may be proposed without 25(OH)D testing",
"Vitamin D is hydroxylated in the liver and kidneys to its active form , which can bind to the vitamin D receptor ( VDR ) . The VDR is present in a wide variety of different cells types and tissues and acts as a transcription factor . Although activation of the VDR is estimated to regulate expression of up to 5 % of the human genome , our study is the first analysing gene expression after supplementation in more than 10 subjects . Subjects of a r and omized controlled trial ( RCT ) received either vitamin D3 ( n=47 ) in a weekly dose of 20,000 IU or placebo ( n=47 ) for a period of three to five years . For this study , blood sample s for preparation of RNA were drawn from the subjects and mRNA gene expression in blood was determined using microarray analysis . The two study groups were similar regarding gender , age , BMI and duration of supplementation , whereas the mean serum 25-hydroxyvitamin D ( 25(OH)D ) level as expected was significantly higher in the vitamin D group ( 119 versus 63nmol/L ) . When analysing all subjects , nearly no significant differences in gene expression between the two groups were found . However , when analysing men and women separately , significant effects on gene expression were observed for women . Furthermore , when only including subjects with the highest and lowest serum 25(OH)D levels , additional vitamin D regulated genes were disclosed . Thus , a total of 99 genes ( p≤0.05 , log2 fold change ≥|0.2| ) were found to be regulated , of which 72 have not been published before as influenced by vitamin D. These genes were particularly involved in the interleukin signaling pathway , oxidative stress response , apoptosis signaling pathway and gonadotropin releasing hormone receptor pathway . Thus , our results open the possibility for many future studies",
"Background Bariatric patients often suffer from vitamin D deficiency ( VDD ) , and both , morbid obesity and VDD , are related to non-alcoholic fatty liver disease . However , limited data are available regarding best strategies for treating VDD , particularly , in bariatric patients undergoing omega-loop gastric bypass ( OLGB ) . Therefore , we examined the efficacy and safety of a forced vitamin D dosing regimen and intervention effects in liver fibrotic patients . Methods In this double-blind , r and omized , placebo-controlled trial , 50 vitamin D-deficient patients undergoing OLGB were r and omly assigned to receive , in the first month postoperatively , oral vitamin D3 ( ≤3 doses of 100,000 IU ; intervention group ) or placebo as loading dose ( control group ) with subsequent maintenance dose ( 3420 IU/day ) in both groups until 6-month visit . Results Compared with control group , higher increase of 25(OH)D ( 67.9 ( 21.1 ) vs. 55.7 nmol/L ( 21.1 ) ; p = 0.049 ) with lower prevalence of secondary hyperparathyroidism ( 10 vs. 24 % ; p = 0.045 ) was observed in intervention group . No ( serious ) adverse events related to study medication were found . The loading dose regimen was more effective in increasing 25(OH)D in patients with significant liver fibrosis while this was not the case for conventional supplementation ( placebo with maintenance dose ) ( 71.5 ( 20.5 ) vs. 22.5 nmol/L ( 13.8 ) ; p = 0.022 ; n = 14 ) . Conclusions Our findings indicate that a high vitamin D3 loading dose , in the first month postoperatively , with subsequent maintenance dose is effective and safe in achieving higher vitamin D concentrations in OLGB patients . Unexpectedly , it is more effective in patients with significant liver fibrosis which is of potentially high clinical relevance and requires further investigation",
"OBJECTIVE The objective was to assess the amount of vitamin D3 stored in adipose tissue after long-term supplementation with high dose vitamin D3 . DESIGN A cross-sectional study on 29 subjects with impaired glucose tolerance who had participated in a r and omized controlled trial with vitamin D3 20 000 IU ( 500 μg ) per week vs placebo for 3 - 5 years . METHODS Abdominal subcutaneous fat tissue was obtained by needle biopsy for the measurements of vitamin D3 and 25-hydroxyvitamin D3 ( 25(OH)D3 ) . Body fat was measured with dual-energy X-ray absorptiometry , and serum 25(OH)D3 level was quantified . RESULTS In the subjects given vitamin D3 , the median concentrations of serum 25(OH)D3 , fat vitamin D3 , and fat 25(OH)D3 were 99 nmol/l , 209 ng/g , and 3.8 ng/g , respectively ; and correspondingly in the placebo group 62 nmol/l , 32 ng/g , and 2.5 ng/g . If assuming an equal amount of vitamin D3 stored in all adipose tissue in the body , the median body store was 6.6 mg vitamin D3 and 0.12 mg 25(OH)D3 in those given vitamin D3 . CONCLUSIONS Subcutaneous adipose tissue may store large amounts of vitamin D3 . The clinical importance of this storage needs to be determined",
"Background Vitamin D insufficiency is highly prevalent . Most of the studies concerning vitamin D status were generated from countries situated at temperate latitudes . It is less clear what the extent of vitamin D insufficiency is in countries situated in the tropics and how geographical regions within country would affect vitamin D status . In the present study , we investigated vitamin D status in Thais according to geographical regions and other risk factors . Methods Subjects consisted of 2,641 adults , aged 15 - 98 years , r and omly selected from the Thai 4th National Health Examination Survey ( 2008 - 9 ) cohort . Serum 25 hydroxyvitamin D were measured by liquid chromatography/t and em mass spectrometry . Data were expressed as mean ± SE . Results Subjects residing in Bangkok , the capital city of Thail and , had lower 25(OH)D levels than other parts of the country ( Bangkok , central , northern , northeastern and southern regions : 64.8 ± 0.7 , 79.5 ± 1.1 , 81.7 ± 1.2 , 82.2 ± 0.8 and 78.3 ± 1.3 nmol/L , respectively ; p lower circulating 25(OH)D ( central , 77.0 ± 20.9 nmol/L vs 85.0 ± 22.1 nmol/L , p the prevalence of vitamin D insufficiency was 64.6 % , 46.7 % , and 33.5 % in Bangkok , municipal areas except Bangkok , and outside municipal area in other parts of the country , respectively . In addition , the prevalence of vitamin D insufficiency according to geographical regions was 43.1 % , 39.1 % , 34.2 % and 43.8 % in the central , north , northeast and south , respectively . After controlling for covariates in multiple linear regression analysis , the results showed that low serum 25(OH)D levels were associated with being female , younger age , living in urban and Bangkok . Conclusions Vitamin D insufficiency is common and varies across geographical regions in Thail and",
"Objective This study sought to investigate the effects of vitamin D supplementation and aquatic exercise on pulmonary function in postmenopausal women . Material s and methods This prospect i ve and controlled study included 104 women ( 62 ± 6.5 years ) divided into three groups : a control group lacking vitamin D and calcium supplementation which remained sedentary ( CG ; n = 17 ) ; a control group receiving vitamin D and calcium supplementation which remained sedentary ( CDG , n = 33 ) ; and a group that completed aquatic exercises three times a week and received vitamin D and calcium supplementation ( DTG , n = 54 ) . Data before and after 6 months of the study were analyzed , including serum 25-hydroxyvitamin D ( 25(OH)D ) and calcium concentrations , peak expiratory flow ( PEF ) , forced vital capacity ( FVC ) , and cirtometry . Results We observed significant increases in 25(OH)D concentrations in CDG ( 52.9 ± 2.4 to 69.1 ± 2.2 ; nmol/L ; p 55.5 ± 3 to 71.5 ± 3 nmol/L ; p increased by 7 ± 2 % ( p = 0.0080 ) in CDG group and 11 ± 2 % ( p whereas FVC increased by 7 ± 2 % ( p = 0.0016 ) in the CDG group and 10 ± 2 % ( p The increment value of cirtometry in DTG group ( + 43 ± 3 % ) were significantly ( p that vitamin D supplementation improves pulmonary function parameters in postmenopausal women",
"Objective : Improvement of vitamin D and K status of about 60 -y-old postmenopausal Dutch women . Design : In a r and omized study postmenopausal women with normal ( T-score > −1 ; n=96 ) and low ( T-score≤−1 ; n=45 ) bone mineral density ( BMD ) of the lumbar spine , were supplemented with 350–400 IU vitamin D3 , 80 μg vitamins K1 , vitamins K1+D3 , or placebo for 1 y. Serum 25-hydroxyvitamin D [ 25(OH)D ] and percentage carboxylated osteocalcin ( % carbOC ) were measured at baseline and after 3 , 6 and 12 months . Results : Baseline % carbOC of the entire study population was positively correlated with BMD of the lumbar spine and femoral neck . Correspondingly , women with low BMD had lower % carbOC at baseline than women with normal BMD but this difference disappeared after 1 y of supplementation with vitamin K1 ( ( mean±s.d . ) 68±11 % ( 95 % CI , 64.5–71.2 % ) vs 72±6 % ( 95 % CI , 70.1–72.9 % ) , respectively ) . One year of supplementation with vitamin D3 showed maximum increases in 25(OH)D of 33±29 % ( 95 % CI , 24.8–41.8 % ) and 68±58 % ( 95 % CI , 50.1–84.6 % ) in women with normal and low BMD , respectively . During winter , however , a 29 % decline in maximum 25(OH)D levels was not prevented in women with low BMD . Conclusion : Daily supplementation of Dutch postmenopausal women with > 400 IU vitamin D3 is indicated to prevent a winter decline in 25(OH)D and to control serum parathyroid hormone levels . Daily supplementation with 80 μg vitamin K1 seems to be necessary to reach premenopausal % carbOC levels . A stimulatory effect of calcium and /or vitamin D on % carbOC can not be excluded . European Journal of Clinical Nutrition ( 2000 ) 54 , 626–631",
"Background Vitamin D deficiency has been associated with multiple diseases , but the causal relevance and underlying processes are not fully understood . Elucidating the mechanisms of action of drug treatments in humans is challenging , but application of functional genomic approaches in r and omized trials may afford an opportunity to systematic ally assess molecular responses . Methods In the Biochemical Efficacy and Safety Trial of Vitamin D ( BEST-D ) , a double-blind , placebo-controlled , dose-finding , r and omized clinical trial , 305 community-dwelling individuals aged over 65 years were r and omly allocated to treatment with vitamin D3 4000 IU , 2000 IU or placebo daily for 12 months . Genome-wide genotypes at baseline , and transcriptome and plasma levels of cytokines ( IFN-γ , IL-10 , IL-8 , IL-6 and TNF-α ) at baseline and after 12 months , were measured . The trial had > 90 % power to detect 1.2-fold changes in gene expression . Findings Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D ( 25[OH]D , 4000 IU regimen ) , but had no significant effect on whole-blood gene expression ( FDR on plasma levels of cytokines compared with placebo . In pre-specified analysis , rs7041 ( intron variant , GC ) had a significant effect on circulating levels of 25(OH)D in the low dose , but not in the placebo or high dose vitamin D regimen . A gene expression quantitative trait locus analysis ( eQTL ) demonstrated evidence of 31,568 cis-eQTLs ( unique SNP-probe pairs ) among individuals at baseline and 34,254 after supplementation for 12 months ( any dose ) . No significant associations involving vitamin D supplementation response eQTLs were found . Interpretation We performed a comprehensive functional genomics and molecular analysis of vitamin D supplementation in a r and omized , placebo-controlled trial . Although this study was limited to mostly Caucasian individuals aged over 65 years , the results differ from many previous studies and do not support a strong effect of vitamin D on long-term transcriptomic changes in blood or on plasma cytokine levels . The trial demonstrates the feasibility of applying functional genomic and genetic approaches in r and omized trials to assess molecular and individual level responses . Key Result Supplementation with high-dose vitamin D in older people for 12 months in a r and omized , placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of selected cytokines . Trial Registration S RCT N registry ( Number 07034656 ) and the European Clinical Trials Data base ( EudraCT Number 2011 - 005763 - 24 )",
"OBJECTIVE To assess the prevalence of osteoporosis in healthy ambulatory postmenopausal Indian women as measured by dual-energy x-ray absorptiometry and to study the dietary calcium intake and vitamin D status and their influence on bone mineral density ( BMD ) . METHODS We conducted a community-based cross-sectional study in a semiurban region . A r and omized cluster sampling technique was used . The study cohort consisted of 150 ambulatory postmenopausal women ( > or = 50 years old ) . Dual-energy x-ray absorptiometry for BMD was performed at the lumbar spine and femoral neck . Dietary calcium intake and biochemical variables were assessed . RESULTS The prevalence of osteoporosis was 48 % at the lumbar spine , 16.7 % at the femoral neck , and 50 % at any site . The mean dietary calcium intake was much lower than the recommended intake for this age-group . There was a significant positive correlation between body mass index and BMD at the lumbar spine and the femoral neck ( r = 0.4 ; P = .0001 ) . BMD at the femoral neck was significantly less ( mean , 0.657 versus 0.694 g/cm(2 ) ) in the vitamin D-insufficient study subjects in comparison with the vitamin D-sufficient women ( P = .03 ) . CONCLUSION The high prevalence of osteoporosis and vitamin D insufficiency in this semiurban group of postmenopausal women in India is a major health concern . Measures such as adequate calcium intake and vitamin D supplementation in women of this age-group may be beneficial",
"Scientific data pertaining to vitamin D supplementation during lactation are scarce . The daily recommended intake for vitamin D during lactation has been arbitrarily set at 400 IU/d ( 10 microg/d ) . This recommendation is irrelevant with respect to maintaining the nutritional vitamin D status of mothers and nursing infants , especially among darkly pigmented individuals . Our objective was to examine the effect of high-dose maternal vitamin D2 supplementation on the nutritional vitamin D status of mothers and nursing infants . Fully lactating women ( n = 18 ) were enrolled at 1 mo after birth to 1 of 2 treatment arms , ie , 1600 IU vitamin D2 and 400 IU vitamin D3 ( prenatal vitamin ) or 3600 IU vitamin D2 and 400 IU vitamin D3 , for a 3-mo study period . High-dose ( 1600 or 3600 IU/d ) vitamin D2 supplementation for a period of 3 mo safely increased circulating 25-hydroxyvitamin D [ 25(OH)D ] concentrations for both groups . The antirachitic activity of milk from mothers receiving 2000 IU/d vitamin D increased by 34.2 IU/L , on average , whereas the activity in the 4000 IU/d group increased by 94.2 IU/L. Nursing infant circulating 25(OH)D2 concentrations reflected maternal intake and the amount contained in the milk . With limited sun exposure , an intake of 400 IU/d vitamin D would not sustain circulating 25(OH)D concentrations and thus would supply only limited amounts of vitamin D to nursing infants in breast milk . A maternal intake of 2000 IU/d vitamin D would elevate circulating 25(OH)D concentrations for both mothers and nursing infants , albeit with limited capacity , especially with respect to nursing infants . A maternal intake of 4000 IU/d could achieve substantial progress toward improving both maternal and neonatal nutritional vitamin D status",
"Background : The Institute of Medicine ( IOM ) dietary guidelines for vitamin D are based on limited pediatric data . Our objective was to estimate the dietary vitamin D requirements for maintaining serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations at the various IOM-considered thresholds of vitamin D status ( 12 , 16 , and 20 ng/ml ) during fall and winter in children . Methods : Ninety-six healthy 8- to 14-y-old Pittsburgh-area black and white children enrolled in a r and omized , placebo-controlled trial of vitamin D3 1,000 IU daily for 6 mo with baseline and 2-mo follow-up assessment s completed during October through April were studied . Vitamin D intake from diet and study supplement adjusted for adherence and serum 25(OH)D were measured . Results : The vitamin D intakes needed to maintain serum 25(OH)D concentrations at 12 , 16 , and 20 ng/ml in 90 % of the children were 581 , 1,062 , and 1543 IU/day , respectively . The estimated vitamin D intakes needed to maintain serum 25(OH)D concentrations at 20 ng/ml in 97.5 % of the children was 2,098 IU/day . Conclusion : Our data suggest that the current vitamin D recommended dietary allowance ( RDA ) ( 600 IU/day ) is insufficient to cover the skeletal health needs of at least 50 % of black and white children",
"Background The high-density lipoprotein cholesterol ( HDL-C ) level has been shown to have a significant role in the prevention of cardiovascular diseases and atherosclerosis . Low vitamin D levels have been shown to be correlated with dyslipidemia , but limited data exist on indigenous children . Objectives We aim ed to investigate the effect of vitamin D supplementation on HDL-C levels in school-aged Iranian children . Methods In this prospect i ve controlled clinical trial , 47 healthy children ( 23 boys ) aged 10 - 14 years , students of Birj and ( Iran ) elementary schools , were selected and r and omly divided into two groups . The study group received a vitamin D supplement ( 1000 mg capsule ) daily for one month , and placebo tablets were prescribed to the controls . Before and after the treatment course , the serum HDL-C and 25-hydroxy vitamin D levels of both groups were measured . The data were analyzed by SPSS , ver . 16 , and Chi-square tests , Fisher ’s exact test , paired- sample t-tests , and Pearson ’s correlation were used , wherever appropriate . The significance level was set at P Forty children completed the study ; their mean age was 11.5 ± 1.175 years . The mean serum levels of both HDL-C and vitamin D showed a significant rise following the treatment in the study group ( P = 0.007 and P the mean serum levels of HDL-C and vitamin D between the two groups after the intervention ( P = 0.11 and P = 0.20 , respectively ) . Conclusions Vitamin D supplements seem to have a positive impact on serum HDL-C levels and may be effective in reducing the risk of cardiovascular diseases in the long term",
"Background . Vitamin D deficiency ( VDD ) is a public health concern in adults worldwide . This study aims to explore the extent of VDD and its associated factors among adults in the United Arab Emirates ( UAE ) . Subjects and Methods . Quantitative , cross-sectional research was used to assess VDD and its associated factors in 216 adults recruited from r and omly selected community-based healthcare setting s over a six-month period . Recent values of vitamin D and glycated hemoglobin ( HbA1c ) were abstract ed from medical records , followed by interviews with participants to obtain information on factors related to VDD and other covariates and to measure their heights and weights . Results . A total of 74 % of participants demonstrated VDD ( vitamin D serum level ≤ 30 nmol/L ) . Emirati participants had higher odds of having VDD compared to non-Emiratis ( OR : 2.95 ; 95 % CI : 1.58–5.52 ) , with also significantly increased odds of the condition appearing in older , less educated , and employed adults . Diabetes type 2 ( HbA1c ≥ 6.5 % ) , depression , and obesity were significantly associated with an increased likelihood of VDD after accounting for other covariates . Conclusion . VDD is a significant problem for UAE adults and requires attention by public health policy makers . Diabetes , obesity , and depression need to be considered when screening for vitamin",
"OBJECTIVE Improve vitamin D status in lactating women and their recipient infants , and measure breast milk calcium concentration [ Ca ] as a function of vitamin D regimen . DESIGN / METHODS Fully breastfeeding mothers were r and omized at 1 month postpartum to 2000 ( n = 12 ) or 4000 ( n = 13 ) IU/day vitamin D for 3 months to achieve optimal vitamin D status [ serum 25(OH)D > or = 32 ng/mL ( 80 nmol/L ) ] . Breast milk [ Ca ] , maternal and infant serum 25(OH)D and serum Ca , and maternal urinary Ca/Cr ratio were measured monthly . RESULTS Mothers were similar between groups for age , race , gestation , and birth weight . 25(OH)D increased from 1 to 4 months in both groups ( mean + /- SD ) : + 11.5 + /- 2.3 ng/mL for group 2000 ( p = 0.002 ) and + 14.4 + /- 3.0 ng/mL for group 4000 ( p = 0.0008 ) . The 4000 IU/day regimen was more effective in raising both maternal and infant serum levels and breast milk antirachitic activity than the 2000 IU/day regimen . Breast milk [ Ca ] fell with continued lactation through 4 months in the 2000 and 4000 IU groups . Decline in breast milk [ Ca ] was not associated with vitamin D dose ( p = 0.73 ) or maternal 25(OH)D ( p = 0.94 ) . No mother or infant experienced vitamin D-related adverse events , and all laboratory parameters remained in the normal range . CONCLUSION High-dose vitamin D was effective in increasing 25(OH)D levels in fully breastfeeding mothers to optimal levels without evidence of toxicity . Breast milk [ Ca ] and its decline in both groups during 1 to 4 months were independent of maternal vitamin D status and regimen . Both the mother and her infant attained improved vitamin D status and maintained normal [ Ca ]",
"Summary There is a huge prevalence of hypovitaminosis D in the Indian population . We studied the efficacy and safety of oral vitamin D supplementation in apparently healthy adult women . Monthly cholecalciferol given orally , 60,000 IU/month during summers and 120,000 IU/month during winters , safely increases 25-hydroxyvitamin D ( 25(OH)D ) levels to near normal levels . Introduction There is a huge burden of hypovitaminosis D in the Indian population . The current recommendation for vitamin D supplementation is not supported by sufficient evidence . Methods Study subjects included 100 healthy adult women of reproductive age group from hospital staff . They were r and omized into group A ( control ) and group B ( supplement ) by simple r and omization . Group B received 60,000 IU of cholecalciferol/month administered orally for 3 months , and then group A received 60,000 IU and group B 120,000 IU/month for 6 months . Results Mean baseline 25(OH)D level was 4.5 ± 3.1 ng/ml and parathyroid hormone level was 50 ± 25 pg/ml . In group B , 25(OH)D levels increased from 4.8 ± 3.5 to 31.6 ± 15.5 ng/ml ( P IU/month ) , mean 25(OH)D level had increased to 22.3 ± 12.4 ng/ml ( P ( 120,000 IU/month ) , 25(OH)D levels were maintained at 30.7 ± 12.8 ng/ml at 9 months ( winter ) . Conclusion Our data show that monthly administration of 60,000 IU cholecalciferol in healthy subjects with hypovitaminosis D may suffice in summer months , but higher doses may be more appropriate during winter months",
"Background : Dark skin and low exposure to sunlight increase the risk of vitamin D insufficiency in children . Objective : The aim of the study was to evaluate the amount of vitamin D needed to ascertain that most children > 4 y of age attain sufficient serum 25-hydroxyvitamin D [ S-25(OH)D ; i.e. , ≥50 nmol/L ] during winter regardless of latitude and skin color . Design : In a longitudinal , double-blind , r and omized , food-based intervention study , 5- to 7-y-old children from northern ( 63 ° N ) and southern ( 55 ° N ) Sweden with fair ( n = 108 ) and dark ( n = 98 ) skin were included . Children , stratified by skin color by using Fitzpatrick 's definition , were r and omly assigned to receive milk-based vitamin D3 supplements that provided 2 ( placebo ) , 10 , or 25 μg/d during 3 winter months . Results : Mean daily vitamin D intake increased from 6 to 17 μg and 26 μg in the intervention groups supplemented with 10 and 25 μg , respectively . In the intention-to-treat analysis , 90.2 % ( 95 % CI : 81.1 % , 99.3 % ) of fair-skinned children r and omly assigned to supplementation of 10 μg/d attained sufficient concentrations , whereas 25 μg/d was needed in dark-skinned children to reach sufficiency in 95.1 % ( 95 % CI : 88.5 % , 100 % ) . In children adherent to the study product , 97 % ( 95 % CI : 91.3 % , 100 % ) and 87.9 % ( 95 % CI : 76.8 % , 99 % ) of fair- and dark-skinned children , respectively , achieved sufficient concentrations if supplemented with 10 μg/d . By using 95 % prediction intervals for 30 and 50 nmol S-25(OH)D/L , intakes of 6 and 20 μg/d are required in fair-skinned children , whereas 14 and 28 μg/d are required in children with dark skin . Conclusion : Children with fair and dark skin require vitamin D intakes of 20 and 28 μg/d , respectively , to maintain S-25(OH)D ≥50 nmol/L , whereas intakes of 6 and 14 μg/d , respectively , are required to maintain concentrations ≥30 nmol/L during winter . This trial was registered at clinical trials.gov as NCT01741324",
"Importance Evidence suggests that low vitamin D status may increase the risk of cancer . Objective To determine if dietary supplementation with vitamin D3 and calcium reduces the risk of cancer among older women . Design , Setting , and Participants A 4-year , double-blind , placebo-controlled , population -based r and omized clinical trial in 31 rural counties ( June 24 , 2009 , to August 26 , 2015—the final date of follow-up ) . A total of 2303 healthy postmenopausal women 55 years or older were r and omized , 1156 to the treatment group and 1147 to the placebo group . Duration of treatment was 4 years . Interventions The treatment group ( vitamin D3 + calcium group ) received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium ; the placebo group received identical placebos . Main Outcomes and Measures The primary outcome was the incidence of all-type cancer ( excluding nonmelanoma skin cancers ) , which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling . Results Among 2303 r and omized women ( mean age , 65.2 years [ SD , 7.0 ] ; mean baseline serum 25-hydroxyvitamin D level , 32.8 ng/mL [ SD , 10.5 ] ) , 2064 ( 90 % ) completed the study . At year 1 , serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D3 + calcium group and 31.6 ng/mL in the placebo group . A new diagnosis of cancer was confirmed in 109 participants , 45 ( 3.89 % ) in the vitamin D3 + calcium group and 64 ( 5.58 % ) in the placebo group ( difference , 1.69 % [ 95 % CI , −0.06 % to 3.46 % ] ; P = .06 ) . Kaplan-Meier incidence over 4 years was 0.042 ( 95 % CI , 0.032 to 0.056 ) in the vitamin D3 + calcium group and 0.060 ( 95 % CI , 0.048 to 0.076 ) in the placebo group ; P = .06 . In unadjusted Cox proportional hazards regression , the hazard ratio was 0.70 ( 95 % CI , 0.47 to 1.02 ) . Adverse events potentially related to the study included renal calculi ( 16 participants in the vitamin D3 + calcium group and 10 in the placebo group ) , and elevated serum calcium levels ( 6 in the vitamin D3 + calcium group and 2 in the placebo group ) . Conclusions and Relevance Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL , supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years . Further research is necessary to assess the possible role of vitamin D in cancer prevention . Trial Registration clinical trials.gov Identifier :",
"The purpose of the study was to determine the effect of vitamin D supplementation on bone turnover and bone loss in elderly women . Three hundred forty-eight women , ages 70 yr and older , were r and omized to receive 400 IU vitamin D3 per day ( n = 177 ) or placebo ( n = 171 ) , double-blind , for a period of 2 yr . Main outcome measures were bone mineral density of both hips ( femoral neck and trochanter ) and the distal radius , as well as biochemical markers of bone turnover . The effect of vitamin D supplementation was expressed as the difference in mean ( percentage ) change between the placebo group and the vitamin D group . The measurements were repeated in 283 women after 1 yr and in 248 women after 2 yr . Vitamin D supplementation significantly increased serum 25-hydroxyvitamin D ( 250HD ) ( + 35 nmol/L ) and 1,25-dehydroxyvitamin D [ 1,25-(OH)2D ] ( + 7.0 pmol/L ) levels and urinary calcium/creatinine ratios ( + 0.5 % ) and significantly decreased PTH(1 - 84 ) secretion ( -0.74 pmol/L ) after 1 yr . No effect was found for the parameters of bone turnover . The effect on the bone mineral density of the left femoral neck was + 1.8 % in the first yr , + 0.2 % in the second yr , and + 1.9 % during the whole period ( 95 % confidence interval 0.4 , 3.4 % ) . At the right femoral neck the effects were + 1.5 % , + 1.1 % , and + 2.6 % ( confidence interval 1.1 , 4.0 % ) , respectively . No effect was found at the femoral trochanter and the distal radius . Supplementation with 400 IU vitamin D3 daily in elderly women slightly decreases PTH secretion and increases bone mineral density at the femoral neck",
"Background / Objectives : Middle Eastern female immigrants are at an increased risk of vitamin D deficiency and their response to prescribed vitamin D dosages may not be adequate and affected by other factors . The objectives were to determine vitamin D deficiency and its determinants in Middle Eastern women living in Auckl and , New Zeal and ( Part-I ) , and to determine serum 25-hydroxyvitamin D ( serum-25(OH)D ) response to two prescribed vitamin D dosages ( Part-II ) in this population . Participants / Methods : Women aged ⩾20 ( n=43 ) participated in a cross-sectional pilot study during winter ( Part-I ) . In Part-II , women aged 20–50 years ( n=62 ) participated in a r and omised , double-blind placebo-controlled trial consuming monthly either 50 000 , 100 000 IU vitamin D3 or placebo for 6 months ( winter to summer ) . Results : All women in Part-I and 60 % women in Part-II had serum-25(OH)D was higher in prescribed vitamin D users than nonusers ( P=0.001 ) and in Iranians than Arab women ( P=0.001 ; Part-I ) . Mean ( s.d . ) serum-25(OH)D increased in all groups ( time effect , P achieved serum-25(OH)D⩾75 nmol/l with 50 000 and 100 000 IU/month , respectively . Predictors of 6-month change in serum-25(OH)D were dose ( B-coefficient±s.e . ; 14.1±2.4 , P ) , baseline serum-25(OH)D ( −0.6±0.1 , P and body fat percentage ( −0.7±0.3 , P=0.01 ) . Conclusions : Vitamin D deficiency/insufficiency is highly prevalent in this population . Monthly 100 000 IU vitamin D for 6 months is more effective than 50 000 IU in achieving serum-25(OH)D ⩾75 nmol/l ; however , a third of women still did not achieve these levels ",
"The purpose of this 6-month r and omized , placebo-controlled trial was to determine the effect of season-long ( September-March ) vitamin D supplementation on changes in vitamin D status , which is measured as 25(OH ) D , body composition , inflammation , and frequency of illness and injury . Forty-five male and female athletes were r and omized to 4,000 IU vitamin D ( n = 23 ) or placebo ( n = 22 ) . Bone turnover markers ( NTx and BSAP ) , 25(OH)D , and inflammatory cytokines ( TNF-alpha , IL-6 , and IL1-β ) were measured at baseline , midpoint , and endpoint . Body composition was assessed by DXA and injury and illness data were collected . All athletes had sufficient 25(OH)D ( > 32 ng/ml ) at baseline ( mean : 57 ng/ml ) . At midpoint and endpoint , 13 % and 16 % of the total sample had 25(OH)D respectively . 25(OH)D was not positively correlated with bone mineral density ( BMD ) in the total body , proximal dual femur , or lumbar spine . In men , total body ( p = .04 ) and trunk ( p = .04 ) mineral-free lean mass ( MFL ) were positively correlated with 25(OH)D. In women , right femoral neck BMD ( p = .02 ) was positively correlated with 25(OH)D. 25(OH)D did not correlate with changes in bone turnover markers or inflammatory cytokines . Illness ( n = 1 ) and injury ( n = 13 ) were not related to 25(OH)D ; however , 77 % of injuries coincided with decreases in 25(OH)D. Our data suggests that 4,000 IU vitamin D supplementation is an inexpensive intervention that effectively increased 25(OH)D , which was positively correlated to bone measures in the proximal dual femur and MFL . Future studies with larger sample sizes and improved supplement compliance are needed to exp and our underst and ing of the effects of vitamin D supplementation in athletes",
"Sarcopenia and osteoporosis represent a growing public health problem . We studied the potential benefit of whole-body vibration ( WBV ) training given a conventional or a high dose of daily vitamin D supplementation in improving strength , muscle mass , and bone density in postmenopausal women . In a 2 × 2 factorial- design trial , 113 institutionalized elderly females aged over 70 years ( mean age 79.6 years ) were r and omly assigned either to a WBV or a no-training group , receiving either a conventional dose ( 880 IU/day ) or a high dose ( 1600 IU/day ) of vitamin D(3 ) . The primary aim was to determine the effects of 6 months of WBV and /or vitamin D supplementation on isometric and dynamic strength , leg muscle mass , and hip bone mineral density ( BMD ) . Additionally , the increase in 25-hydroxyvitamin D [ 25(OH)D ] levels between conventional and high-dose supplementation was compared . After 6 months of treatment , dynamic muscle strength , hip BMD , and vitamin D serum levels improved significantly in all groups , whereas isometric strength and muscle mass did not change . When compared with no training , the WBV program did not result in additional improvements . When compared with 880 IU , a high dose of 1600 IU of vitamin D did result in higher serum vitamin D levels but did not result in additional improvements . In institutionalized women older than 70 years , the WBV training protocol tested is not more efficient in enhancing muscle mass , strength , and hip BMD compared with vitamin D supplementation . A higher dose of 1600 IU of vitamin D does not provide additional musculoskeletal benefit in this population compared with conventional doses",
"Vitamin D status is conventionally defined by the serum concentration of 25-hydroxyvitamin D. However , it has been proposed that the serum cholecalciferol concentration ( D3 ) also determines functional vitamin D sufficiency . The objective of this study was to describe the effect of weekly high-dose vitamin D3 supplementation on inter-dose serum D3 in pregnant women . We conducted a sub- study of a completed r and omized double-blind placebo-controlled trial of vitamin D3 ( 35,000 IU/week ) supplementation in late pregnancy ( AViDD trial ) in Dhaka , Bangladesh . This study included pregnant women enrolled at 26 - 29 weeks gestation who fully adhered to the prenatal supplement intervention for ≥8 consecutive weeks and for whom serum sample s were available for D3 analysis ( n=65 ) . Serum D3 was uniformly low at enrolment . Mean D3 increased and was maximal at 1 day after vitamin D dose administration ( 152.09nmol/L , SD 25.11nmol/L ) and remained significantly higher in VitD vs. Pl at 7 days ( 29.59nmol/L vs. 1.92nmol/L , p=0.007 ) . Daily average of the group mean D3 during the week following dosing was 66.97nmol/L in VitD versus 2.13nmol/L in Pl . In conclusion , serum D3 remained significantly elevated throughout the week following ≥8 consecutive weekly doses of 35,000 IU D3 in pregnant women . However , the clinical ly significant minimum threshold of serum D3 remains to be established",
"Aim : To compare the effect of two different doses ( 500 and 1000 IU/day ) of oral vitamin D3 ( cholecalciferol ) on serum 25-hydroxy vitamin D [ 25(OH)D ] levels in apparently healthy postmenopausal Indian women . Material s and Methods : Serum 25(OH)D , calcium with albumin , phosphorus , and alkaline phosphatase were measured in 92 apparently healthy postmenopausal women . The subjects were r and omly assigned to one of the three groups and received supplementation for 3 months each . Each group received 1000 mg calcium carbonate daily while groups B and C received 500 and 1000 IU of cholecalciferol in addition , respectively . The tests were repeated after 3 months . Results : At baseline , 83.7 % subjects had vitamin D deficiency ( ≤20 ng/mL ) . The difference in the percentage change in mean serum 25(OH)D levels from baseline in group A ( –30.5 ± 5.3 % ) , group B ( + 8.9 ± 19.7 % ) , and in group C ( + 97.8 ± 53.3 % ) was statistically significant ( P groups . Serum 25(OH)D level > 20 ng/mL was achieved in 4.7 % ( 1/21 ) , 16 % ( 4/25 ) , and 66.67 % ( 12/18 ) subjects in groups A , B , and C , respectively . No significant change was found in serum calcium , phosphorus , and alkaline phosphatase levels at 3 months in either of the groups from baseline . Conclusions : St and ard dose of cholecalciferol available in “ calcium tablets ” ( 250 IU per 500 mg calcium carbonate ) is not adequate for achieving optimum serum 25(OH)D levels in Indian postmenopausal women . Higher dose of vitamin D supplementation with 1000 IU/day ( 500 IU per 500 mg calcium carbonate ) daily is superior to the st and ard dose therapy . For achievement of optimum serum 25(OH)D levels ( > 30 ng/mL ) in Indian postmenopausal women , still higher doses of vitamin D are likely to be required",
"Objective : Vitamin D supplementation may be required for certain subgroups in the United States in whom status and intake are inadequate , but the impact of various doses , and whether calcium administration jointly or independently influences vitamin D metabolite levels , is unclear . Methods : In a pilot chemoprevention trial of biomarkers of risk for colorectal adenoma , we measured the impact of vitamin D supplementation and /or calcium supplementation on plasma vitamin D metabolite concentrations . Ninety-two adult men and women living in the southeastern United States were r and omized to 800 IU vitamin D3 , 2000 mg elemental calcium , both , or placebo daily for 6 months . We examined vitamin D status at baseline and postintervention and compared the change in plasma 25-hydroxyvitamin D ( 25(OH)D ) and 1,25(OH)2D levels by intervention group using general linear models . Results : Eighty-two percent of the study population had insufficient plasma 25(OH)D concentrations ( African American participants . Vitamin D supplements , with or without calcium supplementation , raised plasma 25(OH)D concentrations , on average , by 25 to 26 nmol/L. Half of the study participants were classified as having sufficient 25(OH)D status after 6 months of 800 IU of vitamin D3 daily . Calcium alone did not influence 25(OH)D concentrations . Conclusion : In this southeastern U.S. population , half of the study participants receiving 800 IU vitamin D3 daily had blood 25(OH)D concentrations of ≤75 nmol/L after a 6-month intervention period , supporting higher vitamin D dose requirements estimated by some groups . More research is needed to identify the optimal vitamin D dose to improve 25(OH)D status in various at-risk population",
"OBJECTIVES To determine whether relative vitamin D deficiency during the winter months contributes to age-related bone loss and whether rates of change in hard- and soft-tissue mass vary during the year . DESIGN Double-blind , placebo-controlled , 1-year trial in 249 women in which equal numbers of women were r and omized to either placebo or 400 IU of vitamin D daily . All women received 377 mg/d of supplemental calcium largely as calcium citrate malate . PATIENTS Healthy , ambulatory postmenopausal women with usual intakes of vitamin D of 100 IU/d . MEASUREMENTS Duplicate spine and whole-body scans were done by dual energy x-ray absorptiometry at 6-month intervals that were timed to periods when 25-hydroxyvitamin D levels were highest and lowest . Period 1 was June-July to December-January and period 2 was December-January to the next June-July . Serum parathyroid hormone and plasma 25-hydroxyvitamin D levels were measured during periods 1 and 2 . MAIN RESULTS In the placebo group , spinal bone mineral density increased in period 1 , decreased in period 2 , and sustained no net change . Women treated with vitamin D had a similar spinal increase in period 1 ( 1.46 % compared with 1.40 % in placebo ) , less loss in period 2 ( -0.54 % compared with -1.22 % , CI for the difference , 0.05 % to 1.31 % , P = 0.032 ) and a significant overall benefit ( 0.85 % compared with 0.15 % , CI for the difference , 0.03 % to 1.37 % , P = 0.04 ) . In period 2 , 25-hydroxyvitamin D levels were lower and parathyroid hormone levels were higher in the placebo than in the vitamin D group . Whole-body lean and fat tissue and bone mineral density varied during the year but did not change overall . CONCLUSIONS At latitude 42 degrees , healthy postmenopausal women with vitamin D intakes of 100 IU daily can significantly reduce late wintertime bone loss and improve net bone density of the spine over one year by increasing their intake of vitamin D to 500 IU daily . A long-term benefit of preventing vitamin D insufficiency in the winter seems likely although it remains to be shown . Observed changes in bone as well as in fat and lean tissue appear to be related to season",
"BACKGROUND AND OBJECTIVES Vitamin D3 ( cholecalciferol ) dose required to maintain sufficiency in non- Caucasian women with postmenopausal osteoporosis ( PMO ) inthe tropics has not been well studied . Some guidelines m and ate 800 - 1000 IU vitamin D/day but the Endocrine Society ( US ) advocates 1500 - 2000 IU/day to maintain 25-hydroxyvitamin-D ( 25(OH)D ) concentration at > 75 nmol/L. We aim ed to establish oral cholecalciferol dose required to maintain 25(OH)D concentration at > 75 nmol/L in PMO Chinese Malaysian women , postulating lower dose requirements amongst light-skinned subjects in the tropics . METHODS AND STUDY DESIGN 90 Chinese Malaysian PMO women in Kuala Lumpur , Malaysia ( 2 ° 30'N ) with baseline serum 25(OH)D levels > = 50 nmol/L were recruited . Prior vitamin D supplements were discontinued and subjects r and omized to oral cholecalciferol 25,000 IU/4-weekly ( Group-A ) or 50,000 IU/4-weekly ( Group- B ) for 16 weeks , administered under direct observation . Serum 25(OH)D , PTH , serum/urinary calcium were measured at baseline , 8 and 16 weeks . RESULTS Baseline characteristics , including osteoporosis severity , sun exposure ( ~3 hours/week ) , and serum 25(OH)D did not differ between treatment arms . After 16 weeks , 91 % of women sufficient at baseline , remained sufficient on 25,000 IU/4-weekly compared with 97 % on 50,000 IU/4-weekly with mean serum 25(OH)D 108.1±20.4 and 114.7±18.4 SD nmol/L respectively ( p=0.273 ) . At trial 's end , 39 % and 80 % of insufficient women at baseline attained sufficiency in Group A and Group B ( p=0.057 ) . Neither dose was associated with hyperparathyroidism or toxicity . CONCLUSIONS Despite pretrial vitamin D supplementation and adequate sun exposure , 25.6 % Chinese Malaysian PMO women were vitamin D insufficient indicating sunshine alone can not ensure sufficiency in the tropics . Both ~900 IU/day and ~1800 IU/day cholecalciferol can safely maintain vitamin D sufficiency in > 90 % of Chinese Malaysian PMO women . Higher doses are required with baseline concentration < 75",
"AIMS Vitamin D deficiency may increase the risk for type 2 diabetes . African Americans tend to have poor vitamin D status and increased risk of diabetes , but effects of vitamin D supplementation on components of diabetes risk have not been tested in this group . This study was conducted to determine whether vitamin D supplementation improves insulin secretion , insulin sensitivity and glycaemia in African Americans with prediabetes or early diabetes . METHODS In this r and omized , placebo-controlled trial , we examined the effect of 4000 IU/day vitamin D(3 , ) on glycaemia and contributing measures including insulin secretion , insulin sensitivity and the disposition index over 12 weeks in 89 overweight or obese African Americans with prediabetes or early diabetes . Outcome measures were derived from oral glucose tolerance testing . RESULTS Mean plasma 25-hydroxyvitamin D was about 40 nmol/l in the placebo and vitamin D groups at baseline and increased to 81 nmol/l with supplementation . Insulin sensitivity decreased by 4 % in the vitamin D group compared with a 12 % increase in the placebo group ( p = 0.034 ) . Insulin secretion increased by 12 % in the vitamin D group compared with a 2 % increase in the placebo group ( p = 0.024 ) , but changes in the disposition index were similar across groups . There was no effect of supplementation on post-load glucose or other measures of glycaemia . CONCLUSIONS Supplementation with 4000 IU/day vitamin D(3 ) successfully corrected vitamin D insufficiency and had divergent effects on insulin secretion and sensitivity with no overall effect on disposition index or glycaemia . In this study , vitamin D supplementation for 3 months did not change the pathophysiology of prediabetes in overweight and obese African Americans",
"Although there have been several studies of the effect of vitamin D status on bone turnover in the elderly , the findings are unclear , and , furthermore , to date very few have investigated this in young adults . The objective of these r and omized , placebo-controlled , double-blind , 2-center intervention studies was to investigate the effect of cholecalciferol supplementation ( 0 , 5 , 10 , and 15 microg cholecalciferol/d ) throughout winter time on indices of vitamin D status and bone turnover in young ( aged 20 - 40 y ; n = 215 ) and elderly ( aged > or = 64 y ; n = 204 ) adults , with relatively high mean calcium intakes of 976 and 874 mg/d , respectively . Fasting serum concentrations of 25-hydroxyvitamin D [ 25(OH)D ] , parathyroid hormone ( PTH ) , osteocalcin , bone-specific alkaline phosphatase , and carboxyterminal collagen crosslinks were measured by enzyme immunoassays at baseline and endpoint . Fok I and Taq I vitamin D receptor ( VDR ) genotypes were determined by real-time PCR . Endpoint serum 25(OH)D increased ( P cholecalciferol ( up to 15 microg/d ) in 20 - 40-y olds and up to 10 microg/d in > or = 64-y olds . Endpoint serum PTH was lower ( P cholecalciferol-supplemented groups compared with that in the placebo group in > or = 64-y olds , but cholecalciferol supplementation did not affect other markers in either cohort and there was no significant interaction with VDR genotype . In conclusion , cholecalciferol supplementation alone throughout winter did not affect bone turnover markers in apparently healthy young and elderly adults , even when stratified by VDR genotype",
"Background : Evidence for the effects of exercise and vitamin D supplementation on quality of life ( QoL ) , fear of falling ( FoF ) and mental wellbeing in older adults is conflicting . Objective : To study the effects of vitamin D supplementation and multimodal group exercise on psychosocial functions of wellbeing , including QoL , mental wellbeing and FoF. Method : This is a 2-year , double-blind , placebo-controlled vitamin D and open exercise intervention trial with 409 older Finnish women ( 70 - 80 years of age ) r and omized to 4 treatment arms : ( 1 ) placebo without exercise , ( 2 ) vitamin D ( 800 IU/day ) without exercise , ( 3 ) placebo and exercise , and ( 4 ) vitamin D ( 800 IU/day ) with exercise . Exercisers participated in group exercise twice per week for 12 months and once per week for the subsequent 12 months , plus home exercises . Results : When comparing with the placebo without exercise group , there were no statistically significant differences between groups receiving either vitamin D , exercise or both treatments for changes in QoL or mental wellbeing ( although a slight decline was seen in mental wellbeing in those receiving vitamin D only , p = 0.044 ) . The initial slight reduction in FoF was significant in all intervention groups compared with controls ( p vitamin D nor exercise contributes to better QoL , FoF or mental wellbeing in community-dwelling healthy older women with sufficient vitamin D levels",
"Summary In 242 community-dwelling seniors , supplementation with either 1000 mg of calcium or 1000 mg of calcium plus vitamin D result ed in a decrease in the number of subjects with first falls of 27 % at month 12 and 39 % at month 20 . Additionally , parameters of muscle function improved significantly . Introduction The efficacy of vitamin D and calcium supplementation on risk of falling in the elderly is discussed controversially . R and omized controlled trials using falls as primary outcome are needed . We investigated long-term effects of calcium and vitamin D on falls and parameters of muscle function in community-dwelling elderly women and men . Methods Our study population consisted of 242 individuals recruited by advertisements and mailing lists ( mean [ ± SD ] age , 77 ± 4 years ) . All serum 25-hydroxyvitamin D ( 25[OH]D ) levels were below 78 nmol/l . Individuals received in a double blinded fashion either 1000 mg of calcium or 1000 mg of calcium plus 800 IU of vitamin D per day over a treatment period of 12 months , which was followed by a treatment-free but still blinded observation period of 8 months . Falls were documented using diaries . The study took place in Bad Pyrmont , Germany ( latitude 52 ° ) and Graz , Austria ( latitude 46 ° ) . Results Compared to calcium mono , supplementation with calcium plus vitamin D result ed in a significant decrease in the number of subjects with first falls of 27 % at month 12 ( RR = 0.73 ; CI = 0.54–0.96 ) and 39 % at month 20 ( RR = 0.61 ; CI = 0.34–0.76 ) . Concerning secondary endpoints , we observed significant improvements in quadriceps strength of 8 % , a decrease in body sway of 28 % , and a decrease in time needed to perform the TUG test of 11 % . Discussion Combined calcium and vitamin D supplementation proved superior to calcium alone in reducing the number of falls and improving muscle function in community-dwelling older individuals",
"AIMS Vitamin D deficiency is considered as a risk factor in cardiometabolic disorders , including cardiovascular diseases , hypertension and Type 2 diabetes mellitus . We have investigated the effect of vitamin D3 supplementation on glucose homeostasis in healthy overweight and obese women . METHODS In a double-blind r and omized placebo-controlled clinical trial , 77 healthy overweight or obese women ( mean age 38 ± 8 years ; BMI 29.9 ± 4.2 kg/m(2 ) ) were r and omly assigned to the vitamin D3 group ( 25 μg/day as cholecalciferol tablets ) or the placebo group . Selected anthropometric indices , glucose , insulin , HbA(1c ) and homeostasis model assessment of insulin resistance at baseline and after 12 weeks were measured . Dietary intakes using 24-h food recall and food frequency question naires were assessed . Physical activity was assessed by the International Physical Activity Question naire . Adjusted mean differences were calculated using analysis of covariance . Correlation coefficients were calculated by Pearson 's analysis . RESULTS Mean fasting blood glucose concentrations declined in the vitamin D3 and placebo groups ( -0.28 ± 0.4 vs. -0.65 ± 0.4 mmol/l , P the mean percentage of HbA(1c ) was decreased ( -13 ± 18 vs. -19 ± 17 mmol/l , P = 0.06 ) in both groups , respectively . Mean 25-hydroxyvitamin D concentrations increased in the vitamin D3 and placebo groups ( 38.2 ± 32 vs. 4.6 ± 14 nmol/l , P correlation between HbA(1c ) and 25-hydroxyvitamin D concentrations ( r = -0.271 ; P = 0.018 ) . CONCLUSIONS The results indicate that the vitamin D3 supplement of 25 μg/day had no beneficial effect on glycaemic indices in healthy overweight or obese women",
"CONTEXT R and omized control trials ( RCT ) of the effect of vitamin D/calcium supplementation on skeletal muscle strength have not shown promising effect in the elderly . OBJECTIVE Our objective was to assess the effect of vitamin D and /or calcium on muscle strength in young adults with vitamin D deficiency . DESIGN AND SETTING We conducted a RCT using a factorial design at a tertiary-care center from September 2010 to April 2011 . SUBJECTS A total of 173 healthy females with mean age , body mass index , and 25-hydroxyvitamin D [ 25(OH)D ] of 21.7 ± 4.4 yr , 20.8 ± 2.96 kg/m(2 ) , and 9.3 ± 3.37 ng/ml , respectively , were block r and omized to 1 ) double placebo , 2 ) calcium/placebo , 3 ) cholecalciferol/placebo , and 4 ) cholecalciferol/calcium for 6 months . Cholecalciferol was given at 60,000 IU/wk for 8 wk followed by 60,000 IU/fortnight . Elemental calcium was given in doses of 500 mg twice per day for 6 months . METHODS Assessment included h and grip ( primary outcome ) and pinch grip strength , distance walked in 6 min , dyspnea score , quality of life by Short Form ( 36 ) Health Survey ( SP-36 ) , serum 25(OH)D , 1,25-dihydroxyvitamin D , and intact PTH . RESULTS The serum 25(OH)D increased significantly to 29.9 ± 8.35 and 27.0 ± 9.54 ng/ml in two groups on cholecalciferol . The mean h and grip strength ( 19.4 ± 3.92 , 21.1 ± 3.31 , 20.6 ± 3.92 , and 20.1 ± 4.00 kg ) and its increase from baseline ( 0.3 ± 2.25 , 0.3 ± 2.64 , -0.3 ± 2.41 , and 0.6 ± 2.30 kg ) were comparable in four groups at 6 months . Quality of life , urinary calcium/creatinine ratio , and adverse effects were also comparable in groups . CONCLUSION Oral cholecalciferol/calcium supplementation in the dose/schedule used is effective and safe in increasing and maintaining serum 25(OH)D. However , this does not lead to improved skeletal muscle strength in young females",
"CONTEXT Dosages of vitamin D necessary to prevent or treat vitamin D deficiency in children remain to be clarified . OBJECTIVE To determine the effects of vitamin D3 1000 IU/d on serum 25-hydroxyvitamin D [ 25(OH)D ] , PTH , and markers of bone turnover ( osteocalcin and collagen type 1 cross-linked C-telopeptide ) in black children and white children , and to explore whether there is a threshold level of 25(OH)D associated with maximal suppression of serum PTH concentration . DESIGN Healthy 8- to 14-year-old Pittsburgh-area black ( n = 84 ) and white ( n = 73 ) children not receiving vitamin supplements , enrolled from October through March from 2008 through 2011 , were r and omized to vitamin D3 1000 IU or placebo daily for 6 months . RESULTS The mean baseline concentration of 25(OH)D was the vitamin D-supplemented group and the placebo group ( 19.8 ± 7.6 and 18.8 ± 6.9 ng/mL , respectively ) . The mean concentration was higher in the supplemented group than in the placebo group at 2 months ( 26.4 ± 8.1 vs 18.9 ± 8.1 ng/mL ; P black children , when examined by race . The association between 25(OH)D and PTH concentrations was inverse and linear , without evidence of a plateau . Overall , vitamin D supplementation had no effect on PTH and bone turnover . CONCLUSIONS Vitamin D3 supplementation with 1000 IU/d in children with mean baseline 25(OH)D concentration their mean 25(OH)D concentration to ≥20 ng/mL but failed to reach 30 ng/mL. Vitamin D supplementation had no effect on PTH concentrations ",
"BACKGROUND Vitamin D deficiency is associated with obesity ; whether repletion supports weight loss and changes obesity-related biomarkers is unknown . OBJECTIVE We compared 12 mo of vitamin D3 supplementation with placebo on weight , body composition , insulin , and C-reactive protein ( CRP ) in postmenopausal women in a weight-loss intervention . DESIGN A total of 218 overweight/obese women ( 50 - 75 y of age ) with serum 25-hydroxyvitamin D [ 25(OH)D ] ≥10 ng/mL but weight loss + 2000 IU oral vitamin D3/d or weight loss + daily placebo . The weight-loss intervention included a reduced-calorie diet ( 10 % weight loss goal ) and 225 min/wk of moderate-to-vigorous aerobic activity . Mean 12-mo changes in weight , body composition , serum insulin , CRP , and 25(OH)D were compared between groups ( intent-to-treat ) by using generalized estimating equations . RESULTS A total of 86 % of participants completed the 12-mo measurements . The mean ( 95 % CI ) change in 25(OH)D was 13.6 ( 11.6 , 15.4 ) ng/mL in the vitamin D3 arm compared with -1.3 ( -2.6 , -0.3 ) ng/mL in the placebo arm ( P [ -7.1 ( -8.7 , -5.7 ) compared with -7.4 ( -8.1 , -5.4 ) kg ] , body mass index ( in kg/m(2 ) : both -2.8 ) , waist circumference [ -4.9 ( -6.7 , -2.9 ) compared with -4.5 ( -5.6 , -2.6 ) cm ] , percentage body fat [ -4.1 ( -4.9 , -2.9 ) compared with -3.5 ( -4.5 , -2.5 ) ] , trunk fat [ -4.1 ( -4.7 , -3.0 ) compared with -3.7 ( -4.3 , -2.9 ) kg ] , insulin [ -2.5 ( -3.4 , -1.7 ) compared with -2.4 ( -3.3 , -1.4 ) μU/mL ] , and CRP [ -0.9 ( -1.2 , -0.6 ) compared with -0.79 ( -0.9 , -0.4 ) mg/L ] [ corrected ] were similar between groups ( all P > 0.05 ) . Compared with women who achieved 25(OH)D lost more weight [ -8.8 ( -11.1 , -6.9 ) compared with -5.6 ( -7.2 , -5.0 ) kg ; P = 0.05 ] , waist circumference [ -6.6 ( -9.3 , -4.3 ) compared with -2.5 ( -4.6 , -2.0 ) cm ; P = 0.02 ] , and percentage body fat [ -4.7 ( -6.1 , -3.5 ) compared with -2.6 ( -3.9 , -2.2 ) ; P = 0.04 ] . Among women with complete pill counts ( 97 % adherence ) , the mean decrease in CRP was 1.18 mg/mL ( 46 % ) in the vitamin D arm compared with 0.46 mg/mL ( 25 % ) in the placebo arm ( P = 0.03 ) . CONCLUSIONS Vitamin D3 supplementation during weight loss did not increase weight loss or associated factors compared with placebo ; however , women who became replete experienced greater improvements . This trial was registered at clinical trials.gov as NCT01240213",
"Background Vitamin D deficiency is common in the general public and athletic population s and may impair skeletal muscle function . We therefore assessed the effects of vitamin D3 supplementation on serum 25[OH]D concentrations and physical performance . Methods 30 club-level athletes were block r and omised ( using baseline 25[OH]D concentrations ) into one of three groups receiving either a placebo ( PLB ) , 20 000 or 40 000 IU/week oral vitamin D3 for 12 weeks . Serum 25[OH]D and muscle function ( 1-RM bench press and leg press and vertical jump height ) were measured presupplementation , 6 and 12 weeks postsupplementation . Vitamin D deficiency was defined in accordance with the US Institute of Medicine guideline ( 57 % of the subject population were vitamin D deficient at baseline ( mean±SD value 51±24 nmol/l ) . Following 6 and 12 weeks supplementation with 20 000 IU ( 79±14 and 85±10 nmol/l , respectively ) or 40 000 IU vitamin D3 ( 98±14 and 91±24 nmol/l , respectively ) , serum vitamin D concentrations increased in all participants , with every individual achieving concentrations greater than 50 nmol/l . In contrast , vitamin D concentration in the PLB group decreased at 6 and 12 weeks ( 37±18 and 41±22 nmol/l , respectively ) . Increasing serum 25[OH]D had no significant effect on any physical performance parameter ( p>0.05 ) . Conclusions Both 20 000 and 40 000 IU vitamin D3 supplementation over a 6-week period elevates serum 25[OH]D concentrations above 50 nmol/l , but neither dose given for 12 weeks improved our chosen measures of physical performance ",
"The risk of vitamin D insufficiency is increased in persons having limited sunlight exposure and dietary vitamin D. Supplementation compliance might be improved with larger doses taken less often , but this may increase the potential for side effects . The objective of the present study was to determine whether a weekly or weekly/monthly regimen of vitamin D supplementation is as effective as daily supplementation without increasing the risk of side effects . Participants were forty-eight healthy adults who were r and omly assigned for 3 months to placebo or one of three supplementation regimens : 50 μg/d ( 2000 IU/d , analysed dose 70 μg/d ) , 250 μg/week ( 10 000 IU/week , analysed dose 331 μg/week ) or 1250 μg/week ( 50 000 IU/week , analysed dose 1544 μg/week ) for 4 weeks and then 1250 μg/ month for 2 months . Daily and weekly doses were equally effective at increasing serum 25-hydroxyvitamin D , which was significantly greater than baseline in all the supplemented groups after 30 d of treatment . Subjects in the 1250 μg treatment group , who had a BMI > 26 kg/m2 , had a steady increase in urinary Ca in the first 3 weeks of supplementation , and , overall , the relative risk of hypercalciuria was higher in the 1250 μg group than in the placebo group ( P=0·01 ) . Although vitamin D supplementation remains a controversial issue , these data document that supplementing with ≤ 250 mg/week ( ≤ 10 000 IU/week ) can improve or maintain vitamin D status in healthy population s without the risk of hypercalciuria , but 24 h urinary Ca excretion should be evaluated in healthy persons receiving vitamin D3 supplementation in weekly single doses of 1250 μg ( 50 000 IU )",
"CONTEXT Public health authorities around the world recommend widely variable supplementation strategies for adults , whereas several professional organizations , including The Endocrine Society , recommend higher supplementation . METHODS We analyzed published r and omized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health . CONCLUSIONS The extraskeletal effects of vitamin D are plausible as based on pre clinical data and observational studies . However , apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly , causality remains yet unproven in r and omized controlled trials ( RCTs ) . The greatest risk for cancer , infections , cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D ( 25OHD ) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis , estimated from serum 1,25-dihydroxyvitamin D and PTH , calcium absorption , or bone mass , can be normalized by 25OHD levels above 20 ng/mL. Moreover , vitamin D supplementation ( 800 IU/d ) in combination with calcium can reduce fracture incidence by about 20 % . Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women . Based on calculations of the metabolic clearance of 25OHD , a daily intake of 500 - 700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore , the recommendations for a daily intake of 1500 - 2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects , as suggested by The Endocrine Society Task Force , are premature . Fortunately , ongoing RCTs will help to guide us to solve this important public health question",
"BACKGROUND It is unclear whether and at what dose vitamin D supplementation affects insulin resistance ( IR ) . OBJECTIVE We sought to investigate whether vitamin D at doses higher than currently recommended decreases indexes of IR in an ambulatory population of overweight elderly subjects . DESIGN This double-blind , r and omized , controlled multicenter trial enrolled 257 elderly overweight individuals aged ≥65 y with baseline 25-hydroxyvitamin D [ 25(OH)D ] concentrations between 10 and 30 ng/mL. All subjects received 1000 mg calcium citrate/d , with vitamin D administered weekly at an equivalent dose of 600 or 3750 IU/d . The homeostasis model assessment ( HOMA ) of IR index at 1 y was the primary outcome . We also assessed the McAuley index . RESULTS In total , 222 subjects ( 55 % women ) with a mean ± SD age and body mass index ( BMI ; in kg/m(2 ) ) of 71 ± 4 y and 30 ± 4 , respectively , completed the study . Subjects ' baseline characteristics , including IR indexes , were similar across groups : 69 % had prediabetes , 54 % had hypertension ( 47 % were taking antihypertensive medications ) , and 60 % had hyperlipidemia , nearly half of whom were receiving lipid-lowering drugs . At 1 y , mean ± SD serum 25(OH)D increased from 20 ± 7 to 26 ± 7 ng/mL in the low-dose arm ( P ( P indexes did not change compared with baseline concentrations and were similar in the high- [ 2.2 ( IQR : 1.5 , 2.9 ) ] and low-dose [ 2.3 ( IQR : 1.6 , 3.3 ] treatment groups . Adjusted analyses showed that HOMA-IR was predicted by the baseline HOMA index and BMI but not by vitamin D dose , baseline serum 25(OH)D , or change in 25(OH)D. CONCLUSION Vitamin D3 at 3750 IU/d did not improve HOMA-IR compared with the Institute of Medicine Recommended Dietary Allowance of 600 IU/d in elderly overweight individuals . This trial was registered at clinical trials.gov as NCT01315366",
"Vitamin D has been shown to be an important immune system regulator . Vitamin D insufficiency during winter may cause increased susceptibility to upper respiratory tract infections ( URIs ) . To determine whether vitamin D supplementation during the winter season prevents or decreases URI symptoms , 162 adults were r and omized to receive 50 microg vitamin D3 ( 2000 IU ) daily or matching placebo for 12 weeks . A bi-weekly question naire was used to record the incidence and severity of URI symptoms . There was no difference in the incidence of URIs between the vitamin D and placebo groups ( 48 URIs vs. 50 URIs , respectively , P=0.57 ) . There was no difference in the duration or severity of URI symptoms between the vitamin D and placebo groups [ 5.4+/-4.8 days vs. 5.3+/-3.1 days , respectively , P=0.86 ( 95 % CI for the difference in duration -1.8 to 2.1 ) ] . The mean 25-hydroxyvitamin D level at baseline was similar in both groups ( 64.3+/-25.4 nmol/l in the vitamin D group ; 63.0+/-25.8 nmol/l in the placebo group ; n.s . ) . After 12 weeks , 25-hydroxyvitamin D levels increased significantly to 88.5+/-23.2 nmol/l in the vitamin D group , whereas there was no change in vitamin D levels in the placebo group . There was no benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URIs during winter . Further studies are needed to determine the role of vitamin D in infection",
"Objectives : To measure prevalence of vitamin D deficiency in Saudi Arabia , unveil the life style , nutritional habits and status , as well as identify the potential risk factors . Method : A school-based survey targeting Saudi school students and employees was conducted during the period from 2013 to 2014 using multistage cluster r and om sample in Central , Western and Eastern regions . The prevalence of vitamin D deficiency and difference between various population subgroups were calculated . Logistic regression analysis was used to determine the predictors of potential risk factors . Results : Prevalence of vitamin D deficiency was 49.5 % in students and 44 % in employees . Life style was not adequate to protect against vitamin D depletion . Unhealthy nutritional habits were widespread , some manifested in childhood while others manifested later in life . Living in the Eastern region , females , 16 - 19 years of age , low economic class , obese and lack of omega 3 supplements were risk factors in students . Employees living in the Eastern region , females , middle-income class , carbonated soft drink consumers , and lack of multivitamin supplements were at higher risk . Conclusion : There is a need for a health awareness program using evidence -based recommendations . Screening for early detection and correction of the condition should be proposed to be part of the national health strategy . There is need for identifying the burden of vitamin D deficiency on other diseases to control and improve the prognosis of these conditions",
"Background : Vitamin D supplementation has been proposed as a potential strategy to prevent type 2 diabetes . Existing clinical trials have been limited by short duration , low doses of vitamin D , variability in participants ' vitamin D-deficiency status , and the use of surrogate measures of body composition , insulin sensitivity , and insulin secretion . Objective : To address existing knowledge gaps , we conducted a double-blind , r and omized , placebo-controlled trial to investigate whether vitamin D supplementation that is provided in a sufficient dose and duration to vitamin D-deficient individuals would improve insulin sensitivity or secretion as measured with the use of gold-st and ard methods . We hypothesized that vitamin D supplementation would improve insulin sensitivity and secretion compared with placebo . Design : Sixty-five overweight or obese , vitamin D-deficient ( 25-hydroxyvitamin D [ 25(OH)D ] concentration ≤50 nmol/L ) adults were r and omly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 wk . Before and after the intervention , participants received gold-st and ard assessment s of body composition ( via dual X-ray absorptiometry ) , insulin sensitivity ( via hyperinsulinemic-euglycemic clamps ) , and insulin secretion [ via intravenous-glucose-tolerance tests ( IVGTTs ) ] . Results : Fifty-four participants completed the study [ 35 men and 19 women ; mean ± SD age : 31.9 ± 8.5 y ; body mass index ( in kg/m2 ) : 30.9 ± 4.4 ] . 25(OH)D increased with vitamin D supplementation compared with placebo ( 57.0 ± 21.3 compared with 1.9 ± 15.1 nmol/L , respectively ; P = 0.02 ) . Vitamin D and placebo groups did not differ in change in insulin sensitivity ( 0.02 ± 2.0 compared with -0.03 ± 2.8 mg · kg-1 · min-1 , respectively ; P = 0.9 ) or first-phase insulin secretion ( -21 ± 212 compared with 24 ± 184 mU/L , respectively ; P = 0.9 ) . Results remained nonsignificant after adjustment for age , sex , percentage of body fat , sun exposure , physical activity , and dietary vitamin D intake ( P > 0.1 ) . Conclusions : Vitamin D supplementation does not improve insulin sensitivity or secretion in vitamin D-deficient , overweight or obese adults , despite using high-dose vitamin D supplementation and robust endpoint measures . Therefore , it is unlikely that vitamin D supplementation would be an effective strategy for reducing diabetes risk even in vitamin D-deficient population s. This trial was registered at clinical trials.gov as NCT02112721",
"BACKGROUND Older adults may be more prone to developing vitamin D deficiency than younger adults . Dietary requirements for vitamin D in older adults are based on limited evidence . OBJECTIVE The objective was to establish the dietary intake of vitamin D required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above various cutoffs between 25 and 80 nmol/L during wintertime , which accounted for the effect of summer sunshine exposure and diet . DESIGN A r and omized , placebo-controlled , double-blind , 22-wk intervention was conducted in men and women aged > /=64 y ( n = 225 ) at supplemental levels of 0 , 5 , 10 , and 15 microg vitamin D(3)/d from October 2007 to March 2008 . RESULTS Clear dose-related increments ( P serum 25(OH)D were observed with increasing supplemental vitamin D(3 ) intakes . The slope of the relation between total vitamin D intake and serum 25(OH)D was 1.97 nmol . L(-1 ) . microg intake(-1 ) . The vitamin D intake that maintained serum 25(OH)D concentrations > 25 nmol/L in 97.5 % of the sample was 8.6 microg/d . Intakes were 7.9 and 11.4 microg/d in those who reported a minimum of 15 min daily summer sunshine exposure or less , respectively . The intakes required to maintain serum 25(OH)D concentrations of > 37.5 , > 50 , and > 80 nmol/L in 97.5 % of the sample were 17.2 , 24.7 , and 38.7 microg/d , respectively . CONCLUSION To ensure that the vitamin D requirement is met by the vast majority ( > 97.5 % ) of adults aged > /=64 y during winter , between 7.9 and 42.8 microg vitamin D/d is required , depending on summer sun exposure and the threshold of adequacy of 25(OH)D. This trial was registered at http://www.controlled-trials.com/IS RCT N20236112 as IS RCT N registration no. IS RCT N20236112",
"Objective : To evaluate the effect of isolated vitamin D supplementation ( VITD ) on the rate of falls and postural balance in postmenopausal women fallers . Methods : In this double-blind , placebo-controlled trial , 160 Brazilian younger postmenopausal women were r and omized into two groups : VITD group , vitamin D3 supplementation 1,000 IU/day/orally ( n = 80 ) and placebo group ( n = 80 ) . Women with amenorrhea at least 12 months , age 50 to 65 years , and a history of falls ( previous 12 months ) were included . Those with neurological or musculoskeletal disorders , vestibulopathies , drugs use that could affect balance and osteoporosis were excluded . The intervention time was 9 months . Postural balance was assessed by stabilometry ( computerized force platform ) and investigation on the occurrence/recurrence of falls was performed by interviews . The plasma concentration of 25-hydroxyvitamin D [ 25(OH)D ] was measured by high-performance liquid chromatography . Statistical analysis was achieved by intention-to-treat , using analysis of variance , Student 's t test , Tukey test , chi-square , and logistic regression . Results : After 9 months , mean values of 25(OH)D increased from 15.0 ± 7.5 ng/mL to 27.5 ± 10.4 ng/mL ( + 45.4 % ) in the VITD group , and decreased from 16.9 ± 6.7 ng/mL to 13.8 ± 6.0 ng/mL ( −18.5 % ) in the placebo group ( P ) . The occurrence of falls was higher in the placebo group ( + 46.3 % ) with an adjusted risk of 1.95 ( 95 % confidence interval [ CI ] 1.23 - 3.08 ) times more likely to fall and 2.80 ( 95 % CI 1.43 - 5.50 ) times higher for recurrent falls compared to the VITD group ( P There was reduction in body sway by stabilometry , with lower amplitude of antero-posterior ( −35.5 % ) and latero-lateral ( −37.0 % ) oscillation , only in the VITD group ( P Brazilian postmenopausal women fallers , isolated vitamin D supplementation for 9 months result ed in a lower incidence of falls and improvement in postural balance ",
"BACKGROUND & AIMS The impact of vitamin D supplementation in overweight and obese adults during resistance training on body composition , muscle function , and glucose tolerance was investigated . METHODS Twenty-three overweight and obese ( age : 26.1±4.7 y ; BMI : 31.3±3.2 kg/m(2 ) ; 25-hydroxyvitamin D : 19.3±7.2 ng/mL ) adults were recruited for participation in a double-blind , placebo-controlled trial . Participants were r and omly divided into vitamin D ( VitD , 4000 IU/d ; 5 females , 5 males ) and placebo ( PL ; 7 females , 6 males ) groups . Both groups completed 12 weeks of resistance training . 25-hydroxyvitamin D , parathyroid hormone , body composition , and glucose tolerance were assessed at baseline and 12 weeks . Muscle function ( strength and power ) was assessed at baseline , 4 , 8 , and 12 weeks . RESULTS During the intervention , 25-hydroxyvitamin D increased and parathyroid hormone decreased in the VitD group ( P ) . Peak power was significantly increased at 4 weeks in the VitD group only ( P in 25-hydroxyvitamin D with the change in waist-to-hip ratio ( R(2)=0.205 , P=0.02 ) . No other improvements were observed with supplementation . CONCLUSIONS Vitamin D supplementation in overweight and obese adults during resistance training induced an early improvement in peak power , and elevated vitamin D status was associated with reduced waist-to-hip ratio . CLINICAL TRIAL REGISTRATION NUMBER NCT01199926",
"BACKGROUND Low serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations have been associated with insulin resistance , the metabolic syndrome , and type 2 diabetes . Because many non-Western immigrants in the Netherl and s are vitamin D deficient , obese , and at high risk of diabetes , vitamin D supplementation may contribute to prevent diabetes and insulin resistance . OBJECTIVE We examined the effect of vitamin D supplementation on insulin sensitivity and β cell function in overweight , vitamin D-deficient , non-Western immigrants at high risk of diabetes . DESIGN The study was a 16-wk , r and omized , placebo-controlled trial . A total of 130 non-Western immigrants with prediabetes ( fasting glucose concentration > 5.5 mmol/L or r and om glucose concentration from 7.8 to 11.1 mmol/L ) and vitamin D deficiency ( serum 25[OH]D concentration were r and omly assigned after stratification by sex to receive either cholecalciferol ( 1200 IU/d ) or a placebo for 16 wk . All participants received 500 mg Ca/d as calcium carbonate . The primary outcome was the difference in the area under the curve of insulin and glucose after a 75-g oral-glucose-tolerance test after 4 mo of treatment . Secondary outcomes were insulin-sensitivity variables , β cell-function variables , and metabolic syndrome . RESULTS Mean serum 25(OH)D concentrations increased significantly in the vitamin D compared with placebo groups . After 4 mo of therapy , the mean between-group difference was 38 nmol/L ( 95 % CI : 32.1 , 43.9 nmol/L ; P effect on insulin sensitivity and β cell function . In a post hoc analysis , when patients with diabetes at baseline were excluded , a significant increase in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L ( P = 0.040 ) . CONCLUSIONS Vitamin D supplementation in non-Western vitamin D-deficient immigrants with prediabetes did not improve insulin sensitivity or β cell function or change the incidence of metabolic syndrome . However , after the exclusion of diabetic subjects , an improvement in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L. This trial was registered at trialregister.nl as NTR1827",
"Summary Sunlight deprivation results in vitamin D deficiency but serum vitamin D levels can be maintained above 50nmol/L when supplemented with 50,000IU at least every alternate month . Introduction Anta rct ic expeditioners are exposed to prolonged sunlight deprivation result ing in vitamin D deficiency . We hypothesised that monthly dosing of 50,000 IU vitamin D ( ~1,600 IU daily ) will increase serum 25-hydroxyvitamin D ( 25(OH)D ) , suppress parathyroid hormone ( PTH ) and improve bone mineral density ( BMD ) , 50,000 IU alternate months ( ~800 IU daily ) will maintain these measures , while a single 50,000 IU dose pre-departure ( ~1,00 IU daily ) will not be protective . Methods This was a r and omised double-blind study involving 110 healthy adults : 91 males , mean age 41 years ( range 24–65 years ) working in Anta rct ica for up to 12 months , who we administered 50,000 IU vitamin D3 monthly , alternate months or a single dose pre-departure . Serum 25(OH)D , PTH , osteocalcin , CTx and calcium were assessed at baseline , mid- and end of expedition . Proximal femur and lumbar spine BMD were assessed pre- and post-expedition . Results Baseline 25(OH)D was 59 ± 14 nmol/L. By mid-expedition , 25(OH)D increased by 7 nmol/L in those supplemented monthly ( p , 25(OH)D decreased by 8 nmol/L ( p PTH increased by 27 % ( p increased by ~22 % in all groups but BMD remained unchanged . If serum 25(OH)D was > 50 nmol/L at baseline , 25(OH)D was maintained above this level with all regimens . If 25(OH)D was 50 nmol/L , the single pre-departure dose was ineffective . Conclusion During sunlight deprivation of up to 12 months , serum 25(OH)D levels can be maintained above 50 nmol/L when expeditioners are provided with 50,000 I U at least every alternate month",
"BACKGROUND Severe vitamin D deficiency causes osteomalacia , yet trials of vitamin D supplementation in the community have not on average demonstrated benefit to bone mineral density ( BMD ) or fracture risk in adults . OBJECTIVE To determine whether monthly high-dose vitamin D supplementation influences BMD in the general population and in those with low 25-hydroxyvitamin D levels . METHODS Two-year sub study of a trial in older community-resident adults . A total of 452 participants were r and omized to receive monthly doses of vitamin D3 100 000 IU , or placebo . The primary end-point was change in lumbar spine BMD . Exploratory analyses to identify thresholds of baseline 25-hydroxyvitamin D for vitamin D effects on BMD were prespecified . RESULTS Intention-to-treat analyses showed no significant treatment effect in the lumbar spine ( between-groups difference 0.0071 g cm-2 , 95%CI : -0.0012 , 0.0154 ) or total body but BMD loss at both hip sites was significantly attenuated by ~1/2 % over 2 years . There was a significant interaction between baseline 25-hydroxyvitamin D and treatment effect ( P = 0.04 ) . With baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 ( n = 46 ) , there were between-groups BMD changes at the spine and femoral sites of ~2 % , significant in the spine and femoral neck , but there was no effect on total body BMD . When baseline 25-hydroxyvitamin D was > 30 nmol L-1 , differences were ~1/2 % and significant only at the total hip . CONCLUSIONS This sub study finds no clinical ly important benefit to BMD from untargeted vitamin D supplementation of older , community-dwelling adults . Exploratory analyses suggest meaningful benefit in those with baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 . This represents a significant step towards a trial-based definition of vitamin D deficiency for bone health in older adults ",
"IMPORTANCE Experts debate optimal 25-hydroxyvitamin D ( 25[OH]D ) levels for musculoskeletal health . OBJECTIVE To compare the effects of placebo , low-dose cholecalciferol , and high-dose cholecalciferol on 1-year changes in total fractional calcium absorption , bone mineral density , Timed Up and Go and five sit-to-st and tests , and muscle mass in postmenopausal women with vitamin D insufficiency . DESIGN , SETTING , AND PARTICIPANTS This r and omized , double-blind , placebo-controlled clinical trial was conducted at a single center in Madison , Wisconsin , from May 1 , 2010 , through July 31 , 2013 , and the final visit was completed on August 8 , 2014 . A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied . INTERVENTIONS Three arms included daily white and twice monthly yellow placebo ( n=76 ) , daily 800 IU vitamin D3 and twice monthly yellow placebo ( n=75 ) , and daily white placebo and twice monthly 50,000 IU vitamin D3 ( n=79 ) . The high-dose vitamin D regimen achieved and maintained 25(OH)D levels≥30 ng/mL. MAIN OUTCOMES AND MEASURES Outcome measures were 1-year change in total fractional calcium absorption using 2 stable isotopes , bone mineral density and muscle mass using dual energy x-ray absorptiometry , Timed Up and Go and five sit-to-st and tests , functional status ( Health Assessment Question naire ) , and physical activity ( Physical Activity Scale for the Elderly ) , with Benjamini-Hochberg correction of P values to control for the false discovery rate . RESULTS After baseline absorption was controlled for , calcium absorption increased 1 % ( 10 mg/d ) in the high-dose arm but decreased 2 % in the low-dose arm ( P = .005 vs high-dose arm ) and 1.3 % in the placebo arm ( P = .03 vs high-dose arm ) . We found no between-arm changes in spine , mean total-hip , mean femoral neck , or total-body bone mineral density , trabecular bone score , muscle mass , and Timed Up and Go or five sit-to-st and test scores . Likewise , we found no between-arm differences for numbers of falls , number of fallers , physical activity , or functional status . CONCLUSIONS AND RELEVANCE High-dose cholecalciferol therapy increased calcium absorption , but the effect was small and did not translate into beneficial effects on bone mineral density , muscle function , muscle mass , or falls . We found no data to support experts ' recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women . Instead , we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL. TRIAL REGISTRATION clinical trials.gov Identifier : NCT00933244",
"The link between African-Americans ’ disproportionate rates of diabetes , obesity and vitamin D deficiency may be marked by C-peptide as an indicator of insulin secretion . We hypothesize that vitamin D supplementation will increase C-peptide , a marker of insulin secretion . During 3 winters from 2007 - 2010 , 328 healthy African-Americans ( median age , 51 years ) living in Boston , MA were r and omized into a 4-arm , double-blind trial for 3 months of placebo , 1000 , 2000 , or 4000 IU of vitamin D3 . The differences in non-fasting C-peptide between baseline and 3 months were −0.44 ng/mL for those receiving placebo , −0.10 ng/mL for those receiving 1000 IU/d , 0 ng/mL for those receiving 2000 IU/d , 1.24 ng/mL for those receiving 4000 IU/d ( C-peptide increased 0.42 ng/mL for each additional 1000 IU/d of vitamin D3 , p ) . Vitamin D supplementation increased C-peptide in overweight African-Americans and may be compatible with other recommendations for diabetes prevention and management including weight loss and increased physical activity ",
"BACKGROUND Adolescents are a population group at high risk of low vitamin D status , yet the evidence base for establishing dietary vitamin D requirements remains weak . OBJECTIVE The aim was to establish the distribution of vitamin D intakes required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above proposed cutoffs ( 25 , 30 , 40 , and 50 nmol/L ) during winter in white males and females ( 14 - 18 y of age ) in the United Kingdom ( 51 ° N ) . DESIGN In a dose-response trial , 110 adolescents ( aged 15.9 ± 1.4 y ; 43 % males ) were r and omly assigned to receive 0 , 10 , or 20 μg vitamin D3 supplements/d for 20 wk during winter . A nonlinear regression model was fit to total vitamin D intake and postintervention serum 25(OH)D concentrations , and regression-predicted values estimated the vitamin D intakes required to maintain serum 25(OH)D concentrations above specific cutoffs . RESULTS Mean ± SD serum 25(OH)D concentrations increased from 49.2 ± 12.0 to 56.6 ± 12.4 nmol/L and from 51.7 ± 13.4 to 63.9 ± 10.6 nmol/L in the 10- and 20-μg/d groups , respectively , and decreased in the placebo group from 46.8 ± 11.4 to 30.7 ± 8.6 nmol/L ( all P ≤ 0.001 ) . Vitamin D intakes required to maintain 25(OH)D concentrations > 25 and > 30 nmol/L in 97.5 % of adolescents were estimated to be 10.1 and 13.1 μg/d , respectively , and 6.6 μg/d to maintain 50 % of adolescents at concentrations > 40 nmol/L. Because the response of 25(OH)D reached a plateau at 46 nmol/L , there is uncertainty in estimating the vitamin D intake required to maintain 25(OH)D concentrations > 50 nmol/L in 97.5 % of adolescents , but it exceeded 30 μg/d . CONCLUSION Vitamin D intakes between 10 and ∼30 μg/d are required by white adolescents during winter to maintain serum 25(OH)D concentrations > 25 - 50 nmol/L , depending on the serum 25(OH)D threshold chosen . This trial was registered at clinical trials.gov as NCT02150122 and as International St and ard R and omized Controlled Trial Number IS RCT N40736890",
"OBJECTIVES To determine the prevalence of hypovitaminosis D ( serum 25-hydroxyvitamin D population of elderly veterans and conduct a preliminary assessment of the efficacy of supplementation with cholecalciferol in correcting HVD . DESIGN R and omized , double-blind , placebo-controlled clinical trial . SETTING Geriatric clinic at the Bruce W. Carter Veterans Affairs Medical Center , Miami , Florida . PARTICIPANTS Veterans aged 70 and older . INTERVENTION Oral cholecalciferol 2,000 IU daily or placebo for 6 months . MEASUREMENTS Serum calcium , 25-hydroxyvitamin D , parathyroid hormone , and 24-hour urinary calcium . RESULTS Of the 34 participants who completed the study , 62 % had HVD at baseline . In the treatment group , mean serum 25-hydroxyvitamin D level rose from 28.4±7.9 ng/mL at baseline to 42.7±10.5 ng/mL at the end of the trial , but levels remained less than 32 ng/mL in three of 17 ( 18 % ) of the participants . In the placebo group , the baseline level of 27.7±8.3 ng/mL remained unchanged ( 28.8±8.7 ng/mL ) . Supplementation did not alter serum or urinary calcium levels and did not result in any adverse events . CONCLUSION These initial observations suggest that , in older veterans , cholecalciferol 2,000 IU daily for 6 months is generally safe and corrects HVD in most but not all individuals",
"Purpose The Nutrition Societies in Germany , Austria , and Switzerl and recommend a daily intake of 20 µg vitamin D3 for adults when endogenous synthesis is absent . The current study aim ed to eluci date whether this vitamin D3 dose impacts cardiovascular risk markers of adults during the winter months . Methods The study was conducted in Halle ( Saale ) , Germany ( 51o northern latitude ) as a placebo-controlled , double-blinded , r and omised trial ( from January to April ) . A total of 105 apparently healthy subjects ( male and female , 20–71 years old ) were included . Subjects were r and omly allocated to two groups . One group received a daily 20-µg vitamin D3 dose ( n = 54 ) , and the other group received a placebo ( n = 51 ) for 12 weeks . Outcome measures included blood pressure , heart rate , concentrations of renin , aldosterone , serum lipids and vascular calcification markers , and haematologic variables such as pro-inflammatory monocytes . Results Blood pressure and systemic cardiovascular risk markers remained unchanged by vitamin D3 supplementation , although serum 25-hydroxyvitamin D3 increased from 38 ± 14 to 73 ± 16 nmol/L at week 12 . The placebo and vitamin D groups did not differ in their final cardiovascular risk profile . Conclusion Daily supplementation of 20 µg vitamin D3 during winter is unlikely to change cardiovascular risk profile",
"Severe vitamin D deficiency in mothers and their breastfed infants is a significant health problem in the Middle East . Supplementation of the breastfed infant alone with the recommended dose of vitamin D may be insufficient in high-risk population . We investigated the effect of combined maternal and infant vitamin D supplementation on vitamin D status of the breastfed infant . We examined also the effect of supplementation on vitamin D antirachitic activity of breast milk in a subset of mothers . Healthy breastfeeding mothers ( n = 90 ) were r and omly assigned to 2000 IU daily ( group 1 ) or 60,000 IU monthly ( group 2 ) of vitamin D(2 ) , and all their infants ( n = 92 ) received 400 IU daily of vitamin D(2 ) for 3 months . Most infants had vitamin D deficiency - 25-hydroxyvitamin D [ 25(OH)D ] Serum 25(OH)D concentrations at 3 months increased significantly from baseline in infants of mothers in group 1 ( 13.9 + /- 8.6 vs. 49.6 + /- 18.5 nmol L(-1 ) , P Maternal and infant serum 25(OH)D concentrations correlated positively at baseline ( r = 0.36 , P = 0.01 ) and 3 months ( r = 0.46 , P = 0.002 ) . Milk antirachitic activity increased from undetectable ( vitamin D supplementation was associated with a threefold increase in infants ' serum 25(OH)D concentrations and a 64 % reduction in the prevalence of vitamin D deficiency without causing hypervitaminosis",
"CONTEXT Two reports suggested that vitamin D2 is less effective than vitamin D3 in maintaining vitamin D status . OBJECTIVE Our objective was to determine whether vitamin D2 was less effective than vitamin D3 in maintaining serum 25-hydroxyvitamin D levels or increased the catabolism of 25-hydroxyvitamin D3 . SUBJECTS AND DESIGN This was a r and omized , placebo-controlled , double-blinded study of healthy adults ages 18 - 84 yr who received placebo , 1000 IU vitamin D3 , 1000 IU vitamin D2 , or 500 IU vitamin D2 plus 500 IU vitamin D3 daily for 11 wk at the end of the winter . RESULTS Sixty percent of the healthy adults were vitamin D deficient at the start of the study . The circulating levels of 25-hydroxyvitamin D ( mean+/-sd ) increased to the same extent in the groups that received 1000 IU daily as vitamin D2 ( baseline 16.9+/-10.5 ng/ml ; 11 wk 26.8+/-9.6 ng/ml ) , vitamin D3 ( baseline 19.6+/-11.1 ng/ml ; 11 wk 28.9+/-11.0 ng/ml ) , or a combination of 500 IU vitamin D2 and 500 IU vitamin D3 ( baseline 20.2+/-10.4 ng/ml ; 11 wk 28.4+/-7.7 ng/ml ) . The 25-hydroxyvitamin D3 levels did not change in the group that received 1000 IU vitamin D2 daily . The 1000 IU dose of vitamin D2 or vitamin D3 did not raise 25-hydroxyvitamin D levels in vitamin D-deficient subjects above 30 ng/ml . CONCLUSION A 1000 IU dose of vitamin D2 daily was as effective as 1000 IU vitamin D3 in maintaining serum 25-hydroxyvitamin D levels and did not negatively influence serum 25-hydroxyvitamin D3 levels . Therefore , vitamin D2 is equally as effective as vitamin D3 in maintaining 25-hydroxyvitamin D status",
"Vitamin D deficiency leads to secondary hyperparathyroidism , increased bone turnover , and bone loss and , when severe , to osteomalacia . Vitamin D deficiency is common in elderly people , especially the institutionalized . The definition of vitamin D deficiency is hampered by the fact that large interlaboratory differences exist in assays for serum 25-hydroxyvitamin D ( 25OHD ) , the main circulating metabolite . The international Multiple Outcomes of Raloxifene Evaluation study , a large prospect i ve intervention trial in postmenopausal women with osteoporosis , offered the opportunity to compare vitamin D status and parathyroid function throughout many countries over the world . For this study , baseline data were available from 7564 postmenopausal women from 25 countries on 5 continents . All women had osteoporosis , i.e. bone mineral density ( BMD ) at femoral neck or lumbar spine was lower than t-score -2.5 , or they had 2 vertebral fractures . Serum 25OHD was measured by RIA , and serum PTH was measured by immunoradiometric assay . BMD was measured by dual x-ray absorptiometry . The mean ( + /-SD ) serum 25OHD was 70.8 + /- 30.9 nmol/L. A low serum 25OHD ( Serum 25OHD was between 25 - 50 nmol/L in 24.3 % of the women . Serum 25OHD showed a significant seasonal relationship , with lower values in all regions in winter . Serum PTH correlated negatively with serum 25OHD ( r = -0.25 ; P serum 25OHD was less than 25 , 25 - 50 , or more than 50 nmol/L , respectively , mean serum PTH levels were 4.8 , 4.1 , and 3.5 pmol/L , respectively ( by ANOVA , P mean alkaline phosphatase levels were 83.7 , 79.1 , and 75.7 U/L ( P serum 25OHD on BMD was only significant for the BMD of the trochanter where a serum 25OHD level less than 25 nmol/L was associated with a 4 % lower BMD . After 6 months of treatment with vitamin D(3 ) ( 400 - 600 IU/day ) and calcium ( 500 mg/day ) , serum 25OHD increased from 70.8 + /- 29.8 to 92.3 + /- 28.6 nmol/L. Serum PTH decreased significantly after 6 months of treatment , and this decrease depended on baseline serum 25OHD . When baseline serum 25OHD was less than 25 , 25 - 50 , or more than 50 nmol/L , respectively , serum PTH decreased by 0.8 , 0.5 , or 0.2 pmol/L , respectively ( P serum 25OHD was less than 25 nmol/L in 4 % of the women , and this was associated with a 30 % higher serum PTH . In 24 % of the women serum 25OHD was between 25 - 50 nmol/L , associated with a 15 % higher level of serum PTH compared with women with a serum 25OHD greater than 50 nmol/L. A low serum 25OHD level was also associated with higher serum alkaline phosphatase and lower BMD of the trochanter . Treatment with vitamin D(3 ) and calcium increased serum 25OHD and decreased serum PTH significantly ; the effect was greater for lower baseline serum 25OHD",
"OBJECTIVES Engagement in high volumes of physical activity coupled with energy restriction during periods of musculoskeletal development may compromise bone health . Jockeys limit caloric intakes on a weekly basis often from their mid-to-late teens . The aim of this study was to establish whether calcium and vitamin D supplementation would improve bone turnover markers ( BTM ) and non-weight bearing bone properties of young male jockeys . DESIGN A six-month r and omised , double-blinded , placebo-controlled trial with two groups of apprentice male jockeys was conducted . METHODS Participants ( age 20.18±3.23years ) were supplemented with 800 mg of calcium and 400IU of vitamin D ( n=8 ) or a placebo ( n=9 ) daily . Bone properties were assessed at the ultra-distal ( 4 % ) and proximal ( 66 % ) radius using pQCT at baseline and six months . Vitamin D , P1NP and CTX were assessed . RESULTS ANCOVA results for blood-borne markers indicated higher vitamin D levels ( 18.1 % , p=0.014 , partial η2=0.38 ) and lower CTX ( ng·L-1 ) ( -24.8 % , p=0.011 , partial η2=0.40 ) in the supplemented group with no differences observed in P1NP . Analysis of bone variables indicated no between group differences in either trabecular or cortical bone properties at the 4 % and 66 % sites post-intervention . CONCLUSIONS This trial is the first to examine the efficacy of calcium and vitamin D supplementation in improving non-weight bearing bone properties in a young male athletic population . Results indicate positive alterations to bone metabolism ; however , longer duration or higher dosage appears to be required to detect changes in bone material properties at the radius . Further examination of such interventions in weight-restricted athletes is warranted",
"Background Insufficiency of 25‐hydroxyvitamin D [ 25(OH)D ] has been associated with dementia and cognitive decline . However , the effects of vitamin D supplementation on cognition are unclear . It was hypothesized that high dose vitamin D3 supplementation would result in enhanced cognitive functioning , particularly among adults whose 25(OH)D levels were insufficient ( Methods Healthy adults ( n = 82 ) from northern British Columbia , Canada ( 54 ° north latitude ) with baseline 25(OH)D levels ≤100 nmol/L were r and omized and blinded to High Dose ( 4000 IU/d ) versus Low Dose ( 400 IU/d ) vitamin D3 ( cholecalciferol ) for 18 weeks . Baseline and follow‐up serum 25(OH)D and cognitive performance were assessed and the latter consisted of : Symbol Digit Modalities Test , verbal ( phonemic ) fluency , digit span , and the CANTAB ® computerized battery . Results : There were no significant baseline differences between Low ( n = 40 ) and High ( n = 42 ) dose groups . Serum 25(OH)D increased significantly more in the High Dose ( from 67.2 ± 20 to 130.6 ± 26 nmol/L ) than the Low Dose group ( 60.5 ± 22 to 85.9 ± 16 nmol/L ) , p = 0.0001 . Performance improved in the High Dose group on nonverbal ( visual ) memory , as assessed by the Pattern Recognition Memory task ( PRM ) , from 84.1 ± 14.9 to 88.3 ± 13.2 , p = 0.043 ( d = 0.3 ) and Paired Associates Learning Task , ( PAL ) number of stages completed , from 4.86 ± 0.35 to 4.95 ± 0.22 , p = 0.044 ( d = 0.5 ) , but not in the Low Dose Group . Mixed effects modeling controlling for age , education , sex and baseline performance revealed that the degree of improvement was comparatively greater in the High Dose Group for these tasks , approaching significance : PRM , p = 0.11 ( d = 0.4 ) , PAL , p = 0.058 ( d = 0.4 ) . Among those who had insufficient 25(OH)D ( Nonverbal ( visual ) memory seems to benefit from higher doses of vitamin D supplementation , particularly among those who are insufficient ( verbal memory and other cognitive domains do not . These findings are consistent with recent cross‐sectional and longitudinal studies , which have demonstrated significant positive associations between 25(OH)D levels and nonverbal , but not verbal , memory . While our findings require confirmation , they suggest that higher 25(OH)D is particularly important for higher level cognitive functioning , specifically nonverbal ( visual ) memory , which also utilizes executive functioning processes . HighlightsNovel trial of high versus low dose vitamin D3 on multiple cognitive domainsHigh dose vitamin D ( 4000 IU/d ) improved nonverbal ( visual ) memory after 18 weeks.25(OH)D levels < 75 nmol/L at baseline may confer more benefit with supplementation",
"Background : Vitamin D insufficiency poses a problem in many parts of the world , the elderly being an especially vulnerable group . This insufficiency results from an inadequate amount of sunshine and a low dietary intake of vitamin D. Typically , insufficiency is accompanied with high intact parathyroid hormone , ( S-iPTH ) concentrations . Aims of the Study : We studied how serum 25-hydroxy vitamin D ( S-25-OHD ) concentrations respond to different doses of vitamin D3 supplementation . Secondly to determine the smallest efficient dose to maintain serum 25-OHD concentration above the insufficiency level . We also studied which dose would be efficient in decreasing S-iPTH concentration in these subjects . Subjects and Methods : Forty-nine 65- to 85-year-old women participated . The women were r and omly assigned into one of four groups receiving 0 ( placebo ) , 5 , 10 or 20 μg of vitamin D3 daily for 12 weeks . Fasting morning blood was drawn at the beginning of the study , and thereafter every second week . Calciotropic variables were assessed from serum and urine sample s. Results : The S-25-OHD concentration increased significantly ( p Equilibrium in S-25-OHD concentration was reached in all groups after 6 weeks of supplementation at 57.7 ( 8.9 ) nmol/L , 59.9 ( 8.9 ) nmol/L and 70.9 ( 8.9 ) nmol/L in the groups with increasing vitamin D supplementation . The dose-response to supplementation decreased with increasing vitamin D status at baseline , r = −0.513 , p = 0.002 . S-iPTH tended to decrease in those with highest dose response to supplementation . Conclusions : A clear dose response was noted in S-25-OHD to different doses of vitamin D3 . The recommended dietary intake of 15 μg is adequate to maintain the S-25-OHD concentration around 40–55 nmol/L during winter , but if the optimal S-25-OHD is higher than that even higher vitamin D intakes are needed . Interestingly , subjects with lower vitamin D status at baseline responded more efficiently to supplementation than those with more adequate status",
"Few year-long vitamin D supplementation trials exist that match seasonal changes . The aim of this study was to determine whether daily oral vitamin D3 at 400 IU or 1000 IU compared with placebo affects annual bone mineral density ( BMD ) change in postmenopausal women in a 1-year double-blind placebo controlled trial in Scotl and . White women aged 60 to 70 years ( n = 305 ) were r and omized to one of two doses of vitamin D or placebo . All participants started simultaneously in January/February 2009 , attending visits at bimonthly intervals with 265 ( 87 % ) women attending the final visit and an additional visit 1 month after treatment cessation . BMD ( Lunar iDXA ) and 1,25-dihydroxyvitamin D[1,25(OH)2 D ] , N-terminal propeptide of type 1 collagen [ P1NP ] , C-terminal telopeptide of type I collagen [ CTX ] , and fibroblast growth factor-23 [ FGF23 ] were measured by immunoassay at the start and end of treatment . Circulating PTH , serum Ca , and total 25-hydroxyvitamin D [ 25(OH)D ] ( latter by t and em mass spectrometry ) were measured at each visit . Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group ( 0.05 % ± 1.46 % ) compared with the 400 IU vitamin D or placebo groups ( 0.57 % ± 1.33 % and 0.60 % ± 1.67 % , respectively ) ( p 0.05 ) . Mean ( ± SD ) baseline 25(OH)D was 33.8 ± 14.6 nmol/L ; comparative 25(OH)D change for the placebo , 400 IU , and 1000 IU vitamin D groups was -4.1 ± 11.5 nmol/L , + 31.6 ± 19.8 nmol/L , and + 42.6 ± 18.9 nmol/L , respectively . Treatment did not change markers of bone metabolism , except for a small reduction in PTH and an increase in serum calcium ( latter with 1000 IU dose only ) . The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome , nor how much vitamin D is being stored",
"Lower urinary tract symptoms ( LUTS ) are common in postmenopausal women , and have been reported inversely associated with vitamin D intake and serum 25-hydroxyvitamin D ( 25(OH)D ) levels . The aim of this study was to investigate if high dose vitamin D supplementation would affect LUTS in comparison to st and ard dose . In a r and omized controlled study including 297 postmenopausal women with low bone mineral density , the participants were allocated to receive capsules of 20 000IU of vitamin D3 twice a week ( high dose group ) or similar looking placebo ( st and ard dose group ) . In addition , all the participants received 1 g of calcium and 800IU of vitamin D daily . A vali date d question naire regarding LUTS was filled in at baseline and after 12 months . At baseline , 76 women in the high dose group and 82 in the st and ard dose group reported any LUTS . Levels of serum 25(OH)D increased significantly more in the high dose group ( from 64.7 to 164.1nmol/l compared to from 64.1 to 81.8nmol/l , p change in LUTS except for a statistically significant reduction in the reported severity of urine incontinence in the high dose group as compared to the st and ard dose group after one year ( p<0.05 ) . The results need confirmation in a study specifically design ed for this purpose",
"Purpose The effect of 40 μg ( 1,600 IU ) per day of vitamin D3 on serum 25-hydroxyvitamin D ( 25(OH)D ) and markers of bone and mineral metabolism was evaluated . Methods This intervention study was design ed as a double-blind r and omised controlled trial . Forty-five community-dwelling subjects ( 32 females ) , age 55–84 years , at 58 ° North latitude were supplemented for 1 year with 40 μg vitamin D3 plus 1,000 mg calcium per day , or with 1,000 mg calcium per day for controls . Safety parameters and 25(OH)D , intact parathyroid hormone ( PTH ) , ionized calcium , bone-specific alkaline phosphatase ( BALP ) , and tartrate-resistant acid phosphatase isoform 5b ( TRACP5b ) were measured over the study period . Results All subjects supplemented with vitamin D3 reached a 25(OH)D level above 50 nmol/L. Mean ( SD ) serum 25(OH)D increased from 50.4 ( 13.5 ) nmol/L to 84.2 ( 17.5 ) nmol/L , range 55.0–125.0 nmol/L in the vitamin D3 supplemented group and the corresponding levels for the control group were 47.3 ( 14.1 ) nmol/L and 45.7 ( 13.4 ) nmol/L , range 26.0–73.0 nmol/L. No serious adverse event was recorded and the highest 25(OH)D level reached , 125.0 nmol/L , is well below toxic levels . BALP and TRACP5b did not change significantly over the study period . Conclusions This trial suggests that a daily supplementation with 40 μg vitamin D3 is sufficient to secure a 25(OH)D level of 50 nmol/L. No side effects were observed in the study group",
"OBJECTIVE The purpose of this study was to determine 1,25-dihydroxyvitamin D3 [ 1,25(OH)2D3 ] and 1,25-dihydroxyvitamin D2 [ 1,25(OH)2D2 ] levels in healthy adults consuming 1000 IU vitamin D2 or vitamin D3 per day for 11 weeks . SUBJECTS AND DESIGN Blood from 34 healthy male and female adults , aged 18 to 79 years , from a placebo-controlled , double-blind study who received a placebo , 1000 IU vitamin D3 , or 1000 IU vitamin D2 daily for 11 weeks at end of winter was analyzed . Serum levels of 25-hydroxyvitamin D2 , 25-hydroxyvitamin D3 , 1,25(OH)2D2 , and 1,25(OH)2D3 were determined by liquid chromatography-t and em mass spectroscopy . RESULTS Of the adults , 82 % were vitamin D insufficient ( serum 25-hydroxyvitamin D [ 25(OH)D Administration of vitamin D2 and vitamin D3 induced similar increases in total 25(OH)D as well as in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 , respectively . Compared with placebo and adjusting for baseline levels , 1000 IU daily of vitamin D2 was associated with a mean increase of 7.4 pg/mL ( 95 % confidence interval , 4.4 - 10.3 ) in 1,25(OH)2D2 , which was accompanied by a mean decrease of 9.9 pg/mL ( -15.8 to -4.0 ) in 1,25(OH)2D3 . No such differences accompanied administration of 1000 IU daily of vitamin D3 . CONCLUSION Vitamin D2 and vitamin D3 were effective in raising and maintaining total serum concentrations of 25(OH)D. Ingestion of vitamin D2 also result ed in an increase in serum concentrations of 1,25(OH)2D2 . This increase was accompanied by a comparable decrease in serum concentrations of 1,25(OH)2D3 ; therefore , the total 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] concentrations did not significantly change after 11 weeks compared with baseline levels . Ingestion of vitamin D3 did not alter serum concentrations of 1,25(OH)2D3 or total 1,25(OH)2D . Therefore , ingestion of 1000 IU vitamin D2 or vitamin D3 for 11 weeks was effective in raising total serum concentrations of 25(OH)D as well as sustaining serum concentrations of total 1,25(OH)2D",
"The comparative efficacy and safety profiles of selected daily 1000 IU , weekly 7000 IU and monthly 30,000 IU vitamin D3—not previously investigated — will be evaluated . Here , a prospect i ve , r and omized clinical trial , comparing efficacy and safety of a daily single dose of 1000 IU ( group A ) to a once-weekly 7000 IU dose ( group B ) , or monthly 30,000 IU dose ( group C ) of vitamin D3 . The present study is a controlled , r and omized , open-label , multicenter clinical trial , 3 months in duration . Sixty-four adult subjects with vitamin D deficiency ( 25OHD Dose-responses for increases in serum vitamin 25OHD were statistically equivalent for each of the three groups : A , B and C. Outcomes were 13.0 ± 1.5 ; 12.6 ± 1.1 and 12.9 ± 0.9 ng/ml increases in serum 25OHD per 1000 IU , daily , weekly and monthly , respectively . The treatment of subjects with selected doses restored 25OHD values to levels above 20 ng/ml in all groups . Treatment with distinct administration frequency of vitamin D3 did not exhibit any differences in safety parameters . The daily , weekly and monthly administrations of daily equivalent of 1000 IU of vitamin D3 provide equal efficacy and safety profiles",
"Background : There are conflicting views in the literature as to whether vitamin D2 and vitamin D3 are equally effective in increasing and maintaining serum concentrations of 25-hydroxyvitamin D [ 25(OH)D ] , particularly at lower doses of vitamin D. Objective : We aim ed to investigate whether vitamin D2 or vitamin D3 fortified in juice or food , at a relatively low dose of 15 μg/d , was effective in increasing serum total 25(OH)D and to compare their respective efficacy in South Asian and white European women over the winter months within the setting of a large r and omized controlled trial . Design : A r and omized , double-blind , placebo-controlled food-fortification trial was conducted in healthy South Asian and white European women aged 20 - 64 y ( n = 335 ; Surrey , United Kingdom ) who consumed placebo , juice supplemented with 15 μg vitamin D2 , biscuit supplemented with 15 μg vitamin D2 , juice supplemented with 15 μg vitamin D3 , or biscuit supplemented with 15 μg vitamin D3 daily for 12 wk . Serum 25(OH)D was measured by liquid chromatography-t and em mass spectrometry at baseline and at weeks 6 and 12 of the study . Results : Postintervention in the 2 ethnic groups combined , both the vitamin D3 biscuit and the vitamin D3 juice groups showed a significantly greater absolute incremental change ( Δ ) in total 25(OH)D when compared with the vitamin D2 biscuit group [ Δ ( 95 % CI ) : 15.3 nmol/L ( 7.4 , 23.3 nmol/L ) ( P ] , the vitamin D2 juice group [ Δ ( 95 % CI ) : 16.3 nmol/L ( 8.4 , 24.2 nmol/L ) ( P the placebo group [ Δ ( 95 % CI ) : 42.3 nmol/L ( 34.4 , 50.2 nmol/L ) ( P vitamin D relevant to public health recommendations ( 15 μg ) and in vehicles relevant to food-fortification strategies , vitamin D3 was more effective than vitamin D2 in increasing serum 25(OH)D in the wintertime . Vitamin D3 may therefore be a preferential form to optimize vitamin D status within the general population . This trial was registered at www.controlled-trials.com as IS RCT N23421591",
"OBJECTIVE To determine whether treatment of low serum vitamin D in pregnant women improves fetal growth indices . STUDY DESIGN In this open-label r and omized clinical trial , 130 Iranian pregnant women ( 24 - 26 weeks of gestation ) with vitamin D deficiency or insufficiency [ 25(OH)D were divided at r and om into an intervention group and a control group . The control group received 200 mg calcium plus a multivitamin ( containing vitamin D3 400U ) each day , and the intervention group received 200 mg calcium plus a multivitamin ( containing vitamin D3 400U ) each day , plus vitamin D3 ( 50,000U ) each week for 8 weeks . At delivery , maternal and cord blood 25(OH)D levels , maternal weight gain , neonatal length , neonatal weight and neonatal head circumference were compared between two groups . Serum vitamin D was measured using enzyme-linked immunosorbent assay . A multivariate regression analysis was performed to examine the independent effect of maternal vitamin D level on fetal growth indices . RESULTS Mean ( ±st and ard deviation ) length ( intervention group : 49±1.6 cm ; control group : 48.2±1.7 cm ; p=0.001 ) , head circumference ( intervention group : 35.9±0.7 cm ; control group : 35.3±1.0 cm ; p=0.001 ) and weight ( intervention group : 3429±351.9 g ; control group : 3258.8±328.2 g ; p=0.01 ) were higher in the intervention group compared with the control group . Mean maternal weight gain was higher in the intervention group compared with the control group ( 13.3±2.4 kg vs 11.7±2.7 kg ; p=0.006 ) . Multivariate regression analysis for maternal weight gain , neonatal length , neonatal weight and neonatal head circumference showed an independent correlation with maternal vitamin D level . CONCLUSION Treatment of low serum vitamin D during pregnancy improves fetal growth indices and maternal weight gain ",
"BACKGROUND Knowledge gaps have contributed to considerable variation among international dietary recommendations for vitamin D. OBJECTIVE We aim ed to establish the distribution of dietary vitamin D required to maintain serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations above several proposed cutoffs ( ie , 25 , 37.5 , 50 , and 80 nmol/L ) during wintertime after adjustment for the effect of summer sunshine exposure and diet . DESIGN A r and omized , placebo-controlled , double-blind 22-wk intervention study was conducted in men and women aged 20 - 40 y ( n = 238 ) by using different supplemental doses ( 0 , 5 , 10 , and 15 microg/d ) of vitamin D(3 ) throughout the winter . Serum 25(OH)D concentrations were measured by using enzyme-linked immunoassay at baseline ( October 2006 ) and endpoint ( March 2007 ) . RESULTS There were clear dose-related increments ( P serum 25(OH)D with increasing supplemental vitamin D(3 ) . The slope of the relation between vitamin D intake and serum 25(OH)D was 1.96 nmol x L(-1 ) x microg(-1 ) intake . The vitamin D intake that maintained serum 25(OH)D concentrations of > 25 nmol/L in 97.5 % of the sample was 8.7 microg/d . This intake ranged from 7.2 microg/d in those who enjoyed sunshine exposure , 8.8 microg/d in those who sometimes had sun exposure , and 12.3 microg/d in those who avoided sunshine . Vitamin D intakes required to maintain serum 25(OH)D concentrations of > 37.5 , > 50 , and > 80 nmol/L in 97.5 % of the sample were 19.9 , 28.0 , and 41.1 microg/d , respectively . CONCLUSION The range of vitamin D intakes required to ensure maintenance of wintertime vitamin D status [ as defined by incremental cutoffs of serum 25(OH)D ] in the vast majority ( > 97.5 % ) of 20 - 40-y-old adults , considering a variety of sun exposure preferences , is between 7.2 and 41.1 microg/d"
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BACKGROUND The ' Theory of Mind ' ( ToM ) model suggests that people with autism spectrum disorder ( ASD ) have a profound difficulty underst and ing the minds of other people - their emotions , feelings , beliefs , and thoughts . As an explanation for some of the characteristic social and communication behaviours of people with ASD , this model has had a significant influence on research and practice . It implies that successful interventions to teach ToM could , in turn , have far-reaching effects on behaviours and outcome . OBJECTIVES To review the efficacy of interventions based on the ToM model for individuals with ASD . SEARCH METHODS In August 2013 we search ed CENTRAL , Ovid MEDLINE , Embase , CINAHL , PsycINFO , ERIC , Social Services Abstract s , Autism Data , and two trials registers . We also search ed the reference lists of relevant papers , contacted authors who work in this field , and h and search ed a number of journals . SELECTION CRITERIA Review studies were selected on the basis that they reported on an applicable intervention ( linked to ToM in one of four clearly-defined ways ) , presented new r and omised controlled trial data , and participants had a confirmed diagnosis of an autism spectrum disorder . Studies were selected by two review authors independently and a third author arbitrated when necessary . DATA COLLECTION AND ANALYSIS Risk of bias was evaluated and data were extracted by two review authors independently ; a third author arbitrated when necessary . Most studies were not eligible for meta- analysis , the principal reason being mis-matching method ologies and outcome measures . Three small meta-analyses were carried out . MAIN RESULTS Twenty-two r and omised trials were included in the review ( N = 695 ) . Studies were highly variable in their country of origin , sample size , participant age , intervention delivery type , and outcome measures . Risk of bias was variable across categories . There were very few studies for which there was adequate blinding of participants and personnel , and some were also judged at high risk of bias in blinding of outcome assessors . There was also evidence of some bias in sequence generation and allocation concealment . Not all studies reported data that fell within the pre-defined primary outcome categories for the review , instead many studies reported measures which were intervention-specific ( e.g. emotion recognition ) . The wide range of measures used within each outcome category and the mixed results from these measures introduced further complexity when interpreting results . Studies were grouped into four main categories according to intervention target/ primary outcome measure . These were : emotion recognition studies , joint attention and social communication studies , imitation studies , and studies teaching ToM itself . Within the first two of these categories , a sub-set of studies were deemed suitable for meta- analysis for a limited number of key outcomes .There was very low quality evidence of a positive effect on measures of communication based on individual results from three studies . There was low quality evidence from 11 studies reporting mixed results of interventions on measures of social interaction , very low quality evidence from four studies reporting mixed results on measures of general communication , and very low quality evidence from four studies reporting mixed results on measures of ToM ability . The meta- analysis results we were able to generate showed that interventions targeting emotion recognition across age groups and working with people within the average range of intellectual ability had a positive effect on the target skill , measured by a test using photographs of faces ( mean increase of 0.75 points , 95 % confidence interval ( CI ) 0.22 to 1.29 points , Z = 2.75 , P Therapist-led joint attention interventions can promote production of more joint attention behaviours within adult-child interaction ( mean increase of 0.55 points , 95 % CI 0.11 to 0.99 points , Z = 2.45 , P value = 0.01 , two studies , N = 88 ) . Further analysis undermines this conclusion somewhat by demonstrating that there was no clear evidence that intervention can have an effect on joint attention initiations as measured using a st and ardised assessment tool ( mean increase of 0.23 points , 95 % CI -0.48 to 0.94 points , Z = 0.63 , P value = 0.53 , three studies , N = 92 ) . No adverse effects were apparent . AUTHORS ' CONCLUSIONS While there is some evidence that ToM , or a precursor skill , can be taught to people with ASD , there is little evidence of maintenance of that skill , generalisation to other setting s , or developmental effects on related skills . Furthermore , inconsistency in findings and measurement means that evidence has been grade d of ' very low ' or ' low ' quality and we can not be confident that suggestions of positive effects will be sustained as high- quality evidence accumulates . Further longitudinal design s and larger sample s are needed to help eluci date both the efficacy of ToM-linked interventions and the explanatory value of the ToM model itself . It is possible that the continuing refinement of the ToM model will lead to better interventions which have a greater impact on development than those investigated to date
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"Background Previous research has suggested that music therapy may facilitate skills in areas typically affected by autism spectrum disorders such as social interaction and communication . However , generalisability of previous findings has been restricted , as studies were limited in either method ological accuracy or the clinical relevance of their approach . The aim of this study is to determine effects of improvisational music therapy on social communication skills of children with autism spectrum disorders . An additional aim of the study is to examine if variation in dose of treatment ( i.e. , number of music therapy sessions per week ) affects outcome of therapy , and to determine cost-effectiveness . Methods / Design Children aged between 4;0 and 6;11 years who are diagnosed with autism spectrum disorder will be r and omly assigned to one of three conditions . Parents of all participants will receive three sessions of parent counselling ( at 0 , 2 , and 5 months ) . In addition , children r and omised to the two intervention groups will be offered individual , improvisational music therapy over a period of five months , either one session ( low-intensity ) or three sessions ( high-intensity ) per week . Generalised effects of music therapy will be measured using st and ardised scales completed by blinded assessors ( Autism Diagnostic Observation Schedule , ADOS ) and parents ( Social Responsiveness Scale , SRS ) before and 2 , 5 , and 12 months after r and omisation . Cost effectiveness will be calculated as man years . A group sequential design with first interim look at N = 235 will ensure both power and efficiency . Discussion Responding to the need for more rigorously design ed trials examining the effectiveness of music therapy in autism spectrum disorders , this pragmatic trial sets out to generate findings that will be well generalisable to clinical practice . Addressing the issue of dose variation , this study 's results will also provide information on the relevance of session frequency for therapy outcome .Trial Registration Current Controlled Trials IS RCT N78923965",
"This study reports results of a r and omized controlled trial aim ed at joint attention ( JA ) and symbolic play ( SP ) in preschool children with autism , with prediction to language outcome 12 months later . Participants were 58 children ( 46 boys ) with autism between 3 and 4 years of age . Children were r and omized to a JA intervention , an SP intervention , or control group . Interventions were conducted 30 min daily for 5 - 6 weeks . Assessment s of JA skills , SP skills , mother-child interactions , and language development were collected at 4 time points : pre- and postintervention and 6 and 12 months postintervention by independent testers . Results indicate that expressive language gains were greater for both treatment groups compared with the control group , and results could not be explained by differences in other interventions in which children participated . For children beginning treatment with the lowest language levels , the JA intervention improved language outcome significantly more than did the SP or control interventions . These findings suggest clinical ly significant benefits of actively treating JA and SP skills in young children with autism",
"Despite the psychosocial difficulties common among young adults with autism spectrum disorders ( ASD ) , little to no evidence -based social skills interventions exist for this population . Using a r and omized controlled trial ( RCT ) design , the current study tested the effectiveness of an evidence -based , caregiver-assisted social skills intervention known as PEERS for Young Adults with high-functioning young adults with ASD ( ages 18–23 ) using self- and caregiver-report measures . Results revealed that treated young adults reported significantly less loneliness and improved social skills knowledge , while caregivers reported significant improvements in young adults ’ overall social skills , social responsiveness , empathy , and frequency of get-togethers . Results support the effectiveness of using this caregiver-assisted , manualized intervention for young adults with ASD",
"BACKGROUND Delays and deficits in joint attention and symbolic play constitute two important developmental problems in young children with autism . These areas of deficit have been well studied in autism but have rarely been the focus of treatment efforts ( see Kasari , Freeman , & Paparella , 2001 ) . In this study , we examine the efficacy of targeted interventions of joint attention and symbolic play . METHODS Participants were 58 children with autism aged 3 and 4 years ( 46 boys ) . Children were r and omized to a joint attention intervention , a symbolic play intervention , or control group . Interventions were conducted 30 minutes daily for 5 - 6 weeks . Both structured assessment s of joint attention and play skills and mother-child interactions were collected pre and post intervention by independent assessors . RESULTS Results indicate that both intervention groups improved significantly over the control group on certain behaviors . Children in the joint attention intervention initiated significantly more showing and responsiveness to joint attention on the structured joint attention assessment and more child-initiated joint attention in the mother-child interaction . The children in the play group showed more diverse types of symbolic play in interaction with their mothers and higher play levels on both the play assessment and in interaction with their mothers . CONCLUSIONS This r and omized controlled trial provides promising data on the specificity and generalizability of joint attention and play interventions for young children with autism . Future studies need to examine the long-term effects of these early interventions on children 's development",
"This study assessed the efficacy of FaceSay , a computer-based social skills training program for children with Autism Spectrum Disorders ( ASD ) . This r and omized controlled study ( N = 49 ) indicates that providing children with low-functioning autism ( LFA ) and high functioning autism ( HFA ) opportunities to practice attending to eye gaze , discriminating facial expressions and recognizing faces and emotions in FaceSay ’s structured environment with interactive , realistic avatar assistants improved their social skills abilities . The children with LFA demonstrated improvements in two areas of the intervention : emotion recognition and social interactions . The children with HFA demonstrated improvements in all three areas : facial recognition , emotion recognition , and social interactions . These findings , particularly the measured improvements to social interactions in a natural environment , are encouraging",
"BACKGROUND The study aim ed to investigate the effectiveness of a new multi-component social skills intervention for children with Asperger syndrome ( AS ) : The Junior Detective Training Program . This 7-week program included a computer game , small group sessions , parent training sessions and teacher h and outs . METHOD Forty-nine children with AS were recruited to participate and r and omly assigned to intervention ( n = 26 ) or wait-list control ( n = 23 ) conditions . RESULTS Relative to children in the wait-list group , program participants showed greater improvements in social skills over the course of the intervention , as indicated by parent-report measures . Teacher-report data also confirmed that children receiving the intervention made significant improvements in social functioning from pre- to post-treatment . Treatment group participants were better able to suggest appropriate emotion-management strategies for story characters at post-intervention than at pre-intervention , whereas control participants were not . However , there was no difference in the improvements made by children in the intervention and control conditions on facial expression and body-posture recognition measures . Follow-up data suggested that treatment gains were maintained by children at 5-months post-intervention . CONCLUSIONS The Junior Detective Training Program appeared to be effective in enhancing the social skills and emotional underst and ing of children with AS . Limitations and suggestions for future research are discussed",
"We piloted a 2-week “ Autism-1 - 2 - 3 ” early intervention for children with autism and their parents immediately after diagnosis that targeted at ( 1 ) eye contact , ( 2 ) gesture and ( 3 ) vocalization/words . Seventeen children were r and omized into the Intervention ( n = 9 ) and Control ( n = 8) groups . Outcome measures included the Autism Diagnostic Observation Schedule , Ritvo-Freeman Real Life Rating Scale , Symbolic Play Test , and Parenting Stress Index . Children with autism improved in language /communication , reciprocal social interaction , and symbolic play . Parents perceived significant improvement in their children ’s language , social interaction , and their own stress level . This intervention can serve as short-term training on communication and social interaction for children with autism , and reduce the stress of their parents during the long waiting time for public health services",
"OBJECTIVE : To conduct a r and omized , controlled trial to evaluate the efficacy of the Early Start Denver Model ( ESDM ) , a comprehensive developmental behavioral intervention , for improving outcomes of toddlers diagnosed with autism spectrum disorder ( ASD ) . METHODS : Forty-eight children diagnosed with ASD between 18 and 30 months of age were r and omly assigned to 1 of 2 groups : ( 1 ) ESDM intervention , which is based on developmental and applied behavioral analytic principles and delivered by trained therapists and parents for 2 years ; or ( 2 ) referral to community providers for intervention commonly available in the community . RESULTS : Compared with children who received community-intervention , children who received ESDM showed significant improvements in IQ , adaptive behavior , and autism diagnosis . Two years after entering intervention , the ESDM group on average improved 17.6 st and ard score points ( 1 SD : 15 points ) compared with 7.0 points in the comparison group relative to baseline scores . The ESDM group maintained its rate of growth in adaptive behavior compared with a normative sample of typically developing children . In contrast , over the 2-year span , the comparison group showed greater delays in adaptive behavior . Children who received ESDM also were more likely to experience a change in diagnosis from autism to pervasive developmental disorder , not otherwise specified , than the comparison group . CONCLUSIONS : This is the first r and omized , controlled trial to demonstrate the efficacy of a comprehensive developmental behavioral intervention for toddlers with ASD for improving cognitive and adaptive behavior and reducing severity of ASD diagnosis . Results of this study underscore the importance of early detection of and intervention in autism",
"Children with autism exhibit significant deficits in imitation skills . Reciprocal Imitation Training ( RIT ) , a naturalistic imitation intervention , was developed to teach young children with autism to imitate during play . This study used a r and omized controlled trial to evaluate the efficacy of RIT on elicited and spontaneous imitation skills in 21 young children with autism . Results found that children in the treatment group made significantly more gains in elicited and spontaneous imitation , replicating previous single-subject design studies . Number of spontaneous play acts at pre-treatment was related to improvements in imitation during the intervention , suggesting that children with a greater play repertoire make greater gains during RIT",
"PURPOSE This r and omized group experiment compared the efficacy of 2 communication interventions ( Responsive Education and Prelinguistic Milieu Teaching [ RPMT ] and the Picture Exchange Communication System [ PECS ] ) on spoken communication in 36 preschoolers with autism spectrum disorders ( ASD ) . METHOD Each treatment was delivered to children for a maximum total of 24 hr over a 6-month period . Spoken communication was assessed in a rigorous test of generalization at pretreatment , posttreatment , and 6-month follow-up periods . RESULTS PECS was more successful than RPMT in increasing the number of nonimitative spoken communication acts and the number of different nonimitative words used at the posttreatment period . Considering growth over all 3 measurement periods , an exploratory analysis showed that growth rate of the number of different nonimitative words was faster in the PECS group than in the RPMT group for children who began treatment with relatively high object exploration . In contrast , analogous slopes were steeper in the RPMT group than in the PECS group for children who began treatment with relatively low object exploration",
"Many children with Autism Spectrum Disorders ( ASD ) participate in social skills or Theory of Mind ( ToM ) treatments . However , few studies have shown evidence for their effectiveness . The current study used a r and omized controlled design to test the effectiveness of a 16-week ToM treatment in 8–13 year old children with ASD and normal IQs ( n = 40 ) . The results showed that , compared to controls , the treated children with ASD improved in their conceptual ToM skills , but their elementary underst and ing , self reported empathic skills or parent reported social behaviour did not improve . Despite the effects on conceptual underst and ing , the current study does not indicate strong evidence for the effectiveness of a ToM treatment on the daily life mindreading skills ",
"A r and omized controlled design was employed to evaluate a social skills intervention for children with pervasive developmental disorders . Aims included evaluating the acceptability of the program and gathering preliminary evidence on efficacy . Forty-four children , ages 8–11 years , were r and omly assigned to treatment or wait list . Treatment consisted of a 16-week group intervention design ed to teach appropriate social behavior . Between group comparisons showed that children in treatment were rated as improved on the primary outcome measure , ( unblinded parent report ) , but not on the secondary outcome measure , a parent question naire . Parents reported a high level of satisfaction with the intervention . The study supports the feasibility of this intervention to families and highlights challenges for future research in social skills intervention",
"This study aim ed to determine if a joint attention intervention would result in greater joint engagement between caregivers and toddlers with autism . The intervention consisted of 24 caregiver-mediated sessions with follow-up 1 year later . Compared to caregivers and toddlers r and omized to the waitlist control group the immediate treatment ( IT ) group made significant improvements in targeted areas of joint engagement . The IT group demonstrated significant improvements with medium to large effect sizes in their responsiveness to joint attention and their diversity of functional play acts after the intervention with maintenance of these skills 1 year post-intervention . These are among the first r and omized controlled data to suggest that short-term parent-mediated interventions can have important effects on core impairments in toddlers with autism . Clinical Trials # : NCT00065910",
"BACKGROUND Deficits in joint attention are considered by many research ers to be an early predictor of childhood autism ( e.g. , Osterling & Dawson , 1994 ) and are considered to be pivotal to deficits in language , play , and social development in this population ( Mundy , 1995 ) . Although many research ers have noted the importance of joint attention deficits in the development of children with autism ( e.g. , Mundy , Sigman , & Kasari , 1994 ) and have called for intervention strategies ( e.g. , Mundy & Crowson , 1997 ) , few studies have attempted to target joint attention . In this study , joint attention behaviors were taught to children with autism using a behavior modification procedure . METHODS A multiple-baseline design was implemented to evaluate intervention effects . The following target behaviors were included in the intervention : 1 ) Responding to showing , pointing , and gaze shifting of adult ; 2 ) Coordinated gaze shifting ( i.e. , coordinated joint attention ) ; and 3 ) Pointing ( with the purpose of sharing , not requesting ) . Generalization to setting and parent , follow-up sessions , and social validation measures were also analyzed . RESULTS Joint attention behaviors were effectively trained and targeted behaviors generalized to other setting s. In addition , positive changes were noted by naive observers using social validation measures . CONCLUSIONS Integrating joint attention training into existing interventions may be important for children with autism . In addition , training parents in these techniques may help to maintain joint attention skills outside of the treatment setting",
"This pilot study tested the effect of cognitive behavioral therapy ( CBT ) on parent-reported autism symptoms . Nineteen children with autism spectrum disorders and an anxiety disorder ( 7–11 years old ) were r and omly assigned to 16 sessions of CBT or a waitlist condition . The CBT program emphasized in vivo exposure supported by parent training and school consultation to promote social communication and emotion regulation skills . Parents completed a st and ardized autism symptom checklist at baseline and posttreatment/postwaitlist and 3-month follow-up assessment s. CBT outperformed the waitlist condition at posttreatment/postwaitlist on total parent-reported autism symptoms ( Cohen ’s d effect size = .77 ) . Treatment gains were maintained at 3-month follow-up . Further investigation of this intervention modality with larger sample s and broader outcome measures appears to be indicated",
"A repeated- measures , waiting list control design was used to assess efficacy of a social skills intervention for autistic spectrum children focused on individual and group LEGO © play . The intervention combined aspects of behavior therapy , peer modeling and naturalistic communication strategies . Close interaction and joint attention to task play an important role in both group and individual therapy activities . The goal of treatment was to improve social competence ( SC ) which was construed as reflecting three components : ( 1 ) motivation to initiate social contact with peers ; ( 2 ) ability to sustain interaction with peers for a period of time ; and ( 3 ) overcoming autistic symptoms of aloofness and rigidity . Measures for the first two variables were based on observation of subjects in unstructured situations with peers ; and the third variable was assessed using a structured rating scale , the SI subscale of the GARS . Results revealed significant improvement on all three measures at both 12 and 24 weeks with no evidence of gains during the waiting list period . No gender differences were found on outcome , and age of clients was not correlated with outcome . LEGO © play appears to be a particularly effective medium for social skills intervention , and other research ers and clinicians are encouraged to attempt replication of this work , as well as to explore use of LEGO © in other method ologies , or with different clinical population",
"Summary Background Results of small trials suggest that early interventions for social communication are effective for the treatment of autism in children . We therefore investigated the efficacy of such an intervention in a larger trial . Methods Children with core autism ( aged 2 years to 4 years and 11 months ) were r and omly assigned in a one-to-one ratio to a parent-mediated communication-focused ( Preschool Autism Communication Trial [ PACT ] ) intervention or treatment as usual at three specialist centres in the UK . Those assigned to PACT were also given treatment as usual . R and omisation was by use of minimisation of probability in the marginal distribution of treatment centre , age ( ≤42 months or > 42 months ) , and autism severity ( Autism Diagnostic Observation Schedule-Generic [ ADOS-G ] algorithm score 12–17 or 18–24 ) . Primary outcome was severity of autism symptoms ( a total score of social communication algorithm items from ADOS-G , higher score indicating greater severity ) at 13 months . Complementary secondary outcomes were measures of parent-child interaction , child language , and adaptive functioning in school . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N58133827 . Results 152 children were recruited . 77 were assigned to PACT ( London [ n=26 ] , Manchester [ n=26 ] , and Newcastle [ n=25 ] ) ; and 75 to treatment as usual ( London [ n=26 ] , Manchester [ n=26 ] , and Newcastle [ n=23 ] ) . At the 13-month endpoint , the severity of symptoms was reduced by 3·9 points ( SD 4·7 ) on the ADOS-G algorithm in the group assigned to PACT , and 2·9 ( 3·9 ) in the group assigned to treatment as usual , representing a between-group effect size of −0·24 ( 95 % CI −0·59 to 0·11 ) , after adjustment for centre , sex , socioeconomic status , age , and verbal and non-verbal abilities . Treatment effect was positive for parental synchronous response to child ( 1·22 , 0·85 to 1·59 ) , child initiations with parent ( 0·41 , 0·08 to 0·74 ) , and for parent-child shared attention ( 0·33 , −0·02 to 0·68 ) . Effects on directly assessed language and adaptive functioning in school were small . Interpretation On the basis of our findings , we can not recommend the addition of the PACT intervention to treatment as usual for the reduction of autism symptoms ; however , a clear benefit was noted for parent-child dyadic social communication . Funding UK Medical Research Council , and UK Department for Children , Schools and Families",
"This study tested the efficacy of a new social skills intervention , SocialSkillsGRoupINtervention-High Functioning Autism ( S.S.GRIN-HFA ) , design ed to improve social behaviors in children with high functioning autism spectrum disorders . Fifty-five children were r and omly assigned to S.S.GRIN-HFA treatment ( n = 27 ) or control ( i.e. , traditional S.S.GRIN intervention ; n = 28 ) . Examination of the direction and magnitude of change in functioning revealed that children who participated in S.S.GRIN-HFA exhibited significantly greater mastery of social skill concepts compared to children in the control group . Parents of S.S.GRIN-HFA group participants reported an improved sense of social self-efficacy , whereas parents of control participants reported a decline . The advantages of a specialized intervention such as S.S.GRIN-HFA , design ed specifically for children with high functioning autism spectrum disorders , are discussed",
"Imitation is an early skill thought to play a role in social development , leading some to suggest that teaching imitation to children with autism should lead to improvements in social functioning . This study used a r and omized controlled trial to evaluate the effect of a focused imitation intervention on initiation of joint attention and social-emotional functioning in 27 young children with autism . Results indicated the treatment group made significantly more gains in joint attention initiations at post-treatment and follow-up and social-emotional functioning at follow-up than the control group . Although gains in social functioning were associated with treatment , a mediation analysis did not support imitation as the mechanism of action . These findings suggest the intervention improves social functioning in children with ASD",
"BACKGROUND This r and omized controlled trial compared Hanen 's ' More than Words ' ( HMTW ) , a parent-implemented intervention , to a ' business as usual ' control group . METHODS Sixty-two children ( 51 boys and 11 girls ; M age = 20 months ; SD = 2.6 ) who met criteria for autism spectrum disorders ( ASD ) and their parents participated in the study . The HMTW intervention was provided over 3.5 months . There were three measurement periods : prior to r and omization ( Time 1 ) and at 5 and 9 months post enrollment ( Times 2 and 3 ) . Children 's communication and parental responsivity were measured at each time point . Children 's object interest , a putative moderator , was measured at Time 1 . RESULTS There were no main effects of the HMTW intervention on either parental responsivity or children 's communication . However , the effects on residualized gains in parental responsivity from Time 1 to both Times 2 and 3 yielded noteworthy effect sizes ( Glass 's Δ = .71 , .50 respectively ) . In contrast , there were treatment effects on child communication gains to Time 3 that were moderated by children 's Time 1 object interest . Children with lower levels of Time 1 object interest exhibited facilitated growth in communication ; children with higher levels of object interest exhibited growth attenuation . CONCLUSIONS The HMTW intervention showed differential effects on child communication depending on a baseline child factor . HMTW facilitated communication in children with lower levels of Time 1 object interest . Parents of children who evidence higher object interest may require greater support to implement the HMTW strategies , or may require different strategies than those provided by the HMTW curriculum",
"The purpose of this study was to investigate the effects of improvisational music therapy on joint attention behaviors in pre-school children with autism . It was a r and omized controlled study employing a single subject comparison design in two different conditions , improvisational music therapy and play sessions with toys , and using st and ardized tools and DVD analysis of sessions to evaluate behavioral changes in children with autism . The overall results indicated that improvisational music therapy was more effective at facilitating joint attention behaviors and non-verbal social communication skills in children than play . Session analysis showed significantly more and lengthier events of eye contact and turn-taking in improvisational music therapy than play sessions . The implication s of these findings are discussed further",
"This r and omized group experiment compared the efficacy of 2 communication interventions ( Responsive Education and Prelinguistic Milieu Teaching [ RPMT ] and the Picture Exchange Communication System [ PECS ] ) in 36 preschoolers with autism spectrum disorders . Each treatment was delivered 3 times per week , in 20-min sessions , for 6 months . The results revealed that the RPMT facilitated the frequency of generalized turn taking and generalized initiating joint attention more than did the PECS . The latter effect occurred only for children who began treatment with at least some initiating joint attention . In contrast , the PECS facilitated generalized requests more than the RPMT in children with very little initiating joint attention prior to treatment . These effect sizes were large",
"This study evaluated Mind Reading , an interactive systematic guide to emotions , for its effectiveness in teaching adults with Asperger syndrome ( AS ) and high-functioning autism ( HFA ) to recognize complex emotions in faces and voices . Experiment 1 tested a group of adults diagnosed with AS/HFA ( n = 19 ) who used the software at home for 10 - 15 weeks . Participants were tested on recognition of faces and voices at three different levels of generalization . A matched control group of adults with AS/HFA ( n = 22 ) were assessed without any intervention . In addition , a third group of general population controls ( n = 24 ) was tested . Experiment 2 repeated the design of Experiment 1 with a group of adults with AS/HFA who used the software at home and met in a group with a tutor on a weekly basis . They were matched to a control group of adults with AS/HFA attending social skills training and to a general population control group ( n = 13 for all three groups ) . In both experiments the intervention group improved significantly more than the control group on close , but not distant , generalization tasks . Verbal IQ had significant effects in Experiment 2 . Using Mind Reading for a relatively short period of time allows users to learn to recognize a variety of complex emotions and mental states . However , additional methods are required to enhance generalization",
"This r and omized controlled trial compared results obtained after 12 months of nonintensive parent training plus care-as-usual and care-as-usual alone . The training focused on stimulating joint attention and language skills and was based on the intervention described by Drew et al. ( Eur Child Adolesc Psychiatr 11:266–272 , 2002 ) . Seventy-five toddlers with autism spectrum disorder ( 65 autism , 10 PDD-NOS , mean age = 34.4 months , SD = 6.2 ) were enrolled . Analyses were conducted on a final sample of 67 children ( lost to follow-up = 8) . No significant intervention effects were found for any of the primary ( language ) , secondary ( global clinical improvement ) , or mediating ( child engagement , early precursors of social communication , or parental skills ) outcome variables , suggesting that the ‘ Focus parent training ’ was not of additional value to the more general care-as-usual",
"OBJECTIVE The vast majority of children with an autism spectrum disorder ( ASD ) attend public preschools at some point in their childhood . Community preschool practice s often are not evidence based , and almost none target the prelinguistic core deficits of ASD . This study investigated the effectiveness of public preschool teachers implementing a vali date d intervention ( the Joint Attention and Symbolic Play/Engagement and Regulation intervention ; JASP/ER ) on a core deficit of autism , initiating joint attention . METHOD Sixteen dyads ( preschoolers with ASD and the public school teachers who worked in the child 's classroom ) were r and omly assigned to the 6-week JASP/ER intervention or a control group . RESULTS At the end of the intervention , JASP/ER teachers used more JASP/ER strategies than the control teachers , and JASP/ER preschoolers used more joint attention in their classroom than control children . Additionally , JASP/ER children spent more time in supported engagement and less time in object engagement than control preschoolers on a taped play interaction . CONCLUSIONS Findings suggest that teachers were able to improve a core deficit of children with ASD in a public preschool context ",
"Adults with autism experience significant impairments in social and non-social information processing for which few treatments have been developed . This study conducted an 18-month uncontrolled trial of Cognitive Enhancement Therapy ( CET ) , a comprehensive cognitive rehabilitation intervention , in 14 verbal adults with autism spectrum disorder to investigate its feasibility , acceptability , and initial efficacy in treating these impairments . Results indicated that CET was satisfying to participants , with high treatment attendance and retention . Effects on cognitive deficits and social behavior were also large ( d = 1.40–2.29 ) and statistically significant ( all p CET is a feasible , acceptable , and potentially effective intervention for remediating the social and non-social cognitive impairments in verbal adults with autism",
"& NA ; This study reports on the results of a r and omized controlled trial that evaluated a caregiverbased intervention program for children with autism in community day‐care centers . Thirty‐five preschool children with a DSM III‐R diagnosis of autism or pervasive developmental disorder were r and omized to an experimental or control group . Children in the experimental group were enrolled in day care and their parents and child care workers received a 12‐week intervention consisting of lectures and on‐site consultations to day‐care centers . In addition , supportive work was undertaken with families . Control subjects received day care alone . In the experimental group , there were greater gains in language abilities , significant increases in caregivers ' knowledge about autism , greater perception of control on the part of mothers , and greater parent satisfaction . We conclude that this research design demonstrated that the intervention was significantly superior to day care alone",
"Young children with pervasive developmental disorder were r and omly assigned to intensive treatment or parent training . The intensive treatment group ( 7 with autism , 8 with pervasive developmental disorder not otherwise specified -- NOS ) averaged 24.52 hours per week of individual treatment for one year , gradually reducing hours over the next 1 to 2 years . The parent training group ( 7 with autism , 6 with pervasive developmental disorder NOS ) received 3 to 9 months of parent training . The groups appeared similar at intake on all measures ; however , at follow-up the intensive treatment group outperformed the parent training group on measures of intelligence , visual-spatial skills , language , and academics , though not adaptive functioning or behavior problems . Children with pervasive developmental disorder NOS may have gained more than those with autism",
"An increasing body of literature has indicated that social stories are an effective way to teach individuals diagnosed with autism appropriate social behavior . This study compared two formats of a social story targeting the improvement of social skills during game play using a pretest posttest repeated measures r and omized control group design . A total of 45 children diagnosed with Autism Spectrum Disorder ( ASD ) ages 7–14 were r and omly assigned to st and ard , directive , or control story conditions . Results demonstrated that the st and ard and directive story formats were equally as effective in eliciting , generalizing and maintaining the targeted social skills in participants who had prior game play experience and Verbal Comprehension Index ( VCI ) scores from the WISC-IV intelligence test in the borderline range or above",
"ABSTRACT . This study compares the effects of relationship-focused early intervention on toddlers and preschool-age children who were classified as having either pervasive developmental disorders ( PDDs ) ( N = 20 ) or developmental disabilities ( DDs ) ( N = 30 ) . The intervention was conducted over a 1-year period through weekly individual parent-child sessions . It focused on helping parents use responsive teaching strategies to encourage their children to acquire and use pivotal developmental behaviors that addressed their individualized developmental needs . Before and after comparisons indicated significant increases in parents ' responsiveness and children 's pivotal behavior . Both groups of children made significant improvements in their cognitive , communication , and socioemotional functioning . However , children with PDDs made statistically greater improvements on the developmental measures than children with DDs . On several developmental measures , children 's improvements were related to increases in both their parents ' responsiveness and their own pivotal behavior",
"The prevalence of pervasive developmental disorders ( PDD ) is not well established and needs monitoring . We investigated the prevalence of PDDs in the 1999 nationwide British survey of child and adolescent mental health . A r and omized stratified sample of children ( n = 12,529 ) aged 5 - 15 was generated from Child Benefit Records . Trained interviewers interviewed parents and youths aged 11 or older with a st and ardized diagnostic interview ( Development and Well-Being Assessment ) and question naire data ( Strengths and Difficulties Question naire ) were obtained from teachers and parents who also completed self-report measures of psychological distress . A team of experienced clinicians using all data sources achieved final diagnostic determination . A total of 10,438 ( 83 % ) interviews were conducted . There were two girls with Rett syndrome ( weighted prevalence : 3.8/10,000 girls ) and 27 children with other PDDs ( weighted prevalence : 26.1/10,000 ) . Compared to children with a psychiatric disorder other than PDD , social but not behavioural problems were more frequent in the PDD group . Parents of children with PDDs had higher rates of psychological distress than those from the two comparison groups . Consistent with other recent surveys , PDD rates are higher than those reported 30 years ago . The burden associated with PDDs is very high",
"BACKGROUND An emerging body of evidence indicates that relative to typically developing children , children with autism are selectively impaired in their ability to recognize facial identity . A critical question is whether face recognition skills can be enhanced through a direct training intervention . METHODS In a r and omized clinical trial , children diagnosed with autism spectrum disorder were pre-screened with a battery of subtests ( the Let 's Face It ! Skills battery ) examining face and object processing abilities . Participants who were significantly impaired in their face processing abilities were assigned to either a treatment or a waitlist group . Children in the treatment group ( N = 42 ) received 20 hours of face training with the Let 's Face It ! ( LFI ! ) computer-based intervention . The LFI ! program is comprised of seven interactive computer games that target the specific face impairments associated with autism , including the recognition of identity across image changes in expression , viewpoint and features , analytic and holistic face processing strategies and attention to information in the eye region . Time 1 and Time 2 performance for the treatment and waitlist groups was assessed with the Let 's Face It ! Skills battery . RESULTS The main finding was that relative to the control group ( N = 37 ) , children in the face training group demonstrated reliable improvements in their analytic recognition of mouth features and holistic recognition of a face based on its eyes features . CONCLUSION These results indicate that a relatively short-term intervention program can produce measurable improvements in the face recognition skills of children with autism . As a treatment for face processing deficits , the Let 's Face It ! program has advantages of being cost-free , adaptable to the specific learning needs of the individual child and suitable for home and school applications",
"High-functioning autism ( HFA ) is characterized by persistent impairment in social interaction despite the absence of mental retardation . Although an increasing number of group-based programs for the improvement of social skills have been described , r and omized controlled trials are needed to evaluate their efficacy . To compare the effect of a Social Skills Training Group-based Program ( SST-GP ) and a Leisure Activities Group-based Program ( LA-GP ) on the perception of facial emotions and quality of life ( QoL ) in young people with HFA . Eligible patients were children and adolescents with HFA . Participants were r and omized to the SST or LA group . The primary outcome was defined as an improvement of 2 points in error rates for facial emotion labeling ( DANVA2 ) from baseline . After the 6-month training period , the SST Group made fewer errors in labeling anger on adult faces , whereas error rates in the LA Group remained stable . Progress in the ability to recognize anger in the SST Group was due to better recognition of low intensity stimuli on adult faces . QoL increased in the SST Group in the dimension of school environment , as a marker of the transfer of skills acquired in the treatment setting to their use in the community . The SST-GP had higher efficacy than the LA-GP . Data justify replication using larger sample",
"Autism is a chronic pervasive neurodevelopmental disorder characterized by the early onset of social and communicative impairments as well as restricted , ritualized , stereotypic behavior . The endophenotype of autism includes neuropsychological deficits , for instance a lack of “ Theory of Mind ” and problems recognizing facial affect . In this study , we report the development and evaluation of a computer-based program to teach and test the ability to identify basic facially expressed emotions . 10 adolescent or adult subjects with high-functioning autism or Asperger-syndrome were included in the investigation . A priori the facial affect recognition test had shown good psychometric properties in a normative sample ( internal consistency : rtt=.91-.95 ; retest reliability : rtt=.89-.92 ) . In a prepost design , one half of the sample was r and omly assigned to receive computer treatment while the other half of the sample served as control group . The training was conducted for five weeks , consisting of two hours training a week . The trained individuals improved significantly on the affect recognition task , but not on any other measure . Results support the usefulness of the program to teach the detection of facial affect . However , the improvement found is limited to a circumscribed area of social-communicative function and generalization is not ensured",
"Data from two groups of children who were r and omly allocated to those groups showed that the ability of children with ASD to identify and label basic and complex facial expressions following a 3-week home based DVD intervention significantly improved when viewing The Transporters DVD . Improvements in emotion recognition appear related to the content of the DVD as participants in a control group who observed an alternate DVD showed no such improvement . Although social behaviour improved significantly as a result of watching The Transporters , a significant improvement in social behaviour was however , also observed in the Thomas the Tank Engine condition suggesting the unique content of The Transporters DVD was not pivotal to the improvement of social behaviour in general",
"Thirty-five children diagnosed with autism were r and omly assigned to either a joint attention or a symbolic play intervention . During the 5—8 week treatment , three novel probes were administered to determine mastery of joint attention skills . The probes consisted of auditory and visual stimuli , such as a loud spider crawling or a musical ball bouncing . The current study examined affect , gaze , joint attention behaviors , and verbalizations at three different time points of intervention . Results revealed that children r and omized to the joint attention group were more likely to acknowledge the probe and engage in shared interactions between intervener and probe upon termination of intervention . Additionally , the joint attention group improved in the proportion of time spent sharing coordinated joint looks between intervener and probe . These results suggest that generalization of joint attention skills to a novel probe did occur for the group targeting joint attention and provides further evidence of the effectiveness of the joint attention intervention",
"Based on earlier studies , an adult ’s imitations of the behaviors of children with autism lead to increased social behavior in the children . The present study explored the effects of repeated sessions of imitation . Twenty children were recruited from a school for children with autism to attend three sessions during which an adult either imitated all of the children ’s behaviors or simply played with the child . During the second session the children in the imitation group spent a greater proportion of time showing distal social behaviors toward the adult including : ( 1 ) looking ; ( 2 ) vocalizing ; ( 3 ) smiling ; and ( 4 ) engaging in reciprocal play . During the third session , the children in the imitation group spent a greater proportion of time showing proximal social behaviors toward the adult including : ( 1 ) being close to the adult ; ( 2 ) sitting next to the adult ; and ( 3 ) touching the adult . These data suggest the potential usefulness of adult imitative behavior as an early intervention",
"BACKGROUND Psychosocial treatments are the mainstay of management of autism in the UK but there is a notable lack of a systematic evidence base for their effectiveness . R and omised controlled trial ( RCT ) studies in this area have been rare but are essential because of the developmental heterogeneity of the disorder . We aim ed to test a new theoretically based social communication intervention targeting parental communication in a r and omised design against routine care alone . METHODS The intervention was given in addition to existing care and involved regular monthly therapist contact for 6 months with a further 6 months of 2-monthly consolidation sessions . It aim ed to educate parents and train them in adapted communication tailored to their child 's individual competencies . Twenty-eight children with autism were r and omised between this treatment and routine care alone , stratified for age and baseline severity . Outcome was measured at 12 months from commencement of intervention , using st and ardised instruments . RESULTS All cases studied met full Autism Diagnostic Interview ( ADI ) criteria for classical autism . Treatment and controls had similar routine care during the study period and there were no study dropouts after treatment had started . The active treatment group showed significant improvement compared with controls on the primary outcome measure -- Autism Diagnostic Observation Schedule ( ADOS ) total score , particularly in reciprocal social interaction-- and on secondary measures of expressive language , communicative initiation and parent-child interaction . Suggestive but non-significant results were found in Vinel and Adaptive Behaviour Scales ( Communication Sub-domain ) and ADOS stereotyped and restricted behaviour domain . CONCLUSIONS A R and omised Treatment Trial design of this kind in classical autism is feasible and acceptable to patients . This pilot study suggests significant additional treatment benefits following a targeted ( but relatively non-intensive ) dyadic social communication treatment , when compared with routine care . The study needs replication on larger and independent sample s. It should encourage further RCT design s in this area",
"The inability to imitate is a salient diagnostic marker for autism . It has been suggested that for children with autism , imitation may be a prerequisite skill that can assist in the development of various skills . Using a multiple baseline design across subjects , the purpose of this research was to determine if two interventions , reciprocal imitation training and video modeling were effective in promoting imitation acquisition in young children with autism . Six boys were matched across various features ( i.e. , age , language , autism severity ) and r and omly placed in a treatment condition . Results indicated that all six participants increased their imitation skills to varying degrees in both conditions , and imitation maintained and generalized at higher than baseline levels post treatment",
"OBJECTIVE To assess the effectiveness of expert training and consultancy for teachers of children with autism spectrum disorder in the use of the Picture Exchange Communication System ( PECS ) . METHOD DESIGN Group r and omised , controlled trial ( 3 groups : immediate treatment , delayed treatment , no treatment ) . PARTICIPANTS 84 elementary school children , mean age 6.8 years . TREATMENT A 2-day PECS workshop for teachers plus 6 half-day , school-based training sessions with expert consultants over 5 months . OUTCOME MEASURES Rates of : communicative initiations , use of PECS , and speech in the classroom ; Autism Diagnostic Observation Schedule-Generic ( ADOS-G ) domain scores for Communication and Reciprocal Social Interaction ; scores on formal language tests . RESULTS Controlling for baseline age , developmental quotient ( DQ ) and language ; rates of initiations and PECS usage increased significantly immediately post-treatment ( Odds Ratio ( OR ) of being in a higher ordinal rate category 2.72 , 95 % confidence interval 1.22 - 6.09 , p in frequency of speech , or improvements in ADOS-G ratings or language test scores . CONCLUSIONS The results indicate modest effectiveness of PECS teacher training/consultancy . Rates of pupils ' initiations and use of symbols in the classroom increased , although there was no evidence of improvement in other areas of communication . TREATMENT effects were not maintained once active intervention ceased",
"Children with autism have specific difficulties underst and ing complex mental states like thought , belief , and false belief and their effects on behaviour . Such children benefit from focused teaching , where beliefs are likened to photographs-in-the-head . Here two studies , one with seven participants and one with 10 , tested a picture- in-the-head strategy for dealing with thoughts and behaviour by teaching children with autism about cartoon thought-bubbles as a device for representing such mental states . This prosthetic device led children with autism to pass not only false belief tests , but also related theory of mind tests . These results confirm earlier findings of the efficacy of picture-in-the-head teaching about mental states , but go further in showing that thought-bubble training more easily extends to children ’s underst and ing of thoughts ( not just behaviour ) and to enhanced performance on several transfer tasks . Thought-bubbles provide a theoretically interesting as well as an especially easy and effective teaching technique",
"This r and omized controlled trial looked at the effect of a new computer program design ed to teach people with autistic spectrum disorders to better recognize and predict emotional responses in others . Two groups of 11 children ( age 12 - 18 ) with autism or Asperger syndrome at two special schools participated : one group used the computer program for 10 half-hour sessions over 2 weeks . Within-program data showed a significant reduction in errors made from first to last use . Students were assessed pre- and post-intervention using facial expression photographs , cartoons depicting emotion-laden situations , and non-literal stories . Scores were not related to age or verbal ability . The experimental group made gains relative to the control group on all three measures . Gains correlated significantly with the number of times the computer program was used and results suggest positive effects . Further research could assess whether these gains generalized into real life or improved performance on theory of mind measures",
"BACKGROUND Social and communication impairments are core deficits and prognostic indicators of autism . We evaluated the impact of supplementing a comprehensive intervention with a curriculum targeting socially synchronous behavior on social outcomes of toddlers with autism spectrum disorders ( ASD ) . METHODS Fifty toddlers with ASD , ages 21 to 33 months , were r and omized to one of two six-month interventions : Interpersonal Synchrony or Non-Interpersonal Synchrony . The interventions provided identical intensity ( 10 hours per week in classroom ) , student-to-teacher ratio , schedule , home-based parent training ( 1.5 hours per month ) , parent education ( 38 hours ) , and instructional strategies , except the Interpersonal Synchrony condition provided a supplementary curriculum targeting socially engaged imitation , joint attention , and affect sharing ; measures of these were primary outcomes . Assessment s were conducted pre-intervention , immediately post-intervention , and , to assess maintenance , at six-month follow-up . R and om effects models were used to examine differences between groups over time . Secondary analyses examined gains in expressive language and nonverbal cognition , and time effects during the intervention and follow-up periods . RESULTS A significant treatment effect was found for socially engaged imitation ( p = .02 ) , with more than doubling ( 17 % to 42 % ) of imitated acts paired with eye contact in the Interpersonal Synchrony group after the intervention . This skill was generalized to unfamiliar context s and maintained through follow-up . Similar gains were observed for initiation of joint attention and shared positive affect , but between-group differences did not reach statistical significance . A significant time effect was found for all outcomes ( p toddlers to identify an active ingredient for enhancing socially engaged imitation . Adding social engagement targets to intervention improves short-term outcome at no additional cost to the intervention . The social , language , and cognitive gains in our participants provide evidence for plasticity of these developmental systems in toddlers with ASD . http://www . clinical trials.gov/ct2/show/NCT00106210?term = l and a&rank = 3",
"In this pilot study , we tested the effects of a novel intervention ( JASPER , Joint Attention Symbolic Play Engagement and Regulation ) on 3 to 5 year old , minimally verbal children with autism who were attending a non-public preschool . Participants were r and omized to a control group ( treatment as usual , 30 h of ABA-based therapy per week ) or a treatment group ( substitution of 30 min of JASPER treatment , twice weekly during their regular program ) . A baseline of 12 weeks in which no changes were noted in core deficits was followed by 12 weeks of intervention for children r and omized to the JASPER treatment . Participants in the treatment group demonstrated greater play diversity on a st and ardized assessment . Effects also generalized to the classroom , where participants in the treatment group initiated more gestures and spent less time unengaged . These results provide further support that even brief , targeted interventions on joint attention and play can improve core deficits in minimally verbal children with ASD",
"This RCT examined the efficacy of a manualized social intervention for children with HFASDs . Participants were r and omly assigned to treatment or wait-list conditions . Treatment included instruction and therapeutic activities targeting social skills , face-emotion recognition , interest expansion , and interpretation of non-literal language . A response-cost program was applied to reduce problem behaviors and foster skills acquisition . Significant treatment effects were found for five of seven primary outcome measures ( parent ratings and direct child measures ) . Secondary measures based on staff ratings ( treatment group only ) corroborated gains reported by parents . High levels of parent , child and staff satisfaction were reported , along with high levels of treatment fidelity . St and ardized effect size estimates were primarily in the medium and large ranges and favored the treatment group",
"BACKGROUND Children with autism have difficulties in emotion recognition and a number of interventions have been design ed to target these problems . However , few emotion training interventions have been trialled with young children with autism and co-morbid ID . This study aim ed to evaluate the efficacy of an emotion training programme for a group of young children with autism with a range of intellectual ability . METHODS Participants were 55 children with autistic disorder , aged 4 - 7 years ( FSIQ 42 - 107 ) . Children were r and omly assigned to an intervention ( n = 28 ) or control group ( n = 27 ) . Participants in the intervention group watched a DVD design ed to teach emotion recognition skills to children with autism ( the Transporters ) , whereas the control group watched a DVD of Thomas the Tank Engine . Participants were assessed on their ability to complete basic emotion recognition tasks , mindreading and theory of mind ( TOM ) tasks before and after the 4-week intervention period , and at 3-month follow-up . RESULTS Analyses controlled for the effect of chronological age , verbal intelligence , gender and DVD viewing time on outcomes . Children in the intervention group showed improved performance in the recognition of anger compared with the control group , with few improvements maintained at 3-month follow-up . There was no generalisation of skills to TOM or social skills . CONCLUSIONS The Transporters programme showed limited efficacy in teaching basic emotion recognition skills to young children with autism with a lower range of cognitive ability . Improvements were limited to the recognition of expressions of anger , with poor maintenance of these skills at follow-up . These findings provide limited support for the efficacy of the Transporters programme for young children with autism of a lower cognitive range",
"Through behavioural analysis , this study investigated the social-motivational aspects of musical interaction between the child and the therapist in improvisational music therapy by measuring emotional , motivational and interpersonal responsiveness in children with autism during joint engagement episodes . The r and omized controlled study ( n = 10 ) employed a single subject comparison design in two different conditions , improvisational music therapy and toy play sessions , and DVD analysis of sessions . Improvisational music therapy produced markedly more and longer events of ` joy ' , ` emotional synchronicity ' and ` initiation of engagement ' behaviours in the children than toy play sessions . In response to the therapist 's interpersonal dem and s , ` compliant ( positive ) responses ' were observed more in music therapy than in toy play sessions , and ` no responses ' were twice as frequent in toy play sessions as in music therapy . The results of this exploratory study found significant evidence supporting the value of music therapy in promoting social , emotional and motivational development in children with autism",
"BACKGROUND Anecdotal reports and some studies suggest that equine-assisted activities may be beneficial in autism spectrum disorders ( ASD ) . OBJECTIVE To examine the effects ofequine-assisted activities on overall severity of autism symptoms using the Childhood Autism Rating Scale ( CARS ) and the quality ofparent-child interactions using the Timberlawn Parent-Child Interaction Scale . In addition , this study examined changes in sensory processing , quality of life , and parental treatment satisfaction . DESIGN AND PARTICIPANTS Children with ASD were evaluated at four time points : ( 1 ) before beginning a 3-to-6 month waiting period , ( 2 ) before starting the riding treatment , and ( 3 ) after 3 months and ( 4 ) 6 months of riding . Twenty-four participants completed the waiting list period and began the riding program , and 20 participants completed the entire 6 months of riding . Pretreatment was compared to posttreatment with each child acting as his or her own control . RESULTS A reduction in the severity of autism symptoms occurred with the therapeutic riding treatment . There was no change in CARS scores during the pretreatment baseline period ; however , there was a significant decrease after treatment at 3 months and 6 months of riding . The Timberlawn Parent-Child Interaction Scale showed a significant improvement in Mood and Tone at 3 months and 6 months of riding and a marginal improvement in the reduction of Negative Regard at 6 months of riding . The parent-rated quality of life measure showed improvement , including the pretreatment waiting period . All of the ratings in the Treatment Satisfaction Survey were between good and very good . CONCLUSION These results suggest that children with ASD benefit from equine-assisted activities",
"The study evaluates a social-communication-based approach to autism intervention aim ed at improving the social interaction skills of children with autism spectrum disorder . We report preliminary results from an ongoing r and omized controlled trial of 51 children aged 2 years 0 months to 4 years 11 months . Participants were assigned to either a target treatment or community treatment group . Families in the target treatment group were given 2 hours of therapy and coaching each week in an intervention emphasizing social-interaction and the parent-child relationship . Children in the community treatment group received a variety of services averaging 3.9 hours per week . After 12 months , outcomes were measured to determine changes in the groups in social interaction and communication . In addition , a regression analysis was conducted to determine whether changes in social interaction skills were associated with language development . Results suggest that children in the treatment group made significantly greater gains in social interaction skills in comparison to the community treatment group , but no between-group differences were found for st and ard language assessment s. Initiation of joint attention , involvement , and severity of language delay were found to be significantly associated with improvement of language skills in children with autism . Finally caregiver skills targeted by the intervention were found to be significantly associated with changes in children ’s interaction skills",
"BACKGROUND Children who show disproportionate difficulty with the pragmatic as compared with the structural aspects of language are described as having pragmatic language impairment ( PLI ) or social communication disorder ( SCD ) . Some children who have PLI also show mild social impairments associated with high-functioning autism or autism spectrum disorder ( ASD ) . There is little robust evidence of effectiveness of speech- language interventions which target the language , pragmatic or social communication needs of these children . AIMS To evaluate the effectiveness of an intensive manualized social communication intervention ( SCIP ) for children who have PLI with or without features of ASD . METHODS & PROCEDURES In a single-blind RCT design , 88 children with pragmatic and social communication needs aged 5;11 - 10;8 , recruited from UK speech and language therapy services , were r and omly assigned in a 2:1 ratio to SCIP or to treatment-as-usual . Children in the SCIP condition received up to 20 sessions of direct intervention from a specialist research speech and language therapist working with supervised assistants . All therapy content and methodology was derived from an intervention manual . A primary outcome measure of structural language and secondary outcome measures of narrative , parent-reported pragmatic functioning and social communication , blind-rated perceptions of conversational competence and teacher-reported ratings of classroom learning skills were taken pre-intervention , immediately post-intervention and at 6-month follow-up . Analysis was by intention to treat . OUTCOMES & RESULTS No significant treatment effect was found for the primary outcome measure of structural language ability or for a measure of narrative ability . Significant treatment effects were found for blind-rated perceptions of conversational competence , for parent-reported measures of pragmatic functioning and social communication , and for teacher-reported ratings of classroom learning skills . CONCLUSIONS & IMPLICATION S There is some evidence of an intervention effect on blind and parent/teacher-reported communication outcomes , but not st and ardized language assessment outcomes , for 6 - 11-year-old children who have pragmatic and social communication needs . These findings are discussed in the context of the increasingly central role of service user outcomes in providing evidence for an intervention . The substantial overlap between the presence of PLI and ASD ( 75 % ) across the whole cohort suggests that the intervention may also be applicable to some verbally able children with ASD who have pragmatic communication needs",
"BACKGROUND Deficits in joint attention ( JA ) and joint engagement ( JE ) represent a core problem in young children with autism as these affect language and social development . Studies of parent-mediated and specialist-mediated JA-intervention suggest that such intervention may be effective . However , there is little knowledge about the success of the intervention when done in preschools . AIM Assess the effects of a preschool-based JA-intervention . METHODS 61 children ( 48 males ) with autistic disorder ( 29 - 60 months ) were r and omized to either 8 weeks of JA-intervention , in addition to their preschool programs ( n = 34 ) , or to preschool programs only ( n = 27 ) . The intervention was done by preschool teachers with weekly supervision by trained counselors from Child and Adolescent Mental Health Clinics ( CAMHC ) . Changes in JA and JE were measured by blinded independent testers using Early Social Communication Scale ( ESCS ) and video taped preschool teacher-child and mother-child play at baseline and post-intervention . CLINICAL TRIALS REGISTRATION Clinical trials.gov : NCT00378157 . RESULTS Intention-to-treat analysis showed significant difference between the intervention and the control group , with the intervention group yielding more JA initiation during interaction with the preschool teachers . The effect generalized to significantly longer duration of JE with the mothers . CONCLUSIONS This is the first r and omized study to show positive and generalized effects of preschool-based JA-intervention",
"The aim of this study was to pilot test a classroom-based intervention focused on facilitating play and joint attention for young children with autism in self-contained special education classrooms . Thirty-three children with autism between the ages of 3 and 6 years participated in the study with their classroom teachers ( n = 14 ) . The 14 preschool special education teachers were r and omly assigned to one of three groups : ( 1 ) symbolic play then joint attention intervention , ( 2 ) joint attention then symbolic intervention , and ( 3 ) wait-list control period then further r and omized to either group 1 or group 2 . In the intervention , teachers participated in eight weekly individualized 1-h sessions with a research er that emphasized embedding strategies targeting symbolic play and joint attention into their everyday classroom routines and activities . The main child outcome variables of interest were collected through direct classroom observations . Findings indicate that teachers can implement an intervention to significantly improve joint engagement of young children with autism in their classrooms . Furthermore , multilevel analyses showed significant increases in joint attention and symbolic play skills . Thus , these pilot data emphasize the need for further research and implementation of classroom-based interventions targeting play and joint attention skills for young children with autism",
"Abstract . Few attempts have been made to conduct r and omised control trials ( RCTs ) of interventions for pre-school children with autism . We report findings of a pilot RCT for a parent training intervention with a focus on the development of joint attention skills and joint action routines . Twenty-four children meeting ICD-10 criteria for childhood autism ( mean age = 23 months ) were identified using the CHAT screen and r and omised to the parent training group or to local services only . A follow-up was conducted 12 months later ( mean age = 35 months ) . There was some evidence that the parent training group made more progress in language development than the local services group . However , the present pilot study was compromised by several factors : a reliance on parental report to measure language , non-matching of the groups on initial IQ , and a lack of systematic checking regarding the implementation of the parent training intervention . Furthermore , three parents in the local services group commenced intensive , home-based behavioural intervention during the course of the study . The difficulties encountered in the conduct of RCTs for pre-school children with autism are discussed . Method ological challenges and strategies for future well- design ed RCTs for autism interventions are highlighted"
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CONTEXT The sideline assessment of concussion is challenging , given its variable presentations , the limited sensitivity and specificity of sideline assessment tools , and how the presentation of the injury evolves over time . In addition , the diagnostic process , as well as the tools used to assess and manage concussion , continue to progress as research and what we know about concussion advance . This paper focuses on the initial assessment on the sideline by review ing the concussion-evaluation literature , drawing from clinical experience to emphasize a st and ardized approach , and underscoring the importance of both familiarity with the athlete and clinical judgment . OBJECTIVE To review the evidence regarding the clinical assessment of sport-related concussion on the sideline . Additional considerations included making same-day return-to-play decisions , the sensitivity and specificity of sideline testing , and the importance of ongoing assessment and follow-up of injured athletes . DATA SOURCES I conducted a systematic literature review of the assessment of concussion on the sideline . The PubMed and MEDLINE data bases were search ed using the key term athletic injuries with concussion and mild traumatic brain injury . The search was refined by adding the key terms sideline assessment and on-field assessment . In addition , select additional position statements and guidelines on concussion were included in the review . RESULTS The PubMed search using athletic injuries and concussion as key terms produced 1492 results . Refining the search by sideline assessment and on-field assessment produced 29 and 35 results , respectively . When athletic injuries and traumatic brain injury were combined , 1912 results were identified . Refining the search by sideline assessment and on-field assessment led to 28 and 35 results , respectively . Only papers that were English- language titles , original work , and limited to human participants and included sideline assessment s of sport-related concussion in athletes older than 13 years were considered for this discussion . A total of 96 papers were review ed , including systematic review s , consensus guidelines , and position statements . CONCLUSIONS The sideline assessment of sport-related concussion is challenging given the elusiveness and variability of presentation , reliance on athlete-reported symptoms , and the varying specificity and sensitivity values of sideline assessment tools . In addition , the recognition of injury and assessment often occur in a time-pressured environment , requiring rapid disposition and decision making . Clinicians should begin the evaluation by assessing for cervical spine injury , intracranial bleeding , and other injuries that can present in a similar fashion or in addition to concussion . The sideline concussion evaluation should consist of a symptom assessment and a neurologic examination that addresses cognition ( briefly ) , cranial nerve function , and balance . Emerging tools that assess visual tracking may provide additional information . The sensitivity and specificity of commonly implemented sideline assessment tools are generally good to very good , especially for symptom scores and cognitive evaluations performed within 48 hours of injury , and they are improved when a baseline evaluation is available for comparison . Serial assessment s are often necessary as objective signs and symptoms may be delayed . A st and ardized assessment is paramount in evaluating the athlete with a suspected concussion , but there is no replacement for being familiar with the athlete and using clinical judgment when the athlete seems " not right " despite a " normal " sideline assessment . Ultimately , the clinician should err on the side of caution when making a return-to-play decision
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"Background Neurocognitive testing has been endorsed as a “ cornerstone ’ of concussion management by recent Vienna and Prague meetings of the Concussion in Sport Group . Neurocognitive testing is important given the potential unreliability of athlete self-report after injury . Relying only on athletes'ormalities after injury . Study Design Case control study ; Level of evidence , 3 . Methods High school and college athletes with a diagnosed concussion were tested 2 days after injury . Postinjury neurocognitive performance ( Immediate Postconcussion Assessment and Cognitive Testing ) and symptom ( postconcussion symptom ) scores were compared with preinjury ( baseline ) scores and with those of an agex and education-matched noninjured athlete control group . “ Abnormal ” test performance was determined statistically with Reliable Change Index scores . Results Sixty-four percent of concussed athletes reported a significant increase in symptoms , as judged by postconcussion symptom scores , compared with preinjury baseline at 2 days after injury . Eighty-three percent of the concussed sample demonstrated significantly poorer neurocognitive test results relative to their own baseline performance . The addition of neurocognitive testing result ed in a net increase in sensitivity of 19 % . Ninety-three percent of the sample had either abnormal neurocognitive test results or a significant increase in symptoms , relative to their own baseline ; 30 % of a control group demonstrated either abnormalities in neurocognitive testing or elevated symptoms , as judged by postconcussion symptom scores . For the concussed group , use of symptom and neurocognitive test results result ed in an increased yield of 29 % overreliance on symptoms alone . In contrast , 0 % of the control group had both symptoms and abnormal neurocognitive testing . Conclusion Reliance on patients ’ self-reported symptoms after concussion is likely to result in underdiagnosis of concussion and may result in premature return to play . Neurocognitive testing increases diagnostic accuracy when used in conjunction with self-reported symptoms",
"CONTEXT Approximately 300 000 sport-related concussions occur annually in the United States , and the likelihood of serious sequelae may increase with repeated head injury . OBJECTIVE To estimate the incidence of concussion and time to recovery after concussion in collegiate football players . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve cohort study of 2905 football players from 25 US colleges were tested at preseason baseline in 1999 , 2000 , and 2001 on a variety of measures and followed up prospect ively to ascertain concussion occurrence . Players injured with a concussion were monitored until their concussion symptoms resolved and were followed up for repeat concussions until completion of their collegiate football career or until the end of the 2001 football season . MAIN OUTCOME MEASURES Incidence of concussion and repeat concussion ; type and duration of symptoms and course of recovery among players who were injured with a concussion during the seasons . RESULTS During follow-up of 4251 player-seasons , 184 players ( 6.3 % ) had a concussion , and 12 ( 6.5 % ) of these players had a repeat concussion within the same season . There was an association between reported number of previous concussions and likelihood of incident concussion . Players reporting a history of 3 or more previous concussions were 3.0 ( 95 % confidence interval , 1.6 - 5.6 ) times more likely to have an incident concussion than players with no concussion history . Headache was the most commonly reported symptom at the time of injury ( 85.2 % ) , and mean overall symptom duration was 82 hours . Slowed recovery was associated with a history of multiple previous concussions ( 30.0 % of those with > or =3 previous concussions had symptoms lasting > 1 week compared with 14.6 % of those with 1 previous concussion ) . Of the 12 incident within-season repeat concussions , 11 ( 91.7 % ) occurred within 10 days of the first injury , and 9 ( 75.0 % ) occurred within 7 days of the first injury . CONCLUSIONS Our study suggests that players with a history of previous concussions are more likely to have future concussive injuries than those with no history ; 1 in 15 players with a concussion may have additional concussions in the same playing season ; and previous concussions may be associated with slower recovery of neurological function",
"Objective The purpose of this pilot study was to document the nature and temporal profile of the clinical symptoms of acute sport-related concussion . Design Prospect i ve cohort study Patient Population A total of 303 elite Australian football players participating in a national competition during a single season . Outcome Measures Number and duration of symptoms , digit symbol substitution test ( DSST ) scores , time of return to play post injury . Results A total of 23 concussions were recorded over the course of the 20-week football season . No catastrophic head injuries occurred . Headache was the most common symptom and the most persistent , with 40 % of players reporting headache symptoms lasting more than 15 minutes . Ten of the players ( 43 % ) returned to sport on the day of the injury with the remainder resuming play within 2 weeks . A low likelihood of return to play on the day of injury was found where 3 or more symptoms were present or where the symptoms lasted more than 15 minutes . These findings were significantly correlated with poor DSST performance . Conclusions This pilot study suggests that both the number of postconcussive symptoms and their duration may be used as a measure of injury severity and a guide for return to play",
"Background : Sports-related concussion commonly affects the visual pathways . Current sideline protocol s test cognition and balance but do not include assessment s of visual performance . We investigated how adding a vision-based test of rapid number naming could increase our ability to identify concussed athletes on the sideline at youth and collegiate levels . Methods : Participants in this prospect i ve study included members of a youth ice hockey and lacrosse league and collegiate athletes from New York University and Long Isl and University . Athletes underwent preseason baseline assessment s using : 1 ) the King – Devick ( K-D ) test , a , 2 ) the St and ardized Assessment of Concussion ( SAC ) , a test of cognition , and 3 ) a timed t and em gait test of balance . The SAC and timed t and em gait are components of the currently used Sport Concussion Assessment Tool , 3rd Edition ( SCAT3 and Child-SCAT3 ) . In the event of a concussion during the athletic season , injured athletes were retested on the sideline/rink-side . Nonconcussed athletes were also assessed as control participants under the same testing conditions . Results : Among 243 youth ( mean age 11 ± 3 years , range 5–17 ) and 89 collegiate athletes ( age 20 ± 1 years , range 18–23 ) , baseline time scores for the K-D test were lower ( better ) with increasing participant age ( P , K-D scores worsened from baseline by an average of 5.2 seconds ; improvement by 6.4 seconds was noted for the nonconcussed controls ( n = 14 ) . The vision-based K-D test showed the greatest capacity to distinguish concussed vs control athletes based on changes from preseason baseline to postinjury ( receiver operating characteristic [ ROC ] curve areas from logistic regression models , accounting for age = 0.92 for K-D , 0.87 for timed t and em gait , and 0.68 for SAC ; P = 0.0004 for comparison of ROC curve areas ) . Conclusions : Adding a vision-based performance measure to cognitive and balance testing enhances the detection capabilities of current sideline concussion assessment . This observation in patients with mild traumatic brain injury reflects the common involvement and widespread distribution of brain pathways dedicated to vision",
"Context With increasing knowledge and research about concussion , there have been few objective studies that have used neuropsychological domain scores and postural stability to assess concussion . Objective To evaluate the recovery curve of athletes who incur sport-related concussion from repeated serial testing of neuropsychological and posturography testing . Design A prospect i ve epidemiological model was used for the course of the study . Setting Division I intercollegiate athletics . Participants Athletes participating in football , soccer , basketball , softball , and cheerleading . Main Outcome Measures Neuropsychological scores and posturography measures were obtained preseason and serially at day 1 , day 2 , day 3 , and day 10 postconcussion . Control participants were tested at the same intervals . Neuropsychological scores were converted to st and ards score and then into domains of attention , learning , speed of information processing , concentration , memory , and verbal fluency . Analysis of covariance with the baseline test as the covariate was used to analyze the data with univariate post hoc tests performed . Results Significant group differences were found for self reported symptoms ( P = 0.001 ) , speed of information processing ( P = 0.005 ) , mean stability ( P = 0.002 ) , and vestibular function ( P = 0.003 ) between injured and control participants . A group , by day , planned comparison found that speed of information processing and composite balance measures demonstrated significant differences through day 10 postinjury , while symptoms and the vestibular ratio remained significant only through day 3 . Conclusions The concussion recovery curve demonstrated short-term neuropsychological and posturography deficits following injury . A comprehensive approach to concussion management should be used to assess the injury and make return-to-play decisions",
"STUDY OBJECTIVE Emergency physicians often use the Glasgow Coma Scale ( GCS ) to help guide decisions in patient care , yet the reliability of the GCS has never been tested in a typical broad sample of emergency department ( ED ) patients . We determined the interrater reliability of the GCS between emergency physicians when adult patients with altered levels of consciousness are assessed . METHODS In this prospect i ve observational study at a university Level I trauma center , we enrolled a convenience sample of ED patients older than 17 years who presented with an altered level of consciousness . Two residency-trained attending emergency physicians independently assessed and recorded the GCS score and its components ( eye , verbal , and motor ) in blinded fashion within a 5-minute period . Data were analyzed for interrater reliability by using st and ard ordinal calculations . We also created scatter plots and Bl and -Altman plots for each GCS component and for the GCS score . RESULTS One hundred thirty-one patients were screened and enrolled in the study , with 15 excluded because of protocol violations . Of the 116 remaining patients , the agreement percentage for exact total GCS was 32 % ( tau-b=0.739 ; Spearman rho=0.864 ; Spearman rho2=75 % ) . Agreement percentage for GCS components were eye 74 % ( tau-b=0.715 ; Spearman rho=0.757 ; Spearman rho2=57 % ) , verbal 55 % ( tau-b=0.587 ; Spearman rho=0.665 ; Spearman rho2=44 % ) , and motor 72 % ( tau-b=0.742 ; Spearman rho=0.808 ; Spearman rho2=65 % ) . Our Spearman 's analyses found that only approximately half ( 44 % to 65 % ) of the observed variance could be explained by the relationship between the paired component measures . For GCS components , only 55 % to 74 % of paired measures were identical , and 6 % to 17 % of them were 2 or more points apart . CONCLUSION We found only moderate degrees of interrater agreement for the GCS and its components ",
"Objective To investigate the clinical utility and sensitivity of a portable , automatic , frontal quantitative electroencephalographic ( QEEG ) acquisition device currently in development in detecting abnormal brain electrical activity after sport-related concussion . Design This was a prospect i ve , non-r and omized study of 396 high school and college football players , including cohorts of 28 athletes with concussion and 28 matched controls . All subjects underwent preseason baseline testing on measures of postconcussive symptoms , postural stability , and cognitive functioning , as well as QEEG . Clinical testing and QEEG were repeated on day of injury and days 8 and 45 postinjury for the concussion and control groups . Main Outcomes and Results The injured group reported more significant postconcussive symptoms during the first 3 days postinjury , which resolved by days 5 and 8 . Injured subjects also performed poorer than controls on neurocognitive testing on the day of injury , but no differences were evident on day 8 or day 45 . QEEG studies revealed significant abnormalities in electrical brain activity in the injured group on day of injury and day 8 postinjury , but not on day 45 . Conclusions Results from the current study on clinical recovery after sport-related concussion are consistent with early reports indicating a typical course of full recovery in symptoms and cognitive dysfunction within the first week of injury . QEEG results , however , suggest that the duration of physiological recovery after concussion may extend longer than observed clinical recovery . Further study is required to replicate and extend these findings in a larger clinical sample , and further demonstrate the utility of QEEG as a marker of recovery after sport-related concussion",
"Background Recent concussion management guidelines have suggested that athletes with mild ( grade 1 ) concussions may be returned to play if asymptomatic for 15 minutes . The purpose of this study was to assess the utility of a current concussion management guideline in classifying and managing mild concussion . Hypothesis High school athletes diagnosed with a grade 1 concussion will demonstrate measurable decline in neuropsychological functioning that persists during the 1st week of recovery . Study Design Prospect i ve study design ed to evaluate neuropsychological functioning both prior to and following concussion . Methods Forty-three high school athletes completed neuropsychological test performance and symptom ratings prior to the season and at two times during the 1st week following mild concussion . Results Thirty-six hours after injury , mildly concussed high school athletes demonstrated a decline in memory ( P self-reported symptoms ( P Athletes with grade 1 concussion demonstrated memory deficits and symptoms that persisted beyond the context in which they were injured . These data suggest that current grade 1 return-to-play recommendations that allow for immediate return to play may be too liberal . Clinical Relevance A reconsideration of current concussion grading systems appears to be warranted",
"The Glasgow Coma Scale ( GCS ) was developed for monitoring the mental status of head-injured patients in the intensive care unit . The purpose of this study is to determine the inter-rater reliability of the GCS for poisoning patients in the emergency department . Methods : This was a prospect i ve , observational study . Two observers used a st and ard assessment checklist to determine the GCS of suspected poisoning patients . Inter-rater reliability was assessed with a weighted Kappa score . Results : A total of 39 patients were enrolled . Weighted kappa for the total GCS demonstrated excellent agreement . Agreement was also good for each component of the score . Conclusion : The GCS is a reliable tool for the evaluation of mental status of poisoning patients in the emergency department",
"Background Concussion is one of the most commonly occurring injuries in sport today . The Sport Concussion Assessment Tool ( SCAT ) is a commonly used paper neurocognitive tool . To date , little is known about SCAT baseline normative values in youth athletes . Objective The purpose of this study was to determine normative values on the SCAT for male and female youth hockey players . Methods This is a secondary data analysis of pooled data from three prospect i ve cohort studies examining the risk of injury in paediatric ice hockey players aged 9–17 years . A preseason baseline demographic and injury history question naire was completed by each player . Results A total of 4193 players completed SCATs at baseline and were included in the analysis . 781 players ( 18.6 % ) reported a previous history of concussion . Fatigue and low energy followed by headache were the most commonly reported symptoms in all players . The majority of youth players could recite all five words immediately but only three words when delayed . A smaller proportion of the males were able to report the months of the year in reverse order compared with females of a similar age . The median number of digits recited in reverse order was 4 . Conclusions Youth ratings varied between age groups , gender and from previously reported ratings of varsity athletes , possibly reflecting developmental and gender differences . An underst and ing of these differences in youth athletes is important to ensure appropriate performance expectations on the SCAT and when making clinical decisions following a concussion",
"CONTEXT Lack of empirical data on recovery time following sport-related concussion hampers clinical decision making about return to play after injury . OBJECTIVE To prospect ively measure immediate effects and natural recovery course relating to symptoms , cognitive functioning , and postural stability following sport-related concussion . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve cohort study of 1631 football players from 15 US colleges . All players underwent preseason baseline testing on concussion assessment measures in 1999 , 2000 , and 2001 . Ninety-four players with concussion ( based on American Academy of Neurology criteria ) and 56 noninjured controls underwent assessment of symptoms , cognitive functioning , and postural stability immediately , 3 hours , and 1 , 2 , 3 , 5 , 7 , and 90 days after injury . MAIN OUTCOME MEASURES Scores on the Grade d Symptom Checklist ( GSC ) , St and ardized Assessment of Concussion ( SAC ) , Balance Error Scoring System ( BESS ) , and a neuropsychological test battery . RESULTS No player with concussion was excluded from participation ; 79 players with concussion ( 84 % ) completed the protocol through day 90 . Players with concussion exhibited more severe symptoms ( mean GSC score 20.93 [ 95 % confidence interval [ CI ] , 15.65 - 26.21 ] points higher than that of controls ) , cognitive impairment ( mean SAC score 2.94 [ 95 % CI , 1.50 - 4.38 ] points lower than that of controls ) , and balance problems ( mean BESS score 5.81 [ 95 % CI , -0.67 to 12.30 ] points higher than that of controls ) immediately after concussion . On average , symptoms gradually resolved by day 7 ( GSC mean difference , 0.33 ; 95 % CI , -1.41 to 2.06 ) , cognitive functioning improved to baseline levels within 5 to 7 days ( day 7 SAC mean difference , -0.03 ; 95 % CI , -1.33 to 1.26 ) , and balance deficits dissipated within 3 to 5 days after injury ( day 5 BESS mean difference , -0.31 ; 95 % CI , -3.02 to 2.40 ) . Mild impairments in cognitive processing and verbal memory evident on neuropsychological testing 2 days after concussion resolved by day 7 . There were no significant differences in symptoms or functional impairments in the concussion and control groups 90 days after concussion . CONCLUSIONS Collegiate football players may require several days for recovery of symptoms , cognitive dysfunction , and postural instability after concussion . Further research is required to determine factors that predict variability in recovery time after concussion . St and ardized measurement of postconcussive symptoms , cognitive functioning , and postural stability may enhance clinical management of athletes recovering from concussion",
"OBJECTIVE To determine the relationship between recorded head accelerations and impact locations and acute clinical outcome of symptomatology , neuropsychological , and postural stability tests after cerebral concussion in Division I collegiate football players . METHODS A prospect i ve field study was used in which accelerometers were embedded in the football helmets of 88 collegiate football players . Linear and rotational accelerations of all head impacts sustained over the course of 2004 to 2006 National Collegiate Athletic Association football seasons were collected in real-time . Change scores were calculated on clinical measures from the players ' preseason baseline to postinjury ( within 48 h ) and regressed against the recorded linear and rotational accelerations of the head at the time of the concussion . RESULTS Thirteen concussions were recorded ranging in impact magnitudes of 60.51 to 168.71 g. Linear regression showed no significant relationships between impact magnitude ( linear or rotational acceleration ) or impact location and change scores for symptom severity , postural stability , or neurocognitive function ( P > 0.05 ) . CONCLUSION Our findings suggest that football players are concussed by impacts to the head that occur at a wide range of magnitudes and that clinical measures of acute symptom severity , postural stability , and neuropsychological function all appear to be largely independent of impact magnitude and location . Because of the varying magnitudes and locations of impacts result ing in concussion as well as other factors such as the frequency of subconcussive impacts and number of previous concussions , it may be difficult to establish a threshold for concussive injury that can be applied to all football players",
"Objective To examine the utility of neuropsychological tests in assessing college athletes prior to and following a sports-related mild Traumatic Brain Injury ( mTBI ) . Design A prospect i ve study of college athletes who sustained mTBI while engaged in sport . Preinjury baseline neuropsychological test data were obtained for athletes at risk for mTBI . Following an mTBI , the athlete and his or her matched noninjured control were evaluated at 2 hours , 48 hours , 1 week , and 1 month postinjury . Setting Male and female athletes from a Division I college . Participants Male and female athletes from the football , men 's ice hockey , men 's and women 's soccer , and men 's and women 's basketball teams at Penn State University . A total of 29 injured and 20 noninjured athletes participated in the study . Interventions Neuropsychological test batteries were administered at baseline and serially following mTBI . Main Outcome Measures Post-Concussion Symptom Checklist , Hopkins Verbal Learning Test , Symbol Digit Modalities Test , Stroop Color-Word Test , Trail Making Test , VIGIL/W , List Learning , Digit Span , Penn State Cancellation Test , and Controlled Oral Word Association . Results Neuropsychological test data yielded significant differences between injured athletes and controls at 2 hours and 48 hours following cerebral concussion ; injured athletes performing significantly worse than controls . Injured athletes reported a significantly greater number of postconcussion symptoms 2 hours following injury but not at the 48-hour assessment . No multivariate group differences were found at 1 week , but univariate analyses suggested significant differences on a few measures . At 1 month postinjury , a statistically significant difference was found on one measure with injured athletes marginally outperforming controls . Conclusions Neuropsychological tests are useful in the detection of cognitive impairment following mTBI . The test data appear to be more effective than subjective report of symptoms in differentiating between injured and noninjured athletes at 48 hours postinjury . Although significant individual variability existed , most injured athletes recovered within 1 week of injury . A battery of tests , rather than any single test , is necessary to capture the variability that exists among injured athletes",
"Objective To identify an objective evaluation technique to guide return-to-play decisions following mild brain injury ( MBI ) using an agility task that incorporates cognitive and motor performance . Design Prospect i ve , controlled , repeated measures study . Setting Collegiate athletic training facility . Participants 84 athletes ( 25 male rugby players , 34 female rugby players , 25 male ice hockey players ) from 3 intercollegiate club teams participated . 9 athletes who suffered MBI during their competitive seasons and 9 matched controls completed the entire study protocol . Main Outcome Measures Time to complete an agility task on the Cybex Reactor and a postconcussive symptoms scale score were assessed in all subjects during the preseason . Injured subjects and matched controls were also assessed 1 , 3 , 5 , and 10 days postinjury . Results Repeated measures analyses of variance revealed significant differences between injured subjects and controls in postconcussion symptoms , but not agility performance . Post hoc testing revealed that injured subjects reported significantly more postconcussion symptoms on Day 1 after injury . Conclusion The methods of agility assessment used in this study appear to not be sensitive enough to detect functional impairment following MBI",
"Abstract Objective : The King-Devick Test ® ( K-D ) is a brief measure of cognitive processing speed and rapid gaze shifting that appears sensitive to the effects of sport-related concussion . This study evaluated its diagnostic and incremental validity in civilian patients with mild traumatic brain injury ( MTBI ) . Methods : Participants with MTBI ( n = 26 ) and controls with non-head injuries ( n = 33 ) were prospect ively recruited from an Emergency Department ( ED ) . They underwent a clinical evaluation including the K-D test and the Sport Concussion Assessment Tool 2 ( SCAT2 ) . Magnetic resonance imaging ( MRI ) was conducted within 10 days post-injury . Results : The patients with MTBI differed from those without MTBI on components of the SCAT2 , including the Symptom Scale ( Cohen ’s d = 1.02–1.15 , p St and ardized Assessment of Concussion ( d = 0.81 , p = 0.004 ) , but not the K-D test ( d = 0.40 , p = 0.148 ) . In a logistic regression analysis , the K-D Test did not contribute over and above these two measures in predicting group membership ( MTBI vs. control ) , p = 0.191 . Low K-D Test scores in the MTBI group ( poor SCAT2 performance , loss of consciousness or traumatic abnormalities on MRI , suggesting these cases may have been false positives . Conclusions : The present findings do not support the K-D Test for the assessment of civilian MTBI in an ED setting",
"PURPOSE We have developed a reliable and valid clinical test of reaction time ( RTclin ) that is sensitive to the acute effects of concussion . If RTclin is to be used as a sideline concussion assessment tool then the acute effects of exercise on RTclin may need to be controlled for . The purpose of this study was therefore to determine the effect of exercise on RTclin . METHODS A gender-balanced group of 42 collegiate athletes were assigned to an exercise ( n = 28 ) and a control ( n = 14 ) group using 2:1 block r and omization . The exercise group completed a grade d four-stage exercise protocol on a stationary bicycle ( 100 W × 5 min ; 150 W × 5 min ; 200 W × 5 min ; sprint × 2 min ) , whereas the control group was tested at identical periods without exercising . Mean RTclin was calculated for eight trials as the fall time of a vertically suspended rigid shaft after its release by the examiner before being caught by the athlete . RTclin was measured at baseline and after each of the four stages . RESULTS As both HR and RPE significantly increased for the four stages in the exercise group ( P 0.001 ) , mean RTclin showed a significant overall decline during repeated test administration ( P ( exercise vs control , P = 0.822 ) or group-by-stage interaction ( P = 0.169 ) effects on RTclin as assessed by repeated- measures analysis of variance . CONCLUSIONS Exercise did not appear to affect RTclin performance in this study . This suggests that RTclin measured during a sideline concussion assessment does not need to be adjusted to account for the acute effects of exercise"
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OBJECTIVES The aim of this study was to summarize and systematic ally review the literature on the prevalence of different research diagnostic criteria for temporom and ibular disorders ( RDC/TMD ) version 1.0 axis I diagnoses in patient and in the general population s. STUDY DESIGN For each of the relevant papers , the following data /information were recorded for meta- analysis and discussion : sample size and demographic features ( mean age , female-to-male ratio ) ; prevalence of the assigned diagnoses ; prevalence of the diagnoses assigned to the left and right joints , if available ; prevalence of the diagnoses assigned to the 2 genders , if available ; prevalence of the different combinations of multiple diagnoses , if available ; and prevalence of TMD ( only for community studies ) . RESULTS Twenty-one ( n = 21 ) papers were included in the review ( 15 dealing with TMD patient population s and 6 with community sample s ) . The studies on TMD patients accounted for a total of 3,463 subjects ( mean age 30.2 - 39.4 years , female-to-male ratio 3.3 ) , with overall prevalences of 45.3 % for group I muscle disorder diagnoses , 41.1 % for group II disc displacements , and 30.1 % for group III joint disorders . Studies on general population s accounted for a total of 2,491 subjects , with an overall 9.7 % prevalence for group I , 11.4 % for group IIa , and 2.6 % for group IIIa diagnoses . CONCLUSIONS Prevalence reports were highly variable across studies . Myofascial pain with or without mouth opening limitation was the commonest diagnosis in TMD patient population s , and disc displacement with reduction was the commonest diagnosis in community sample
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"Single items from a typical clinical examination have proved disappointing in their predictive value for temporom and ibular joint ( TMJ ) disc displacement . Only one criterion ( the 12 o'clock ) is used to diagnose normal disc position . According to this criterion , the posterior b and of the disc should be located at the top of the condyle , at the 12 o'clock position . The purpose of this study was to determine which signs and symptoms provide a valid prediction of the condition of the joint based on 4 magnetic resonance imaging ( MRI ) criteria used to define normal disc position . Sagittal MRI and clinical findings of 137 temporom and ibular disorder patients and 23 normal asymptomatic volunteers were used . Three calibrated and blinded observers interpreted the images . Disc position with the mouth closed was evaluated based on 4 MRI criteria : 12 , 11 , 10 o'clock , and the intermediate zone . Disc position with the mouth open was determined based on one criterion . It was considered normal if the intermediate zone of the disc was located between the condyle and the articular eminence . Joints were classified as normal or as having disc displacement with or without reduction . The sensitivity and specificity of multiple clinical parameters for predicting the condition of the joint established by each of these 4 gold-st and ard MRI criteria were then determined . Regarding disc displacement with reduction , significant differences were observed in the sensitivity and specificity of all of the clinical parameters used to predict the imaging diagnosis established by each of the criteria . Concerning disc displacement without reduction , no significant differences were observed . The intermediate zone criterion was the criterion that most accurately reflected the condition of the joint . The clinical predictability of the disorder diagnosed according to this criterion suggests that clinical findings alone are too often nonspecific as predictors of the imaging stage of disc displacement . However , we found that combining the most sensitive clinical items to predict the disorder and using an overall criterion for positivity to interpret the results led to an impressive increase in the specificity of the combination , enabling false-positive diagnoses to be excluded",
"To assess the diagnostic and behavioural overlap of headache patients with temporom and ibular disorders ( TMD ) , individuals recruited from the general population with self-described headaches were compared with non-headache controls . The examination and diagnostic procedures in the Research Diagnostic Criteria ( RDC ) for TMD were applied to both sets of subjects by a blinded examiner . Following their examination , subjects used experience sampling methods to obtain data on pain , tooth contact , masticatory muscle tension , emotional states and stress . Results showed that a significantly higher proportion of the headache patients received an RDC/TMD diagnosis of myofascial pain than non-headache controls . Headache patients also reported significantly more frequent and intense tooth contact , more masticatory muscle tension , more stress and more pain in the face/head and other parts of the body than non-headache controls . These results are similar to those reported for TMD patients and they suggest that headache patients and TMD patients overlap considerably in diagnosis and oral parafunctional behaviours",
"& NA ; Temporom and ibular disorders ( TMD ) diagnoses can be viewed as the most useful clinical summary for classifying subtypes of TMD . The Research Diagnostic Criteria for TMD ( RDC/TMD ) is the most widely used TMD diagnostic system for conducting clinical research . It has been translated into 18 language s and is used by a consortium of 45 RDC/TMD‐based international research ers . While reliability of RDC/TMD signs and symptoms of TMD has been amply reported , the reliability of RDC/TMD diagnoses has not . The aim of the study was to determine the reliability of clinical TMD diagnoses using st and ardized methods and operational definitions contained in the Research Diagnostic Criteria for Temporom and ibular Disorders ( RDC/TMD ) . Data came from reliability assessment trials conducted at 10 international clinical centers , involving 30 clinical examiners assessing 230 subjects . Intraclass correlation coefficients ( ICC ) were calculated to characterize the reliability . The reliability of the diagnoses was fair to good . Median ICCs for the diagnoses myofascial pain with and without limited opening were 0.51 and 0.60 , respectively . Median ICC for arthralgia was 0.47 and 0.61 for disc displacement with reduction . RDC/TMD diagnoses of disc displacement without reduction , osteoarthritis and osteoarthrosis were not prevalent enough to calculate ICC 's , but percent agreement was always > 95 % . The reliability of diagnostic classification improved when diagnoses were grouped into pain versus non‐pain diagnoses ( ICC=0.72 ) and for detecting any diagnosis versus no diagnosis ( ICC=0.78 ) . In clinical decision‐making and research , arriving at a reliable diagnosis is critical in establishing a clinical condition and a rational approach to treatment . The RDC/TMD demonstrates sufficiently high reliability for the most common TMD diagnoses , supporting its use in clinical research and decision making",
"The objective of the study is to assess the prevalence of myofascial pain in a threshold country and to isolate occlusal risk factors . One hundred and seventy-one r and omized selected women were examined by a trained examiner in accordance with the Research Diagnostic Criteria for Temporom and ibular Disorders ( RDC/TMD ) examination procedure . Subscales of the SCL 90-R , grade d chronic pain status , and anamnestic question naires were also used . Logistic regression was performed to compute the odds ratios for six common occlusal features with regard to the presence of myofascial pain , in accordance with the RDC/TMD criteria . Fifteen subjects ( 15 / 151 = 9.93 % ) suffered from myofascial pain . Results from logistic regression analysis showed that non-occlusion ( posterior teeth , at least one side ) and open bite increased the risk of myofascial pain . The prevalence of myofascial pain in this study is comparable with that in another study , in a highly industrialized environment , in which the RDC/TMD was used . The role of occlusion in a non-patient population seems to be restricted to serious alterations of normality . This article presents the prevalence of myofascial pain and its association with occlusal factors . This issue will help the clinicians to assess the influence of occlusion in myofascial pain patients and to send the patient to the appropriate specialist",
"AIMS To apply the Finnish version of the Research Diagnostic Criteria for Temporom and ibular Disorders ( RDC/TMD ) Axis I to assess the occurrence of symptoms , signs , and specific subgroups of TMD , and to study the associations between the most common diagnoses and categoric demographic characteristics ( gender , age group , marital status , type of work ) . METHODS All 30- to 55-year-old employees of the Finnish Broadcasting Company with at least 5 years at their current employment received postal question naires ( n = 1784 ) . Of the 1339 respondents ( 75 % ) , a r and omly selected one fifth were clinical ly examined according to the RDC/TMD Axis I ( n = 241 , males 48 % ) . RESULTS Pain symptoms in the face or jaw regions were perceived by 14.9 % and pain with 1 or more jaw movements by 9.1 % . Diagnoses by the RDC/TMD criteria were : Group I : myofascial pain in 12.9 % , myofascial pain with limited opening in 0.4 % ; Group II : disc displacement with reduction in the right temporom and ibular joint ( TMJ ) in 9.1 % and in the left TMJ in 10.8 % ; Group III : arthralgia in 0.4 % and 0.8 % , osteoarthritis in 0 % and 0.4 % , and osteoarthrosis in 1.2 % and 1.2 % , respectively , in the right and left TMJs . The most common diagnoses were found more often among women than among men . No TMD diagnosis based on the RDC/TMD was obtained in 73 % of the subjects . CONCLUSION The RDC/TMD appear to be of benefit in diagnosing TMD among these multiprofessional media personnel and thus may be suggested for use among nonpatient population",
"This study estimates the prevalence of the myofascial subtype of temporom and ibular disorders ( M-TMD ) defined by Research Diagnostic Criteria ( RDC ) , and relates that prevalence to the surveyed report of facial pain . From among 20 000 women selected at r and om in the NY metropolitan area who completed a telephone survey of facial pain , 2000 were invited for an RDC/TMD examination ; 782 examinations were completed . Prevalence was estimated in analyses that were weighted to correct sampling biases . Differences among demographic strata were evaluated with logistic regression . The prevalence of M-TMD was estimated to be 10.5 % ( 95 % CL = 8.5 - 13.0 % ) . Prevalence was significantly higher among younger women , among women of lower socio-economic status , among Black women , and among non-Hispanic women . The report of facial pain in the telephone survey ( 10.1 % ) had high specificity for M-TMD diagnosis ( 94.7 % ) , but low sensitivity ( 42.7 % ) . M-TMD is a fairly common disorder among American women . Among those reporting facial pain during the last month , half met RDC palpation criteria for M-TMD ; thus , a formal physical examination is imperative to establish this diagnosis . Prevalence varies with age , socio-economic status , race and Hispanic ethnicity . A substantial number of RDC-diagnosed cases of M-TMD did not report facial pain in the survey ; the reason for this requires further study",
"Objectives The aim of this study is to examine the difference in the report of bodily pain experienced by patients who develop temporom and ibular disorders ( TMD ) and by those who do not develop TMD over a 3-year observation period . Methods This is a 3-year prospect i ve study of 266 females aged 18 to 34 years initially free of TMD pain . All patients completed the Symptom Report Question naire ( SRQ ) at baseline and yearly intervals , and at the time they developed TMD ( if applicable ) . The SRQ is a self-report instrument evaluating the extent and location of pain experienced in the earlier 6 months . Statistical analysis was carried out using repeated measures ANOVA . Results Over the 3-year period , 16 patients developed TMD based on the Research Diagnostic Criteria for TMD . Participants who developed TMD reported more headaches ( P=0.0089 ) , muscle soreness or pain ( P=0.005 ) , joint soreness or pain ( P=0.0012 ) , back pain ( P=0.0001 ) , chest pain ( P=0.0004 ) , abdominal pain ( P=0.0021 ) , and menstrual pain ( P=0.0036 ) than Participants who did not develop TMD at both the baseline and final visits . Participants who developed TMD also reported significantly more headache ( P=0.0006 ) , muscle soreness or pain ( P=0.0059 ) , and other pains ( P=0.0188 ) when they were diagnosed with TMD compared with the baseline visit . Discussion The development of TMD was accompanied by increases in headaches , muscle soreness or pain , and other pains that were not observed in the Participants who did not develop TMD . Participants who developed TMD also report higher experience of joint , back , chest , and menstrual pain at baseline",
"UNLABELLED The Research Diagnostic Criteria for Temporom and ibular Disorders ( RDC/TMD ) is a well-known diagnostic tool for clinical trials on TMD . OBJECTIVES This study aims to assess the reliability , validity and feasibility of a new method of physically diagnosing temporom and ibular disorders ( TMD ) , design ed for routine clinical use . This version , known as Clinical Examination Protocol -TMD ( CEP-TMD ) , was compared to the gold st and ard original RDC/TMD . METHODS A total of 49 subjects ( 41 referred TMD patients and 8 symptom free subjects ) were examined using both RDC/TMD and CEP-TMD versions . Three examiners , with varying levels of experience in diagnosing TMD , worked in pairs . Each member of a pair saw the same patient twice , once for the RDC/TMD and once for the CEP-TMD examination . The examination order was r and omized . Each patient 's examinations alternated between examiners to reduce the memory effect . Examinations could yield single , multiple or no diagnosis . Kappa statistics were calculated to estimate reliability . RESULTS There was substantial overall agreement between the CEP-TMD and the RDC/TMD ( kappa=0.70 ) . Intra-examination agreements were substantial in both RDC/TMD ( kappa=0.70 ) and CEP-TMD ( kappa=0.90 ) . For examination and diagnosis , the CEP-TMD was almost 3 min faster than the RDC/TMD ( p<0.05 ) . CONCLUSIONS It was concluded that the CEP-TMD 's diagnosis is comparable to the RDC/TMD thus providing a convenient and intuitive approach for dentists to physically diagnose TMD in clinical practice . The well-established RDC/TMD remains the gold st and ard for research diagnosis of TMD"
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Children with attention deficit hyperactivity disorder ( ADHD ) are educated in classrooms along with typically developing children . Those with ADHD , however , find it difficult to participate in routine educational and recreational activities as they encounter problems associated with behaviour , attention , motor skills and physical endurance . Traditionally , the management of children with ADHD has focussed primarily on problems with cognition and has been heavily dependent on pharmaceutical interventions and , to a lesser extent , on non-pharmaceutical measures . More recently , experts have increasingly advocated the use of exercises in alleviating symptoms associated with ADHD . The primary objective of this review was to summarize research that examined the role of exercises on deficits related to attention , motor skills and fitness in children with ADHD . A search of the available literature was conducted using a combination of relevant key words in the following data bases : PubMed , MEDLINE , Google Scholar , Embase and Cochrane review . The search filtered 3016 studies of potential relevance , of which 2087 were excluded after screening titles and abstract s as per the inclusion criteria . Thirty-four ( 34 ) studies were analysed in greater depth , and 16 were excluded after detailed consideration as they did not match the inclusion ( PEDro score > 4 ) and exclusion criteria . Three ( 3 ) additional studies were excluded as they lacked exercise prescription details such as intensity , duration and frequency of exercise . Finally , 15 studies were analysed with a focus on the effects of physical exercises on attention , hyperactive behaviour , motor skills and physical fitness in ADHD children . Overall , the studies review ed were of moderate-to-high quality and reported benefits of a variety of exercise programmes in improving motor skills , physical fitness , attention and social behaviour in children with ADHD . However , there was limited information regarding school-based programmes , the effects of structured exercise programmes independently or in combination with cognitive-based therapies , and the long-term benefits of exercises in alleviating behavioural problems in these children
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"This study was conducted to determine the effect of acute aerobic exercise on executive function in children with attention deficit hyperactivity disorder ( ADHD ) . Forty children with ADHD were r and omly assigned into exercise or control groups . Participants in the exercise group performed a moderate intensity aerobic exercise for 30 min , whereas the control group watched a running/exercise-related video . Neuropsychological tasks , the Stroop Test and the Wisconsin Card Sorting Test ( WCST ) , were assessed before and after each treatment . The results indicated that acute exercise facilitated performance in the Stroop Test , particularly in the Stroop Color-Word condition . Additionally , children in the exercise group demonstrated improvement in specific WCST performances in Non-perseverative Errors and Categories Completed , whereas no influences were found in those performances in the control group . Tentative explanations for the exercise effect postulate that exercise allocates attention re sources , influences the dorsolateral prefrontal cortex , and is implicated in exercise-induced dopamine release . These findings are promising and additional investigations to explore the efficacy of exercise on executive function in children with ADHD are encouraged",
"Attention Deficit Hyperactivity Disorder ( ADHD ) mainly affects the academic performance of children and adolescents . In addition to bringing physical and mental health benefits , physical activity has been used to prevent and improve ADHD comorbidities ; however , its effectiveness has not been quantified . In this study , the effect of physical activity on children 's attention was measured using a computer game . Intense physical activity was promoted by a relay race , which requires a 5-min run without a rest interval . The proposed physical stimulus was performed with 28 volunteers : 14 with ADHD ( GE-EF ) and 14 without ADHD symptoms ( GC-EF ) . After 5 min of rest , these volunteers accessed the computer game to accomplish the tasks in the shortest time possible . The computer game was also accessed by another 28 volunteers : 14 with ADHD ( GE ) and 14 without these symptoms ( GC ) . The response time to solve the tasks that require attention was recorded . The results of the four groups were analyzed using D'Agostino statistical tests of normality , Kruskal-Wallis analyses of variance and post-hoc Dunn tests . The groups of volunteers with ADHD who performed exercise ( GE-EF ) showed improved performance for the tasks that require attention with a difference of 30.52 % compared with the volunteers with ADHD who did not perform the exercise ( GE ) . The ( GE-EF ) group showed similar performance ( 2.5 % difference ) with the volunteers in the ( GC ) group who have no ADHD symptoms and did not exercise . This study shows that intense exercise can improve the attention of children with ADHD and may help their school performance",
"OBJECTIVE In the intent-to-treat analysis of the Multimodal Treatment Study of Children With ADHD ( MTA ) , the effects of medication management ( MedMgt ) , behavior therapy ( Beh ) , their combination ( Comb ) , and usual community care ( CC ) differed at 14 and 24 months due to superiority of treatments that used the MTA medication algorithm ( Comb+MedMgt ) over those that did not ( Beh+CC ) . This report examines 36-month outcomes , 2 years after treatment by the study ended . METHOD For primary outcome measures ( attention-deficit/hyperactivity disorder [ ADHD ] and oppositional defiant disorder [ ODD ] symptoms , social skills , reading scores , impairment , and diagnostic status ) , mixed-effects regression models and orthogonal contrasts examined 36-month outcomes . RESULTS At 3 years , 485 of the original 579 subjects ( 83.8 % ) participated in the follow-up , now at ages 10 to 13 years , ( mean 11.9 years ) . In contrast to the significant advantage of MedMgt+Comb over Beh+CC for ADHD symptoms at 14 and 24 months , treatment groups did not differ significantly on any measure at 36 months . The percentage of children taking medication > 50 % of the time changed between 14 and 36 months across the initial treatment groups : Beh significantly increased ( 14 % to 45 % ) , MedMed+Comb significantly decreased ( 91 % to 71 % ) , and CC remained constant ( 60%-62 % ) . Regardless of their treatment use changes , all of the groups showed symptom improvement over baseline . Notably , initial symptom severity , sex ( male ) , comorbidity , public assistance , and parental psychopathology ( ADHD ) did not moderate children 's 36-month treatment responses , but these factors predicted worse outcomes over 36 months , regardless of original treatment assignment . CONCLUSIONS By 36 months , the earlier advantage of having had 14 months of the medication algorithm was no longer apparent , possibly due to age-related decline in ADHD symptoms , changes in medication management intensity , starting or stopping medications altogether , or other factors not yet evaluated",
"We examined the effect of methylpheni date ( Mph ) on inhibition and several other cognitive abilities in 43 adults with Attention Deficit Hyperactivity Disorder ( ADHD ) by use of Conners ’ Continuous Performance Test ( CPT ) and the Change Task ( ChT ) , an extension of the Stop Signal Test ( SST ) . In a double blind , cross-over , placebo controlled study with Mph , tests were administered during the third week of individually titrated treatment with Mph ( maximum dose 1 mg / kg / day ) and during the third week of treatment with placebo . We established large medication effects for commission errors , st and ard error of mean reaction time , and attentiveness on the CPT , as well as moderate medication effects for mean reaction time on the CPT and response re-engagement speed on the ChT. For Stop Signal Reaction Time ( SSRT ) on the ChT , we also established large effects of Mph , but only in a group of participants who showed slow SSRTs on placebo . Mph indeed ameliorates inhibition , which is the core problem of ADHD , and certain other cognitive abilities in adults with ADHD . This research was supported by grants from Mental Health Institute GGZ Delfl and , Health Insurance Company DSW , Nationaal Fonds Geestelijke Volksgezondheid ( National Foundation for Mental Health ) , and De Hersenstichting ( Brain Foundation ) . We thank Alex de Jager , Judith Rietjens , and Susan ter Linden for their help in collecting the data . We thank the Board of Scientific Activities of the Reinier de Graaf Hospital in Delft for their financial contribution to the preparation of the study medication . We thank Paul van der Linden for his help with the r and omization procedure",
"The cardinal symptoms of attention-deficit/hyperactivity disorder ( ADHD ) are inattention , hyperactivity and impulsivity . Etiologically , ADHD is mainly put down to genetic causes ; it entails a considerable range of psychosocial problems for those affected and their social environment . The parents of a total of 7,569 boys ( B ) and 7,267 girls ( G ) aged 3 - 17 who took part in the German Health Interview and Examination Survey for Children and Adolescents ( KiGGS ) answered a self-administered question naire including an ADHD diagnosis question and the Strengths and Difficulties Question naire ( SDQ ) . In addition behavioural observations of 7,919 children ( aged 3 - 11 ) were carried out during the medical and physical tests . Participants whose parents reported that they had ever been given an ADHD diagnosis by a doctor or psychologist were classified as ADHD cases . Participants were classified as suspected cases of ADHD if they had a value of > or = 7 on the SDQ inattention/hyperactivity scale . ADHD had ever been diagnosed in 4.8 % of the children and adolescents altogether ( B : 7.7 % , G : 1.8 % ) . Another 4.9 % of the participants can be considered as suspected cases . Already 1.8 % of the preschoolers had been given an ADHD diagnosis . At primary school age ( 7 - 10 years old ) the frequency of diagnosis rises sharply . At age 11 - 17 , ADHD had ever been diagnosed in 1 in 10 boys and 1 in 43 girls . ADHD had been diagnosed significantly more frequently among participants of low socio-economic status ( SES ) than among participants of high SES . A diagnosis of ADHD is reported less often for migrants , they rank more frequently among the suspected cases . The discrepancy between confirmed and suspected cases of ADHD among migrants may point to lower diagnosis rates or lower utilization of medical services . The short- and long-term medical , social and health-economic effects of ADHD illustrate the major public health relevance of the disorder . As for prevention , the high share of genetic factors in ADHD etiology primarily suggests secondary prevention ( early support and early diagnosis ) and tertiary prevention measures . Further analysis of the KiGGS data could prospect ively identify risk groups more precisely and refine preventional approaches",
"Objective : In the general population , attention is reliably enhanced after exposure to certain physical environments , particularly natural environments . This study examined the impacts of environments on attention in children with ADHD . Method : In this within subjects design , each participant experienced each of three treatments ( environments ) in single blind controlled trials . Seventeen children 7 to12 years old professionally diagnosed with ADHD experienced each of three environments — a city park and two other well-kept urban setting s — via individually guided 20-minute walks . Environments were experienced 1 week apart , with r and omized assignment to treatment order . After each walk , concentration was measured using Digit Span Backwards . Results : Children with ADHD concentrated better after the walk in the park than after the downtown walk ( p = .0229 ) or the neighborhood walk ( p = .0072 ) . Effect sizes were substantial ( Cohen 's d = .52 and .77 , respectively ) and comparable to those reported for recent formulations of methylpheni date . Conclusion : Twenty minutes in a park setting was sufficient to elevate attention performance relative to the same amount of time in other setting s. These findings indicate that environments can enhance attention not only in the general population but also in ADHD population s. “ Doses of nature ” might serve as a safe , inexpensive , widely accessible new tool in the tool kit for managing ADHD symptoms . ( J. of Att . Dis . 2009 ; 12(5 ) 402 - 409",
"Objective : To compare the effects of multimodal therapy including supervised high-intensity interval training ( HIIT ) with those of st and ard multimodal therapy ( TRAD ) concerning key variables of physical fitness ( peak power and oxygen uptake ) , motor skills , social behavior , and quality of life in boys with ADHD . Method : A single-center , two-arm r and omized , controlled design was used , with 28 boys ( 8 - 13 years of age , IQ = 83 - 136 ) being r and omly assigned to multimodal HIIT ( three sessions/week , 4 × 4-min intervals at 95 % of peak heart rate ) or TRAD . The Movement Assessment Battery for Children II evaluated motor skills and the German version of the hyperkinetic disorder question naire for external evaluation by the guardians ( FBB-HKS ) or German version of the hyperkinetic disorder question naire for self- assessment by the children ( SBB-HKS ) and the KINDL-R question naires mental health and health-related quality of life . Results : Both interventions enhanced peak power , and HIIT also reduced submaximal oxygen uptake . HIIT was more effective than TRAD in improving the total score for motor skills ( including manual dexterity and ball skills ; p , moreover , improved subjective ratings of attention . Conclusion : Three weeks of multimodal therapy including HIIT improved physical fitness , motor skills , certain aspects of quality of life , competence , and attention in boys with ADHD",
"The goal of this study was to compare the effects of before school physical activity ( PA ) and sedentary classroom-based ( SC ) interventions on the symptoms , behavior , moodiness , and peer functioning of young children ( Mage = 6.83 ) at risk for attention-deficit/hyperactivity disorder ( ADHD-risk ; n = 94 ) and typically developing children ( TD ; n = 108 ) . Children were r and omly assigned to either PA or SC and participated in the assigned intervention 31 min per day , each school day , over the course of 12 weeks . Parent and teacher ratings of ADHD symptoms ( inattention , hyperactivity/impulsivity ) , oppositional behavior , moodiness , behavior toward peers , and reputation with peers , were used as dependent variables . Primary analyses indicate that the PA intervention was more effective than the SC intervention at reducing inattention and moodiness in the home context . Less conservative follow-up analyses within ADHD status and intervention groups suggest that a PA intervention may reduce impairment associated with ADHD-risk in both home and school domains ; interpretive caution is warranted , however , given the liberal approach to these analyses . Unexpectedly , these findings also indicate the potential utility of a before school SC intervention as a tool for managing ADHD symptoms . Inclusion of a no treatment control group in future studies will enable further underst and ing of PA as an alternative management strategy for ADHD symptoms",
"[ Purpose ] The purpose of the present study was to determine the effect of a jump rope and ball combined exercise program on the physical fitness the neurotransmitter ( epinephrine , serotonin ) levels of children with attention-deficit hyperactivity disorder . [ Subjects and Methods ] The subjects were 12 boys attending elementary school , whose grade levels ranged from 1–4 . The block r and omization method was used to distribute the participants between the combined exercise group ( n = 6 ) and control group ( n = 6 ) . The program consisted of a 60-min exercise ( 10-min warm-up , 40-min main exercise , and 10-min cool down ) performed three times a week , for a total of 12 weeks . [ Results ] The exercise group showed a significant improvement in cardiorespiratory endurance , muscle strength , muscle endurance and flexibility after 12 weeks . A significant increase in the epinephrine level was observed in the exercise group . [ Conclusion ] The 12-week combined exercise program in the current study ( jump rope and ball exercises ) had a positive effect on overall fitness level , and neurotransmission in children with attention-deficit hyperactivity disorder",
"AIM The purpose of this study was intended to evaluate the effects of a high intensity interval training ( HIIT ) program on the body composition , cardiac function and aerobic capacity in overweight young women . METHODS Sixty female university students ( aged 19 - 20 , BMI ≥25kg/m2 and percentage body fat ≥ 30 % ) were chosen and then r and omly assigned to each of the HIIT group , the moderate intensity continuous training ( MICT ) group and the non-training control group . The subjects in both the HIIT and MICT groups underwent exercise training five times per week for 12 weeks . In each of the training sessions , the HIIT group performed interval exercises at the individualized heart rate ( HR ) of 85 % of VO2max and separated by brief periods of low intensity activity ( HR at 50 % of VO2max ) , while the MICT group did continuous walking and /or jogging at the individualized HR of 50 % of VO2max . RESULTS Both of these exercise training programs produced significant improvements in the subjects ' body composition , left ventricular ejection fraction , heart rate at rest , maximal oxygen uptake and ventilatory threshold . However , the HIIT group achieved better results than those in the MICT group , as it was evaluated by the amount of the effect size . The control group did not achieve any change in all of the measured variables . CONCLUSION The tangible results achieved by our relatively large groups of homogeneous subjects have demonstrated that the HIIT program is an effective measure for the treatment of young women who are overweight",
"Objective : The effect of stimulant medication on exercise responses was studied in 14 boys ( 10.9 ± 1.1 years ) with attention deficit/hyperactivity disorder ( ADHD ) . Method : Exercise , with and without medication , was performed at 25 W , 50 W , and 75 W , followed by a peak exercise test . Result : Submaximal heart rate ( HR ) was significantly higher by ~8 to 13 b·min—1 across the three intensities during the medication trial , but oxygen uptake ( VO2 ) , respiratory exchange ratio ( RER ) , and perceived exertion were similar ( p > .05 ) . At peak exercise , VO2 , HR , and work rate were attenuated ( p ≤ .05 ) in the absence of medication but not RER or perceived exertion . The decreased peak exercise responses were apparent in 6 of 13 participants . Conclusion : Stimulant medication raises submaximal HR but does not affect other cardiorespiratory measures or perceived exertion . Without medication physiological responses at peak exercise are attenuated in some but not all boys with ADHD . ( J. of Att . Dis . 2008 ; 12(2 ) 170 - 176",
"The aim of the present study was to underst and if sport improves attention symptoms , social competency , and cognitive functions in children with attention deficit and hyperactivity disorder ( ADHD ) . The present study was design ed as a 6-week , prospect i ve trial , including 12 sessions of education/sports therapy . 13 ADHD children participated in a 90-min athletic activity ( sports-cADHD ) twice a week , while 15 ADHD children received education on behavior control ( edu-cADHD ) . During the 6-week treatment period , the sports-cADHD group showed greater improvements in DuPaul 's ADHD Rating Scale scores , parent and teacher version ( K-ARS-PT ) , compared to those of the edu-sADHD group . The cognitive functions assessed with the digit symbol and Trail-Making Test part B ( TMT B ) were improved in the sports-cADHD group , while the cognitive functions observed in the edu-sADHD group were not significantly changed . The cooperativeness scores in the sports-cADHD group were greatly increased compared to those of the edu-sADHD group . The results demonstrated a positive correlation with sports and improvement in attention symptoms , cognitive symptoms and social skills . The results of the present study suggest that therapy in the form of athletic activity may increase social competency in children with ADHD , as demonstrated by improved cognitive functions",
"PURPOSE The effects of exercise on children with attention-deficit hyperactivity disorder ( ADHD ) were evaluated by study ing the rate of spontaneous eye blinks , the acoustic startle eye blink response ( ASER ) , and motor impersistence among 8- to 12-yr-old children ( 10 boys and 8 girls ) meeting DSM-III-R criteria for ADHD . METHODS Children ceased methylpheni date medication 24 h before and during each of three daily conditions separated by 24 - 48 h. After a maximal treadmill walking test to determine cardiorespiratory fitness ( VO(2peak ) ) , each child was r and omly assigned to counterbalanced conditions of treadmill walking at an intensity of 65 - 75 % VO(2peak ) or quiet rest . Responses were compared with a group of control participants ( 11 boys and 14 girls ) equated with the ADHD group on several key variables . RESULTS Boys with ADHD had increased spontaneous blink rate , decreased ASER latency , and decreased motor impersistence after maximal exercise . Girls with ADHD had increased ASER amplitude and decreased ASER latency after submaximal exercise . CONCLUSIONS The findings suggest an interaction between sex and exercise intensity that is not explained by physical fitness , activity history , or selected personality attributes . The clinical meaning of the eye blink results is not clear , as improvements in motor impersistence occurred only for boys after maximal exercise . Nonetheless , these preliminary findings are sufficiently positive to encourage additional study to determine whether a session of vigorous exercise has efficacy as a dopaminergic adjuvant in the management of behavioral features of ADHD",
"Introduction . The aim of this study was to examine the effectiveness of a Selected exercise program on the executive function of children with ADHD . Method . The participants were 40 male students , aged 7 - 11 years . The participants were r and omly assigned into two groups ( experimental and control ) . The experimental group participated in an exercise program for 24 sessions , 90 minutes per session . The control group did not receive any intervention . Before and after the exercise period , all the participants were assessed with Stroop and Go-No-Go tests , and the result ing data were analyzed by using MANCOVA . Result . The results showed that the cognitive inhibition of the children in the experimental group was significantly different compared with the control group ( p behavioral inhibition ( p organized physical activity helps to improve the executive function in children with ADHD",
"ABSTRACT .Thirty-six boys , aged 11 - 13 , were tested on a bicycle ergometer prior to and following a six week training program . The subjects were ranked according to their Vo2 max , blocked into three fitness levels and then r and omly assigned to one of the four treatment groups . The first group ( T1 )"
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[ Purpose ] The present literature review was conducted on the use of different measures for the evaluation of balance in patients with Parkinson 's disease . [ Material s and Methods ] The PubMed , Bireme , SciELO , Lilacs , and PEDro electronic data bases were search ed for relevant studies . [ Results ] The search es initially led to the retrieval of 3,623 articles , 540 of which were potentially eligible after limiting the search to clinical trials published in the last five years . A total of 264 duplicates were removed , and 276 articles were excluded based on their titles and abstract s. The full texts of 84 articles were analyzed , and only those with a PEDro score higher than four points ( n=25 ) were included in the review . [ Conclusion ] Different methods , such as scales , tests , and equipment , are used for the evaluation of balance in patients with Parkinson 's disease . More than one measure has been employed in most studies , and there is no consensus on a single precise measure for the evaluation of balance in this population
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"Objective : To determine whether falls can be prevented with minimally supervised exercise targeting potentially remediable fall risk factors , i.e. , poor balance , reduced leg muscle strength , and freezing of gait , in people with Parkinson disease . Methods : Two hundred thirty-one people with Parkinson disease were r and omized into exercise or usual-care control groups . Exercises were practice d for 40 to 60 minutes , 3 times weekly for 6 months . Primary outcomes were fall rates and proportion of fallers during the intervention period . Secondary outcomes were physical ( balance , mobility , freezing of gait , habitual physical activity ) , psychological ( fear of falling , affect ) , and quality -of-life measures . Results : There was no significant difference between groups in the rate of falls ( incidence rate ratio [ IRR ] = 0.73 , 95 % confidence interval [ CI ] 0.45–1.17 , p = 0.18 ) or proportion of fallers ( p = 0.45 ) . Preplanned subgroup analysis revealed a significant interaction for disease severity ( p falls in the exercise group compared with controls ( IRR = 0.31 , 95 % CI 0.15–0.62 , p Short Physical Performance Battery , sit-to-st and , fear of falling , affect , and quality of life , after adjusting for baseline performance . Conclusions : An exercise program targeting balance , leg strength , and freezing of gait did not reduce falls but improved physical and psychological health . Falls were reduced in people with milder disease but not in those with more severe Parkinson disease . Classification of evidence : This study provides Class III evidence that for patients with Parkinson disease , a minimally supervised exercise program does not reduce fall risk . This study lacked the precision to exclude a moderate reduction or modest increase in fall risk from exercise . Trial registration : Australian New Zeal and Clinical Trials Registry ( ACTRN12608000303347 )",
"Background People with idiopathic Parkinson ’s disease ( PD ) frequently have low activity levels , poor mobility and reduced quality of life . Although increased physical activity may improve mobility , balance and wellbeing , adherence to exercises and activity programs over the longer term can be challenging , particularly for older people with progressive neurological conditions such as PD . Physical activities that are engaging and enjoyable , such as dancing , might enhance adherence over the long term . The objective of this study was to evaluate the feasibility of a r and omized controlled trial of Irish set dancing compared with routine physiotherapy for people with mild to moderately severe PD . Methods Twenty-four people with idiopathic PD referred for movement rehabilitation were r and omized to receive st and ard physiotherapy exercises or Irish set dancing classes once per week plus a weekly home program for 6 months ( 12 in each group ) . The feasibility and safety of the proposed RCT protocol was the main focus of this evaluation . The primary outcome was motor disability measured by the motor component of the UPDRS , which was assessed prior to and after therapy by trained assessors blinded to group assignment . The Timed Up and Go , the Berg Balance Scale and the modified Freezing of Gait Question naire were secondary measures . Quality of life of the people with PD was evaluated using the PDQ-39 . Results Both the Irish set dancing and physiotherapy exercise program were shown to be feasible and safe . There were no differences between groups in the rate of adverse events such as falls , serious injuries , death or rates of admission to hospital . The physiotherapists who provided usual care remained blind to group allocation , with no change in their st and ard clinical practice . Compliance and adherence to both the exercise and dance programs were very high and attrition rates were low over the 6 months of therapy . Although improvements were made in both groups , the dance group showed superior results to st and ard physiotherapy in relation to freezing of gait , balance and motor disability . Conclusions Irish dancing and physiotherapy were both safe and feasible in this sample from Venice , with good adherence over a comparatively long time period of 6 months . A larger multi-centre trial is now warranted to establish whether Irish set dancing is more effective than routine physiotherapy for enhancing mobility , balance and quality of life in people living with idiopathic PD.Trial registration EudraCT number 2012 - 005769 -",
"Purpose . To trial four-week 's physiotherapy targeting chair transfers for people with Parkinson 's disease ( PwPD ) and explore the feasibility of reliance on remote outcome measurement to preserve blinding . Scope . We recruited 47 PwPD and r and omised 24 to a focused home physiotherapy programme ( exercise , movement strategies , and cueing ) and 23 to a control group . We evaluated transfers ( plus mobility , balance , posture , and quality of life ) before and after treatment and at followup ( weeks 0 , 4 , 8 , and 12 ) from video produced by , and question naires distributed by , treating physiotherapists . Participants fed back via end-of- study question naires . Thirty-five participants ( 74 % ) completed the trial . Excluding dropouts , 20 % of question naire data and 9 % of video data were missing or unusable ; we had to evaluate balance in situ . We noted trends to improvement in transfers , mobility , and balance in the physiotherapy group not noted in the control group . Participant feedback was largely positive and assessor blinding was maintained in every case . Conclusions . Intense , focused physiotherapy at home appears acceptable and likely to bring positive change in those who can participate . Remote outcome measurement was successful ; question naire followup and further training in video production would reduce missing data . We advocate a fully powered trial , design ed to minimise dropouts and preserve assessor blinding , to evaluate this intervention",
"BACKGROUND Patients with Parkinson 's disease have substantially impaired balance , leading to diminished functional ability and an increased risk of falling . Although exercise is routinely encouraged by health care providers , few programs have been proven effective . METHODS We conducted a r and omized , controlled trial to determine whether a tailored tai chi program could improve postural control in patients with idiopathic Parkinson 's disease . We r and omly assigned 195 patients with stage 1 to 4 disease on the Hoehn and Yahr staging scale ( which ranges from 1 to 5 , with higher stages indicating more severe disease ) to one of three groups : tai chi , resistance training , or stretching . The patients participated in 60-minute exercise sessions twice weekly for 24 weeks . The primary outcomes were changes from baseline in the limits-of-stability test ( maximum excursion and directional control ; range , 0 to 100 % ) . Secondary outcomes included measures of gait and strength , scores on functional-reach and timed up- and -go tests , motor scores on the Unified Parkinson 's Disease Rating Scale , and number of falls . RESULTS The tai chi group performed consistently better than the resistance-training and stretching groups in maximum excursion ( between-group difference in the change from baseline , 5.55 percentage points ; 95 % confidence interval [ CI ] , 1.12 to 9.97 ; and 11.98 percentage points ; 95 % CI , 7.21 to 16.74 , respectively ) and in directional control ( 10.45 percentage points ; 95 % CI , 3.89 to 17.00 ; and 11.38 percentage points ; 95 % CI , 5.50 to 17.27 , respectively ) . The tai chi group also performed better than the stretching group in all secondary outcomes and outperformed the resistance-training group in stride length and functional reach . Tai chi lowered the incidence of falls as compared with stretching but not as compared with resistance training . The effects of tai chi training were maintained at 3 months after the intervention . No serious adverse events were observed . CONCLUSIONS Tai chi training appears to reduce balance impairments in patients with mild-to-moderate Parkinson 's disease , with additional benefits of improved functional capacity and reduced falls . ( Funded by the National Institute of Neurological Disorders and Stroke ; Clinical Trials.gov number , NCT00611481 . )",
"INTRODUCTION Pisa syndrome ( PS ) is a tonic lateral flexion of trunk that represents a disabling complication of advanced Parkinson disease ( PD ) . Conventional rehabilitation treatment ( CT ) ameliorates axial posture and trunk mobility in PD patients , but the improvement tends to wane in 4 - 6 months . Botulin toxin ( BT ) may reduce muscle hyperactivity , therefore improving CT effectiveness . We evaluated whether the injection of incabotulinum toxin type A ( iBTA ) into the hyperactive trunk muscles might improve the effectiveness of rehabilitation in a group of PD patients with PS . METHODS Twenty-six PD patients were enrolled in a r and omized placebo-controlled trial . Group A was treated with iBTA before undergoing CT ( a 4-week intensive programme ) , while Group B received saline before the 4-week CT treatment . Patients were evaluated at baseline , at the end of the rehabilitative period , 3 and 6 months with kinematic analysis of movement , UPDRS , Functional Independence Measure and Visual Analog Scale for pain . RESULTS At the end of the rehabilitation period , both groups improved significantly in terms of static postural alignment and of range of motion . Group A showed a significantly more marked reduction in pain score as compared with Group B and a more prolonged efficacy on several clinical and kinematic variables . CONCLUSIONS Our preliminary data suggest that BT may be considered an important addition to the rehabilitation programme for PD subjects with PS for improving axial posture and trunk mobility , as well as for a better control of pain",
"Background Exercise confers short-term benefits for individuals with Parkinson disease ( PD ) . Objective The purpose of the study was to compare short- and long-term responses among 2 supervised exercise programs and a home-based control exercise program . Design The 16-month r and omized controlled exercise intervention investigated 3 exercise approaches : flexibility/balance/function exercise ( FBF ) , supervised aerobic exercise ( AE ) , and home-based exercise ( control ) . Setting This study was conducted in outpatient clinics . Patients The participants were 121 individuals with PD ( Hoehn & Yahr stages 1–3 ) . Interventions The FBF program ( individualized spinal and extremity flexibility exercises followed by group balance/functional training ) was supervised by a physical therapist . The AE program ( using a treadmill , bike , or elliptical trainer ) was supervised by an exercise trainer . Supervision was provided 3 days per week for 4 months , and then monthly ( 16 months total ) . The control group participants exercised at home using the National Parkinson Foundation Fitness Counts program , with 1 supervised , clinic-based group session per month . Measurements Outcomes , obtained by blinded assessors , were determined at 4 , 10 , and 16 months . The primary outcome measures were overall physical function ( Continuous Scale — Physical Functional Performance [ CS-PFP ] ) , balance ( Functional Reach Test [ FRT ] ) , and walking economy ( oxygen uptake [ mL/kg/min ] ) . Secondary outcome measures were symptom severity ( Unified Parkinson 's Disease Rating Scale [ UPDRS ] activities of daily living [ ADL ] and motor subscales ) and quality of life ( 39-item Parkinson 's Disease Quality of Life Scale [ PDQ-39 ] ) . Results Of the 121 participants , 86.8 % , 82.6 % , and 79.3 % completed 4 , 10 , and 16 months , respectively , of the intervention . At 4 months , improvement in CS-PFP scores was greater in the FBF group than in the control group ( mean difference=4.3 , 95 % confidence interval [CI]=1.2 to 7.3 ) and the AE group ( mean difference=3.1 , 95 % CI=0.0 to 6.2 ) . Balance was not different among groups at any time point . Walking economy improved in the AE group compared with the FBF group at 4 months ( mean difference=−1.2 , 95 % CI=−1.9 to −0.5 ) , 10 months ( mean difference=−1.2 , 95 % CI=−1.9 to −0.5 ) , and 16 months ( mean difference=−1.7 , 95 % CI=−2.5 to −1.0 ) . The only secondary outcome that showed significant differences was UPDRS ADL subscale scores : the FBF group performed better than the control group at 4 months ( mean difference=−1.47 , 95 % CI=−2.79 to −0.15 ) and 16 months ( mean difference=−1.95 , 95 % CI=−3.84 to −0.08 ) . Limitations Absence of a non-exercise control group was a limitation of the study . Conclusions Findings demonstrated overall functional benefits at 4 months in the FBF group and improved walking economy ( up to 16 months ) in the AE group",
"Background . Fear of falling has been identified as an important and independent fall-risk predictor in patients with Parkinson ’s disease ( PD ) . However , there are inconsistent findings on the effects of balance and gait training on balance confidence . Objective . To explore whether balance and gait training with augmented feedback can enhance balance confidence in PD patients immediately after treatment and at 3- and 12-month follow-ups . Methods . A total of 51 PD patients were r and omly assigned to a balance and gait training ( BAL ) group or to an active control ( CON ) group . The BAL group received balance and gait training with augmented feedback , whereas CON participants received lower-limb strength training for 12 weeks . Outcome measures included Activities-Specific Balance Confidence ( ABC ) Scale , limits-of-stability test , single-leg-stance test , and spatiotemporal gait characteristics . All tests were administered before intervention ( Pre ) , immediately after training ( Post ) , and at 3 months ( Post3 m ) and 12 months ( Post12 m ) after treatment completion . Results . The ABC score improved marginally at Post and significantly at Post3 m and Post12 m only in the BAL group ( P end point excursion at Post , but only the BAL group maintained the improvement at Post3 m . The BAL group maintained significantly longer time-to-loss-of-balance during the single-leg stance test than the CON group at Post3 m and Post12 m ( P gait velocity , but only the BAL group increased stride length at Post , Post3 m , and Post12 m ( P < .017 ) . Conclusions . Positive findings from this study provide evidence that BAL with augmented feedback could enhance balance confidence and balance and gait performance in patients with PD",
"The primary goal of the present research is to study the effect of a neurofeedback training ( NFT ) period on balance problems associated with Parkinson 's disease . Sixteen patients were selected through purposive sampling and were r and omly divided into experimental and control groups . The research procedure included eight sessions . Prior to and after training , pre-tests and post-tests of static and dynamic balance were administered using \" limit of stability \" for the Biodex as well as the Berg scale . The results revealed that , after neurofeedback training , a statistically significant improvement in both static and dynamic balance in the experimental group was achieved . The means of the Biodex and Berg scores in the experimental group increased from 18.87 to 42.87 and 17.62 to 46.37 , respectively . The means of the Biodex and Berg scores in the control group in the pretest were 18.25 and 17.75 and increased to 20.00 and 20.50 , respectively . The results suggest that NFT can improve static and dynamic balance in PD patients",
"Background . Tango dancing has been effective in improving measures of physical function in people with Parkinson disease ( PD ) . However , all previous studies were institution-based , tested participants on medication , and employed short-term interventions . Objective . To determine the effects of a 12-month community-based tango program for individuals with PD on disease severity and physical function . Methods . Sixty-two participants were r and omly assigned to a twice weekly , community-based Argentine Tango program or a Control group ( no intervention ) . Participants were assessed off anti-Parkinson medication at baseline , 3 , 6 , and 12 months . The primary outcome measure was the Movement Disorders Society – Unified Parkinson Disease Rating Scale 3 ( MDS-UPDRS-3 ) . Secondary outcome measures were the MDS-UPDRS-1 , MDS-UPDRS-2 , MiniBESTest balance test ; Freezing of Gait Question naire ( FOG_Q ) ; 6-Minute Walk Test ( 6MWT ) ; gait velocity for comfortable forward , fast as possible forward , dual task , and backward walking ; and Nine-Hole Peg Test ( 9HPT ) . Results . Groups were not different at baseline . Overall , the Tango group improved whereas the Control group showed little change on most measures . For the MDS-UPDRS-3 , there was no significant change in the Control group from baseline to 12 months , whereas the Tango group had a reduction of 28.7 % ( 12.8 points ) . There were significant group by time interactions for MDS-UPDRS-3 , MiniBESTest , FOG_Q , 6MWT , forward and dual task walking velocities , and 9HPT in favor of the dance group . Conclusions . Improvements in the Tango group were apparent off medication , suggesting that long-term participation in tango may modify progression of disability in PD",
"This r and omized controlled trial with blinded assessment aim ed to determine the effect of a 6-month minimally supervised exercise program on fall risk factors in people with Parkinson 's disease ( PD ) . Forty-eight participants with PD who had fallen or were at risk of falling were r and omized into exercise or control groups . The exercise group attended a monthly exercise class and exercised at home three times weekly . The intervention targeted leg muscle strength , balance , and freezing . The primary outcome measure was a PD falls risk score . The exercise group had no major adverse events and showed a greater improvement than the control group in the falls risk score , which was not statistically significant ( between group mean difference = -7 % , 95 % CI -20 to 5 , P = 0.26 ) . There were statistically significant improvements in the exercise group compared with the control group for two secondary outcomes : Freezing of Gait Question naire ( P = 0.03 ) and timed sit-to-st and ( P = 0.03 ) . There were statistically nonsignificant trends toward greater improvements in the exercise group for measures of muscle strength , walking , and fear of falling , but not for the measures of st and ing balance . Further investigation of the impact of exercise on falls in people with PD is warranted",
"Objective . The concept of forced exercise has drawn attention for the treatment of Parkinson 's disease symptoms with anecdotal reports of success . This study sought to ascertain any significant effect of forced exercise using a motorized stationary bicycle when compared to controls on Parkinson 's disease symptoms in a blinded , r and omized , and controlled setting . Setting . Parkinson 's disease outpatient clinic , Veterans Administration Medical Center . Method . We assessed 23 patients ( 13 experimental and 10 controls ) on a number of st and ard Parkinson 's measures at baseline , after participation in eight weeks of twice weekly forced exercise or eight weeks of conventional clinic care , and then after a three-month period had elapsed . Dependent measures were UPDRS-III , Berg Balance Scale , finger taping test , and the PDQ-39 . Results . Results did not demonstrate any main effect differences between the exercise and control groups on any measure at any point in time . A within subjects effect was demonstrated for the forced exercise group on overall UPDRS-III scores at the three-month end point . No other within group effects were noted . Results suggest that early enthusiasm for forced exercise may need tempering . Limitations of the study are discussed as well as numerous logistical challenges to this type of study",
"Background . Postural instability ( PI ) is a disabling sign of Parkinson ’s disease ( PD ) not easily amenable to treatment with medication . Objective . To evaluate the effects of balance training on PI in patients with PD . Methods . A total of 64 patients with PI were r and omly assigned to the experimental group ( n = 33 ) for balance training or to the control group ( n = 31 ) for general physical exercises . Each patient received 21 treatment sessions of 50 minutes each . Patients were evaluated by a blinded rater before and after treatment as well as 1 month posttreatment using the Berg Balance Scale ( BBS ) , Activities-Specific Balance Confidence Scale ( ABC ) , postural transfer test , self-destabilization of the center of foot pressure test , number of falls , Unified Parkinson ’s Disease Rating Scale ( UPDRS ) , modified Hoehn and Yahr ( H&Y ) Staging Scale , and Geriatric Depression Scale ( GDS ) . Results .At the end of treatment , the experimental group showed significant improvements in all outcome measures , except for the UPDRS and the H&Y scale . Improvement was maintained at the 1-month follow-up in all outcome measures except for the GDS . No significant changes in performance were observed in the control group . Conclusions . A program of balance training can improve PI in patients with PD",
"An impaired ability to initiate walking is a common feature of postural instability and gait impairment in Parkinson 's disease . While progressive resistance training ( PRT ) has been proposed to be an effective modality to improve balance and gait function in people with Parkinson 's disease , there are a limited number of r and omized trials and no studies have evaluated gait initiation performance . Thus , the purpose of this study was to examine the potential benefits PRT on GI performance in people with Parkinson 's disease . Eighteen individuals with idiopathic PD were r and omly assigned to either a twice weekly PRT program or a non-contact control group for 10 weeks . Biomechanical analysis of GI was performed pre- and post-intervention . Dependent variables of interest included the displacement of the center-of-pressure ( COP ) during the anticipatory postural phase of GI as well as the initial stride length and velocity . The PRT group demonstrated improvements in the posterior displacement of the COP and the initial stride length and velocity . There were no improvements in any variables for the control subjects . These results suggest that PRT may be an effective non-pharmacological and nonsurgical treatment to improve GI performance in PWP",
"Objective . To examine the effects of technology-assisted balance and gait training on reducing falls in patients with Parkinson ’s disease ( PD ) . Methods . Eligible subjects were r and omly allocated to an experimental group given technology-assisted balance and gait training ( BAL , n = 26 ) and an active control group undertaking strengthening exercises ( CON , n = 25 ) . The training in each group lasted for 3 months . The number of fallers and fall rate were used as primary outcomes , and single-leg-stance-time , latency of postural response to perturbation , self-selected gait velocity , and stride length as secondary outcomes . Fall incidence was recorded over 15 months after the baseline assessment ( Pre ) . Other tests were performed at Pre , after 3-month intervention ( Post3 m ) , at 3 months ( Post6 m ) , and 12 months ( Post15 m ) after treatment completion . Results . Forty-five subjects who completed the 3-month training were included in the data analysis . There were fewer fallers in the BAL than in the CON group at Post3 m , Post6 m , and Post15 m ( P fall rate than the CON group at Post3 m and Post6 m ( incidence rate ratio : 0.111 - 0.188 , P postural response latency and increase in the stride length against baseline at each assessment interval ( P single-leg-stance-time at Post3 m ( P = .064 ) , Post6 m ( P = .041 ) and Post15 m ( P = .087 ) . Conclusions . Our positive findings provide evidence for the clinical use of technology-assisted balance and gait training in reducing falls in people with PD",
"Objective : To determine the effects of leg muscle power training in people with Parkinson ’s disease . Design : R and omized controlled trial . Setting : University laboratory ( outcome measures and experimental intervention ) , community ( control intervention ) . Subjects : Community-dwelling people with Parkinson ’s disease . Interventions : Leg muscle power training using pneumatic variable resistance equipment ( experimental ) was compared with low intensity sham exercise ( control ) . Both groups exercised twice weekly for 12 weeks . Main measures : Primary outcomes were peak power of four leg muscle groups . Secondary outcomes were measures of muscle strength , mobility , balance and falls . Results : Exercise adherence was high in both groups . Leg muscle power was significantly better in the experimental group than the control group in all four primary outcome measures at 12 weeks after adjusting for baseline values : leg extensors ( 57.9 watts , 95 % confidence interval ( CI ) 22.0–93.7 , p = 0.002 ) ; knee flexors ( 29.6 watts , 95 % CI 7.4–51.8 , p = 0.01 ) ; hip flexors ( 68.1 watts , 95 % CI 19.6–116.5 , p = 0.007 ) ; and hip abductors ( 37.4 watts , 95 % CI 19.9–54.9 , p tests of leg muscle strength ( p Timed Up and Go ( p = 0.13 ) and choice stepping reaction time ( p = 0.11 ) . There was a non-significant reduction in the rate of falls in the experimental group compared with the control group ( incidence rate ratio 0.84 , p = 0.76 ) . Conclusions : This programme significantly improved muscle power in all trained muscle groups",
"Background : Postural balance and potentially fall risk increases among older adults living with neurological diseases , especially Parkinson 's disease ( PD ) . Since conventional therapies such as levodopa or deep brain stimulation may fail to alleviate or may even worsen balance , interest is growing in evaluating alternative PD therapies . Objective : The purpose of the current study was to assess improvement in postural balance in PD patients following electroacupuncture ( EA ) as an alternative therapy . Methods : 15 aging adults ( 71.2 ± 6.3 years ) with idiopathic PD and 44 healthy age-matched participants ( 74.6 ± 6.5 years ) were recruited . The PD participants were r and omly assigned ( at a ratio of 2:1 ) to an intervention ( n = 10 ) or to a control group ( n = 5 ) . The intervention group received a 30-min EA treatment on a weekly basis for 3 weeks , while the control group received a sham treatment . Outcomes were assessed at baseline and after the final therapy . Measurements included balance assessment , specifically the ratio of medial-lateral ( ML ) center-of-gravity ( COG ) sway to anterior-posterior ( AP ) sway ( COGML/AP ) and ankle/hip sway during eyes-open , eyes-closed , and eyes-open dual-task trials , the Unified Parkinson 's Disease Rating Scale ( UPDRS ) , as well as quality of life , concerns for fall , and pain question naires . Results : No difference was observed for the assessed parameters between the intervention and the control group at baseline . After treatment , an improvement in balance performance was observed in the intervention group . Compared with the healthy population , PD patients prior to treatment had larger COGML/AP sway with more dependency on upper-body movements for maintaining balance . Following EA therapy , COGML/AP sway was reduced by 31 % and ankle/hip sway increased by 46 % in the different conditions ( p = 0.02 for the dual-task condition ) . The clinical rating revealed an overall improvement ( p ) in mentation , behavior , and mood ( UPDRS part I , 49 % ) , activities of daily living ( UPDRS part II , 46 % ) , and motor examination ( UPDRS part III , 40 % ) . There was a significant reduction ( p specific items regarding UPDRS fall status ( 67 % ) and rigidity ( 48 % ) . Changes were small and nonsignificant in the controls ( p > 0.29 ) . Conclusions : This pilot study demonstrates improvement in rigidity and balance following EA . These preliminary results suggest EA could be a promising alternative treatment for balance disturbance in PD",
"Background . Exercise may decrease the risk of Parkinson ’s disease ( PD ) in humans and reduce PD symptoms in animal models . The beneficial effects have been linked to increased levels of neurotrophic factors . Objective . We examined whether intensive rehabilitation treatment reduces motor disability in patients in the early stages of PD and increases brain-derived neurotrophic factor ( BDNF ) serum levels . Methods . Thirty participants in the early stages of PD treated with rasagiline were r and omly assigned to 3 hours of rehabilitation treatment that included aerobic exercise for 28 days ( Group 1 ) or to not therapy ( control ; Group 2 ) . BDNF serum levels were assessed at time T0 ( baseline , before treatment ) , T1 ( 10 days ) , T2 ( 20 days ) , and T3 ( 28 days ) . At T0 and T3 , we assessed the Unified Parkinson ’s Disease Rating Scale ( UPDRS ) III in both groups , as well as the UPDRS II and total , Berg Balance Scale , and 6-minute walking test only in Group 1 . Results . BDNF levels significantly increased at T1 in Group 1 , an increase that was maintained throughout the treatment period . At T3 compared to T0 , UPDRS III scores significantly improved in Group 1 along with scores for UPDRS II , total , Berg Balance Scale , and 6-minute walking test . Conclusions . Intensive rehabilitation treatment increases the BDNF levels and improves PD signs in patients in the early stages of the disease . These results are in line with studies on animal models of PD and healthy subjects",
"OBJECTIVE To examine the effects of repetitive volitional and compensatory step training with preparatory signals on the limits of stability , postural and gait skills , and spatiotemporal gait characteristics in patients with Parkinson 's disease with no falls during the previous 12 months . DESIGN R and omized clinical trial with assessor blinded to group assignment . SUBJECTS Twenty-eight patients with Parkinson 's disease with no falls during the previous 12 months . METHODS Eligible patients were r and omly assigned to an experimental group , which undertook repetitive step training with preparatory visual cues , or a control group , which undertook lower limb strength training for 4 weeks . Outcome measures included limits of stability test , postural and gait sub-scores from Unified Parkinson 's Disease Rating Scale motor score ( UPDRS-PG ) , and spatiotemporal gait characteristics . All tests were conducted before and after training at patients ' peak medication cycle . RESULTS The experimental group showed significant improvements in reaction time , movement velocity , and endpoint excursion of limits of stability , as well as UPDRS-PG score and stride length ( p gait velocity ( p Repetitive step training with preparatory cues can enhance limits of stability , postural and gait skills and spatiotemporal gait characteristics in patients with Parkinson 's disease with no falls during the previous 12 months",
"Objectives : To examine the effects of Tai Chi on balance and functional mobility in people with Parkinson ’s disease , and determine whether fall incidence could be reduced by the Tai Chi exercise . Design : Single blinded r and omized control trial with 6 months ’ follow-up . Setting : A hospital and general community . Participants : Patients ( n=76 ) diagnosed with idiopathic Parkinson ’s disease , over 40 years old , able to walk independently and fell at least one time during the past 12 months . Interventions : The Tai Chi group ( n=37 ) received 24-form Yang style Tai Chi exercise for 60 minutes each time , three times a week and lasted for 12 weeks . The control group ( n=39 ) received no intervention . Main outcome measures : Berg Balance Scale ( BBS ) , Unified Parkinson ’s Disease Rating Scale ( UPDRS ) III , Timed Up&Go ( TUG ) and occurrences of falls . Results : The Tai Chi group improved more than the control group on the BBS ( p UPDRS III scores and Timed Up&Go ( p>0.05 ) . During the 6-month follow-up , only 8 ( 21.6 % ) out of 37 patients in the Tai Chi group had experience of falls comparing to 19 ( 48.7 % ) out of 39 patients in the control group ( p average times of falls were 0.30±0.62 in the Tai Chi group compared with 0.64±0.74 in the control group ( p that Tai Chi exercise could improve the balance and decrease the fall risks in patients with Parkinson ’s disease",
"OBJECTIVES To investigate the effect of Nintendo Wii ™ -based motor cognitive training versus balance exercise therapy on activities of daily living in patients with Parkinson 's disease . DESIGN Parallel , prospect i ve , single-blind , r and omised clinical trial . SETTING Brazilian Parkinson Association . PARTICIPANTS Thirty-two patients with Parkinson 's disease ( Hoehn and Yahr stages 1 and 2 ) . INTERVENTIONS Fourteen training sessions consisting of 30 minutes of stretching , strengthening and axial mobility exercises , plus 30 minutes of balance training . The control group performed balance exercises without feedback or cognitive stimulation , and the experimental group performed 10 Wii Fit ™ games . MAIN OUTCOME MEASURE Section II of the Unified Parkinson 's Disease Rating Scale ( UPDRS-II ) . R AND OMISATION Participants were r and omised into a control group ( n=16 ) and an experimental group ( n=16 ) through blinded drawing of names . STATISTICAL ANALYSIS Repeated- measures analysis of variance ( RM-ANOVA ) . RESULTS Both groups showed improvement in the UPDRS-II with assessment effect ( RM-ANOVA P CONCLUSION Patients with Parkinson 's disease showed improved performance in activities of daily living after 14 sessions of balance training , with no additional advantages associated with the Wii-based motor and cognitive training . Registered on http://www . clinical trials.gov ( identifier : NCT01580787 )",
"Background . Freezing of gait ( FOG ) is a disabling impairment for people with Parkinson ’s disease ( PD ) and may not respond to medications . The effectiveness of physical therapy for FOG is debatable . Action observation strategies to overcome FOG may enhance physical training . Objective . To assess whether action observation , combined with practicing the observed actions , may reduce FOG episodes . Methods . Twenty patients with PD entered a single-blind trial and were r and omly assigned to the experimental ( Action ) or control ( L and scape ) groups . Those in the Action group watched video clips showing specific movements and strategies to circumvent FOG episodes , whereas those in the L and scape group watched video clips of static pictures showing different l and scapes . All patients underwent identical physical therapy training , 3 sessions a week for 4 weeks . Results . The FOG Question naire score and the number of FOG episodes were significantly reduced in both groups after the training period . At follow-up examination ( 4 weeks after the end of the intervention ) , a significant reduction in the number of FOG episodes was observed only in the Action group . Motor performance ( walking and balance ) and quality -of-life assessment s were significantly improved in both groups at the end of training and at follow-up . Conclusions . Our results suggest that action observation has a positive additional effect on recovery of walking ability in PD patients with FOG . Further studies on the combination of observation and imitation to supplement a physical training program may result in an innovative rehabilitative approach for FOG",
"BACKGROUND Treadmill training ( with or without robotic assistance ) has been reported to improve balance skills in patients with Parkinson 's disease ( PD ) . However , its effectiveness on postural instability has been evaluated mainly in patients with mild to moderate PD ( Hoehn & Yahr stage ≤3 ) . Patients with more severe disease may benefit from robot-assisted gait training performed by the Gait-Trainer GT1 , as a harness supports them with their feet placed on motor-driven footplates . The aim of this study was to determine whether robot-assisted gait training could have a positive influence on postural stability in patients with PD at Hoehn & Yahr stage 3 - 4 . METHODS Thirty-four patients with PD at Hoehn & Yahr stage 3 - 4 were r and omly assigned into two groups . All patients received twelve , 40-min treatment sessions , three days/week , for four consecutive weeks . The Robotic Training group ( n = 17 ) underwent robot-assisted gait training , while the Physical Therapy group ( n = 17 ) underwent a training program not specifically aim ed at improving postural stability . Patients were evaluated before , immediately after and 1-month post-treatment . Primary outcomes were : Berg Balance scale ; Nutt 's rating . RESULTS A significant improvement was found after treatment on the Berg Balance Scale and the Nutt 's rating in favor of the Robotic Training group ( Berg : 43.44 ± 2.73 ; Nutt : 1.38 ± 0.50 ) compared to the Physical Therapy group ( Berg : 37.27 ± 5.68 ; Nutt : 2.07 ± 0.59 ) . All improvements were maintained at the 1-month follow-up evaluation . CONCLUSIONS Robot-assisted gait training may improve postural instability in patients with PD at Hoehn & Yahr stage 3 - 4"
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The use of dual-task training paradigm to enhance postural stability in patients with balance impairments is an emerging area of interest . The differential effects of dual tasks and dual-task training on postural stability still remain unclear . A systematic review and meta- analysis were conducted to analyze the effects of dual task and training application on static and dynamic postural stability among various population groups . Systematic identification of published literature was performed adhering to Preferred Reporting Items for Systematic Review s and Meta- analysis ( PRISMA ) guidelines , from inception until June 2016 , on the online data bases Scopus , PEDro , MEDLINE , EMBASE , and SportD iscus . Experimental studies analyzing the effects of dual task and dual-task training on postural stability were extracted , critically appraised using PEDro scale , and then summarized according to modified PEDro level of evidence . Of 1,284 records , 42 studies involving 1,480 participants met the review ’s inclusion criteria . Of the studies evaluating the effects of dual-task training on postural stability , 87.5 % of the studies reported significant enhancements , whereas 30 % of the studies evaluating acute effects of dual tasks on posture reported significant enhancements , 50 % reported significant decrements , and 20 % reported no effects . Meta- analysis of the pooled studies revealed moderate but significant enhancements of dual-task training in elderly participants ( 95 % CI : 1.16–2.10 ) and in patients suffering from chronic stroke ( −0.22 to 0.86 ) . The adverse effects of complexity of dual tasks on postural stability were also revealed among patients with multiple sclerosis ( −0.74 to 0.05 ) . The review also discusses the significance of verbalization in a dual-task setting for increasing cognitive – motor interference . Clinical implication s are discussed with respect to practical applications in rehabilitation setting
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"BACKGROUND Although postural recovery is attentionally dem and ing in healthy elderly persons , an inability to recover balance due to competition for attentional re sources between the postural system and a second task could contribute to falls in older adults with poor balance . This study examined the attentional dem and s of balance recovery from a mild postural disturbance in balance-impaired elderly persons . A second purpose of this research was to determine the effect of performing a cognitive task on the recovery of balance in balance-impaired elderly persons . METHODS Fifteen healthy older adults and 13 older adults with clinical balance impairment were exposed to balance disturbances by means of sudden movement of a platform on which they stood . A dual-task paradigm where postural recovery served as the primary task and verbal reaction time to auditory tones served as the secondary task was used to assess attentional dem and . To determine the effect of the cognitive task on postural recovery , kinetic , kinematic , and neuromuscular measures of a feet-in-place response were investigated . RESULTS Balance recovery using a feet-in-place response was attentionally dem and ing in both groups of older adults and was more dem and ing in balance-impaired than in healthy elderly persons . With the concurrent performance of a cognitive task , balance-impaired elderly persons took longer to stabilize their center of pressure and regain balance than in a single task , while healthy elderly persons showed no change between conditions . In addition , only balance-impaired elderly individuals had a greater center-of-pressure result ant velocity during recovery in a dual-task compared with a single-task situation . CONCLUSIONS The ability to recover balance using a feet-in-place response was more attentionally dem and ing in balance-impaired than in healthy elderly persons . The recovery of balance was also slower and less efficient in balance-impaired elderly persons when simultaneously performing a cognitive task , whereas the ability of healthy elderly individuals to recover was not influenced by concurrent task dem and s. This suggests that dual-task performance may contribute to postural instability and falls in balance-impaired elderly individuals",
"BACKGROUND Decreased fitness of the lower extremities is a potentially modifiable fall risk factor . This study aim ed to compare two exercise programs -- square-stepping exercise ( SSE ) , which is a low-cost indoor program , and walking -- for improving the fitness of the lower extremities . METHODS We r and omly allocated 68 community-dwelling older adults ( age 65 - 74 years ) to either the SSE or walking group ( W group ) . During the 12-week regimen , the SSE group participated in 70-minute exercise sessions conducted twice a week at a local health center , and the W group participated in outdoor supervised walking sessions conducted weekly . The W group was instructed to increase the number of daily steps . Prior to and after the program , we obtained information on 11 physical performance tests for known fall risk factors and 3 self-reported scales . The fall incidence was followed-up for 8 months . RESULTS At 12 weeks postregimen , significant differences were observed between the two exercise groups with respect to leg power ( 1 item ) , balance ( 2 items ) , agility ( 2 items ) , reaction time ( 2 items ) , and a self-reported scale ( 1 item ) ; the SSE group demonstrated a marked improvement in the above-mentioned items with Group x Time interactions . Significant time effects were observed in the tests involving chair st and s , functional reach , and st and ing up from a lying-down position without Group x Time interactions . During the follow-up period , the fall rates per person-year in the SSE and W groups were 23.4 % and 33.3 % , respectively ( p = .31 ) . CONCLUSION Although further studies are required , SSE is apparently more effective than walking in reducing fall risk factors , and it appears that it may be recommended as a health promotion exercise in older adults",
"When people perform two tasks simultaneously , the tasks are often executed slower and with more errors than when they are carried out as single tasks . This is called dual task interference . With functional magnetic resonance imaging ( fMRI ) , we show that concurrently performed visual and somatosensory reaction time ( RT ) tasks engage almost identical volumes of cortical and subcortical motor structures . Moreover , dual RT tasks engaged additional cortical regions that are not activated by the component RT tasks had they been performed as single tasks . When the inter-stimulus interval was task performance . Thus , the performance of single RT tasks , dual RT tasks and dual RT tasks that interfere differ psychophysically and in the brain structures subserving these tasks . A short occupancy of the common motor structures can explain the interference effect . The increased activity of the RIFG correlated with the interference effect is very likely to be a specific outcome of situations where two concurrent tasks interfere with each other . The brain appears to recruit the RIFG for a subsequent ( delayed ) response when there is interference between dual tasks",
"Postural control during normal upright stance in humans is a well-learned task . Hence , it has often been argued that it requires very little attention . However , many studies have recently shown that postural control is modified when a cognitive task is executed simultaneously especially in the elderly and in the presence of pathology . This study examined postural control modifications when a cognitive task of varying difficulty levels is added . Postural stance difficulty was also varied . Results from this study suggest that a generalized capacity interference may occur due to the larger interference found with the addition of a cognitive task in the more novel and difficult postural task . Because the performance of the cognitive task was tapered by a speed-difficulty trade-off , it was not possible to determine whether a change in the level of difficulty of the cognitive task occurred and if it would produce larger dual-task interference",
"Objective To investigate the effect of dual-task training on the recovery of balance ability and cognitive function in patients with subacute stroke . Methods Twenty patients ( 12 males and eight females ; average age , 59.70 years ) with subacute stroke were enrolled in this study . All participants were r and omly assigned to one of two groups , the dual-task group ( n=10 ) or the control group ( n=10 ) . The dual task was simultaneous balance and cognitive training using the BioRescue . All patients were evaluated with posturographic parameters and the Berg Balance Scale for balance ability , a computerized neuropsychological test and the Korean version of the Mini-Mental State Examination for cognitive function , the Fugl-Meyer Assessment for motor function , and the Korean-Modified Barthel Index for activities of daily living ( ADL ) function before and after 4 weeks of rehabilitation . Results The dual-task group showed significant improvements in the pressure of the weight distribution index ( WDI ) , surface area , and length of the stability index during the eyes-open condition ; surface area of the limit of stability ( LOS ) on the hemiparetic and intact sides , and the auditory continuous performance test and backward visual span test after rehabilitation . Although no significant difference was observed for the changes in balance ability or cognitive , motor , and ADL functions between the groups , changes in the WDI pressure during the eyes-open condition and in the area ratio of LOS ( hemiparetic/intact ) showed a tendency to improve in the dual-task group . Conclusion Our findings suggest that dual-task training could be as effective as conventional balance training for improving balance and cognition in subacute post-stroke patients",
"Abstract . The goal of the present experiment was to test the predictions of Central Bottleneck and Central Capacity Sharing models . According to the Central Bottleneck model , dual task interference , as observed in the PRP paradigm , is caused by an all-or-none bottleneck in information processing . The Central Capacity Sharing model postulates that dual task interference is caused by a capacity limited process that can allocate capacity in a grade d fashion . The Central Bottleneck model predicts no change in RT1 with decreasing SOA , whereas the Central Capacity Sharing model predicts that RT1 will increase with decreasing SOA and that the slope of the RT1 SOA effect will depend upon the difficulty of task 2 . Subjects were required to perform a tone pitch judgement and shape-matching task in rapid succession . Task order was r and omized and the SOA between the first and second stimulus varied from 50 to 1250 ms . Results from this experiment favour the Central Capacity Sharing model . The results were then run through simulations of both the Central Bottleneck and Central Capacity Sharing models . Results from the simulations also favoured the Central Capacity Sharing model . As the difficulty of the second task increased , more capacity was allocated to it , confirming the prediction that as task 2 difficulty increases , the RT1 SOA slope increases . The proportion of capacity allocated to the first task varied from .78 to .91 indicating that capacity can be allocated in a grade d fashion",
"QUESTIONS Does the PEDro scale measure only one construct ie , the method ological quality of clinical trials ? What is the hierarchy of items of the PEDro scale from least to most adhered to ? Is there any effect of year of publication of trials on item adherence ? Are PEDro scale ordinal scores equivalent to interval data ? DESIGN Rasch analysis of two independent sample s of 100 clinical trials from the PEDro data base scored using the PEDro scale . RESULTS Both sample s of PEDro data showed fit to the Rasch model with no item misfit . The PEDro scale item hierarchy was the same in both sample s , ranging from the most adhered to item r and om allocation , to the least adhered to item therapist blinding . There was no differential item functioning by year of publication . Original PEDro ordinal scores were highly correlated with transformed PEDro interval scores ( r = 0.99 ) . CONCLUSION The PEDro scale is a valid measure of the method ological quality of clinical trials . It is valid to sum PEDro scale item scores to obtain a total score that can be treated as interval level measurement and subjected to parametric statistical analysis",
"The present study sought to determine whether the increased postural instability produced by a spoken mental task was due to competing dem and s for attentional re sources or perturbation of posture by articulation . Postural sway was measured in 36 normal subjects under the following conditions : repeating a number aloud ( articulation ) , counting backwards aloud in multiples of seven ( articulation and attention ) , counting backwards silently ( attention ) , and no mental task ( neither articulation nor attention ) . Articulation result ed in a significant increase in sway , whereas no effect of attention was observed . We conclude that in order to accurately assess the effect of attentional dem and s on postural control , it is important to eliminate or control the effects of articulation",
"Speaking is one of the most complex motor behaviors developed to facilitate human communication . The underlying neural mechanisms of speech involve sensory-motor interactions that incorporate feedback information for online monitoring and control of produced speech sounds . In the present study , we adopted an auditory feedback pitch perturbation paradigm and combined it with functional magnetic resonance imaging ( fMRI ) recordings in order to identify brain areas involved in speech production and motor control . Subjects underwent fMRI scanning while they produced a steady vowel sound /a/ ( speaking ) or listened to the playback of their own vowel production ( playback ) . During each condition , the auditory feedback from vowel production was either normal ( no perturbation ) or perturbed by an upward ( + 600 cents ) pitch-shift stimulus r and omly . Analysis of BOLD responses during speaking ( with and without shift ) vs. rest revealed activation of a complex network including bilateral superior temporal gyrus ( STG ) , Heschl 's gyrus , pre central gyrus , supplementary motor area ( SMA ) , Rol and ic operculum , post central gyrus and right inferior frontal gyrus ( IFG ) . Performance correlation analysis showed that the subjects produced compensatory vocal responses that significantly correlated with BOLD response increases in bilateral STG and left pre central gyrus . However , during playback , the activation network was limited to cortical auditory areas including bilateral STG and Heschl 's gyrus . Moreover , the contrast between speaking vs. playback highlighted a distinct functional network that included bilateral pre central gyrus , SMA , IFG , post central gyrus and insula . These findings suggest that speech motor control involves feedback error detection in sensory ( e.g. auditory ) cortices that subsequently activate motor-related areas for the adjustment of speech parameters during speaking",
"BACKGROUND AND PURPOSE Balance disability is common after stroke , but there is little detailed information about it . The aims of this study were to investigate the frequency of balance disability ; to characterize different levels of disability ; and to identify demographics , stroke pathology factors , and impairments associated with balance disability . SUBJECTS The subjects studied were 75 people with a first-time anterior circulation stroke ; 37 subjects were men , the mean age was 71.5 years ( SD=12.2 ) , and 46 subjects ( 61 % ) had left hemiplegia . METHODS Prospect i ve hospital-based cross-sectional surveys were carried out in 2 British National Health Service trusts . The subjects ' stroke pathology , demographics , balance disability , function , and neurologic impairments were recorded in a single testing session 2 to 4 weeks after stroke . RESULTS A total of 83 % of the subjects ( n=62 ) had a balance disability ; of these , 17 ( 27 % ) could sit but not st and , 25 ( 40 % ) could st and but not step , and 20 ( 33 % ) could step and walk but still had limited balance . Subjects with the most severe balance disability had more severe strokes , impairments , and disabilities . Weakness and sensation were associated with balance disability . Subject demographics , stroke pathology , and visuospatial neglect were not associated with balance disability . DISCUSSION AND CONCLUSION Subjects with the most severe balance disability had the most severe strokes , impairments , and disabilities . Subject demographics , stroke pathology , and visuospatial neglect were not associated with balance disability",
"BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However , the reliability of data obtained with most quality assessment scales has not been established . This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions . METHOD In the first study , 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base . In the second study , 2 raters rated 120 RCTs r and omly selected from the PEDro data base , and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings . The process was repeated by independent raters to create a second set of individual and consensus ratings . Reliability of ratings of PEDro scale items was calculated using multirater kappas , and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ) . RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters . The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals , and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ) . DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from \" fair \" to \" substantial , \" and the reliability of the total PEDro score was \" fair \" to \" good .",
"Postural sway increases with age . The decreased stability associated with postural sway often has been related to the reduced peripheral sensibility in the visual , vestibular , and proprioceptive systems . We examined whether the micropostural adjustments necessary for maintaining balance also require some cognitive processing . Young and older subjects were su bmi tted to an auditory reaction time task while maintaining an upright posture on a force platform . The auditory stimuli were presented r and omly when subjects were in a central or in an eccentric less stable postural position in four conditions of vision/surface . If the postural adjustments require some cognitive processing , a more eccentric position of the center of foot pressure ( COP ) would require more attention than a stable position of the COP because when an eccentric position is identified , a corrective response subsequently needs to be selected , programmed , and executed . The visual and surface conditions were altered to determine if additional attentional re sources need to be allocated to the postural task when there is a reduction of the sensory information available . Results showed that as the sensory information decreased , the postural task became increasingly difficult for the elderly and required more of their attentional capacity ( as indexed by increases in reaction time ) ",
"The purpose of the present project was to determine whether postural sway varied with the difficulty of a concurrent unrelated cognitive task . Participants stood on a compliant surface under four conditions of varied attentional dem and . Information reduction tasks ( digit reversal , digit classification , counting backward by 3s ) were used to quantify the attentional dem and s of the cognitive activity . Results showed attentional dem and s of the cognitive task impacted postural sway , with the most difficult cognitive task having the greatest influence",
"Postural sway increases when a cognitive task is performed concurrently with a postural task . The author examined the hypothesis that following dual-task training , a concurrent cognitive task would not amplify postural sway . Participants ( N = 18 ) were assigned to no-training , single-task training , or dual-task training groups . Single-task training consisted of 3 sessions in which the postural task , quiet st and ing on a compliant surface , and the cognitive task , counting backward by 3s , were practice d separately . Dual-task training consisted of 3 sessions of concurrent practice of the cognitive and postural tasks . After training , performance of a concurrent cognitive task increased postural sway in the no-training and single-task training groups but not in the dual-task training group . Results suggest that dual-task practice improves dual-task performance",
" Seventy-one \" negative \" r and omized control trials were re-examined to determine if the investigators had studied large enough sample s to give a high probability ( greater than 0.90 ) of detecting a 25 per cent and 50 per cent therapeutic improvement in the response . Sixty-seven of the trials had a greater than 10 per cent risk of missing a true 25 per cent therapeutic improvement , and with the same risk , 50 of the trials could have missed a 50 per cent improvement . Estimates of 90 per cent confidence intervals for the true improvement in each trial showed that in 57 of these \" negative \" trials , a potential 25 per cent improvement was possible , and 34 of the trials showed a potential 50 per cent improvement . Many of the therapies labeled as \" no different from control \" in trials using inadequate sample s have not received a fair test . Concern for the probability of missing an important therapeutic improvement because of small sample sizes deserves more attention in the planning of clinical trials",
"Contrary to general findings in the attention and memory literature , some studies have shown that performing a secondary cognitive task produces an improvement in balance performance . The purpose of the present experiment was to investigate under what condition such an improvement would occur . Young and older adults were asked to hold as still as possible on a platform that measured sway while performing or not performing the encoding phase of the Brooks ' ( 1967 ) spatial or non-spatial memory task . The difficulty of maintaining balance was manipulated by varying the availability of visual input and sway-referenced motion of the platform . Sway scores were computed based on the distance between the individual pressure centres and the average centre of pressure during each 20-s trial . The results indicated that both the spatial and non-spatial memory tasks improved balance for older adults under the most difficult balance condition",
"Objective : To investigate the effects of dual task balance training in the elderly on st and ing postural control while performing a cognitive task . Design : A r and omized two-group parallel controlled trial . Participants : Forty-three subjects ( all > 65 years old ) were enrolled in the study and were assigned r and omly to either an experimental group ( n = 21 ) or a control group ( n = 22 ) . Interventions : Subjects in the experimental group were given strength and balance training while performing cognitive tasks simultaneously . Subjects in the control group were given strength and balance training only . The training was administered twice a week for three months . Measurements : The Chair St and Test , Functional Reach Test , Timed Up and Go Test and Trail Making Test were measured . The sway length of the centre of gravity was measured during st and ing while performing the Stroop task . The rate of Stroop task was also measured . All measurements were collected at baseline and after the training period . Results : There were no significant differences in Functional Reach Test , Timed Up and Go Test and sway length at baseline and after training between the two groups . However , the rate of Stroop task ( P task balance training in elderly people improves their dual task performance during st and ing postural control"
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BACKGROUND Early enteral feeding practice s are potentially modifiable risk factors for necrotising enterocolitis ( NEC ) in very preterm or very low birth weight ( VLBW ) infants . Observational studies suggest that conservative feeding regimens , including slowly advancing enteral feed volumes , reduce the risk of NEC . However , slow feed advancement may delay establishment of full enteral feeding and may be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition . OBJECTIVES To determine effects of slow rates of enteral feed advancement on the incidence of NEC , mortality , and other morbidities in very preterm or VLBW infants . SEARCH METHODS We used the st and ard Cochrane Neonatal search strategy to search the Cochrane Central Register of Controlled Trials ( CENTRAL ; 2017 , Issue 5 ) , MEDLINE via PubMed ( 1966 to June 2017 ) , Embase ( 1980 to June 2017 ) , and the Cumulative Index to Nursing and Allied Health Literature ( CINAHL ; 1982 to June 2017 ) . We search ed clinical trials data bases , conference proceedings , previous review s , and reference lists of retrieved articles for r and omised controlled trials ( RCTs ) and quasi-r and omised trials . SELECTION CRITERIA R and omised or quasi-r and omised controlled trials that assessed effects of slow ( up to 24 mL/kg/d ) versus faster rates of advancement of enteral feed volumes upon the incidence of NEC in very preterm or VLBW infants . DATA COLLECTION AND ANALYSIS Two review authors assessed trial eligibility and risk of bias and independently extracted data . We analysed treatment effects in individual trials and reported risk ratio ( RR ) and risk difference ( RD ) for dichotomous data , and mean difference ( MD ) for continuous data , with respective 95 % confidence intervals ( CIs ) . We used a fixed-effect model for meta-analyses and explored potential causes of heterogeneity via sensitivity analyses . We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) approach . MAIN RESULTS We identified 10 RCTs in which a total of 3753 infants participated ( 2804 infants participated in one large trial ) . Most participants were stable very preterm infants of birth weight appropriate for gestation . About one-third of all participants were extremely preterm or extremely low birth weight ( ELBW ) , and about one-fifth were small for gestational age ( SGA ) , growth-restricted , or compromised in utero , as indicated by absent or reversed end-diastolic flow velocity ( AREDFV ) in the fetal umbilical artery . Trials typically defined slow advancement as daily increments of 15 to 20 mL/kg , and faster advancement as daily increments of 30 to 40 mL/kg . Trials generally were of good method ological quality , although none was blinded . Meta-analyses did not show effects on risk of NEC ( typical RR 1.07 , 95 % CI 0.83 to 1.39 ; RD 0.0 , 95 % CI -0.01 to 0.02 ) or all-cause mortality ( typical RR 1.15 , 95 % CI 0.93 to 1.42 ; typical RD 0.01 , 95 % CI -0.01 to 0.03 ) . Subgroup analyses of extremely preterm or ELBW infants , or of SGA or growth-restricted or growth-compromised infants , showed no evidence of an effect on risk of NEC or death . Slow feed advancement delayed establishment of full enteral nutrition by between about one and five days . Meta- analysis showed borderline increased risk of invasive infection ( typical RR 1.15 , 95 % CI 1.00 to 1.32 ; typical RD 0.03 , 95 % CI 0.00 to 0.05 ) . The GRADE quality of evidence for primary outcomes was " moderate " , down grade d from " high " because of lack of blinding in the included trials . AUTHORS ' CONCLUSIONS Available trial data do not provide evidence that advancing enteral feed volumes at daily increments of 15 to 20 mL/kg ( compared with 30 to 40 mL/kg ) reduces the risk of NEC or death in very preterm or VLBW infants , extremely preterm or ELBW infants , SGA or growth-restricted infants , or infants with antenatal AREDFV . Advancing the volume of enteral feeds at a slow rate results in several days of delay in establishing full enteral feeds and may increase the risk of invasive infection
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"Objective To determine whether feeding with 2-hourly or 3-hourly feeding interval reduces the time to achieve full enteral feeding and to compare their outcome in very low birthweight preterm infants . Design Parallel-group r and omised controlled trial with a 1:1 allocation ratio . Setting Two regional tertiary neonatal intensive care units . Patients 150 preterm infants less than 35 weeks gestation with birth weight between 1.0 and 1.5 kg were recruited . Interventions Infants were enrolled to either 2-hourly or 3-hourly interval feeding after r and omisation . Blinding was not possible due to the nature of the intervention . Main outcome measures The primary outcome was time to achieve full enteral feeding ( ≥100 mL/kg/day ) . Secondary outcomes include time to regain birth weight , episode of feeding intolerance , peak serum bilirubin levels , duration of phototherapy , episode of necrotising enterocolitis , nosocomial sepsis and gastro-oesophageal reflux . Results 72 infants were available for primary outcome analysis in each group as three were excluded due to death — three deaths in each group . The mean time to full enteral feeding was 11.3 days in the 3-hourly group and 10.2 days in the 2-hourly group ( mean difference 1.1 days ; 95 % CI −0.4 to 2.5 ; p=0.14 ) . The mean time to regain birth weight was shorter in 3-hourly group ( 12.9 vs 14.8 days , p=0.04 ) . Other subgroup analyses did not reveal additional significant results . No difference in adverse events was found between the groups . Conclusion 3-hourly feeding was comparable with 2-hourly feeding to achieve full enteral feeding without any evidence of increased adverse events . Trial registration number ACTRN12611000676910 , pre- result",
"Background of the study Enteral feeding in preterm neonates with intrauterine growth restriction ( IUGR ) and absent or reversed end diastolic flow ( AREDF ) on umbilical artery ( UA ) Doppler is delayed owing to an increased risk of necrotizing enterocolitis ( NEC ) . Delaying enteral feeding with longer duration of parenteral nutrition ( PN ) carries an increased risk of sepsis . Objectives To study early versus late feeding in preterm IUGR neonates for time required to attain sufficient feed volume to discontinue PN and increased risk of NEC or feed intolerance ( FI ) . Design Open-label r and omized controlled trial . Setting Tertiary care neonatal unit and fetal-maternal medicine unit in India . Participants Preterm intrauterine growth restricted neonates ' ≤32 weeks with AREDF on UA Doppler enrolled from 1 January 2014 to 31 July 2015 . Intervention R and omized to receive early or late feeding using mothers own or donor breast milk as per a feed initiation and advancement protocol . Primary outcome Time in days required to attain sufficient feed volume allowing discontinuation of PN and incidence of NEC in neonates fed early versus late . Results There were 77 eligible neonates . Sixty-two neonates were included and stratified as extreme preterm ( 27 - 29 weeks ) ( n = 20 ) and very preterm ( 30 - 32 weeks ) ( n = 42 ) . Ten extreme preterm and 21 very preterm neonates were r and omized to each early feeding and late feeding arm . There was a significantly faster attainment of sufficient feeds in the early feeding arm of both the stratified groups [ extreme preterm : median 14 days ( Interquartile range IQR : 12 - 15 ) compared with 18 days ( IQR : 18 - 20 ) , hazard ratio ( HR ) : 1.59 , 95 % CI : 0.626 - 4.078 ; very preterm : 12 days ( IQR : 10 - 14 ) as compared with 16 days ( IQR 15 - 17 ) , HR : 1.89 , 95 % CI : 1.011 - 3.555 ] . There was no difference in the incidence of NEC , FI and combined outcome of NEC and FI . Conclusion Early feeding in preterm IUGR neonates with AREDF on antenatal UA Doppler allowed earlier discontinuation of PN , allowing birth weight to be regained earlier and did not increase the incidence of NEC and FI ",
"OBJECTIVE Approximately 90 % of infants who develop necrotizing enterocolitis ( NEC ) do so after being fed . Previous prospect i ve studies have shown that infants given small enteral feedings for the first 7 to 10 days of feeding do not have an increased risk for NEC compared with those given no feedings . Although neonatologists now commonly increase feeding volumes , no study has compared the risk for NEC between infants fed these small volumes and those fed volumes that are increased slowly . The purpose of this study was to compare the risks and benefits of small and increasing feeding volume . METHODS In a r and omized , controlled trial , we r and omly assigned 141 preterm infants in the newborn intensive care unit to be fed 10 days using 1 of 2 schedules . One group was fed 20 mL/kg/d for the first 10 study days ( minimal ) . The other group ( advancing ) was fed 20 mL/kg/d on study day 1 ; feeding volume was increased by 20 mL/kg/d up to 140 mL/kg/d , which was maintained until study day 10 . The main outcome measure was incidence of NEC ; secondary outcomes were maturation of intestinal motor patterns , time to reach full enteral feedings , and incidence of late sepsis . RESULTS The study was closed early because 7 infants who were assigned to advancing feeding volumes developed NEC , whereas only 1 infant fed minimal feeding volumes did , or 10 % versus 1.4 % . Although infants who were fed minimal volumes established full enteral feeding volumes later than infants who were fed advancing volumes , maturation of intestinal motor patterns and the incidence of late sepsis and feeding intolerance was similar in the 2 groups . CONCLUSION Given that advancing feeding volumes increase the risk of NEC without providing benefits for motor function or feeding tolerance , neonatologists should consider using minimal feeding volumes until future trials assess the safety of advancing feeding volumes",
"Background : Breastfeeding at discharge among sick low-birth-weight ( LBW ) infants is low despite counseling and intervention like kangaroo mother care ( KMC ) . Research aim : The aim was to study the effects of early initiation of KMC on exclusive human milk feeding , growth , mortality , and morbidities in LBW neonates compared with late initiation of KMC during the hospital stay and postdischarge . Methods : A r and omized controlled trial was conducted in level 2 and 3 areas of a tertiary care neonatal unit over 15 months . Inborn neonates weighing 1 to 1.8 kg and hemodynamically stable were r and omized to receive either early KMC , initiated within the first 4 days of life , or late KMC ( off respiratory support and intravenous fluids ) . Follow-up was until 1 month postdischarge . Outcomes were proportion of infants achieving exclusive human milk feeding and direct breastfeeding , growth , mortality and morbidities during hospital stay , and postdischarge feeding and KMC practice s until 1 month . Results : The early KMC group ( n = 80 ) achieved significantly higher exclusive human milk feeding ( 86 % vs. 45 % , p direct breastfeeding ( 49 % vs. 30 % , p = .021 ) in hospital and almost exclusive human milk feeding ( 73 % vs. 36 % , p incidence of apnea ( 11.9 % vs. 20 % , p = .027 ) and recurrent apnea requiring ventilation ( 8.8 % vs. 15 % , p = .02 ) were significantly reduced in the early KMC group . There was no significant difference in mortality , morbidities , and growth during the hospital stay and postdischarge . Conclusion : Early KMC significantly increased exclusive human milk feeding and direct breastfeeding in LBW infants",
"AIM To compare the long-term growth and neurodevelopmental outcomes at 36 months adjusted age in preterm infants ( birthweight ( BW ) METHODS This is a case control study performed at a regional tertiary care neonatal intensive care unit . Infants with stage II or III NEC admitted to a regional tertiary care neonatal unit between 1995 and 2000 were identified . Each infant with NEC was matched by BW ( + /-100 g ) to next two infants admitted in the unit without NEC . Growth and neurodevelopmental outcomes at 36 months are compared . RESULTS In total , 51 infants with NEC and 102 controls met study eligibility criteria and 146/153 ( 94.3 % ) were prospect ively followed for 36 months . Infants with NEC had more culture-proven sepsis ( 35.3 % vs. 10.8 % , P patent ductus arteriosus requiring therapy ( 64.7 % vs. 45 % , P = 0.02 ) , chronic lung disease ( 60.7 % vs. 45 % , P = 0.04 ) and longer hospital stay ( 84 days vs. 71 days , P growth outcomes between the two groups at 36 months . Overall 24 % of infants with NEC had one major neurodevelopmental disability compared with 10 % among control infants . Infants who developed NEC had significantly higher cognitive delay ( i.e. cognitive index visual impairment . A logistic regression model identified NEC as a predictor of cognitive delay . CONCLUSION Preterm infants who develop NEC are at a significantly higher risk for developing neurodevelopmental disability . We recommend close neurodevelopmental follow up for all < or = 1250 g infants who develop stage II or III NEC",
"Background In the UK , 1–2 % of infants are born very preterm ( Very preterm infants are initially unable to be fed nutritional volumes of milk and therefore require intravenous nutrition . Milk feeding strategies influence several long and short term health outcomes including growth , survival , infection ( associated with intravenous nutrition ) and necrotising enterocolitis ( NEC ) ; with both infection and NEC being key predictive factors of long term disability . Currently there is no consistent strategy for feeding preterm infants across the UK . The SIFT trial will test two speeds of increasing milk feeds with the primary aim of determining effects on survival without moderate or severe neurodevelopmental disability at 24 months of age , corrected for prematurity . The trial will also examine many secondary outcomes including infection , NEC , time taken to reach full feeds and growth . Methods / design Two thous and eight hundred very preterm or very low birth weight infants will be recruited from approximately 30 hospitals across the UK to a r and omised controlled trial . Infants with severe congenital anomaly or no realistic chance of survival will be excluded . Infants will be r and omly allocated to either a faster ( 30 ml/kg/day ) or slower ( 18 ml/kg/day ) rate of increase in milk feeds . Data will be collected during the neonatal hospital stay on weight , infection rates , episodes of NEC , length of stay and time to reach full milk feeds . Long term health outcomes comprising vision , hearing , motor and cognitive impairment will be assessed at 24 months of age ( corrected for prematurity ) using a parent report question naire . Discussion Extensive search es have found no active or proposed studies investigating the rate of increasing milk feeds . The results of this trial will have importance for optimising incremental milk feeding for very preterm and /or very low birth weight infants . No additional re sources will be required to implement an optimal feeding strategy , and therefore if successful , the trial results could rapidly be adopted across the NHS at low cost . Trial registration IS RCT N Registry ; IS RCT N76463425 on 5 March , 2013",
"Background : The interrelations between early enteral feeding , necrotising enterocolitis ( NEC ) , and nosocomial sepsis ( NS ) remain unclear . Objective : To evaluate the effect of age at the introduction of enteral feeding on the incidence of NS and NEC in very low birthweight ( VLBW Methods : Data were collected on the pattern of enteral feeding and perinatal and neonatal morbidity on all VLBW infants born in one centre during 1995–2001 . Enteral feeding was compared between infants with and without NS and /or NEC . Results : The study sample included 385 infants . Of these , 163 ( 42 % ) developed NS and 35 ( 9 % ) developed NEC . Enteral feeding was started at a significantly earlier mean ( SD ) age in infants who did not develop nosocomial sepsis ( 2.8 ( 2.6 ) v 4.8 ( 3.7 ) days , p = 0.0001 ) . Enteral feeding was introduced at the same age in babies who did or did not develop NEC ( 3.1 ( 2 ) v 3.7 ( 3 ) days , p = 0.28 ) . Over the study period , the mean annual age at the start of enteral feeding fell consistently , and this correlated with the mean annual incidence of NS ( r2 = 0.891 , p = 0.007 ) . Multiple logistic regression analysis showed age at start of enteral feeding , respiratory distress syndrome , and birth weight to be the most significant predictors of risk of NS ( p = 0.0005 , p = 0.024 , p = 0.011 ) . Conclusions : Early enteral feeding was associated with a reduced risk of NS but no change in the risk of NEC in VLBW infants . These findings support the use of early enteral feeding in this high risk population , but this needs to be confirmed in a large r and omised controlled trial",
"CONTEXT Neonatal infections are frequent complications of extremely low-birth-weight ( ELBW ) infants receiving intensive care . OBJECTIVE To determine if neonatal infections in ELBW infants are associated with increased risks of adverse neurodevelopmental and growth sequelae in early childhood . DESIGN , SETTING , AND PARTICIPANTS Infants weighing 401 to 1000 g at birth ( born in 1993 - 2001 ) were enrolled in a prospect ively collected very low-birth-weight registry at academic medical centers participating in the National Institute of Child Health and Human Development Neonatal Research Network . Neurodevelopmental and growth outcomes were assessed at a comprehensive follow-up visit at 18 to 22 months of corrected gestational age and compared by infection group . Eighty percent of survivors completed the follow-up visit and 6093 infants were studied . Registry data were used to classify infants by type of infection : uninfected ( n = 2161 ) , clinical infection alone ( n = 1538 ) , sepsis ( n = 1922 ) , sepsis and necrotizing enterocolitis ( n = 279 ) , or meningitis with or without sepsis ( n = 193 ) . MAIN OUTCOME MEASURES Cognitive and neuromotor development , neurologic status , vision and hearing , and growth ( weight , length , and head circumference ) were assessed at follow-up . RESULTS The majority of ELBW survivors ( 65 % ) had at least 1 infection during their hospitalization after birth . Compared with uninfected infants , those in each of the 4 infection groups were significantly more likely to have adverse neurodevelopmental outcomes at follow-up , including cerebral palsy ( range of significant odds ratios [ ORs ] , 1.4 - 1.7 ) , low Bayley Scales of Infant Development II scores on the mental development index ( ORs , 1.3 - 1.6 ) and psychomotor development index ( ORs , 1.5 - 2.4 ) , and vision impairment ( ORs , 1.3 - 2.2 ) . Infection in the neonatal period was also associated with impaired head growth , a known predictor of poor neurodevelopmental outcome . CONCLUSIONS This large cohort study suggests that neonatal infections among ELBW infants are associated with poor neurodevelopmental and growth outcomes in early childhood . Additional studies are needed to eluci date the pathogenesis of brain injury in infants with infection so that novel interventions to improve these outcomes can be explored",
"OBJECTIVE To compare the effects of continuous versus intermittent feeding on gastrointestinal tolerance and growth in very low birth weight ( VLBW ) infants . STUDY DESIGN In a r and omized , controlled trial conducted at 3 neonatal units , 70 premature infants with a gestational age 24 to 29 weeks and birth weight were assigned to 1 of 3 feeding methods : continuous nasogastric feeding , intermittent nasogastric feeding , or intermittent orogastric feeding . Feeding was initiated within 30 hours of birth . Daily enteral and parenteral volumes , caloric and protein intakes , growth , enteral intolerance , and clinical complications were recorded . Cox regression analysis was used to determine primary outcome , the time to achieve full enteral feeding . RESULTS The continuously fed infants achieved full enteral feeding significantly faster than the intermittently fed infants ( hazard ratio [ HR ] = 1.86 ; 95 % confidence interval [ CI ] = 1.07 to 3.22 ) . In stratified analysis according to birth weight , the improvement was even more pronounced in the smallest infants , those with birth weight Growth rate was significantly faster in the continuously fed infants ( P = .002 ) . CONCLUSION In VLBW infants , continuous feeding seems to be better than intermittent feeding with regard to gastrointestinal tolerance and growth",
"In a prospect i ve multicentre study on 926 preterm infants formally assigned to their early diet , necrotising enterocolitis developed in 51 ( 5.5 % ) . Mortality was 26 % in stringently confirmed cases . In exclusively formula-fed babies confirmed disease was 6 - 10 times more common than in those fed breast milk alone and 3 times more common than in those who received formula plus breast milk . Pasteurised donor milk seemed to be as protective as raw maternal milk . Among babies born at more than 30 weeks ' gestation confirmed necrotising enterocolitis was rare in those whose diet included breast milk ; it was 20 times more common in those fed formula only . Other risk factors included very low gestational age , respiratory disease , umbilical artery catheterisation , and polycythaemia . In formula-fed but not breast-milk-fed infants , delayed enteral feeding was associated with a lower frequency of necrotising enterocolitis . With the fall in the use of breast milk in British neonatal units , exclusive formula feeding could account for an estimated 500 extra cases of necrotising enterocolitis each year . About 100 of these infants would die",
"Background and Objectives : Controversy exists regarding the optimal enteral feeding regimen of very low birth weight infants ( VLBW ) . Rapid advancement of enteral feeding has been associated with an increased rate of necrotizing enterocolitis . In contrast , delaying enteral feeding may have unfavorable effects on nutrition , growth , and neurodevelopment . The aim is to compare the short-term outcomes of VLBW infants in tertiary care centers according to their enteral feeding advancement . Patients and Methods : We prospect ively studied the influence of center-specific enteral feeding advancement in 1430 VLBW infants recruited from 13 tertiary neonatal intensive care units in Germany on short-term outcome parameters . The centers were post hoc stratified to “ rapid advancement to full enteral feeds ” ( median duration of advancement to full enteral feeds ≤12.5 days ; 6 centers ) , that is , rapid advancement ( RA ) , or “ slow advancement to full enteral feeds ” ( median duration of advancement to full enteral feeds > 12.5 days ; 7 centers ) , that is , slow advancement ( SA ) . Results : VLBW infants born in centers with SA ( n = 713 ) had a significantly higher rate of sepsis compared with VLBW infants born in centers with RA ( n = 717 ) , which was particularly evident for late-onset sepsis ( 14.0 % vs 20.4 % ; P = 0.002 ) . Furthermore , more central venous lines ( 48.6 % vs 31.1 % , P on short-term outcomes such as nosocomial sepsis . Large , multicenter , prospect i ve trials are required to further eluci date the optimal feeding strategy for VLBW infants",
"Background : Most preterm infants who develop necrotising enterocolitis ( NEC ) have received enteral feeds . Uncertainty exists about which aspects of the feeding regimen affect the risk of NEC . Aim : To examine associations between various enteral feeding practice s and the development of NEC in preterm infants . Methods : Multicentre case – control study . 53 preterm infants with NEC were enrolled together with a gestational age frequency-matched control without NEC from a r and omly selected neonatal unit . Clinical and feeding data were extracted and compared between the groups . Results : Significantly fewer cases than controls had received human breast milk ( 75 % vs 91 % ; OR 0.32 , 95 % CI 0.11 to 0.98 ) . The day on which enteral feeding was started did not differ significantly ( mean ( SD ) days after birth : cases 2.9 ( 2.8 ) and controls 2.8 ( 1.8 ) ) . The mean ( SD ) duration of trophic feeding ( fully fed significantly earlier than controls ( mean ( SD ) days after birth : cases 9.9 ( 4.2 ) and controls 14.3 ( 9.8 ) ; MD −4.4 , 95 % CI −7.3 to −1.5 ) . Conclusions : These data suggest that the duration of trophic feeding and rate of advancement of feed volumes may be modifiable risk factors for NEC in preterm infants . Further r and omised controlled trials are warranted to assess the effect of different rates of feed advancement on the incidence of NEC , as well as other outcomes",
"Abstract Objective : Incidence of feed intolerance ( FI ) and necrotizing enterocolitis ( NEC ) in preterm neonates with Doppler evidence of absent end diastolic flow ( AEDF ) velocities in the fetal umbilical artery when enteral feed volumes were started by 6–72 h and advanced either slowly or rapidly . Methods : Stable inborn neonates , 30–36 weeks gestation , weighing ≥1000 g and with antenatal evidence of AEDF were included in this pilot study . Infants ( stratified in were allocated under r and omized controlled trial , to receive either slow or rapid advancement of enteral feeding , while initiating the feeds after 6 h of birth if bowel sounds were present . Primary outcome measure was , FI and NEC till day 7 after reaching full feeds . Results : Of 159 eligible infants , 83 were r and omized : 53 infants in the ≥1250 g category ( 28 in rapid and 25 in slow group ) and 30 in the group ) . FI was present in 11 % versus 16 % in ≥1250 g ( p = 0.570 ) and 27 % versus 33 % in 0.690 ) , NEC developed in 8.4 % ( 3 versus 1 ) in ≥1250 g and ( 1 versus 2 ) in incidence of feed intolerance with very early introduction and rapid advancement of enteral feeds in stable preterm neonates with AEDF and birth weight ≥1250",
"NECROTIZING ENTEROCOLITIS is a serious disorder of the newborn infant that rarely occurs before the institution of oral feedings . ' -3 Various feeding practice s have been shown to be important in the pathogenesis of the disease . Low-birth-weight infants fed a hyperosmolar , 650 mOsm/1 , elemental formula have an increased incidence of NEC when compared to low-birth-weight infants fed a cow milk formula . 4 It has also been suggested that cow milk feedings themselves or the exclusion of breast milk from the diet of small newborn infants may be predisposing factors ? The quantity of feedings in the first weeks of life may also be important , and Krouskop and associates ~ have associated the development of NEC with early institution of oral feedings . In another retrospective study , however , there were no differences between the volume of formula offered NEC patients at the time symptoms developed and infants of similar size and age who did not develop NEC . 1 Conflicting opinions therefore exist regarding the relationship of oral feeding to the development of NEC ; there have been no r and omized , prospect i ve , clinical trials dealing with this issue . The purpose s of this paper are to report the relationship of different feeding practice s in the Intermountain Newborn Intensive Care Center to the incidence of NEC , and the results of a prospect i ve controlled investigation comparing two different feeding schedules in low-birth-weight infants",
"The National Institute of Child Health and Human Development conducts and supports research on all stages of human development from preconception to adulthood in order to better underst and the health of children , youths , adults , families , and communities . Health and human development information is made easily available on the site with a simple A to Z list , along with clinical trials and health education campaign information . Links to clinical trials , news releases , publications , and related web sites are also available , as well as information on research being conducted at present and supported by the National Institute of Child Health and Human Development",
"Objectives . To determine whether infants who are fed initially and advanced at 30 mL/kg per day ( intervention ) take fewer days to get to full feedings than those who are fed initially and advanced at 20 mL/kg per day ( control ) , without increasing their incidence of feeding complications and necrotizing enterocolitis ( NEC ) . We also examined whether these infants regain birth weight earlier , have fewer days of intravenous fluids , and a have shorter hospital stay . Methods . A r and omized , controlled , single-center trial was conducted in a Neonatal Intensive Care Unit of a community-based county hospital in Houston , Texas . Infants between 1000 and 2000 g at birth , gestational age ≤35 weeks , and weight appropriate for gestational age were allocated r and omly to feedings of expressed human milk or Enfamil formula starting and advanced at either 30 mL/kg per day or 20 mL/kg per day . Infants remained in the study until discharge or development of stage ≥IIA NEC . Results . A total of 155 infants were enrolled : 72 infants in the intervention group and 83 in the control group . Infants in the intervention group achieved full-volume feedings sooner ( 7 vs 10 days , median ) , regained birth weight faster ( 11 vs 13 days , median ) , and had fewer days of intravenous fluids ( 6 vs 8 days , median ) . Three infants in the intervention group and 2 control infants developed NEC for an overall incidence of 3.2 % ( relative risk : 1.73 ; 95 % confidence interval : 0.30–10.06 ) . Conclusion . Among infants between 1000 and 2000 g at birth , starting and advancing feedings at 30 mL/kg per day seems to be a safe practice and results in fewer days to reach full-volume feedings than using 20 mL/kg per day . This intervention also leads to faster weight gain and fewer days of intravenous fluids",
"OBJECTIVE To evaluate whether the mean gastric residual volume ( GRV ) and green gastric residuals ( GR ) themselves are significant predictors of feeding intolerance in the early enteral feeding advancement in extremely low birth weight ( ELBW ; DESIGN Ninety-nine ELBW infants were fed following a st and ardized protocol ( day 3 - -14 ) . At 48 hours of age , milk feeding was started ( 12 mL/kg/d increments , 12 meals per day ) . GR were checked before each feeding , and a GRV up to 2 mL/3 mL in infants less-than-or-equal750 g/>750 g was tolerated . In cases of increased GRV , feedings were reduced or withheld . The color of GR was assessed as clear , milky , green-clear , green-cloudy , blood-stained , or hemorrhagic . Multiple regression analysis was used to study the effect of the mean GRV and the color of GR on the feeding volume on day 14 ( V14 ) . RESULTS The median V14 was 103 mL/kg/d ( 0 - -166 ) . V14 increased with an increasing percentage of milky GR , whereas the mean GRV and the color green did not have a significant effect . CONCLUSIONS 1 ) Early enteral feeding could be established in ELBW infants . The critical GRV seems to be above 2 mL/3 mL because there was no significant negative correlation between the mean GRV and V14 . 2 ) Green GR were not negatively correlated with V14 and should not slow down the advancement of feeding volumes in absence of other clinical signs and symptoms",
"OBJECTIVE To determine whether the rate of feed advancement affects the incidence of necrotizing enterocolitis ( NEC ) . STUDY DESIGN Prospect i ve r and omized controlled trial involving 185 formula-fed infants with birth weight 501 to 1500 g and gestational age Infants were r and omized into 2 groups : \" slow \" ( n = 98 ) , who received 15 cc/kg/d increments ( a 10-day schedule to full feeds ) and \" fast \" ( n = 87 ) , who received 35 cc/kg/d increments ( a 5-day schedule to full feeds ) of Similac Special Care 20 cal/oz . Feeds were increased only if well tolerated as defined by a protocol . RESULTS The incidence of NEC ( Bell stage > /=II ) was similar in both groups ( slow 13 % and fast 9 % , P = .5 ) . The incidence of perforation ( Bell stage III ) was also similar in both groups ( slow 4 % and fast 2 % , P = .8 ) . Feeds were started at a comparable postnatal age in both groups ( median age : slow 5 days and fast 4 days , P = .9 ) . Although the neonates in the fast group attained full enteral intake earlier ( median days [ 25th and 75th percentiles ] : slow 15 [ 12 , 21 ] and fast 11 [ 8 , 15 ] , P regained their birth weight earlier ( slow 15 [ 11 , 20 ] and fast 12 [ 8 , 15 ] , P ages at discharge were not statistically different ( slow 47 [ 31 , 67 ] and fast 43 [ 29 , 62 ] , P = .3 ) CONCLUSIONS A greater than twofold difference in the rate of feed advancement from 15 cc/kg/d to 35 cc/kg/d did not affect the incidence of NEC > /= stage II . Factors other than feed advancement appear to be more important in the pathogenesis or progression of NEC",
"We sought to describe neonatal morbidities and therapeutic interventions in very low-birth-weight ( VLBW ) and extremely low-birth-weight ( ELBW ) infants cared for in Spanish hospitals . We preformed a prospect i ve collection of data covering the perinatal period until discharge by the SEN1500 network . This network , set up by the Spanish Society of Neonatology , targets VLBW and ELBW infants ( 400 to 1500 g ) admitted to neonatal units in Spanish hospitals . Data were recorded in electronic form and controlled for possible errors or inconsistencies before analysis . We report data for 8836 neonates admitted to 48 neonatal units from January 2002 to December 2005 . Prenatal steroids were given to significantly more newborns in 2003 to 2005 ( 79.4 % ) than in 2002 ( 73.4 % ) , although the remaining perinatal data examined failed to significantly vary . Delivery was by cesarean section in 69.8 % of cases but significantly lower ( 35.9 % ) for infants under a postmenstrual age of 26 weeks . Hyaline membrane disease was diagnosed in 53.9 % of the newborns and bronchopulmonary dysplasia ( BPD ) in 10.46 % . Mechanical ventilation was employed in 69.1 % , surfactant in 50.3 % , and steroids for BPD in 5.3 % . Intraventricular hemorrhage grade s 3 to 4 ( 8.1 % ) and cystic leukomalacia ( 2.6 % ) were the most relevant brain ultrasonography findings . Rates of early- and late-onset septicemia were 5 % and 29.4 % , respectively . Further diagnoses were necrotizing enterocolitis ( NEC ; 6.9 % ) and persistent ductus arteriosus ( PDA ; 24.2 % ) ; 40.6 % of the cases of NEC and 15.3 % of those of PDA required surgery . In addition , 26.6 % of the newborns required supplementary oxygen at 28 days of life . The number of newborns who had not recovered their birth weight at this age fell from 3.1 % in 2002 to 1.5 % in 2005 . Rates of prenatal steroid use , cesarean delivery , and main morbidities were comparable to figures cited for other patient series , although our BPD rate was among the lowest reported and nosocomial sepsis rate among the highest",
"OBJECTIVE To evaluate the effect of slow vs rapid rates of advancement of enteral feed volumes on the clinical outcomes in preterm infants with 750 - 1250 g birth weight . STUDY DESIGN A total of 92 stable neonates 750 - 1250 g and gestational age were r and omly allocated to enteral feeding advancement of 20 mL/kg/d ( n = 46 ) or 30 mL/kg/d ( n = 46 ) . The primary outcome was days to reach full enteral feeding , defined as 180 mL/kg/d . Secondary outcomes included rates of necrotizing enterocolitis ( NEC ) and culture-proven sepsis , days of parenteral nutrition ( PN ) , length of hospital stay , and growth end points . RESULTS Neonates in the rapid-feeding advancement group achieved full enteral volume of feedings earlier than the slower advancement group . They received significantly fewer days of PN , exhibited a shorter time to regain birth weight , and had a shorter duration of hospital stay . The incidence of NEC and the number of episodes of feeding intolerance were not significantly different between the groups , whereas the incidence of culture-proven late-onset sepsis was significantly less in infants receiving a rapid feeding advancement . Excluding infants who were small for gestational age at birth , the incidence of extrauterine growth restriction was significantly reduced in the rapid-advancement group at 28 days and at hospital discharge . CONCLUSION Rapid enteral feeding advancements in 750 - 1250 g birth weight infants reduce the time to reach full enteral feeding and the use of PN administration . Rapid-advancement enteral feed also decreases extrauterine growth restriction with improved short-term outcomes for these high-risk infants",
"OBJECTIVE To evaluate the tolerance of rapid advancement of enteral feeds in VLBW babies . SETTING Tertiary teaching hospital . DESIGN R and omized controlled trial . METHODS All stable neonates with birth weight less than 1250 grams were included in the study . The primary outcome variable was the time taken to achieve full enteral feeds ( defined as 180 ml/kg/day ) . The secondary outcome variables were incidence of Necrotizing enterocolitis ( NNEC ) and incidence of apnea . At 48 hours , the infants were r and omized into the slow advancement group ( enteral feeds advanced by increments of 15 ml/kg/day ) or fast advancement group ( enteral feeds advanced by increments of 30 ml/kg/day ) . The monitoring during feeding included daily weight record , two hourly abdominal girth charting , gastric aspirates , apnea , time taken to reach full enteral feedings and for NNEC . RESULTS There were 53 infants who were enrolled for the study ( 27 in the fast advancement group and 26 in the slow advancement group ) . In the fast advancement group , 20 percent completed the trial ; whereas 14 ( 53.8 percent ; ) in the slow advancement group completed the study . The two groups were comparable for birth weights , gestational age , sex , intrauterine growth status , Apgar and CRIB scores . The infants in the fast group reached full enteral intake of 180 ml/kg/day significantly earlier ( 10 + /- 1.8 days ) than in the slow group ( 14.8 + /- 1.5 days ) . The two groups were comparable for episodes of feed intolerance , apnea , NNEC . Infants in the fast group regained birth weight significantly earlier ( median 18 days ) than in the slow advancement group ( median 23 days ) . CONCLUSIONS Stable VLBW neonates can tolerate rapid advancements of enteral feeding without increased risk of adverse effects"
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Background This study aims to evaluate the 12–24-month impact of bariatric surgery on the foremost modifiable traditional risk factors of cardiovascular disease . Methods A systematic review and meta- analysis of prospect i ve interventional studies reporting the most commonly performed laparoscopic surgical procedures , i.e. , Roux-en-Y gastric bypass ( RYGB ) , adjustable gastric b and ing ( AGB ) , and cardiovascular risk reduction after surgery . Results The bibliographic research conducted independently by two authors yielded 18 records . When looking at RYGB and AGB separately , we observed a relevant heterogeneity ( I2 index ≥87 % ) when BMI reduction was considered as the main outcome . When hypertension , type II diabetes , and hyperlipidemia risk reduction was estimated , a highly significant beneficial effect was found . The risk reduction was 0.33 [ 0.26 ; 0.42 ] for type II diabetes , 0.52 [ 0.42 ; 0.64 ] for hypertension , and 0.39[0.27 ; 0.56 ] for hyperlipidemia ( P significant risk reduction for all outcomes considered was found . Results from the meta-regression approach showed an inverse relation between cardiovascular risks and BMI reduction . Conclusions The present study showed an overall reduction of cardiovascular risk after bariatric surgery . According to our analysis a BMI reduction of 5 after surgery corresponds to a type II diabetes reduction of 33 % ( as reported by Peluso and Vanek ( Nutr Clin Pract 22(1):22–28 , 2007 ) ; SAS Institute Inc. , ( 2000–2004 ) ) , a hypertension reduction of 27 % ( as reported by Buchwald and Oien ( Obes Surg 23(4):427–436 , 2013 ) ; Valera-Mora et al. ( Am J Clin Nutr 81(6):1292–1297 , 2005 ) ) , and a hyperlipidemia reduction of 20 % ( as reported by Adams et al. ( JAMA 308(11):1122–31 , 2012 ) ) ; Alex and rides et al. ( Obes Surg 17(2):176–184 , 2007 ) . In summary , our study showed that laparoscopic bariatric surgery is an effective therapeutic option to reduce the cardiovascular risk in severe obese patients
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"Background Laparoscopic Roux-en-Y gastric bypass ( LRYGB ) surgery is known to have a significant effect on obesity-related comorbidities such as hypertension curing it in some ( 50–70 % ) while improving control in others . Our aim was to observe the changes in blood pressure ( BP ) in a cohort of 100 patients followed prospect ively for 1 year after LRYGB . Methods BP measurements were recorded prospect ively in 100 consecutive patients preoperatively and then postoperatively at weeks 1 , 5 , 9 , and months 6 and 12 . In order to reduce bias , three BP measurements were made by the same nurse at each office visit and the mean recorded . Pre- and postoperative usage of antihypertensive medication was also noted . Results Eighty-nine women and 11 men underwent LRYGB and their BP monitored for 1 year . There was an 85 % follow-up rate with mean % excess body weight loss of 60 . Reductions in systolic ( 9 mmHg ) and diastolic ( 7 mmHg ) BP measurements were seen as early as week 1 postoperatively and maintained for the duration of the observation period ( P postoperative usage of antihypertensive medication is reduced to a third of preoperative use . Conclusion LRYGB is associated with an early reduction in BP and antihypertensive medication usage which is maintained at 1 year after surgery . This early impact on blood pressure occurs before any significant weight loss is achieved thereby suggesting a hormonal mechanism that may be involved for the changes observed",
"Background : The objective of this study was to determine the weight loss , changes in co-morbidities , medication usage and general health status at 1 year after laparoscopic adjustable gastric b and ing ( LAGB ) . Methods : Prospect i ve data were obtained from all subjects undergoing LAGB . These measurements included a medical history and review of systems , medications , height and weight and the SF-36 general health survey . Patients were seen for b and adjustments as needed throughout the year . At the 1-year follow-up visit , patients were weighed and interviewed about the status of their health conditions and their current medications , and the SF-36 was repeated . Results : Between November 2002 and November 2003 , 195 patients had LAGB . The majority of subjects were female ( 82.8 % ) , married ( 65.1 % ) , and white ( 94.9 % ) . Complications occurred in 18 subjects ( 9.2 % ) . These included 3 slipped b and s ( 1.5 % ) , 4 port problems ( 2.1 % ) , 8 patients with temporary stoma occlusion ( 4.1 % ) , 1 explantation ( 0.5 % ) , and 1 mortality ( 0.5 % ) . Mean BMI decreased from 45.8 kg/m2 ( ± 7.7 ) to 32.3 kg/m2 ( ± 7.0 ) . Mean percent excess body weight lost was 45.7 % ( ± 17.1 ) during the first year . Major improvements occurred in arthritis , asthma , depression , diabetes , gastro-esophageal reflux disease , hyperlipidemia , hypertension , joint and back pain , sleep apnea and stress incontinence . Medication usage declined remarkably . Quality of life ( QoL ) by the SF-36 showed highly significant improvements . Conclusions : At 1 year after LAGB , patients had experienced significant weight loss , resolution of comorbidities , decreases in medication usage , and improvements in",
"BACKGROUND Roux-en-Y gastric bypass is currently considered the gold st and ard surgical option for the treatment of morbid obesity . Open RYGB is associated with a high risk of complications . Laparoscopic RYGB has been shown to reduce perioperative morbidity and improve recovery . OBJECTIVES To review our experience with laparoscopic RYGB during a 19 month period . METHODS The data were collected prospect ively . The study group comprised all patients who underwent laparoscopic RYGB for treatment of morbid obesity as their primary operation between February 2006 and July 2007 . The reported outcome included surgical results , weight loss , and improved status of co-morbidities , with follow-up of up to 19 months . RESULTS The mean age of the 50 patients was 36.7 years . Mean body mass index was 44.7 kg/m2 ( range 35 - 76 kg/m2 ) ; mean duration of surgery was 171 minutes . There was no conversion to open surgery . The mean length of stay was 4 days ( range 2 - 7 days ) . Five patients ( 10 % ) developed a complication , but none of them required early reoperation and there were no deaths . Mean follow-up was 7 months ( range 40 days-19 months ) . The excess body weight loss was 55 % and 61 % at 6 and 12 months respectively . Diabetes resolved completely or significantly improved in all five patients with this condition , as did hypertension in eight patients out of nine . CONCLUSIONS Laparoscopic RYGB is feasible and safe . The results in terms of weight loss and correction of co-morbidities are comparable to other previously published studies . However , only surgeons with experience in advanced laparoscopic as well as bariatric surgery should attempt this procedure",
"HYPOTHESIS Outcome following laparoscopic adjustable gastric b and ing ( LAGB ) in super morbidly obese patients is significantly worse compared with the st and ard laparoscopic Roux-en-Y gastric bypass ( LRYGB ) . DESIGN Prospect i ve case series . SETTING Community teaching hospital ( 490 beds ) . PATIENTS A prospect ively maintained data base identified patients who underwent operative treatment for morbid obesity between February 2001 and June 2004 . The study group included super morbidly obese patients ( body mass index > 50 [ calculated as weight in kilograms divided by the square of height in meters ] ) following LAGB and LRYGB . INTERVENTIONS Among 106 patients with super morbid obesity , 60 ( 57 % ) and 46 ( 43 % ) underwent LAGB and LRYGB , respectively . MAIN OUTCOME MEASURES Patient demographics , weight loss , percentage of excess weight loss , change in body mass index , early ( or = 30 days ) complications , reoperations , medical comorbidity , and patient satisfaction were studied . Analysis was performed using the t test and Pearson chi 2 analysis . RESULTS Overall median follow-up was 16.2 months ( range , 1 - 40 months ) . Preoperative factors of patient age , sex , weight , body mass index , and medical comorbidity were similar between the 2 groups . Compared with LRYGB , patients who underwent LAGB experienced a greater incidence of late complications ( P reoperations ( P less weight loss ( P decreased overall satisfaction ( P LRYGB had a greater resolution of concomitant diabetes mellitus ( P sleep apnea ( P weight loss for LAGB recipients ranged from 1 to 15 manipulations . Our single mortality was in the LAGB group . CONCLUSIONS In super morbidly obese patients , LAGB is significantly associated with more late complications , reoperations , less weight loss , less reduction of medical comorbidity , and patient dissatisfaction compared with LRYGB . Further evaluation of LAGB in this patient population appears warranted",
"The Program on the Surgical Control of the Hyperlipidemias ( POSCH ) was a secondary atherosclerosis intervention trial employing partial ileal bypass surgery as the intervention modality . For this report , we analyzed 105 subgroups in 35 variables in POSCH , chosen predominantly for their potential relationship to the risk of atherosclerotic coronary heart disease ( ACHD ) . We defined potential differential effects as those with : ( 1 ) an absolute z-value > or = 2.0 for the subgroup , if the absolute z-value for the overall effect was or = 3.0 for the subgroup and a relative risk or = 2.0 . For each of three major POSCH endpoints of overall mortality , ACHD mortality and ACHD mortality or confirmed nonfatal myocardial infa rct ion , we found seven subgroups with a differential risk reduction in the surgery group as compared to the control group . Allowing for identical subgroups for more than one endpoint , there were 13 individual subgroups with differential effects . Of these , seven demonstrated internal consistency across endpoints , and five of these seven displaced external consistency with known ACHD risk factors and for biological plausibility : triglyceride concentration > or = 200 mg/dl ; cigarette smoking ; overt or borderline diabetes mellitus ; a Minnesota ECG Q-QS code of 1 - 1 ; and obesity . A greater risk reduction , in comparison to the overall treatment effect , by the reduction of a single risk factor , hypercholesterolemia , in patients with at least two major ACHD risk factors was a provocative and an hypothesis-generating outcome of this analysis . The clinical implication s of this finding may lead to more aggressive cholesterol intervention in patients with multiple ACHD risk factors",
"Background : Obesity is now one of our major public health problems . Effective and acceptable treatment options are needed . The Lap-B and ® system is placed laparoscopically and allows adjustment of the level of gastric restriction . Methods : A prospect i ve study of 709 severely obese patients was conducted over a 6-year period at a university-based multidisciplinary referral center . After extensive preoperative evaluation , patients with a body mass index > 35 were treated by LapB and ® placement . Close follow-up with progressive adjustment of gastric restriction continued permanently . Medical co-morbidities were monitored as part of comprehensive prospect i ve data collection . Results : There have been no deaths perioperatively or during follow-up . Significant perioperative adverse events occurred in 1.2 % only . Reoperation has been needed for prolapse ( slippage ) in 12.5 % , erosion of the b and into the stomach in 2.8 % and for tubing breaks in 3.6 % . A steady progression of weight loss has occurred through the duration of the study with 52 ± 19 % EWL at 24 months ( n=333 ) , 53±22 % EWL at 36 months ( n=264 ) , 52 ± 24 % EWL at 48 months ( n=108 ) , 54 ± 24 % EWL at 60 months ( n=30 ) , and 57 ± 15 % EWL at 72 months ( n=10 ) . Major improvements have occurred in diabetes , asthma , gastroesophageal reflux , dyslipidemia , sleep apnea and depression . Quality of life as measured by R and SF-36 shows highly significant improvement . Conclusions : Placement of the Lap-B and ® system provides safe and effective control of severe obesity . The effect on weight loss is durable and is associated with major improvement in health and quality of life . It has the potential to provide a broadly acceptable option for this common and serious disease",
"AIMS To evaluate the effect of weight loss after bariatric surgery ( BS ) on peripheral adipocytokines , renal parameters and other cardiovascular risk factors ( CVRFs ) . METHODS A total of 70 ( 41 women ) extremely obese adults were prospect ively studied before and 12 months after surgery . CONTROLS 24 ( 15 women ) normal-weight adults . Anthropometric , biochemical and renal parameters were recorded . RESULTS Presurgery , adiponectin ( ADPN ) was lower , whereas leptin , insulin resistance , C-reactive protein , creatinine clearance and albuminuria were higher in patients than controls ( P Changes in ADPN correlated negatively with leptin , insulin resistance , albumin , C-reactive protein , and creatinine clearance . Multiple regression analysis : using changes in ADPN as the dependent variable , only changes in insulin resistance ( P=0.005 ) and albumin ( P=0.019 ) were significant independent determinants for changes in ADPN . No statistical differences were found in relation to the degree of obesity . CONCLUSION Patients changed to obesity type I after surgery . This implies a substantial improvement of CVRFs including ADPN , creatinine clearance and albuminuria . Changes in plasma ADPN correlated negatively with insulin resistance and with albuminemia but not with renal parameters . The lack of differences between different degrees of obesity suggests that the relationship between weight and CVRFs no longer exists when obesity becomes very extreme",
"Background : Severe obesity is associated with type 2 diabetes and hypertension . Improvement in these comorbidities after surgically-induced weight loss has been documented , and laparoscopic adjustable gastric b and ing ( LAGB ) is an effective weight loss operation . Methods : Of 840 patients who underwent Lap-B and ® , data are available in 402 out of 413 patients whose surgery took place at ≥ 1 year ago . Preoperative and follow-up data were studied retrospectively to examine the effect of Lap-B and ® -induced weight loss on diabetes and hypertension . Results : Of 413 patients with at least 1 year postoperative follow-up , 53 ( 12.8 % ) were taking medications for type 2 diabetes preoperatively and 189 ( 45.7 % ) were on antihypertensive medications . 66 % ( n=35 ) of diabetic patients were also hypertensive . Resolution of diabetes was observed in 66 % at 1-year and 80 % at 2-year follow-up . HbA1c dropped from 7.25 % ( 5.6 - 11.0 , n=53 ) preoperatively to 5.58 % ( 5.0 - 6.2 , n=15 ) at 2 years after surgery . Hypertension resolved in 59.8 % and 74 % at 1 and 2 years , respectively . Percent excess weight loss ( % EWL ) was lower for diabetic patients than for our cohort population ( 39.2 % vs 41.2 % at 1 year , 46.7 % vs 54.2 % at 18 months , and 52.6 % vs 63.3 % at 2 years , respectively ) . Patients in whom diabetes was improved but not resolved had lower % EWL than did those whose diabetes went into remission ( 27.0 % at 1 year and 26.5 % at 2 years ) . Patients with the shortest duration of diabetes ( better weight loss after surgery achieved higher resolution rates . Conclusions : Dramatic improvement in – and frequent resolution of – diabetes and hypertension have been observed as a result of weight loss after Lap-B and ® surgery",
"Objective To compare outcomes , quality of life ( QOL ) , and costs of laparoscopic and open gastric bypass ( GBP ) . Summary Background Data Laparoscopic GBP has been reported to be a safe and effective approach for the treatment of morbid obesity . The authors performed a prospect i ve r and omized trial to compare outcomes , QOL , and costs of laparoscopic GBP with those of open GBP . Methods From May 1999 to March 2001 , 155 patients with a body mass index ( BMI ) of 40 to 60 kg/m2 were r and omly assigned to undergo laparoscopic ( n = 79 ) or open ( n = 76 ) GBP . The two groups were similar in age , sex ratio , mean BMI , and comorbidities . Main outcome measures included operative time , estimated blood loss , length of hospital stay , operative complications , percentage of excess body weight loss , and time to return to activities of daily living and work . Changes in QOL were assessed using the SF-36 Health Survey and the bariatric analysis of reporting outcome system ( BAROS ) . Operative and hospital costs of the two operations were also compared . Results There were no deaths in either group . Mean operative time was longer for laparoscopic GBP than for open GBP , but operative blood loss was less . Two ( 2.5 % ) of the 79 patients in the laparoscopic group required conversion to laparotomy . Median length of hospital stay was shorter for laparoscopic GBP patients ( 3 vs 4 days ) . The rate of postoperative anastomotic leak was similar between groups . Wound-related complications such as infection ( 10.5 vs 1.3 % ) and incisional hernia ( 7.9 vs 0 % ) were more common after open GBP ; late anastomotic stricture was less frequent after open GBP ( 2.6 vs 11.4 % ) . Time to return to activities of daily living and work were shorter after laparoscopic GBP than after open GBP . Weight loss at 1 year was similar between groups . Preoperative SF-36 scores were similar between groups ; however , at 1 month after surgery , laparoscopic patients had better physical conditioning , social functioning , general health , and less body pain than open GBP patients . At 6 months , the BAROS outcome was classified as good or better in 97 % of laparoscopic GBP patients compared with 82 % of open GBP patients . Operative costs were higher for laparoscopic GBP patients , but hospital costs were lower . Conclusions Laparoscopic GBP is a safe and cost-effective alternative to open GBP . Despite a longer operative time , patients undergoing laparoscopic GBP benefited from less blood loss , a shorter hospital stay , and faster convalescence . Laparoscopic GBP patients had comparable weight loss at 1 year but a more rapid improvement in QOL than open GBP patients . The higher initial operative costs for laparoscopic GBP were adequately offset by the lower hospital costs",
"CONTEXT Extreme obesity is associated with health and cardiovascular disease risks . Although gastric bypass surgery induces rapid weight loss and ameliorates many of these risks in the short term , long-term outcomes are uncertain . OBJECTIVE To examine the association of Roux-en-Y gastric bypass ( RYGB ) surgery with weight loss , diabetes mellitus , and other health risks 6 years after surgery . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve Utah-based study conducted between July 2000 and June 2011 of 1156 severely obese ( body mass index [ BMI ] ≥ 35 ) participants aged 18 to 72 years ( 82 % women ; mean BMI , 45.9 ; 95 % CI , 31.2 - 60.6 ) who sought and received RYGB surgery ( n = 418 ) , sought but did not have surgery ( n = 417 ; control group 1 ) , or who were r and omly selected from a population -based sample not seeking weight loss surgery ( n = 321 ; control group 2 ) . MAIN OUTCOME MEASURES Weight loss , diabetes , hypertension , dyslipidemia , and health-related quality of life were compared between participants having RYGB surgery and control participants using propensity score adjustment . RESULTS Six years after surgery , patients who received RYGB surgery ( with 92.6 % follow-up ) lost 27.7 % ( 95 % CI , 26.6%-28.9 % ) of their initial body weight compared with 0.2 % ( 95 % CI , -1.1 % to 1.4 % ) gain in control group 1 and 0 % ( 95 % CI , -1.2 % to 1.2 % ) in control group 2 . Weight loss maintenance was superior in patients who received RYGB surgery , with 94 % ( 95 % CI , 92%-96 % ) and 76 % ( 95 % CI , 72%-81 % ) of patients receiving RYGB surgery maintaining at least 20 % weight loss 2 and 6 years after surgery , respectively . Diabetes remission rates 6 years after surgery were 62 % ( 95 % CI , 49%-75 % ) in the RYGB surgery group , 8 % ( 95 % CI , 0%-16 % ) in control group 1 , and 6 % ( 95 % CI , 0%-13 % ) in control group 2 , with remission odds ratios ( ORs ) of 16.5 ( 95 % CI , 4.7 - 57.6 ; P incidence of diabetes throughout the course of the study was reduced after RYGB surgery ( 2 % ; 95 % CI , 0%-4 % ; vs 17 % ; 95 % CI , 10%-24 % ; OR , 0.11 ; 95 % CI , 0.04 - 0.34 compared with control group 1 and 15 % ; 95 % CI , 9%-21 % ; OR , 0.21 ; 95 % CI , 0.06 - 0.67 compared with control group 2 ; both P bariatric surgery-related hospitalizations were 33 ( 7.9 % ) , 13 ( 3.9 % ) , and 6 ( 2.0 % ) for the RYGB surgery group and 2 control groups , respectively . CONCLUSION Among severely obese patients , compared with nonsurgical control patients , the use of RYGB surgery was associated with higher rates of diabetes remission and lower risk of cardiovascular and other health outcomes over 6 years",
"BACKGROUND Weight loss is associated with short-term amelioration and prevention of metabolic and cardiovascular risk , but whether these benefits persist over time is unknown . METHODS The prospect i ve , controlled Swedish Obese Subjects Study involved obese subjects who underwent gastric surgery and contemporaneously matched , conventionally treated obese control subjects . We now report follow-up data for subjects ( mean age , 48 years ; mean body-mass index , 41 ) who had been enrolled for at least 2 years ( 4047 subjects ) or 10 years ( 1703 subjects ) before the analysis ( January 1 , 2004 ) . The follow-up rate for laboratory examinations was 86.6 percent at 2 years and 74.5 percent at 10 years . RESULTS After two years , the weight had increased by 0.1 percent in the control group and had decreased by 23.4 percent in the surgery group ( P weight had increased by 1.6 percent and decreased by 16.1 percent , respectively ( P Energy intake was lower and the proportion of physically active subjects higher in the surgery group than in the control group throughout the observation period . Two- and 10-year rates of recovery from diabetes , hypertriglyceridemia , low levels of high-density lipoprotein cholesterol , hypertension , and hyperuricemia were more favorable in the surgery group than in the control group , whereas recovery from hypercholesterolemia did not differ between the groups . The surgery group had lower 2- and 10-year incidence rates of diabetes , hypertriglyceridemia , and hyperuricemia than the control group ; differences between the groups in the incidence of hypercholesterolemia and hypertension were undetectable . CONCLUSIONS As compared with conventional therapy , bariatric surgery appears to be a viable option for the treatment of severe obesity , result ing in long-term weight loss , improved lifestyle , and , except for hypercholesterolemia , amelioration in risk factors that were elevated at baseline",
"Background : Morbid obesity has been described as a continuing epidemic affecting a growing portion of our population . We report an outcome analysis of our early experience with laparoscopic Roux-en-Y gastric bypass ( LRYGB ) in the treatment of morbid obesity . Methods : Two surgeons performed 116 consecutive LRYGBs at a single institution , creating a 25-ml pouch and a 90- to 150-cm Roux limb . The prospect ively collected data included patient demographics , comorbidities , postoperative weight loss , and complications . Results : All eight conversions to an open procedure occurred early during the experience of the surgeons . The mean operating room time for the first 50 cases was 272 min , which decreased to 198 min with experience . The mean length of hospital stay was 3 days . There were 34 complications in 27 patients ( 23.3 % ) , 14 of which ( 12 % ) required reoperation . At 18 months postoperatively , the patients had lost 77 % of their excess weight , and their body mass index had decreased from a mean of 49.3 to 32.6 kg/m2 . As a result of LRYGB , 25 % of the patients were rendered completely free of any pharmacologic treatment for their preexisting comorbidities . Conclusions : Although technically challenging , LRYGB can be performed safely with excellent long-term results . The mean operating room time and conversion rate improved with experience . As this study showed , LRYGB achieves an excellent rate of weight loss and improvement in preoperative comorbidities with a minimal length of hospital stay and an acceptable complication rate"
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Objective The purpose of this systematic review and meta- analysis was to examine the effect of health information technology ( HIT ) diabetes self-management education ( DSME ) interventions on glycemic control in medically underserved patients . Material s and Methods Following an a priori protocol , 5 data bases were search ed . Studies were appraised for quality using the Cochrane Risk of Bias assessment . Studies reporting either hemoglobin A1c pre- and post-intervention or its change at 6 or 12 months were eligible for inclusion in the meta- analysis using r and om effects models . Results Thirteen studies met the criteria for the systematic review and 10 for the meta- analysis and represent data from 3257 adults with diabetes ( mean age 55 years ; 66 % female ; 74 % racial/ethnic minorities ) . Most studies ( n = 10 ) reflected an unclear risk of bias . Interventions varied by HIT type : computer software without Internet ( n = 2 ) , cellular/automated telephone ( n = 4 ) , Internet-based ( n = 4 ) , and telemedicine/telehealth ( n = 3 ) . Pooled A1c decreases were found at 6 months ( -0.36 ( 95 % CI , -0.53 and -0.19 ] ; I 2 = 35.1 % , Q = 5.0 ) , with diminishing effect at 12 months ( -0.27 [ 95 % CI , -0.49 and -0.04 ] ; I 2 = 42.4 % , Q = 10.4 ) . Discussion Findings suggest that medically underserved patients with diabetes achieve glycemic benefit following HIT DSME interventions , with dissipating but significant effects at 12 months . Telemedicine/telehealth interventions were the most successful HIT type because they incorporated interaction with educators similar to in-person DSME . Conclusion These results are similar to in-person DSME in medically underserved patients , showing that well- design ed HIT DSME has the potential to increase access and improve outcomes for this vulnerable group
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"An important objective of diabetes care is to provide patients with self-regulation skills . For patients to assume responsibility for their own regimens , they need to have good problem-solving skills to cope with ongoing personal , social , and environmental barriers to adherence . Therefore , a Diabetes Problem Solving Interview for adults was developed and evaluated with 126 non-insulin-dependent out patients . Interviewers elicited problem-solving strategies patients would use to cope with a variety of situations potentially interfering with dietary , exercise , and glucose testing adherence . Interviews were tape recorded and coded by trained raters to produce scores on both overall problem-solving skill ratings and frequency of use of different types of strategies . Results revealed only minor influences of patient characteristics on problem-solving measures . Prospect i ve analyses revealed that problem-solving measures were significant and independent predictors of levels of dietary and exercise self-care at a 6-month follow-up",
"Adults with type 2 diabetes mellitus often struggle with their antihyperglycemic medication regimens . To improve medication management , providers must ensure that their patients underst and potential benefits , harms , and burdens of available options and elicit patients ' preferences and barriers to taking medications . Patients who are actively involved in treatment decision making tend to be more satisfied with their health care , be more adherent to treatment , and have improved clinical outcomes ( 13 ) . Such discussion s , however , can be too time-consuming for clinic visits . For inner-city low-income African American and Latino adults , low health literacy and limited English proficiency are often additional barriers ( 4 ) that reduce the exchange of information and decrease patient participation during primary care visits ( 58 ) . This contributes to less optimal treatment decisions and lower patient satisfaction , leading to poor medication adherence and outcomes ( 3 , 911 ) . There is therefore an urgent need for cost-effective approaches to enable low-re source health systems to help these high-risk population s gain information and decision support so that they can more actively participate in and improve satisfaction with their treatment decision making . Since 2000 , the REACH ( Racial and Ethnic Approaches to Community Health 2010 ) Detroit Partnership , a coalition of community , health system , and academic partners , has used community-based participatory research principles to guide development , implementation , and evaluation of interventions to meet this need among African American and Latino adults with diabetes in Detroit , Michigan . These interventions have built on evidence that community health workers ( CHWs ) are effective in improving diabetes outcomes , particularly among racial and ethnic minority communities ( 12 ) . CHW interventions train community members to work as bridges between their ethnic , cultural , or geographic communities and health care providers ( 13 ) . Two cohorts of participants in our previous CHW-led diabetes self-management support interventions improved hemoglobin A1c ( HbA1c ) levels and diabetes distress compared with usual care ( 14 , 15 ) . An important next step in increasing the potential effect of CHWs and other lay health care workers is to develop and test effective tools they can use to better present evidence -based information to patients and to help patients make better self-management decisions ( 16 ) . Little is known about the effectiveness of different approaches for nontraditional care providers , such as CHWs , to deliver health information to ethnic minority and low-literacy population s ( 17 ) . By definition , CHWs and other lay workers do not have medical expertise and thus rely on effectively sharing printed educational and support material s with patients as part of their coaching and counseling efforts . Decision aids can increase satisfaction with treatment decisions and result in treatments that better reflect patients ' preferences ( 18 , 19 ) . There is also evidence that tailored health messages are more effective than generic group messages ( 20 , 21 ) , including for patients with diabetes ( 22 , 23 ) . Tailoring individualizes information and behavior change strategies to reach each person based on characteristics unique to that person derived from an individual assessment and related to the outcome of interest ( 24 ) . Software programs that are being developed to automatically embed tailored content into portable e-health Web applications show promise in improving health behaviors and outcomes ( 25 , 26 ) . To date , however , most e-health applications have been design ed for use by patients with relatively high literacy and the skills to navigate them ( 27 ) . Do more sophisticated , tailored , interactive e-health tools increase the effectiveness of CHW outreach with underserved patients compared with reliance on printed educational material s alone ? We addressed this question by developing and evaluating a personally tailored , interactive diabetes medication decision aid ( iDecide [ in English ] or iDecido [ in Spanish ] ) design ed for CHWs to deliver on tablet computers with 3 G wireless access to African American and Latino adults with diabetes and low health literacy . We then evaluated the effectiveness of iDecide in improving key diabetes outcomes compared with CHW delivery of the same evidence -based information , without tailoring , through print consumer booklets developed by the Agency for Healthcare Research and Quality ( AHRQ ) . Methods Setting This study was developed and implemented by using community-based participatory research principles ( 28 ) in partnership with the REACH Detroit Partnership and the Community Health and Social Services Center ( CHASS ) , a federally qualified health center in Southwest Detroit serving more than 13000 patients with 47099 visits in 2012 ( 29 ) . The University of Michigan and CHASS institutional review boards approved the study . Content of AHRQ Consumer Guides The AHRQ guides ( Pills for Type 2 Diabetes and Premixed Insulin for Type 2 Diabetes ) ( 30 , 31 ) provide information on diabetes and summarize the effectiveness of currently available medication classes ( oral and insulin ) on HbA1c . They also provide information on administration methods , costs , medication adverse effects , risks for diabetes complications , suggested questions to discuss with health care providers , and prompts to make notes of any questions for the doctor . The booklets include pictures of patients and tables and graphs summarizing information . Content of iDecide The development process and content of the iDecide program have been described in detail elsewhere ( 32 ) . Briefly , we used community-based participatory research and user-centered design ( 33 , 34 ) principles to iteratively develop and refine the iDecide tool . iDecide is available in English and Spanish , can be delivered via tablet computers , and enables navigation by the CHW and participant to selectively explore issues most important to the participant . The iDecide program is organized into 4 main sections and includes the same content as the AHRQ consumer guides . However , its information is presented in a more graphical style suited to patients with low literacy . Table 1 summarizes key differences between the presentation of information in iDecide and the printed material s. The first section illustrates , through animations , how diabetes affects the way glucose is processed in the body and how different medication classes , foods , and physical activity affect blood glucose . The second section includes pictographs showing participants ' own risk for diabetes complications ( tailored according to their baseline HbA1c ) and enabling participants to explore how their risk for different complications changes with their HbA1c levels . In the third section , participants review their current diabetes medications and barriers to taking the medications they had reported on the baseline survey . This section includes an interactive issue card approach to help elicit patient preferences and priorities about different medication characteristics ( for example , cost , adverse effects , effects on weight , and dosing schedules ) ( 22 , 35 ) . The fourth section prompts participants to set goals and develop specific action plans to address identified barriers or other concerns and identify specific questions and concerns to discuss with their doctor about their medications or making lifestyle changes . Personal information from the baseline assessment is interwoven throughout the program ( high-depth tailoring within sentences ) . Motivational interviewingbased , tailored discussion prompts encourage autonomy-supportive CHWpatient interactions at key points with open-ended questions and values exploration to help participants discover their motivation , overcome barriers to change , and develop an action plan ( 36 ) . Table 1 . Comparison of Content and Mode of Delivery Between the iDecide Study Group and the Printed Material s Group Recruitment and R and omization From September 2011 to August 2012 , potentially eligible participants were identified from a computer-generated list of CHASS patients with physician-diagnosed type 2 diabetes . Inclusion criteria required a HbA1c value greater than 7.5 % in the previous 6 months or expressed concerns about current diabetes medications during the screening assessment . Exclusion criteria were age younger than 21 years , terminal health conditions , self-reported alcohol or drug abuse , and conditions ( such as blindness and dementia ) that would impede meaningful participation . Pregnant women and individuals who reported that they could not be contacted by telephone were also excluded . Introductory letters were sent in timed batches . Research staff then telephoned patients and screened them for eligibility . Interested eligible patients met with research staff , who facilitated completion of written informed consent , administered baseline surveys in English or Spanish , and measured HbA1c and blood pressure . Participants received a stipend of $ 20 after each assessment . Within 1 to 14 days , participants were scheduled for a visit with a CHW ( at home , the clinic , or another agreed-upon place ) . At the beginning of the CHW visits , participants were registered into the iDecide program and r and omly assigned by the computer program , through use of a r and om-sequence algorithm , into 1 of 2 study groups . There were no differences between the steps to participate in either study group . Patients , research staff , and CHWs were blinded to r and omization results through completion of all baseline measures up to the start of the intervention . Data assessors remained blinded to group assignment throughout the study . CHW Intervention for Both Study Groups All participants received an initial one-on-one , face-to-face session with a CHW and a copy of the printed material s to take home . The iDecide sessions lasted approximately 2 hours , and the sessions using printed material s lasted",
"OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with st and ard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS A cluster-r and omized clinical trial , the Mobile Diabetes Intervention Study , r and omly assigned 26 primary care practice s to one of three stepped treatment groups or a control group ( usual care ) . A total of 163 patients were enrolled and included in analysis . The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period . Secondary outcomes were changes in patient-reported diabetes symptoms , diabetes distress , depression , and other clinical ( blood pressure ) and laboratory ( lipid ) values . Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support . Patients received automated , real-time educational and behavioral messaging in response to individually analyzed blood glucose values , diabetes medications , and lifestyle behaviors communicated by mobile phone . Providers received quarterly reports summarizing patient ’s glycemic control , diabetes medication management , lifestyle behaviors , and evidence -based treatment options . RESULTS The mean declines in glycated hemoglobin were 1.9 % in the maximal treatment group and 0.7 % in the usual care group , a difference of 1.2 % ( P = 0.001 ) over 12 months . Appreciable differences were not observed between groups for patient-reported diabetes distress , depression , diabetes symptoms , or blood pressure and lipid levels ( all P > 0.05 ) . CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data , lifestyle behaviors , and patient self-management data individually analyzed and presented with evidence -based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year",
"OBJECTIVE To evaluate a clinic-based multimedia intervention for diabetes education targeting individuals with low health literacy levels in a diverse population . RESEARCH DESIGN AND METHODS Five public clinics in Chicago , Illinois , participated in the study with computer kiosks installed in waiting room areas . Two hundred forty-four subjects with diabetes were r and omized to receive either supplemental computer multimedia use ( intervention ) or st and ard of care only ( control ) . The intervention includes audio/video sequences to communicate information , provide psychological support , and promote diabetes self-management skills without extensive text or complex navigation . HbA(1c ) ( A1C ) , BMI , blood pressure , diabetes knowledge , self-efficacy , self-reported medical care , and perceived susceptibility of complications were evaluated at baseline and 1 year . Computer usage patterns and implementation barriers were also examined . RESULTS Complete 1-year data were available for 183 subjects ( 75 % ) . Overall , there were no significant differences in change in A1C , weight , blood pressure , knowledge , self-efficacy , or self-reported medical care between intervention and control groups . However , there was an increase in perceived susceptibility to diabetes complications in the intervention group . This effect was greatest among subjects with lower health literacy . Within the intervention group , time spent on the computer was greater for subjects with higher health literacy . CONCLUSIONS Access to multimedia lessons result ed in an increase in perceived susceptibility to diabetes complications , particularly in subjects with lower health literacy . Despite measures to improve informational access for individuals with lower health literacy , there was relatively less use of the computer among these participants",
"Technology and improved care coordination models can help diabetes educators and providers meet national care st and ards and provide culturally sensitive diabetes education that may improve diabetes outcomes . The purpose of the study was to evaluate the clinical usefulness of a nurse-led diabetes care program ( Comprehensive Diabetes Management Program , CDMP ) for poorly controlled Hispanic type 2 diabetes ( T2DM ) patients in an urban community health center setting . Patients were r and omized to the intervention condition ( IC ; n = 21 ) or an attention control condition ( AC ; n = 18 ) . IC and AC conditions were compared on rates of adherence to national clinical practice guidelines ( blood glucose , blood pressure , foot exam , eye exam ) , and levels of diabetes distress , depression , and treatment satisfaction . IC patients had a significant improvement in A1C from baseline to 12-month follow-up compared with AC ( −1.6 % ± 1.4 % versus −0.6 % ± 1.1 % ; P = .01 ) . The proportion of IC patients meeting clinical goals at follow-up tended to be higher than AC for A1c ( IC = 45 % ; AC = 28 % ) , systolic blood pressure ( IC = 55 % ; AC = 28 % ) , eye screening ( IC = 91 % ; AC = 78 % ) , and foot screening , ( IC = 86 % ; AC = 72 % ) . Diabetes distress and treatment satisfaction also showed greater improvement for IC than AC ( P = .05 and P = .06 , respectively ) , with no differences for depression . The CDMP intervention was more effective than an attention control condition in helping patients meet evidence -based guidelines for diabetes care",
"Background Culturally appropriate interventions are needed to assist Latinas in making multiple healthful lifestyle changes . Purpose The purpose of this study was to test a cultural adaptation of a successful multiple health behavior change program , ¡ Viva Bien ! Methods R and om assignment of 280 Latinas with type 2 diabetes to usual care only or to usual care + ¡ Viva Bien ! , which included group meetings for building skills to promote the Mediterranean diet , physical activity , stress management , supportive re sources , and smoking cessation . Results ¡ Viva Bien ! participants compared to usual care significantly improved psychosocial and behavioral outcomes ( fat intake , stress management practice , physical activity , and social – environmental support ) at 6 months , and some improvements were maintained at 12 months . Biological improvements included hemoglobin A1c and heart disease risk factors . Conclusions The ¡ Viva Bien ! multiple lifestyle behavior program was effective in improving psychosocial , behavioral , and biological/ quality of life outcomes related to heart health for Latinas with type 2 diabetes ( Clinical Trials.gov no : NCT00233259 )",
"OBJECTIVE We hypothesized that people with type 2 diabetes in an online diabetes self-management program , compared with usual-care control subjects , would 1 ) demonstrate reduced A1C at 6 and 18 months , 2 ) have fewer symptoms , 3 ) demonstrate increased exercise , and 4 ) have improved self-efficacy and patient activation . In addition , participants r and omized to listserve reinforcement would have better 18-month outcomes than participants receiving no reinforcement . RESEARCH DESIGN AND METHODS A total of 761 participants were r and omized to 1 ) the program , 2 ) the program with e-mail reinforcement , or 3 ) were usual-care control subjects ( no treatment ) . This sample included 110 American Indians/Alaska Natives ( AI/ANs ) . Analyses of covariance models were used at the 6- and 18-month follow-up to compare groups . RESULTS At 6 months , A1C , patient activation , and self-efficacy were improved for program participants compared with usual care control subjects ( P health or behavioral indicators . The AI/AN program participants demonstrated improvements in health distress and activity limitation compared with usual-care control subjects . The subgroup with initial A1C > 7 % demonstrated stronger improvement in A1C ( P = 0.01 ) . At 18 months , self-efficacy and patient activation were improved for program participants . A1C was not measured . Reinforcement showed no improvement . CONCLUSIONS An online diabetes self-management program is acceptable for people with type 2 diabetes . Although the results were mixed they suggest 1 ) that the program may have beneficial effects in reducing A1C , 2 ) AI/AN population s can be engaged in and benefit from online interventions , and 3 ) our follow-up reinforcement appeared to have no value",
"BACKGROUND : Interactive Health Communication Applications ( IHCAs ) are computer-based , usually web-based health information packages for patients that combine information with at least one of social support , decision support , or behaviour change support . These are innovations in health care and their effects on health are uncertain . OBJECTIVES : To assess the effects of IHCAs for people with chronic disease . SEARCH STRATEGY : We design ed a four-part search strategy . First , we search ed electronic bibliographic data bases for published work ; second , we search ed the grey literature and third , we search ed for ongoing and recently completed clinical trials in the appropriate data bases . Finally , research ers of included studies were contacted , and reference lists from relevant primary and review articles were followed up . As IHCAs require relatively new technology , the search commenced at 1990 where possible . SELECTION CRITERIA : R and omised controlled trials ( RCTs ) of Interactive Health Communication Applications for adults and children with chronic disease . DATA COLLECTION AND ANALYSIS : One review er screened abstract s. Two review ers screened all c and i date studies to determine eligibility , apply quality criteria , and extract data from included studies . Authors of included RCTs were contacted for missing data . Results of RCTs were pooled using a r and om effects model and st and ardised mean differences ( SMDs ) were calculated to provide net effect sizes . MAIN RESULTS : We screened 24,757 unique citations and retrieved 958 papers for further assessment , yielding 28 RCTs involving 4042 participants . One of these had an inadequate method of concealment of allocation , and sensitivity analyses were performed to determine the effects of including or excluding these data in the meta-analyses . Results in the abstract are from the meta-analyses excluding data from this study .IHCAs were found to have a positive effect on knowledge ( SMD 0.49 ; 95 % confidence interval ( CI ) 0.14 to 0.84 ) and on social support ( SMD 0.47 ; 95 % CI 0.28 to 0.66 ) . IHCAs were found to have no effect on self-efficacy ( SMD 0.15 ; 95 % CI -0.13 to 0.43 ) or behavioural outcomes ( SMD -0.09 ; 95 % CI -0.49 to 0.32 ) . IHCAs had a negative effect on clinical outcomes ( SMD -0.32 ; 95 % CI -0.63 to -0.02 ) . REVIEW ERS ' CONCLUSIONS : The number and range of IHCAs is increasing rapidly ; however there is a shortage of high quality evaluative data . Consumers who wish to increase their knowledge or social support amongst people with a similar problem may find an IHCA helpful . However , consumers whose primary aim is to achieve optimal clinical outcomes should not use an IHCA at present . Further research is needed to determine the reason for this negative effect on clinical outcomes , whether an optimal IHCA can achieve behaviour change and improved health outcomes , and if so , what are the essential features of such an IHCA , and the extent to which they differ according to patient group or condition",
"OBJECTIVE This paper presents an approach to usability evaluation of computer-based health care systems design ed for patient use in their homes . Although such devices are becoming more prevalent , there is very little known about their usability . DESIGN The theoretical foundations for the methods are discussed . The approach incorporates a cognitive walkthrough usability evaluation and new methods for usability testing that can be conducted in patient 's homes . The method was applied to the IDEATel intervention , a multi-institution r and omized controlled trial of the feasibility , acceptability , and clinical utility of a home-based telemedicine system for diabetic Medicare population . The usability study was design ed to assess barriers to optimal use of the system . The focus was both on dimensions of the interface and on dimensions of patient skills and competency . The usability field research involved testing 25 patients in their homes using the system . The analysis included a range of video-analytic methods of varying levels of granularity . RESULTS The usability evaluation revealed aspects of the interface that were sub-optimal and impeded the performance of certain tasks . It also found a range of patient-related factors such as numeracy and psychomotor skills that constituted barriers to productive use . CONCLUSIONS A multifaceted usability approach provided important insight regarding use of technology by an elderly chronic-care patient population and more generally , for underst and ing how home health initiatives can more effectively use such technology",
"OBJECTIVE To conduct a 1-year r and omized clinical trial to evaluate a remote comprehensive diabetes self-management education ( DSME ) intervention , Diabetes TeleCare , administered by a dietitian and nurse/certified diabetes educator ( CDE ) in the setting of a federally qualified health center ( FQHC ) in rural South Carolina . RESEARCH DESIGN AND METHODS Participants were recruited from three member health centers of an FQHC and were r and omized to either Diabetes TeleCare , a 12-month , 13-session curriculum delivered using telehealth strategies , or usual care . RESULTS Mixed linear regression model results for repeated measures showed a significant reduction in glycated hemoglobin ( GHb ) in the Diabetes TeleCare group from baseline to 6 and 12 months ( 9.4 ± 0.3 , 8.3 ± 0.3 , and 8.2 ± 0.4 , respectively ) compared with usual care ( 8.8 ± 0.3 , 8.6 ± 0.3 , and 8.6 ± 0.3 , respectively ) . LDL cholesterol was reduced at 12 months in the Diabetes TeleCare group compared with usual care . Although not part of the original study design , GHb was reduced from baseline to 12 and 24 months in the Diabetes TeleCare group ( 9.2 ± 0.4 , 7.4 ± 0.5 , and 7.6 ± 0.5 , respectively ) compared with usual care ( 8.7 ± 0.4 , 8.1 ± 0.4 , and 8.1 ± 0.5 , respectively ) in a post hoc analysis of a subset of the r and omized sample who completed a 24-month follow-up visit . CONCLUSIONS Telehealth effectively created access to successfully conduct a 1-year remote DSME by a nurse CDE and dietitian that improved metabolic control and reduced cardiovascular risk in an ethnically diverse and rural population",
"Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more",
"Introduction Diabetes Mellitus is a chronic illness that increases the risk of microvascular complication and results in blindness , kidney failure , and lower extremity amputations , and macrovascular complication of coronary artery disease and stroke . In the State of Hawaii , an estimated eight to ten percent of the population have diabetes mellitus , i.e. about 80,000 to 100,000 individuals , primarily adults with type 2 diabetes . Alarmingly , native Hawaiian adults over 30 years of age have been identified with a diabetes prevalence rate of 20 % . Several studies clearly document the increasing rate of diabe tes among native Hawaiians over the past 30 years . Based on recent data , it is estimated that about 20,000 adult native Hawaiians ( 1820 % prevalence rate ) have diabetes mellitus ) It would appear that interventions to prevent diabetes and diabetic complications receive the highest priority in the effort to improve the health status of the people of Hawaii , especially native Hawaiians . Two major intervention trials have clearly demonstrated that intensive glycemic control prevents and delays the development of microvascular complication in patients with type 1 diabetes : the Diabetes Control and Complications Trial ( DCCT ) and the Stockholm Diabetes Intervention Study ( SDIS ) . 23 Results from a r and omized prospect i ve 6-year study in Japan show that intensive insulin treat ment of type 2 diabetic patients reduces microvascular complica tion . 4Many studies have demonstrated the association of hypergly cemia with macrovascular complications of ischemic heart disease and stroke and increased cardiovascular disease risk factors , e.g. , dyslipidemia , hypertension , and obesity . The 12-year cardiovascu lar mortality of men screened in the Multiple Risk Factor Interven tion Trial ( MRFIT ) showed that diabetic patients consistently had higher cardiovascular mortality than non-diabetic men matched for one or more of the major risk factors for CVD . 5 The data from",
"OBJECTIVE To explore the relationship between inpatient diabetes education ( IDE ) and hospital readmissions in patients with poorly controlled diabetes . RESEARCH DESIGN AND METHODS Patients with a discharge diagnosis of diabetes ( ICD-9 code 250.x ) and HbA1c > 9 % who were hospitalized between 2008 and 2010 were retrospectively identified . All-cause first readmissions were determined within 30 days and 180 days after discharge . IDE was conducted by a certified diabetes educator or trainee . Relationships between IDE and hospital readmission were analyzed with stepwise backward logistic regression models . RESULTS In all , 2,265 patients were included in the 30-day analysis and 2,069 patients were included in the 180-day analysis . Patients who received IDE had a lower frequency of readmission within 30 days than did those who did not ( 11 vs. 16 % ; P = 0.0001 ) . This relationship persisted after adjustment for sociodemographic and illness-related factors ( odds ratio 0.66 [ 95 % CI 0.51–0.85 ] ; P = 0.001 ) . Medicaid insurance and longer stay were also independent predictors in this model . IDE was also associated with reduced readmissions within 180 days , although the relationship was attenuated . In the final 180-day model , no IDE , African American race , Medicaid or Medicare insurance , longer stay , and lower HbA1c were independently associated with increased hospital readmission . Further analysis determined that higher HbA1c was associated with lower frequency of readmission only among patients who received a diabetes education consult . CONCLUSIONS Formal IDE was independently associated with a lower frequency of all-cause hospital readmission within 30 days ; this relationship was attenuated by 180 days . Prospect i ve studies are needed to confirm this association",
"Purpose The purpose of this study was to determine the impact of diabetes self-management education ( DSME ) in improving processes and outcomes of diabetes care as measured by a five component diabetes bundle and HbA1c , in individuals with type 2 diabetes mellitus ( T2DM ) . Methods A retrospective analysis was performed for adult T2DM patients who received DSME training in 2011–2012 from an accredited American Diabetes Association center at Intermountain Healthcare ( IH ) and had an HbA1c measurement within the prior 3 months and 2–6 months after completing their first DSME visit . Control patients were selected from the same clinics as case- patients using r and om number generator to achieve a 1 to 4 ratio . Case and control patients were included if 1 ) pre-education HbA1c was between 6.0%–14.0 % ; 2 ) their main provider was a primary care physician ; 3 ) they met the national Healthcare Effectiveness Data and Information Set criteria for inclusion in the IH diabetes registry . The IH diabetes bundle includes retinal eye exam , nephropathy screening or prescription of angiotensin converting enzyme or angiotensin receptor blocker ; blood pressure achievement of the five element IH diabetes bundle and in HbA1c % compared to those without DSME . After adjusting for possible confounders in a multivariate logistic regression model , DSME patients had a 1.5 fold difference in improvement in their diabetes bundle and almost a 3 fold decline in HbA1c compared to the control group . Conclusion St and ardized DSME taught within an IH American Diabetes Association center is strongly associated with a substantial improvement in patients meeting all five elements of a diabetes bundle and a decline in HbA1c beyond usual care . Given the low operating cost of the DSME program , these results strongly support the value adding benefit of this program in treating T2DM patients",
" This article describes the design and implementation of an online diabetes self-management intervention for a sample of inner-city African Americans with diabetes . Study participants were r and omly assigned to the treatment ( 26 ) and control ( 21 ) conditions . The results indicate that treatment group participants were more likely to achieve positive outcomes in terms of lowered hemoglobin A1c and body mass index measurements than were control group members . These findings support the development of telehealth interventions to promote effective chronic disease management in medically underserved communities",
"CONTEXT Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions and lower access to care . OBJECTIVES To examine the effectiveness of a telemedicine intervention to achieve clinical management goals in older , ethnically diverse , medically underserved patients with diabetes . DESIGN , Setting , and Patients A r and omized controlled trial was conducted , comparing telemedicine case management to usual care , with blinded outcome evaluation , in 1,665 Medicare recipients with diabetes , aged > /= 55 years , residing in federally design ated medically underserved areas of New York State . Interventions Home telemedicine unit with nurse case management versus usual care . Main Outcome Measures The primary endpoints assessed over 5 years of follow-up were hemoglobin A1c ( HgbA1c ) , low density lipoprotein ( LDL ) cholesterol , and blood pressure levels . RESULTS Intention-to-treat mixed models showed that telemedicine achieved net overall reductions over five years of follow-up in the primary endpoints ( HgbA1c , p = 0.001 ; LDL , p systolic and diastolic blood pressure , p = 0.024 ; p HgbA1c , 3.84 ( -0.08 , 7.77 ) mg/dL for LDL cholesterol , and 4.32 ( 1.93 , 6.72 ) mm Hg for systolic and 2.64 ( 1.53 , 3.74 ) mm Hg for diastolic blood pressure . There were 176 deaths in the intervention group and 169 in the usual care group ( hazard ratio 1.01 [ 0.82 , 1.24 ] ) . CONCLUSIONS Telemedicine case management result ed in net improvements in HgbA1c , LDL-cholesterol and blood pressure levels over 5 years in medically underserved Medicare beneficiaries . Mortality was not different between the groups , although power was limited . Trial Registration http:// clinical trials.gov Identifier : NCT00271739",
"OBJECTIVE To compare usual diabetes care ( UDC ) to a comprehensive diabetes care intervention condition ( IC ) involving an Internet-based “ diabetes dashboard ” management tool used by clinicians . RESEARCH DESIGN AND METHODS We used a parallel-group r and omized design . Diabetes nurses , diabetes dietitians , and providers used the diabetes dashboard as a clinical decision support system to deliver a five-visit , 6-month intervention to 199 poorly controlled ( HbA1c > 7.5 % [ 58 mmol/mol ] ) Latino type 2 diabetic ( T2D ) patients ( mean age 55 years , 60 % female ) at urban community health centers . We compared this intervention to an established , in-house UDC program ( n = 200 ) for its impact on blood glucose control and psychosocial outcomes . RESULTS Recruitment and retention rates were 79.0 and 88.5 % , respectively . Compared with UDC , more IC patients reached HbA1c targets of baseline HbA1c , adjusted mean ± SE HbA1c at follow-up was significantly lower in the IC compared with the UDC group ( P showed lower diabetes distress at follow-up for IC patients ( 40.4 ± 2.1 ) as compared with UDC patients ( 48.3 ± 2.0 ) ( P , and also lower social distress ( 32.2 ± 1.3 vs. 27.2 ± 1.4 , P the proportion of patients moving from depressed status at baseline to nondepressed at follow-up ( 41.8 vs. 40 % ; no significance between groups ) . CONCLUSIONS The diabetes dashboard intervention significantly improved diabetes-related outcomes among Latinos with poorly controlled T2D compared with a similar diabetes team condition without access to the diabetes dashboard",
"OBJECTIVE The public is increasingly aware of the importance of HbA(1c ) testing , yet the vast majority of patients with diabetes do not know their HbA(1c ) status or goal . We set forth to evaluate the impact of a system that provides uniquely formatted and personalized reports of diabetes status and goals on changes in HbA(1c ) levels . RESEARCH DESIGN AND METHODS A total of 150 patients with diabetes were r and omized to receive either st and ard care or intervention inclusive of a computer-generated 11 \" x 17 \" color poster depicting an individual 's HbA(1c ) status and goals along with personalized steps to aid in goal achievement . All patients enrolled received diabetes education during the 3 months before enrollment . HbA(1c ) was performed at baseline and 6 months . RESULTS At baseline , there were no significant differences between patient groups in terms of age , sex , education level , race , and HbA(1c ) or lipid levels . Among patients with baseline HbA(1c ) > or = 7.0 % , there was an 8.6 % ( 0.77 % absolute ) reduction in HbA(1c ) among control subjects compared with a 17.0 % ( 1.69 % absolute ) decline in the intervention group ( P = 0.032 ) . There were no differences between the control and intervention groups with respect to the frequency of patients experiencing any decline in HbA(1c ) ( 63 vs. 69 % , P = 0.87 ) ; among these patients experiencing a decline , the most substantial reductions were seen with the control group , which had a 13.3 % ( 1.15 % absolute ) decline compared with the intervention patients , who reduced their HbA(1c ) by 24.2 % ( 2.26 % absolute reduction ; P = 0.0048 ) . At study close , 77 % of the patients had their poster displayed on their refrigerator . CONCLUSIONS This unique and personalized computer-generated intervention result ed in HbA(1c ) lowering comparable to that of hypoglycemic agents",
"PURPOSE The use of technology to implement cost-effective health care management on a large scale may be an alternative for diabetes management but needs to be evaluated in controlled trials . This study assessed the utility and cost-effectiveness of an automated Diabetes Remote Monitoring and Management System ( DRMS ) in glycemic control versus usual care . METHODS In this r and omized , controlled study , patients with uncontrolled diabetes on insulin were r and omized to use of the DRMS or usual care . Participants in both groups were followed up for 6 months and had 3 clinic visits at 0 , 3 , and 6 months . The DRMS used text messages or phone calls to remind patients to test their blood glucose and to report results via an automated system , with no human interaction unless a patient had severely high or low blood glucose . The DRMS made adjustments to insulin dose(s ) based on vali date d algorithms . Participants reported medication adherence through the Morisky Medication Adherence Scale-8 , and diabetes-specific quality of life through the diabetes Daily Quality of Life question naire . A cost-effectiveness analysis was conducted based on the estimated overall costs of DRMS and usual care . FINDINGS A total of 98 patients were enrolled ( 59 [ 60 % ] female ; mean age , 59 years ) ; 87 participants ( 89 % ) completed follow-up . HbA1c was similar between the DRMS and control groups at 3 months ( 7.60 % vs 8.10 % ) and at 6 months ( 8.10 % vs 7.90 % ) . Changes from baseline to 6 months were not statistically significant for self-reported medication adherence and diabetes-specific quality of life , with the exception of the Daily Quality of Life-Social/Vocational Concerns subscale score ( P = 0.04 ) . IMPLICATION S An automated system like the DRMS may improve glycemic control to the same degree as usual clinic care and may significantly improve the social/vocational aspects of quality of life . Cost-effectiveness analysis found DRMS to be cost-effective when compared to usual care and suggests DRMS has a good scale of economy for program scale up . Further research is needed to determine how to sustain the benefits seen with the automated system over longer periods"
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BACKGROUND Early studies demonstrated relatively low success rates for pulmonary vein isolation ( PVI ) alone in patients with persistent atrial fibrillation ( PeAF ) . However , the advent of new technologies and the observation that additional substrate ablation does not improve outcomes have created a new focus on PVI alone for treatment of PeAF . OBJECTIVE The purpose of this study was to systematic ally review the recent medical literature to determine current medium-term outcomes when a PVI-only approach is used for PeAF . METHODS An electronic data base search ( MEDLINE , Embase , Web of Science , PubMed , Cochrane ) was performed in August 2016 . Only studies of PeAF patients undergoing a " PVI only " ablation strategy using contemporary radiofrequency ( RF ) technology or second-generation cryoballoon ( CB2 ) were included . A r and om-effects model was used to assess the primary outcome of pooled single-procedure 12-month arrhythmia-free survival . Predictors of recurrence were also examined and a meta- analysis performed if ≥4 studies examined the parameter . RESULTS Fourteen studies of 956 patients , of whom 45.2 % underwent PVI only with RF and 54.8 % with CB2 , were included . Pooled single-procedure 12-month arrhythmia-free survival was 66.7 % ( 95 % confidence interval [ CI ] 60.8%-72.2 % ) , with the majority of patients ( 80.5 % ) off antiarrhythmic drugs . Complication rates were very low , with cardiac tamponade occurring in 5 patients ( 0.6 % ) and persistent phrenic nerve palsy in 5 CB2 patients ( 0.9 % of CB2 ) . Blanking period recurrence ( hazard ratio 4.68 , 95 % CI 1.70 - 12.9 ) was the only significant predictor of recurrence . CONCLUSION A PVI-only strategy in PeAF patients with a low prevalence of structural heart disease using contemporary technology yields excellent outcomes comparable to those for paroxysmal AF ablation
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"Background — Data regarding the long-term efficacy of atrial fibrillation ( AF ) ablation are still lacking . Methods and Results —Two hundred four consecutive patients symptomatic for paroxysmal or persistent/permanent AF were r and omly assigned to 2 different ablation schemes : pulmonary vein isolation ( PVI ) and PVI plus left linear lesions ( LL ) . Primary end point was to assess the maintenance of sinus rhythm ( SR ) after procedures 1 and 2 in the absence of antiarrhythmic drugs in a long-term follow-up of at least 3 years . Paroxysmal AF — With a single procedure at 12-month follow-up , 46 % of patients treated with PVI maintained SR , whereas at 3-year follow-up , 29 % were in SR ; using the “ PVI plus LL ” at the 12-month follow-up , 57 % of patients were in SR , whereas at the 3-year follow-up , 53 % remained in SR . After a second procedure , the long-term overall success rate without antiarrhythmic drugs was 62 % with PVI and 85 % with PVI plus LL . Persistent/Permanent AF — With a single procedure at the 12-month follow-up , 27 % of patients treated with PVI were in SR , whereas at the 3-year follow-up , 19 % maintained SR ; using the PVI plus LL with a single procedure at the 12-month follow-up 45 % of patients were in SR , whereas at the 3-year follow-up , 41 % remained in SR . After a second procedure , the long-term overall success rate without antiarrhythmic drugs was 39 % with PVI and 75 % with PVI plus LL . Conclusions —A long-term follow-up of AF ablation shows that short-term results can not be considered permanent because AF recurrences are still present after the first year especially in patients who have had “ PVI ” strategy . PVI isolation plus LL is superior to the PVI strategy in maintaining SR without antiarrhythmic drugs after procedures 1 and 2 both in paroxysmal and persistent AF",
"AIMS To investigate the effectiveness of additional substrate modification ( SM ) by left atrial ( LA ) linear lesions as compared with pulmonary vein isolation ( PVI ) alone in patients with persistent atrial fibrillation ( AF ) in a prospect i ve r and omized study . Percutaneous PVI has evolved as an accepted treatment for paroxysmal AF but seemed to be less effective in patients with persistent AF . The benefit of PVI alone and additional linear lesions has not been vali date d in a r and omized study so far . METHODS AND RESULTS Sixty-two patients with persistent AF ( median duration 7 , range 1 - 18 months ) were r and omly assigned to either PVI alone ( n = 30 ) or additional SM ( n = 32 ) consisting of a roof line connecting both left superior and right superior PV and LA isthmus ablation between left inferior PV and mitral annulus . Procedures including SM were performed using a three-dimensional mapping system ( EnSite NavX , St Jude Medical , St Paul , MN , USA ) . Anti-arrhythmic drugs were discontinued within 8 weeks after ablation in both groups . Follow-up included daily trans-telephonic ECG transmitted irrespective of the patient 's symptoms . PVI was successful in 98 % of all targeted veins in both groups . Additional SM did not increase fluoroscopy time ( 72.1+/-18.7 vs. 72.9+/-17.3 min , P=0.92 ) because of the use of three-dimensional navigation in the PVI+SM group . AF recurrences within the first 4 weeks following ablation were more common after PVI alone ( 77 % ) than additional SM ( 44 % , P=0.002 ) . After a follow-up time of 487 ( 429 - 570 ) days , only 20 % of patients undergoing st and alone PVI remained in sinus rhythm when compared with 69 % following PVI combined with SM ( P=0.0001 ) . Two patients assigned to PVI+SM experienced procedure-related complications ( cardiac tamponade and minor stroke ) which resolved without sequelae . CONCLUSION PVI alone is insufficient in the treatment of persistent AF . However , additional left linear lesions increase the success rate significantly . Early AF-relapses are associated with a negative outcome after PVI alone but not following additional SM",
"BACKGROUND Different catheter ablation ( CA ) strategies have been established in the treatment of persistent atrial fibrillation ( persAF ) . Pulmonary vein isolation ( PVI ) only might be an option for the initial ablation procedure . There is a paucity of outcome data on second-generation cryoballoon ( CBG2 ) PVI in persAF . METHODS Patients with symptomatic drug-refractory persAF who underwent initial CA of AF were prospect ively enrolled and PVI was performed with CBG2 . The primary composite endpoint was freedom from AF , atrial tachycardia , or related symptoms after a 3-month blanking period . The secondary endpoint referred to periprocedural complications . RESULTS One hundred seventy-three consecutive patients ( 64±10 years , 29 % female ) with symptomatic drug-refractory persAF were identified . Acute PVI was achieved in 100 % of pulmonary veins with the CB technique . The left atrial procedure time was 112±30min . Major complications occurred in 1.7 % ( 3 of 173 patients ) including two phrenic nerve palsies ( 1 % ) , which resolved until discharge , and one pericardial effusion ( 0.6 % ) . Follow-up ≥12 months was completed for 157 of 173 patients ( 91 % ) . Median follow-up was 14 months . At 12 months , the primary composite endpoint was achieved in 129 of 157 patients ( 82 % ) . However , 22 of 129 patients at risk ( 17 % ) were still on antiarrhythmic drugs . A relapse during the blanking period was identified as the only independent predictor for AF recurrence . CONCLUSION PVI using the second-generation cryoballoon is a reasonable treatment option for patients with symptomatic drug-refractory persAF with a favorable rate of freedom from AF and a low complication rate",
"BACKGROUND Focal impulse and rotor modulation ( FIRM ) was based on the premise that atrial fibrillation ( AF ) is sustained by rotors that are sufficiently stable to be eliminated by targeted ablation . Early experience reported high success as compared to conventional strategies . OBJECTIVE The purpose of this study was to report on a single-center experience with extended follow-up by using FIRM in a variety of patients with AF . METHODS All FIRM-guided ablation procedures were included . During spontaneous or induced AF , FIRM software constructed phase maps to identify putative AF sources , then targeted for radiofrequency ablation , with adjunctive pulmonary vein isolation ( PVI ) , if needed . All mapped rotors and /or sources were eliminated on the basis of repeated FIRM mapping . RESULTS Of 47 patients , sustained AF was not present or induced in 4 patients who did not undergo FIRM ablation . Of the remaining 43 patients , prior AF was paroxysmal in 9 ( 21 % ) and 72 % had a median of 1 prior PVI . Spontaneous AF ( n = 22 , 52 % ) and induced AF ( n = 21 , 49 % ) were mapped , and all patients had rotors identified ( 1.8 ± 0.8 per patient ; 70 % in the left atrium ) . AF termination occurred in 2 patients ( 5 % ) and none organized to atrial tachycardia . Touch-up redo PVI was also performed in 31 patients ( 72 % ) . At 16.0 ± 10.7 months ( range 1 - 34 months ) , only 9 patients ( 21 % ) were free of recurrent AF ; and only 5 patients ( 12 % ) were free of AF and off antiarrhythmic drugs . CONCLUSION Long-term clinical results after FIRM ablation in this diverse challenging cohort showed poor efficacy . R and omized clinical trials are needed to evaluate the efficacy and clinical utility of the FIRM ablation approach for treating AF",
"AIMS Irrigated multi-electrode ablation ( IMEA ) is a novel tool to perform pulmonary vein isolation ( PVI ) . The aim was to compare IMEA with point-by-point radiofrequency ( RF ) ablation in patients with persistent atrial fibrillation ( AF ) undergoing PVI . METHODS AND RESULTS Forty-nine patients ( age 60 ± 9 years , 82 % male ) were studied . In 24 patients , the IMEA catheter was used in conjunction with an electroanatomic mapping system . Twenty-five patients undergoing RF point-by-point ablation ( RF-PVI ) served as a control group . Validation of PVI based on the IMEA catheter was performed using a st and ard circular mapping catheter . Ninety-two of 94 pulmonary veins ( PVs ) ( 98 % ) were isolated using IMEA alone . Procedure time was 125 ± 23 min in the IMEA group and 127 ± 31 min in the RF-PVI group ( P = 0.79 ) . Fluoroscopy time was 12.2 ( 11 - 16.1 ) min with IMEA compared with 5.2 ( 4.1 - 9.3 ) min in the RF-PVI group ( P was 11.8 ( 10.2 - 15.4 ) min in the IMEA group compared with 33.6 ( 30.3 - 40.1 ) min in the RF-PVI group ( P IMEA ablation , validation using a st and ard circular mapping catheter showed persistent PV potentials in 33 PVs ( 35 % ) , requiring additional IMEA ablation . At 12 months , 16 of 24 patients ( 67 % ) in the IMEA group compared with 17 of 25 patients ( 68 % ) in RF-PVI group were free from AF ( P > 0.99 ) . CONCLUSION With similar total procedure duration , IMEA-PVI was associated with shorter net ablation time and longer fluoroscopy time . Irrigated multi-electrode ablation recordings were not sufficient to confirm isolation in 35 % of PVs . Single-procedure efficacy after 12 months was similar between the two groups",
"BACKGROUND Long-term success rates using ablation for persistent atrial fibrillation ( AF ) are disappointing and usually do not exceed 60 % . OBJECTIVES This study sought to compare arrhythmia-free survival between pulmonary vein isolation ( PVI ) and a stepwise approach ( full defrag ) consisting of PVI , ablation of complex fractionated electrograms , and additional linear ablation lines in the setting of atrial tachycardias ( AT ) in patients with persistent AF after PVI . METHODS From November 2010 to February 2013 , 205 patients ( 151 men ; 61.7 ± 10.2 years of age ) underwent de novo ablation for persistent AF . Subsequently , patients were prospect ively r and omized to either PVI alone ( n = 78 ) or full defrag ( n = 75 ) , with 52 patients not r and omized due to AF termination with the original PVI . The primary endpoint was recurrence of any AT after a blanking period of 3 months . RESULTS During the entire study , 241 ablations were performed ( mean : 1.59 in the PVI-alone group , 1.55 in the full-defrag group ) . With the stepwise approach , termination of AF occurred in 45 ( 60 % ) patients . However , arrhythmia-free survival did not differ whether patients underwent single or multiple procedures ( p = 0.468 ) . Procedure duration , fluoroscopy time , and radiofrequency duration were significantly longer in the full-defrag group ( all p longer procedural and fluoroscopic duration as well as radiofrequency application time . ( The R and omized Catheter Ablation of Persist End Atrial Fibrillation Study [ CHASE-AF ] ; NCT01580124 )",
"AIMS To assess the 1 year efficacy of pulmonary vein isolation ( PVI ) as index procedure for persistent atrial fibrillation ( PersAF ) comparing conventional radiofrequency irrigated-tip catheter ablation ( RFCA ) using contact-force technology and ablation using the second-generation cryoballoon ( CB-AdvA ) . METHODS AND RESULTS One hundred consecutive patients ( 74 male , 74 % ; mean age 62.4 ± 9.6 years ) with drug-refractory PersAF undergoing PVI using RFCA and CB-AdvA were enrolled . Follow-up was based on outpatient clinic visits including Holter-electrocardiograms . Recurrence of atrial tachyarrhythmias ( ATas ) was defined as a symptomatic or documented episode > 30 s. Among 100 patients , 50 underwent RFCA whereas 50 CB-AdvA. Mean procedure and fluoroscopy times were 90.5 ± 41.7 vs. 140.2 ± 46.9 min and 14.5 ± 6.6 vs. 19.8 ± 6.8 min in the CB-Adv and in the RFCA group , respectively ( P BP ) , freedom from ATas off-drugs after a single procedure was 60 % ( 28/50 patients ) in the CB-Adv and 56 % ( 27/50 patients ) in the RFCA group ( P = 0.71 ) . Multivariate analysis demonstrated that PersAF duration ( P = 0.01 ) and relapses during BP ( P = 0.02 ) were independent predictors of ATa recurrences following the index procedure . CONCLUSION Freedom from ATas following PersAF ablation with RFCA and CB-Adv is comparable at 1 year follow-up after a single procedure . Ablation with the CB-Adv is associated with shorter procedure time and radiation exposure as compared with RFCA . Atrial tachyarrhythmias occurrence during BP and longer time of PersAF seem to be significant predictors of arrhythmia recurrences after the index procedure",
"INTRODUCTION Cryoballoon PVI has emerged as an alternative to radiofrequency PVI for the treatment of paroxysmal AF . The optimal strategy for patients with persistent AF is unclear as data are limited . METHODS We analyzed a prospect i ve registry of consecutive patients with persistent AF who underwent Cryoballoon PVI at a single center between 2011 and 2014 . Patients were assessed for atrial arrhythmia recurrence after a 3-month blanking period at 6 months , 1 year , and 2 years postprocedure . Recurrence was based on typical symptoms , ECG , or event monitor evidence of AF . Kaplan-Meier analysis was used to estimate arrhythmia-free survival . RESULTS Final analysis included 69 patients who underwent Cryoballoon PVI with a mean age 59.4 ± 8.1 years , 85.5 % male , 53.6 % HTN patients , CHA2DS2-VASC score 1.6 ± 1.2 , and LA size 4.5 ± 0.6 cm . The single procedure atrial arrhythmia recurrence-free rate at 1-year postprocedure after a 3-month blanking period was 59 % and 50 % at a mean follow-up of 607 days . Of the recurrence-free group , 17 % were taking previously ineffective antiarrhythmic medications . In comparing patients with persistent AF duration 1 year , there was a trend toward greater AF recurrence-free rates in the CONCLUSION Cryoballoon PVI appears to be an effective initial strategy in treating persistent AF , with an AF recurrence-free rate of 59 % at 1 year",
"BACKGROUND More advanced atrial fibrillation ( AF ) is associated with lower success rates after pulmonary vein isolation ( PVI ) , and the optimal ablation strategy is uncertain . OBJECTIVES To assess the impact of additional linear ablation ( lines ) compared to PVI alone . METHODS In this multicenter r and omized controlled trial , 122 patients ( mean age 61.9 ± 10.5 years ; left atrial diameter 43 ± 6 mm ) with persistent AF ( PeAF ) or sustained ( > 12 hours ) paroxysmal AF ( SusPAF ) with risk factors for atrial substrate were included and followed up for 12 months . Patients were r and omized to PVI-only or PVI + lines ( left atrial roof line , mitral isthmus line , and tricuspid isthmus line ) group . Holter monitoring was performed at 3 , 6 , and 12 months and according to symptoms . The primary outcome was atrial tachyarrhythmia recurrence lasting ≥30 seconds . RESULTS Baseline characteristics were comparable between groups ; 61 % had PeAF and 39 % SusPAF . Successful PVI was achieved for 98 % of pulmonary veins , and bidirectional block was obtained in 90 % of lines . The primary end point occurred in 38 % of the PVI + lines group and 32 % of the PVI-only group ( P = .50 ) , which was consistent in both PeAF ( 36 % vs 28 % ; P = .45 ) and SusPAF ( 42 % vs 39 % ; P = .86 ) . Compared with the PVI-only group , the PVI + lines group had higher procedure duration ( 209 ± 52 minutes vs 172 ± 44 minutes ; P .001 ) , ablation time ( 4352 ± 1084 seconds vs 2503 ± 1061 seconds ; P ) , and radiation exposure ( Dose-area product 3992 ± 6496 Gy·cm(2 ) vs 2106 ± 1679 Gy·cm(2 ) ; P = .03 ) . Quality of life ( disease-specific Atrial Fibrillation Effect on Quality of Life question naire and mental component scale of the Short Form 36 Health Survey ) improved significantly during the study but did not differ between groups . CONCLUSION Adding lines to wide antral PVI in substrate-based AF requires significantly more ablation , increases procedure duration and radiation dose , but provides no additional clinical benefit",
"BACKGROUND Catheter ablation is less successful for persistent atrial fibrillation than for paroxysmal atrial fibrillation . Guidelines suggest that adjuvant substrate modification in addition to pulmonary-vein isolation is required in persistent atrial fibrillation . METHODS We r and omly assigned 589 patients with persistent atrial fibrillation in a 1:4:4 ratio to ablation with pulmonary-vein isolation alone ( 67 patients ) , pulmonary-vein isolation plus ablation of electrograms showing complex fractionated activity ( 263 patients ) , or pulmonary-vein isolation plus additional linear ablation across the left atrial roof and mitral valve isthmus ( 259 patients ) . The duration of follow-up was 18 months . The primary end point was freedom from any documented recurrence of atrial fibrillation lasting longer than 30 seconds after a single ablation procedure . RESULTS Procedure time was significantly shorter for pulmonary-vein isolation alone than for the other two procedures ( P pulmonary-vein isolation alone were free from recurrent atrial fibrillation , as compared with 49 % of patients assigned to pulmonary-vein isolation plus complex electrogram ablation and 46 % of patients assigned to pulmonary-vein isolation plus linear ablation ( P=0.15 ) . There were also no significant differences among the three groups for the secondary end points , including freedom from atrial fibrillation after two ablation procedures and freedom from any atrial arrhythmia . Complications included tamponade ( three patients ) , stroke or transient ischemic attack ( three patients ) , and atrioesophageal fistula ( one patient ) . CONCLUSIONS Among patients with persistent atrial fibrillation , we found no reduction in the rate of recurrent atrial fibrillation when either linear ablation or ablation of complex fractionated electrograms was performed in addition to pulmonary-vein isolation . ( Funded by St. Jude Medical ; Clinical Trials.gov number , NCT01203748 . )",
"BACKGROUND Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation . Radiofrequency ablation is the most common method , and cryoballoon ablation is the second most frequently used technology . METHODS We conducted a multicenter , r and omized trial to determine whether cryoballoon ablation was noninferior to radiofrequency ablation in symptomatic patients with drug-refractory paroxysmal atrial fibrillation . The primary efficacy end point in a time-to-event analysis was the first documented clinical failure ( recurrence of atrial fibrillation , occurrence of atrial flutter or atrial tachycardia , use of antiarrhythmic drugs , or repeat ablation ) following a 90-day period after the index ablation . The noninferiority margin was prespecified as a hazard ratio of 1.43 . The primary safety end point was a composite of death , cerebrovascular events , or serious treatment-related adverse events . RESULTS A total of 762 patients underwent r and omization ( 378 assigned to cryoballoon ablation and 384 assigned to radiofrequency ablation ) . The mean duration of follow-up was 1.5 years . The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 in the radiofrequency group ( 1-year Kaplan-Meier event rate estimates , 34.6 % and 35.9 % , respectively ; hazard ratio , 0.96 ; 95 % confidence interval [ CI ] , 0.76 to 1.22 ; P primary safety end point occurred in 40 patients in the cryoballoon group and in 51 patients in the radiofrequency group ( 1-year Kaplan-Meier event rate estimates , 10.2 % and 12.8 % , respectively ; hazard ratio , 0.78 ; 95 % CI , 0.52 to 1.18 ; P=0.24 ) . CONCLUSIONS In this r and omized trial , cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation , and there was no significant difference between the two methods with regard to overall safety . ( Funded by Medtronic ; FIRE AND ICE Clinical Trials.gov number , NCT01490814 . )"
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4117c3aa-06ff-11f0-808a-c43d1ab1c353
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BACKGROUND The aim of this study was to perform a systematic review ( SR ) of r and omized controlled trials ( RCTs ) to explore if periodontal plastic surgery procedures for the treatment of single and multiple gingival recessions ( Rec ) may improve aesthetics at patient and professional levels . MATERIAL AND METHODS In order to combine evidence from direct and indirect comparisons by different trials a Bayesian network meta- analysis ( BNM ) was planned . A literature search on PubMed , Cochrane libraries , EMBASE , and h and - search ed journals until January 2016 was conducted to identify RCTs presenting aesthetic outcomes after root coverage using st and ardized evaluations at patient and professional level . RESULTS A total of 16 RCTs were selected in the SR ; three RTCs presenting professional aesthetic evaluation with Root coverage Aesthetic Score ( RES ) and three showing final self-perception using the Visual Analogue Scale ( VAS Est ) could be included in a BNM model . Coronally Advanced Flap plus Connective Tissue Graft ( CAF + CTG ) and CAF + Acellular Dermal Matrix ( ADM ) and Autologous Fibroblasts ( AF ) were associated with the best RES outcomes ( best probability = 24 % and 64 % , respectively ) , while CAF + CTG and CAF + CTG + Enamel matrix Derivatives ( EMD ) obtained highest values of VAS Est score ( best probability = 44 % and 26 % , respectively ) . CONCLUSIONS Periodontal Plastic Surgery ( PPS ) techniques applying grafts underneath CAF with or without the adding of EMD are associated with improved aesthetics assessed by final patient perception and RES as professional evaluation system
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"AIM To compare the clinical outcomes of laterally moved , coronally advanced flap ( LMCAF ) versus Bilaminar technique ( BT ) in the treatment of single gingival recession on molar teeth . MATERIAL AND METHODS Fifty patients showing Miller I and II gingival recessions at first molar teeth were treated : 25 were r and omly assigned to the BT group and 25 belonged to the LMCAF group . Patient 's post-operative morbidity was assessed 1 week after the surgery , while aesthetic evaluation and the clinical evaluation were made 1 year later . RESULTS No statistically significant difference was demonstrated in terms of recession and PPD reduction . Statistically greater probability of complete root coverage ( CRC , Odds Ratio 22.1 ) and greater increase in gingival thickness were observed in the BT group . Greater increase in keratinized tissue was obtained in the LMCAF . Patient satisfaction with aesthetics was very high in both treatment groups . Better post-operative course was observed in the LMCAF , while better post-operative sensitivity and root coverage evaluation were demonstrated in patients treated with BT . CONCLUSIONS Gingival recession at first molar teeth can be successfully treated with LMCAF and BT . Better CRC was achieved with BT , while more comfortable post-operative course was associated with the LMCAF",
"BACKGROUND The effective treatment of gingival recession ( GR ) defects is crucial for predictable outcomes . The most common treatment is the subepithelial connective tissue graft ( CTG ) , but good outcomes have also been obtained using enamel matrix derivative ( EMD ) . A split-mouth , r and omized controlled trial was previously performed during a 12-month period to evaluate primary and secondary outcomes in Miller Class I and II GR defects treated with CTG or EMD , both in combination with coronally advanced flap ( CAF ) . The purpose of the current study is to examine the major qualitative and quantitative parameters of this study after a 10-year follow-up . METHODS Nine of 17 original patients were available for follow-up evaluation 10 years after the original surgery . The parameters measured were : ( 1 ) GR depth ; ( 2 ) probing depth ( PD ) ; ( 3 ) clinical attachment level ; ( 4 ) width of keratinized tissue ( wKT ) ; ( 5 ) percentage of root coverage ; ( 6 ) root dentin hypersensitivity ; ( 7 ) color , texture , and contour of treatment sites ; and ( 8) patient satisfaction at 10 years . Results at 1 and 10 years of these nine patients ( nine test and nine control teeth ) were compared to original baseline values . In addition , results within treatment groups between 1 and 10 years and between treatment groups ( i.e. , EMD versus CTG ) at the same time points were examined . RESULTS At 10 years , all quantitative parameters except PD for both treatment protocol s showed statistically significant improvements from baseline values , including wKT in the EMD group , which at 1 year was not significantly improved compared with baseline wKT . In addition , at 10 years , there were no statistically significant differences between EMD + CAF and CTG + CAF for any measured parameter . The only statistically significant finding in this study was the difference in wKT found at 1 year ( EMD , 3.00 mm ; CTG , 3.89 mm ; P = 0.031 ) . Qualitative parameters at 10 years demonstrated similar stability . The only major qualitative difference was the marginal tissue contour , which was similar to adjacent tissues at EMD-treated sites but greater than adjacent tissues at all CTG sites except one . Esthetically , both EMD- and CTG-mediated treatments were similar at 10 years . However , given the choice , six of nine patients would choose EMD over CTG treatment to avoid a secondary harvesting procedure . CONCLUSIONS This paper highlights the importance of long-term data as it relates to procedural effectiveness in selecting optimally effective protocol s to treat gingival recession . Based on the results of this 10-year follow-up investigation , treatment with either EMD + CAF or CTG + CAF for Miller Class I and II GR defects appears stable , clinical ly effective , and similar to each other on all measured parameters",
"BACKGROUND In the presence of a thin and narrow zone of gingival tissue root recessions caused by trauma or inflammatory reactions seem to be a common feature of the buccal tissue morphology . The surgical coverage is mainly indicated for aesthetic reasons and may be accomplished with pedicled flaps in conjunction with or without the use of connective tissue grafts . AIM The purpose of the present study was to evaluate the degree of vascularization of connective tissue grafts by applying a microsurgical approach . In addition , the clinical outcome was followed for 1 year . MATERIAL AND METHODS The study population consisted of 10 patients with bilateral Class I and II recessions at maxillary canines . In split-mouth design , the defects were r and omly selected for recession coverage either by a microsurgical ( test ) or macrosurgical ( control ) approach . Immediately after the surgical procedures , and after 3 and 7 days of healing , fluorescent angiograms were performed to evaluate graft vascularization . In addition , the clinical parameters were assessed before the surgical intervention , and 1 , 3 , 6 and 12 months postoperatively . RESULTS The results of the angiographic evaluation at test sites revealed a vascularization of 8.9+/-1.9 % immediately after the procedure . After 3 days and after 7 days , the vascularization rose to 53.3+/-10.5 % and 84.8+/-13.5 % , respectively . The corresponding vascularization at control sites were 7.95+/-1.8%/44.5+/-5.7 % and 64.0+/-12.3 % , respectively . All the differences between test and control sites were statistically significant . The clinical measurements revealed a mean recession coverage of 99.4+/-1.7 % for the test and 90.8+/-12.1 % for the control sites after the first month of healing . Again , this difference was statistically significant . The percentage of root coverage both test and control sites remained stable during the first year at 98 % and 90 % , respectively . CONCLUSIONS The present controlled clinical study has demonstrated that in root surface coverage , a microsurgical approach substantially improved the vascularization of the grafts and the percentages of root coverage compared with applying a conventional macroscopic approach",
"AIM The aim of this r and omized controlled clinical study was to evaluate the outcomes of acellular dermal matrix ( ADM ) graft in combination with tunnel technique ( TUN ) on root coverage , aesthetics , and patient satisfaction and to compare with coronally advanced flap (CAF)+ADM in the treatment of multiple gingival recessions . MATERIAL AND METHODS A total of 20 patients with 58 Miller Class I multiple recessions ≥3 mm were included and divided into TUN+ADM and CAF+ADM groups . At baseline and 12 months , probing depth ( PD ) , clinical attachment level ( CAL ) , recession height ( RH ) and width ( RW ) , keratinized tissue height ( KT ) , gingival thickness , and complete and mean root coverage ( CRC , MRC ) were evaluated . Patient satisfaction and root coverage aesthetic scores ( RES ) were also assessed . RESULTS Mean root coverage was 75.72 % in TUN+ADM and 93.81 % in CAF+ADM . Intragroup comparisons revealed significant differences at 12 months for all parameters in both groups ( p for RH and RW reduction , KT increase , CAL gain , MRC , CRC , and RES in favour of CAF+ADM group ( p effective in root coverage of multiple recessions ; however , better clinical results were achieved with CAF and ADM combination",
"Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed",
"BACKGROUND The root coverage esthetic score ( RES ) system was proposed for evaluating esthetic outcomes of root coverage procedures . The aim of this multicenter study is to assess the interrater agreement of the RES among expert periodontists . METHODS Eleven periodontists were selected in different clinical centers . Each operator had ≥15 years of experience in mucogingival surgery . Each periodontist was trained to use RES before the beginning of the study . Subsequently , baseline and post-treatment ( 6 months ) photographs of 41 Class I and II gingival recessions in 41 patients were separately given to each operator who evaluated the outcomes according to the RES method . A two-way r and om interclass correlation coefficient and 95 % confidence interval ( CI ) were used to assess the global interrater agreement for RESs . RESULTS The total interrater agreement for RESs was 0.92 ( 95 % CI : 0.88 to 0.95 ) , which indicated that an almost perfect agreement was achieved . CONCLUSION Tested individually by a group of periodontists , the RES seems to be a reliable method for assessing the esthetic outcomes of root coverage procedures ",
"BACKGROUND Periodontal root coverage procedures to treat recession areas are indicated for unesthetic , exposed , and /or painful root surfaces . Many methods , most using autogenous soft tissue grafts , have been utilized , but with associated morbidity at the donor sites . An alternative donor material would reduce the morbidity and provide for sufficient available donor tissue . METHODS An acellular allogeneic dermal connective tissue matrix ( AD ) and autogenous palatal connective tissue ( CT ) were compared as subepithelial grafts for the treatment of gingival recession . Twenty-two patients with similar isolated gingival recession of > or = 2 mm on 2 separate teeth were treated with the subepithelial graft technique . Exposed roots were h and root planed only and , by r and om allocation , either a fitted AD or fitted CT graft was secured in place and covered by coronally positioned flaps . RESULTS Mann Whitney U test analysis found the following changes at 6 months for AD and CT , respectively , compared to presurgical conditions : root coverage of 1.7 + /- 1.2 ( 65.9 % ) and 2.2 + /- 1.1 mm ( 74.1 % ) ( both P in keratinized tissue ( KT ) of 1.2 + /- 1.3 and 1.6 + /- 1.9 ( both P increase in gingival thickness with both ; 83.2 % of expected root coverage was obtained with AD and 88.6 % with CT ( P= 0.43 ) . There were no significant differences between treatments for any parameter . Global assessment s by clinicians and patients suggested a more esthetic clinical result with AD . CONCLUSIONS These results suggest that acellular allogeneic dermal matrix may be a useful substitute for autogenous connective tissue grafts in root coverage procedures",
"BACKGROUND The aim of this r and omized clinical trial ( RCT ) was to evaluate the adjunctive benefit of Connective Tissue Graft ( CTG ) to Coronally Advanced Flap ( CAF ) for the treatment of gingival recession associated with inter-dental clinical attachment loss equal or smaller to the buccal attachment loss ( RT2 ) . MATERIAL AND METHODS A total of 29 patients with one recession were enrolled ; 15 patients were r and omly assigned to CAF+CTG while 14 to CAF alone . Measurements were performed by a blind and calibrated examiner . Outcome measures included complete root coverage ( CRC ) , recession reduction ( RecRed ) , Root coverage Esthetic Score ( RES ) , intra-operative and post-operative morbidity , and root sensitivity . RESULTS After 6 months , CAF+CTG result ed in better outcomes in terms of CRC ( adjusted OR = 15.51 , p = 0.0325 ) than CAF alone . CRC was observed in > 80 % of the cases treated with CAF+CTG when the baseline amount of inter-dental CAL was ≤ 3 mm . No difference was detected in term of RecRed . CAF+CTG was associated with longer surgical-time ( p higher number of days with post-operative morbidity ( p = 0.0222 ) and the need for a greater number of analgesics ( p = 0.0178 ) than CAF alone . No difference for final RES score was detected ( p = 0.1612 ) . CONCLUSION Both treatments can provide CRC in single gingival recession with inter-dental CAL loss . The application of CTG under CAF result ed in predictable CRC when inter-dental CAL was ≤ 3 mm",
"BACKGROUND Recession defects around teeth have been treated with a variety of surgical techniques . Most of the literature suggests that the subepithelial connective tissue graft has the highest percentage of mean root coverage with the least variability . Previous studies have demonstrated that enamel matrix derivative ( EMD ) has the ability to improve clinical parameters . The purpose of this study was to compare the clinical efficacy of enamel matrix derivative placed under a coronally advanced flap to subepithelial connective tissue placed under a coronally advanced flap in patients with recession type defects . METHODS Twenty patients with incisors or premolars presenting with a facial recession of > or = 4 mm in contralateral quadrants of the same jaw were treated ; 17 patients completed the study . One tooth in each patient was r and omized to receive either a coronally advanced flap with a subepithelial connective tissue graft ( control ) or a coronally advanced flap with EMD ( test ) . Clinical parameters measured at baseline and at 6 , 9 , and 12 months included amount of recession ; width at the coronal extent of the gingival defect ; width of keratinized tissue ; probing depth ; clinical attachment level ; inflammation score ; plaque score ; plaque index ; alveolar bone level ; tissue texture and color ; and patient perception of pain , bleeding , swelling , and sensitivity . RESULTS Results for both the test and control groups were similar for all measured clinical parameters with the exception of early healing , self-reported discomfort , and the amount of keratinized tissue obtained . The coronally advanced flap with EMD was superior to the subepithelial connective tissue graft with regard to early healing and patient-reported discomfort , whereas the subepithelial connective tissue graft demonstrated greater amount of keratinized tissue during the 12-month evaluation period . However , both the test and control showed a significant increase in the amount of keratinized tissue at 9 and 12 months compared to baseline . No significant difference in the amount of root coverage was found between the test and control groups ( n = 19 ; P = 0.82 ) . On average , a gain of 4.5 mm ( range 4 to 8 mm ) tissue covering the previously exposed root surfaces was achieved with both treatment groups . The average percentages of root coverage for control and test groups were 93.8 % and 95.1 % , respectively . One hundred percent root coverage was obtained 89.5 % of the time with the coronally advanced flap with EMD and 79 % of the time with the subepithelial connective tissue graft . CONCLUSION Based on the results of this investigation , the addition of EMD to the coronally advanced flap result ed in root coverage similar to the subepithelial connective tissue graft but without the morbidity and potential clinical difficulties associated with the donor site surgery",
"BACKGROUND The aim of this study was to evaluate whether the combination of enamel matrix derivative ( EMD ) with subepithelial connective tissue graft ( SCTG ) plus coronally advanced flap ( CAF ) would improve the treatment outcomes of Miller class I and II gingival recessions when compared with the same technique ( SCTG plus CAF ) alone . METHODS The study was design ed as a r and omized , parallel , controlled , double-blinded clinical trial . Forty-two patients were r and omly assigned in the test group ( SCTG plus EMD ) and in the control group ( SCTG ) . Patients had at least one gingival recession ≥ 2 mm . The clinical parameters were evaluated at baseline and at 14 d , 1 , 3 , 6 and 12 mo follow-up time points . RESULTS Forty-two patients , 21 in the test group ( SCTG plus EMD ) and 21 in the control group ( SCTG ) , aged 21 - 48 years ( mean age 31 ± 8.56 ) were initially included in the study . Both treatments , STCG plus EMD and SCTG , result ed in a significant final mean root coverage ( 2.91 ± 0.95 mm and 2.91 ± 1.29 mm , respectively ) ( p high mean percentage of root coverage ( 82.25 ± 22.20 % and 89.75 ± 17.33 % , respectively ) ( p in mean root coverage recorded for the two techniques after 1 year , were not statistically significant ( p = 0.19 ) . Complete root coverage was achieved in 56.5 % of patients treated with SCTG plus EMD and in 70.6 % of patients treated with SCTG ( p = 0.275 ) , 1 year after treatment . CONCLUSIONS The present study failed to demonstrate any additional clinical benefits when EMD was added to SCTG plus CAF ",
"BACKGROUND A newly developed collagen matrix ( CM ) of porcine origin has been shown to represent a potential alternative to palatal connective tissue grafts ( CTG ) for the treatment of single Miller Class I and II gingival recessions when used in conjunction with a coronally advanced flap ( CAF ) . However , at present it remains unknown to what extent CM may represent a valuable alternative to CTG in the treatment of Miller Class I and II multiple adjacent gingival recessions ( MAGR ) . The aim of this study was to compare the clinical outcomes following treatment of Miller Class I and II MAGR using the modified coronally advanced tunnel technique ( MCAT ) in conjunction with either CM or CTG . METHODS Twenty-two patients with a total of 156 Miller Class I and II gingival recessions were included in this study . Recessions were r and omly treated according to a split-mouth design by means of MCAT + CM ( test ) or MCAT + CTG ( control ) . The following measurements were recorded at baseline ( i.e. prior to surgery ) and at 12 months : Gingival Recession Depth ( GRD ) , Probing Pocket Depth ( PD ) , Clinical Attachment Level ( CAL ) , Keratinized Tissue Width ( KTW ) , Gingival Recession Width ( GRW ) and Gingival Thickness ( GT ) . GT was measured 3-mm apical to the gingival margin . Patient acceptance was recorded using a Visual Analogue Scale ( VAS ) . The primary outcome variable was Complete Root Coverage ( CRC ) , secondary outcomes were Mean Root Coverage ( MRC ) , change in KTW , GT , patient acceptance and duration of surgery . RESULTS Healing was uneventful in both groups . No adverse reactions at any of the sites were observed . At 12 months , both treatments result ed in statistically significant improvements of CRC , MRC , KTW and GT compared with baseline ( p CRC was found at 42 % of test sites and at 85 % of control sites respectively ( p Mean KTW measured 2.4 ± 0.7 mm at test sites versus 2.7 ± 0.8 mm at control sites ( p > 0.05 ) . At test sites , GT values changed from 0.8 ± 0.2 to 1.0 ± 0.3 mm , and at control sites from 0.8 ± 0.3 to 1.3 ± 0.4 mm ( p ) . Duration of surgery and patient morbidity was statistically significantly lower in the test compared with the control group respectively ( p CM may represent an alternative to CTG by reducing surgical time and patient morbidity , but yielded lower CRC than CTG in the treatment of Miller Class I and II MAGR when used in conjunction with MCAT",
"AIM To evaluate the reliability of professional qualitative scoring methods used in evaluating aesthetic results after root coverage therapy and to evaluate the relationship between subjective and objective measurements . MATERIAL AND METHODS A review panel of seven professional and non-professional , trained and untrained observers used photographic records to assess the overall cosmetic results of 162 root coverage surgical procedures in 133 patients ( mean follow-up 17.51+/-17.37 months ) . Two different methods were used . In the before-after panel scoring system , observers evaluated the difference between preoperative and postoperative views , whereas in the r and om panel scoring system , observers rated each photograph independently . RESULTS For both methods , intrarater agreement ranged from substantial to almost perfect for the periodontists . The best interrater agreement was found for trained periodontists using the five-point ordinal scale of the before-after panel scoring system ( kappa=0.68 ) . Neither root coverage percentage nor gingival augmentation was correlated to cosmetic assessment . CONCLUSIONS The before-after scoring system is an acceptable and reliable method for professional cosmetic assessment of root coverage therapy . The overall cosmetic evaluation does not appear to be related to the percentage of root coverage",
"AIMS This parallel-group , multi-centre , double-blind , r and omized-controlled clinical trial was undertaken to compare the clinical outcomes and patient morbidity of coronally advanced flap ( CAF ) alone or in combination with a connective tissue graft ( CAF+CTG ) in single Miller Class I and II gingival recessions . MATERIAL AND METHODS Three centres enrolled 85 patients with one recession each . Surgery was performed elevating a pedicle flap ; 42 sites r and omly received a graft under the flap . Measurements were taken by blind and calibrated examiners . Outcome measures included recession reduction , complete root coverage ( CRC ) , intra-operative and post-operative morbidity , dentine sensitivity , and side effects . RESULTS No differences were noted in the intra-operative and post-operative patient-related variables between the two groups . Surgical time was significantly shorter in the CAF group . Recession reduction was not statistically different between the two groups , even though a model showed a tendency towards improved outcomes in sites treated with CAF+CTG ( adjusted difference 0.33 mm , 95 % CI=-0.06 to 0.72 , p=0.1002 ) . Significantly greater probability of CRC was observed after CAF+CTG ( adjusted OR=5.09 , 95 % CI=1.69 - 17.57 , p=0.0033 ) . Dentine hypersensitivity improved in both the groups . CONCLUSIONS Both treatments were effective in providing a significant reduction of the baseline recession and dentine hypersensitivity , with only limited intra-operative and post-operative morbidity and side effects . Adjunctive application of a CTG under a CAF increased the probability of achieving CRC in maxillary Miller Class I and II defects",
"BACKGROUND AND OBJECTIVE Gingival recession is defined as soft and hard tissue displacement result ing in root surface exposure . The optimal outcome of gingival recession treatment is complete , predictable and long-lasting root coverage with a significant level of tissue regeneration . Tissue engineering , which applies active regeneration principles , presents the contemporary treatment approach in the restitution and regeneration of lost tissues . The objective of the present study was to evaluate and compare the clinical results of application of an autologous fibroblast cell culture ( AFCC ) on a collagen matrix and a connective tissue graft ( CTG ) placed under a coronally advanced flap ( CAF ) , in the treatment of single and multiple gingival recessions . MATERIAL AND METHODS Eighteen patients from the Department of Periodontology , School of Dentistry , University of Bel grade , were r and omly enrolled in this study . Inclusion criteria were the bilateral presence of Miller Class I or II single or multiple maxillary gingival recessions . A split-mouth design was used in the study . The experimental group was treated with AFCC on a collagen scaffold , which was placed under a CAF . The control group received a combination of CTG and CAF . Clinical parameters such as gingival recession coverage , keratinized tissue width , clinical attachment level and gingival index were recorded at baseline and at 12 mo postoperatively . The oral hygiene level was assessed by plaque index evaluation . Postoperative healing was evaluated through the healing index , recorded 1 , 2 and 3 wk postoperatively . The final esthetic outcome was assessed using the mean root coverage esthetic score ( RES ) . RESULTS Statistically significant improvement of all parameters assessed was found compared with baseline . A statistically significant difference between groups was observed only in keratinized tissue width . Greater keratinized tissue width is still obtained with the use of CTG . Regarding the tissue-healing results , no statistically significant difference was achieved . The RES results were similar for both groups . CONCLUSIONS Within the limitations of the present study , both procedures proved to be efficient in gingival recession treatment . AFCC , as a novel tissue-engineering concept and living cell-based therapy , proved to be a reliable and successful treatment concept"
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4117c3e6-06ff-11f0-808a-c43d1ab1c353
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Background There are no r and omised and properly blinded trials directly comparing one PDE-5 inhibitor with another in a normal home setting . Valid indirect comparisons with a common comparator must examine equivalent doses , similar duration , similar population s , with the same outcomes reported in the same way . Methods Published r and omised , double-blind trials of oral PDE-5 inhibitors for erectile dysfunction were sought from reference lists in previous review s and electronic search ing . Analyses of efficacy and harm were carried out for each treatment , and results compared where there was a common comparator and consistency of outcome reporting , using equivalent doses . Results Analysis was limited by differential reporting of outcomes . Sildenafil trials were clinical ly and geographically more diverse . Tadalafil and vardenafil trials tended to use enriched enrolment . Using all trials , the three interventions were similar for consistently reported efficacy outcomes . Rates of successful intercourse for sildenafil , tadalafil and vardenafil were 65 % , 62 % , and 59 % , with placebo rates of 23–28 % . The rates of improved erections were 76 % , 75 % and 71 % , respectively , with placebo rates of 22–24 % , and NNTs of 1.9 or 2.0 . Reporting of withdrawals was less consistent , but all-cause withdrawals for sildenafil , tadalafil and vardenafil were 8 % 13 % and 20 % . All three drugs were well tolerated , with headache being the most commonly reported event at 13–17 % . There were few serious adverse events . Conclusion There were differences between trials in outcomes reported , limiting comparisons , and the most useful outcomes were not reported . For common outcomes there was similar efficacy between PDE-5 inhibitors
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"Objective To assess the efficacy and safety of sildenafil citrate ( Viagra ® , Pfizer Inc. , USA ) in a double‐blind , placebo‐controlled , dose‐escalation study over a period of 26 weeks in men with erectile dysfunction of a broad spectrum of aetiology",
"OBJECTIVE To evaluate the efficacy and safety of tadalafil taken as needed before sexual activity by men with diabetes and erectile dysfunction ( ED ) . RESEARCH DESIGN AND METHODS Men with type 1 or type 2 diabetes and a minimum 3-month history of ED were r and omly allocated to one of three groups : placebo ( n = 71 ) , tadalafil 10 mg ( n = 73 ) , or tadalafil 20 mg ( n = 72 ) taken up to once daily for 12 weeks . Changes from baseline in mean scores on the erectile function domain of the International Index of Erectile Function ( IIEF ) and changes from baseline in the proportion of \" yes \" responses to question 2 , \" Were you able to penetrate ? , \" and 3 , \" Were you able to complete intercourse ? , \" of the Sexual Encounter Profile were co primary outcome measures . RESULTS A total of 191 ( 88 % ) of 216 patients completed the study . Treatment with tadalafil significantly improved all primary efficacy variables , regardless of baseline HbA(1c ) level . Therapy with tadalafil also significantly improved a number of secondary outcome measures , including changes in other IIEF domains , individual IIEF questions , and percentage of positive responses to a global assessment question measuring erection improvement . Treatment with tadalafil did not alter mean HbA(1c ) levels . Tadalafil was well tolerated , with headache and dyspepsia being the most frequent adverse events with active treatment . CONCLUSIONS Tadalafil therapy significantly enhanced erectile function and was well tolerated by men with diabetes and ED",
"Abstract Variability in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size",
"BACKGROUND In fixed-dose studies , vardenafil 5 , 10 , and 20 mg improves erectile function in men with erectile dysfunction ( ED ) . Here , the efficacy and tolerability of vardenafil when used in a flexible-dose regimen was assessed . METHODS In this multicenter trial , 323 patients r and omly received vardenafil 10 mg or placebo . After 4 weeks , patients could switch to 5 or 20 mg ( or corresponding placebo ) , or remain on 10 mg for an additional 4 weeks ; dose-switching was optional for the last 4 weeks . Efficacy variables included the IIEF-EF domain score , GAQ , and percentage of positive responses to SEP2/SEP3 questions . RESULTS The IIEF-EF domain score significantly improved from a baseline of moderate ED ( 12.6 - 13.1 ) to mild ED in men on vardenafil ( 21.0 - 24.2 ) compared with placebo ( 13.7 - 15.6 ) at weeks 4 , 8 , 12 , and last observation carried forward ( LOCF ) ( p improved erections ( 80 - 86 % vs. 21 - 36 % for placebo , p Successful SEP2 rates increased after vardenafil , reaching 84 % at weeks 8 and 12 vs. 49 - 53 % receiving placebo ( p successful SEP3 rates ranging from 58 % to 74 % compared to 22 - 34 % for placebo . The most common adverse events , flushing and headache , were generally mild and transient . CONCLUSION In this flexible dose study , vardenafil was well-tolerated , and produced clinical ly relevant improvements in erectile function in men with ED",
"PURPOSE Now that individuals with spina bifida live well into adulthood erectile dysfunction has become a recognized associated medical disorder . To our knowledge no study has dealt specifically with treatment of erectile dysfunction in men with spina bifida . Therefore , we conducted a prospect i ve , blinded , r and omized , placebo controlled , dose escalation , crossover study to determine the ability to treat erectile dysfunction in men with spina bifida with sildenafil citrate . MATERIAL S AND METHODS Erectile dysfunction was diagnosed in 15 men 19 to 35 years old with spina bifida who were assigned to take 4 sets of tablets , 5 tablets per set , in a r and om order . All patients took 25 and 50 mg . sildenafil and 2 identical looking sets of corresponding placebos 1 hour before planned sexual activity . Efficacy was assessed by the effect of treatment compared to baseline , that is before treatment , on rating of erections ( scored from 0 to 10 ) , duration of erections , frequency of erections based on response to question 1 ( scored from 0 to 5 ) of the International Index of Erectile Function and confidence to obtain an erection based on response to question 15 ( scored from 1 to 5 ) of the International Index of Erectile Function . RESULTS Improved erectile function was reported while on sildenafil by 12 ( 80 % ) men compared to baseline and placebos . There was a significant dose dependent improvement of erectile function with both 25 and 50 mg . sildenafil compared to baseline ( p mean erectile score increased by 50 % and 88 % , mean duration of erections increased by 192 % and 266 % , mean frequency of erections increased by 61 % and 96 % , and mean level of confidence increased by 33 % and 63 % , respectively . Furthermore , 50 mg . sildenafil provided greater improvement in all 4 parameters compared to 25 mg . The placebo results were not significantly different compared to baseline for any of the parameters . CONCLUSIONS Erectile dysfunction in patients with spina bifida is a medically treatable condition . Sildenafil is effective in this patient population and improves level of sexual confidence",
"OBJECTIVE To determine whether crossover trials with simple pooling of data over different study periods leads to a different estimate of treatment effect compared with parallel group trials in infertility research using pregnancy as the outcome measure . DESIGN An observational study using nine overviews that included trials with both crossover and parallel group design s. These overviews comprised 17 crossover and 17 parallel group trials . In total , there were 5,291 outcomes including 775 pregnancies . The association between study design and treatment effect estimate was analyzed using multiple logistic regression , controlling for differences in the therapeutic interventions and variations in the method ological quality of the trials . SETTING Infertile patients in an academic research environment . PATIENTS Infertile patients undergoing treatment efficacy evaluation in controlled trials . INTERVENTIONS R and om allocation to a variety of treatments including clomiphene citrate , hCG , IUI , tamoxifen , and bromocriptine . MAIN OUTCOME MEASURE Estimate of bias between study design s , based on the interaction of study design and treatment in the logistic regression model . RESULTS Crossover trials produced a larger average estimate of treatment effect compared with trials with a parallel group design , overestimating the odds ratio by 74 % ( 95 % confidence interval , 2 % to 197 % ) . CONCLUSION The use of a crossover design for evaluating infertility treatments with outcomes that prevent patients from completing later phases of the trial should be avoided because it leads to exaggerated estimates of treatment effect and may result in erroneous inferences and clinical decisions . Furthermore , the type of study design should be taken into account when assessing the method ological quality of therapy trials in infertility",
"OBJECTIVES To determine the efficacy , safety , and treatment satisfaction of tadalafil 20 mg for erectile dysfunction ( ED ) in patients evaluated at tertiary-care academic centers . METHODS In this r and omized , double-blind , placebo-controlled trial , patients were r and omly allocated to receive fixed-dose tadalafil 20 mg ( n = 146 ) or placebo ( n = 49 ) for 12 weeks . Efficacy was assessed by the International Index of Erectile Function ( IIEF ) , Sexual Encounter Profile ( SEP ) , and Global Assessment Question ( GAQ ) ; patient and partner treatment satisfaction by the Erectile Dysfunction Inventory of Treatment Satisfaction ( EDITS ) and SEP ; and safety by adverse events , laboratory values , and vital signs . RESULTS Mean baseline IIEF erectile function ( EF ) domain was 12.98 . Fifty-one percent of enrolled patients had severe baseline ED , and 82 % had organic ED . Pre-existing , ED-associated comorbid conditions were common . When compared with patients treated with placebo , those receiving tadalafil reported significant improvement from baseline in the IIEF EF domain ( P successful penetration attempts ( SEP question 2 ; P successful intercourse ( SEP question 3 ; P all secondary efficacy outcomes ( P satisfied with tadalafil treatment ( P overall satisfaction ( P length of time the treatment worked ( P Mild or moderate headache , dyspepsia , and myalgia were the most frequent treatment-emergent adverse events reported . CONCLUSIONS Tadalafil significantly improved erectile function and patient and partner satisfaction and was well tolerated . These results were observed in a tertiary-care , academic center population with a high incidence of severe , organic ED , and comorbid medical conditions , factors known to compromise erectile function and treatment outcome",
"OBJECTIVE In the 5 - 10 % of diabetic men with type 1 diabetes , erectile dysfunction ( ED ) may be a particularly common and unwanted complication . This is the first study focusing exclusively on the effects of sildenafil in men with type 1 diabetes and ED . RESEARCH DESIGN AND METHODS A total of 188 patients were entered into a double-blind , placebo-controlled , parallel-group , flexible-dose study and were r and omized to receive sildenafil ( 25 - 100 mg ; n = 95 ) or placebo ( n = 93 ) for 12 weeks . Efficacy was evaluated using questions three ( Q3 ; achieving an erection ) and four ( Q4 ; maintaining an erection ) from the International Index of Erectile Function ( IIEF ) , a global efficacy question ( GEQ ; \" Did treatment improve your erections ? \" ) , and a patient event log of sexual activity . RESULTS Improvements in mean scores from baseline to end-of-treatment for IIEF Q3 ( 35.7 vs. 19.9 % ) and Q4 ( 68.4 vs. 26.5 % ) were significant in patients receiving sildenafil compared with those receiving placebo ( P = 0.0001 ) . Moreover , the percent of improved erections ( GEQ , 66.6 vs. 28.6 % ) and successful intercourse attempts ( 63 vs. 33 % ) was significantly increased with sildenafil compared with placebo . Improvements in sexual function were seen irrespective of the degree of ED severity . Adverse events were generally mild to moderate in severity , with headache ( 20 vs. 8 % ) , flushing ( 18 vs. 3 % ) , and dyspepsia ( 8 vs. 1 % ) reported more often in the sildenafil than in placebo-treated patients . CONCLUSIONS Treatment with sildenafil for ED was effective , result ing in an increased percentage of successful attempts at intercourse , and was well tolerated among men with type 1 diabetes",
"Section Editor",
"The long-term efficacy and safety of oral Viagra ® ( sildenafil citrate ) , a selective phosphodiesterase 5 inhibitor , and the effect of withdrawing treatment were evaluated in men with erectile dysfunction ( ED ) . In 233 men with ED of psychogenic or mixed organic/psychogenic aetiology , 16 weeks of open-label , flexible-dose sildenafil treatment ( 10–100 mg ) was followed by eight weeks of double-blind , fixed-dose , r and omised withdrawal to placebo or continued treatment with sildenafil . Sildenafil was taken as needed ( not more than once daily ) approximately 1 h prior to sexual activity . The main outcome measures were a global efficacy question , a sexual function question naire , an event log of erections , and adverse event recording . In the open-label phase , 200 of 216 patients ( 93 % ) reported improved erections with sildenafil ; 28 patients ( 12 % ) discontinued treatment . In the double-blind phase , the significant improvements in the frequency and duration of erections were maintained in the sildenafil group but returned to pre-treatment values in patients on placebo ( P values adverse events in the sildenafil group during the double-blind phase were flushing ( 7 % ) , headache ( 6 % ) , and dyspepsia ( 5 % ) . Of the 192 patients enrolled in the 1-y extension , 90 % completed the study ; only two patients ( 1 % ) were withdrawn due to lack of efficacy . In men with ED of psychogenic or mixed aetiology , oral sildenafil is effective and well-tolerated both at the initiation of therapy and during long-term treatment . For most patients , sildenafil treatment must be continued for improvements in erectile function to be maintained",
"Our objectives were : ( 1 ) to determine the efficacy , safety , and tolerability of sildenafil citrate ( Viagra ® ) administered to men with broad-spectrum erectile dysfunction ( ED ) in southern Latin America ; and ( 2 ) to correlate Rigiscan ® measurements assessing ED etiology with the investigator 's assessment . A total of 141 men with broad-spectrum ED ( mean age 57 ) were enrolled in a r and omized , 12-week , double-blind , placebo-controlled , flexible-dose escalation study of sildenafil . After the 12-week treatment period , the mean score for the primary efficacy variables had risen significantly : for the sildenafil group , 66.2 % from baseline for question 3 of the International Index of Erectile Function and 77.6 % for question 4 , vs 15.1 % and 21.2 % for the placebo group , respectively ( P Headache and flushing , usually mild and transient , were the most common adverse events . Sildenafil was an effective , well-tolerated treatment for men in southern Latin America with broad-spectrum ED",
"OBJECTIVE This study evaluated the efficacy and safety of vardenafil treatment for erectile dysfunction ( ED ) in men with diabetes . RESEARCH DESIGN AND METHODS In this prospect i ve multicenter double-blind placebo-controlled fixed-dose parallel-group phase III trial , 452 patients with diabetes ( type 1 or type 2 ) and ED were r and omized to take 10 or 20 mg vardenafil or placebo as needed for 12 weeks . Efficacy responses were assessed by International Index of Erectile Function domain scores , rates of vaginal penetration and successful intercourse , and a global assessment question ( GAQ ) about erection improvement during the previous 4 weeks . RESULTS After 12 weeks of treatment , a dose-dependent ( P = 0.02 ) improvement in erections was noted for the GAQ , with 57 and 72 % of men taking 10 mg or 20 mg vardenafil , respectively , reporting improved erections , in contrast to 13 % after taking placebo ( P erectile function domain , dose-dependent ( P = 0.03 ) final scores for the 10- and 20-mg dose were 17.1 and 19.0 compared with 12.6 for placebo ( P rates of successful penetration ( P successful intercourse ( P intercourse success rates at all levels of baseline ED severity , at each level of plasma HbA(1c ) , and for type 1 and 2 diabetes . Treatment-emergent adverse events were primarily mild to moderate headache ( flushing ( rhinitis ( erectile function and was generally well tolerated in these diabetic patients with ED",
"BACKGROUND The aim of this study was to evaluate the safety and effectiveness of sildenafil in male peritoneal dialysis patients with erectile dysfunction . METHODS Sixteen peritoneal dialysis patients were recruited to this prospect i ve , r and omized , double-blind , placebo-controlled , crossover study of sildenafil during a period of 8 weeks . Efficacy was assessed by using the International Index of Erectile Function and a Global Assessment Question . Penile arterial supply was assessed by means of Doppler ultrasound in all patients , and adverse events were recorded . RESULTS Three patients failed to complete the study ( 1 patient received a renal transplant , 1 patient died unrelated to the study , and 1 patient withdrew for personal reasons ) . In the remainder , there was a significant improvement in erectile function with sildenafil compared with placebo ( P = 0.01 ) and the baseline assessment ( P = 0.002 ) . There were also significant improvements in intercourse satisfaction ( P = 0.002 ) and overall satisfaction ( P = 0.005 ) compared with baseline . In response to the Global Assessment Question , 75 % of patients reported improvement in erections . Only 1 adverse event was reported : a headache , which resolved after the third dose of sildenafil . CONCLUSION Sildenafil caused a significant improvement in erectile function in peritoneal dialysis patients , with a success rate at least as high as that reported in other patient groups . The drug was well tolerated , with few adverse events",
"Erectile dysfunction ( ED ) and depression are highly prevalent and frequently comorbid . Sildenafil effectively treats ED in men with depression and in men taking antidepressants . We evaluated the efficacy of sildenafil in men with depression in remission and ED . Patients with a history of ED when major depressive disorder ( MDD ) was diagnosed , which persisted after MDD was treated to remission , were r and omized to 12 weeks of treatment with sildenafil ( 50 mg , flexible ) or placebo . Efficacy was assessed using intercourse success rates , a global efficacy question ( Has treatment improved your erections ? ) , the International Index of Erectile Function ( IIEF ) and Life Satisfaction Checklist ( LSC ) . By week 12 , intercourse success rates were significantly higher among sildenafil- ( 74 % ) compared to placebo-treated patients ( 29 % ; P=0.0001 ) . About 83 % and 34 % of sildenafil- and placebo-treated patients , respectively , reported improved erections ( odds ratio=9.4 , P=0.0001 ) . IIEF scores in the sildenafil group ( n=83 ) were significantly improved compared to those in the placebo group ( n=85 ; P LSC sexual life item improved significantly among sildenafil- versus placebo-treated patients . The most frequently reported adverse events were transient and mild-to-moderate . Sildenafil is an effective and well-tolerated treatment for ED in patients with a history of ED at the time of MDD diagnosis , and which persisted after the MDD was treated to remission",
"AIM Vardenafil is a selective and highly potent phosphodiesterase type 5 ( PDE5 ) inhibitor for the treatment of erectile dysfunction ( ED ) , with improved selectivity for PDE5 and demonstrated efficacy for improving sexual function in men with ED . The current study investigated the safety and efficacy of this new PDE5 inhibitor in Japanese men with ED . METHODS This was a prospect i ve , double blind , r and omized clinical trial design ed to evaluate the efficacy and safety of vardenafil . Following a 4-week treatment-free observation period , 283 eligible patients were r and omized to 12 weeks treatment with vardenafil 5 mg , 10 mg , 20 mg , or placebo . Primary efficacy responses were assessed using the scores of Q3 and Q4 of the international index of erectile function ( IIEF ) . RESULTS All three vardenafil doses showed significantly better improvement than the placebo group in Q3 and Q4 scores of the IIEF question naire , either at 12 weeks or at the ' last observation carried forward ' ( LOCF , P Q3 scores were improved to 4.06 with vardenafil 5 mg , 4.53 with vardenafil 10 mg , and 4.64 with vardenafil 20 mg , versus 3.17 with placebo . Comparable scores for Q4 were 3.47 , 4.15 and 4.31 versus 2.31 for placebo . Up to 86 % of patients achieved improved erections as assessed by the global assessment question ( GAQ ) . Reported adverse event rates were 35.3 % , 45.3 % and 54.5 % with vardenafil 5 mg , 10 mg and 20 mg , respectively , versus 21.1 % in the placebo group . No serious adverse drug reactions were reported . The most common treatment-emergent adverse events were transient headache , flushing and rhinitis , which were mostly mild . CONCLUSION Vardenafil is an effective and well-tolerated treatment for ED and provides improvement in key indices of erectile function among Japanese men with ED . The results of our trial show that up to nearly 90 % of patients achieve improved erections with the administration of vardenafil ",
"The efficacy of sildenafil citrate ( Viagra ® ) , an oral agent for the treatment of erectile dysfunction ( ED ) , has been demonstrated in global studies . This 12-week r and omized , double-blind , placebo-controlled , parallel-group , flexible-dose study assessed the efficacy and safety of sildenafil to treat ED in men in Egypt and South Africa . Men with ED of varied etiology were r and omized to receive sildenafil 50 mg ( n=128 ) or placebo ( n=126 ) ; doses could be adjusted to 100 or 25 mg . Questions from the International Index of Erectile Function ( IIEF ) assessing the ability to achieve ( Q3 ) and maintain ( Q4 ) erections demonstrated a significant improvement with sildenafil compared with placebo ( P . Improved erections were reported by 74 % of patients receiving sildenafil and 27 % of those receiving placebo ( P were the most common adverse events in sildenafil-treated patients . These results are consistent with clinical trials in other countries . We conclude that sildenafil is an efficacious and well-tolerated treatment for men with ED in Egypt and South Africa",
"Associate Editor",
"The aim of this study was to evaluate the efficacy and safety of oral sildenafil to treat erectile dysfunction ( ED ) in chronic renal failure in patients on hemodialysis ( HD ) . A double-blind , r and omized , placebo-controlled study of oral sildenafil ( 50 mg ) administered as required in HD patients with ED was design ed . Patients on HD for at least 6 mo and who had a stable relationship with a female sexual partner were included . Patients older than 70 yr with penile anatomic abnormalities , cirrhosis , diabetes , angina , severe anemia , and those who were on nitrate treatment or with a recent history of stroke or myocardial infa rct ion were not included . The International Index of Erectile Dysfunction ( IIEF ) was employed to evaluate ED and treatment response . Forty-one patients were evaluated ( 21 received placebo , and 20 sildenafil ) . Baseline clinical and demographic parameters were similar in both groups . Sildenafil was associated with improvement in the score of all questions and domains of the IIEF , except those related to sexual desire . Using the erectile function domain to evaluate primary efficacy , improvement was observed in 85 % of the sildenafil patients compared with 9.5 % of placebo patients . Sildenafil use result ed in normal EF scores in 35 % of sildenafil patients . Sildenafil was well tolerated . Headaches and flushing occurred in both groups . Dyspepsia was reported by two patients in the sildenafil group . In conclusion , oral sildenafil seems to be an effective and safe treatment for ED in selected patients with chronic renal failure on hemodialysis",
"Objective : Identifying and effectively treating erectile dysfunction ( ED ) can result in an improvement of the quality of life ( QoL ) in men with multiple sclerosis ( MS ) . Methods : This r and omised , double blind ( DB ) , placebo controlled , flexible dose study with an open label extension ( OLE ) assessed efficacy , QoL , and safety of sildenafil citrate in men with MS and ED . Overall , 217 men received sildenafil ( 25–100 mg ; n = 104 ) or placebo ( n = 113 ) for 12 weeks . Efficacy was assessed by the International Index of Erectile Function ( IIEF ) question naire that includes questions on achieving ( Q3 ) and maintaining ( Q4 ) an erection as well as a global efficacy question ( GEQ ) . QoL was also assessed . Results : After 12 weeks , patients receiving sildenafil had higher mean scores for IIEF Q3 and Q4 compared with those receiving placebo ( p improved erections compared with 24 % ( 27/112 ) of patients receiving placebo ( p improved erections . Patients receiving placebo during the DB phase showed a nearly fourfold increase in improved erections ( 97 % v 26 % ) . Men receiving sildenafil also showed improvements in five of the eight general QoL questions compared with men receiving placebo ( p total mean score for the QoL question naire improved by 43 % for the sildenafil group versus 13 % for the placebo group ( p Sildenafil treatment for ED in men with MS was effective and well tolerated , and result ed in significant improvements in both general and disease specific QoL variables",
"Study design : A r and omized , blinded , crossover clinical trial comparing sildenafil versus tadalafil for erectile dysfunction ( ED ) in male spinal cord-injured ( SCI ) patients . Objectives : To compare the safety , time/ duration effectiveness , and the impact on the quality of life ( QoL ) of tadalafil 10 mg versus sildenafil 50 mg . Setting : Neurourology Section , Careggi Hospital , Florence , Italy . Methods : During a screening ( visit 1 ) , a diary card was distributed , in which the subjects assessed , after each attempt at intercourse the quality of their erection , responding ( Yes/No ) to both Sexual Encounter Profile Questions 2 ( SEP2 ) and 3 ( SEP3 ) . The subjects made at least four attempts at intercourse . At visit 2 , 15 patients ( group 1 ) were assigned sildenafil and 15 ( group 2 ) started with tadalafil . Responses to baseline International Index of Erectile Function 5 items ( IIEF-5 ) , Questions 13–14 ( IIEF 15 items ) and SEP diary were recorded . Patients attempted intercourse on four separate occasions : within 4 h of taking the first tablet , within 12 h for the second tablet , 24 h for the third , and the fourth from 24 to 36 h. At visit 3 , the investigators evaluated the effectiveness with the same measures used at baseline . After a wash-out period , at visit 4 , Group 1 was given tadalafil , and Group 2 was given sildenafil . Patients were required to observe the same criteria in taking the four tablets as in visit 2 . After 4 weeks ( visit 5 ) , we evaluated the patients as we did in visit 3 . Results : Overall , 28 patients completed the study . No subjects discontinued the drugs due to drawbacks . Tadalafil allowed a majority of men in this trial to achieve both normal sexual functioning up to 24 h postdosing compared to sildenafil ( P improved overall sex life satisfaction as well as sexual relations with partner . Conclusion : Based on these data , tadalafil may have the potential to become an important treatment option for ED in SCI patients .Sponsorship : This study was not sponsored",
"Vardenafil , a novel selective phosphodiesterase type 5 inhibitor , was evaluated in its first large-scale at-home trial . A total of 601 men with mild to severe erectile dysfunction ( ED ) were enrolled in this multi-centre , r and omized , double-blind , placebo-controlled trial of 12 weeks of treatment with either placebo or 5 , 10 and 20 mg of vardenafil . Primary endpoints were Q3 ( vaginal penetration ) and Q4 ( maintenance of erection ) of the International Index of Erectile Function ( IIEF ) . In the intent-to-treat population ( n=580 ) , the changes from baseline for 5 , 10 and 20 mg vardenafil ( 1.2 , 1.3 and 1.5 , respectively ) were all improved ( P vardenafil doses improved all IIEF domains compared to placebo ( P percentage of successful intercourses was between 71 and 75 % for the three vardenafil doses . For the 20 mg dose , 80 % of the patients experienced improved erections ( GAQ ) compared to 30 % for placebo . Most frequent treatment-emergent adverse events were headache ( 7–15 % ) , flushing ( 10–11 % ) and up to 7 % for dyspepsia or rhinitis . Vardenafil treatment result ed in a high efficacy and low adverse-event profile in a population with mixed ED etiologies",
"Abstract PURPOSE : Controlled trials have demonstrated the efficacy of sildenafil for “ mixed etiology ” erectile dysfunction , but this may not be the case if there is underlying pelvic parasympathetic nerve damage . We aim ed to determine the efficacy of sildenafil after rectal excision for rectal cancer and inflammatory bowel disease . METHODS : Patients with erectile dysfunction after rectal excision were r and omly assigned in a double-blind manner to sildenafil or placebo groups . After unblinding , placebo patients crossed over to open sildenafil . Primary end points were improvement in erectile function on a global efficacy question and erectile function question naire scores . Secondary end points were frequency and severity of side effects . RESULTS : Thirty-two patients were r and omly assigned , and two dropped out before r and omization . Fourteen received sildenafil , and 18 received placebo . Eleven ( 79 percent ) of 14 responded to sildenafil , on global efficacy assessment , compared with 3 ( 17 percent ) of 18 taking placebo ( mean difference , 61.9 percent ; 95 percent confidence interval , 34.4 to 89.4 percent ; P = 0.0009 ) . Sildenafil improved both erectile function domain scores ( mean difference , 13.3 ; 95 percent confidence interval , 7.9 to 18.7 ; P = 0.0001 ) and total International Index of Erectile Function scores ( mean difference , 30.6 ; 95 percent confidence interval , 18.7 to 42.6 ; P Placebo did not produce improvement in either erectile function ( mean difference , 1.7 ; 95 percent confidence interval , −0.8 to 4.2 ; P = 0.16 ) or total International Index of Erectile Function scores ( mean difference , 5 ; 95 percent confidence interval , −1.1 to 11.1 ; P = 0.1 ) . Ten ( 100 percent ) of 10 crossover patients not responding to placebo did respond to sildenafil ( difference , 100 percent ; P improved both erectile function domain scores ( mean difference , 16.8 ; 95 percent confidence interval , 9.7 to 24 ; P = 0.002 ) and total International Index of Erectile Function scores ( mean difference , 29.5 ; 95 percent confidence interval , 15.8 to 43.2 ; P = 0.003 ) from precrossover baseline scores . Seven ( 50 percent ) of 14 patients on sildenafil compared with 4 ( 22 percent ) of 18 on placebo experienced side effects ( difference , 28 percent ; 95 percent confidence interval , −4.4 to 60.4 percent ; P = 0.14 ) , 91 percent of which were mild and well tolerated . CONCLUSION : Sildenafil completely reverses or satisfactorily improves postproctectomy erectile dysfunction in 79 percent of patients . Side effects are usually mild and well tolerated . The damage incurred by the pelvic nerves after proctectomy , less profound than after prostatectomy , is likely to result in a partial parasympathetic nerve lesion",
"The efficacy and safety of sildenafil were evaluated in a r and omised , double-blind , placebo-controlled , flexible-dose study in Taiwanese men aged 26 to 80 y with erectile dysfunction ( ED ) of broad-spectrum aetiology and more than 6 months ' duration . A total of 236 patients were r and omised at six medical centres in Taiwan to receive either sildenafil ( 50 mg initially increased if necessary to 100 mg or decreased to 25 mg depending on efficacy and toleration ) ( n=119 ) or matching placebo ( n=117 ) taken on an ‘ as needed ’ basis 1 h prior to anticipated sexual activity for a period of 12 weeks . At the end of 12 weeks , the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse , and the secondary efficacy variables , which included : ( 1 ) the five separate domains of sexual functioning of the IIEF ( International Index of Erectile Function ) scale , ( 2 ) the percentage of successful intercourse attempts ; and ( 3 ) a global assessment of erections , were all statistically significantly improved by sildenafil in comparison with placebo ( P adverse events occurred in 43.7 % of patients receiving sildenafil and 18.8 % receiving placebo . The most common adverse events with sildenafil were flushing , dizziness and headache ( 25.2 , 6.7 and 5.9 % of patients , respectively ) , and most were mild in nature . The efficacy and safety of sildenafil in the population of Taiwanese men appears similar to that reported in other studies in western population ",
"The objective of this work was to assess the efficacy and safety of sildenafil in patients with erectile dysfunction ( ED ) from Colombia , Ecuador , and Venezuela . One hundred and fifty-eight out patients with ED participated in a double-blind , flexible-dose , r and omized-controlled trial . Efficacy measures included question 3 ( achieving an erection ) and question 4 ( maintaining an erection ) from the International Index of Erectile Function ( IIEF ) , the five functional domains of the IIEF , a global efficacy question , and patient event log . Sildenafil increased patients ' ability to achieve/maintain erections ( P sildenafil- vs 46 % of placebo-treated patients reported improved erections ( P intercourse attempts were successful among sildenafil and placebo patients , respectively ( P improvements in three of the five IIEF functional domains ( P . Adverse events were reported for 51 % and 33 % of sildenafil and placebo patients , respectively . It can be concluded that sildenafil is an effective , well-tolerated treatment for ED in patients from Latin America",
"This was a double-blind , placebo-controlled , flexible-dose study of the efficacy and safety of sildenafil in men with erectile dysfunction ( ED ) and clinical ly stable coronary artery disease ( CAD ) . Patients were r and omized to receive sildenafil or placebo for 12 weeks . Primary outcomes were questions 3 and 4 of the International Index of Erectile Function ( IIEF ) . Secondary outcomes included the other IIEF questions and functional domains , the Life Satisfaction Checklist , the Erectile Dysfunction Inventory of Treatment Satisfaction , 2 global efficacy assessment questions , and intercourse success rate . By week 12 , sildenafil-treated patients ( n = 70 ) showed significant improvements on questions 3 and 4 compared with placebo-treated patients ( n = 72 ; p improved erections ( 64 % ) and improved intercourse ( 65 % ) compared with placebo-treated patients ( 21 % and 19 % , respectively ) . Sildenafil-treated patients were highly satisfied with treatment and their sexual life compared with placebo-treated patients . Forty-seven percent of sildenafil- and 32 % of placebo-treated patients experienced adverse events , including transient headache , hypertension , flushing , and dyspepsia . There were no serious drug-related cardiovascular effects . Thus , sildenafil is an effective and well-tolerated treatment for ED in men with CAD . Sildenafil was not associated with additional safety risks in this patient population",
"PURPOSE We evaluated the efficacy and safety of tadalafil 20 mg , taken on dem and , in men with erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy ( BNSRRP ) . MATERIAL S AND METHODS This r and omized , double-blind , placebo controlled multicenter study consisted of a 4-week treatment-free run-in period ( baseline ) followed by 12 weeks of treatment . A total of 303 men ( mean age 60 years ) with preoperative normal erectile function who had undergone a BNSRRP 12 to 48 months before study were r and omized ( 2:1 ) to tadalafil ( 201 ) or placebo ( 102 ) . The 3 co- primary end points were changes from baseline in the International Index of Erectile Function erectile function domain score , and the percentage of positive responses to Sexual Encounter Profile questions 2 ( successful penetration ) and 3 ( successful intercourse ) . The Global Assessment Question and the Erectile Dysfunction Inventory of Treatment Satisfaction question naire were secondary end points . We defined a priori a subgroup of 201 patients reporting evidence of postoperative tumescence , defined as 50 % or greater \" yes \" responses to Sexual Encounter Profile question 1 ( ability to achieve at least some erection ) during baseline intercourse attempts and stratified r and omization based on this criterion . RESULTS Patients receiving tadalafil reported greater improvement on all primary and secondary end points ( p placebo . For all r and omized patients and for the subgroup with evidence of postoperative tumescence , the mean International Index of Erectile Function erectile function domain score increased for patients receiving tadalafil ( mean + /- SEM 5.3 + /- 0.5 and 5.9 + /- 0.7 , respectively , p tadalafil , the mean percentage of successful penetration attempts was 54 % and the mean percentage of successful intercourse attempts was 41 % . For the subgroup with evidence of postoperative tumescence these values were 69 % and 52 % , respectively . Of all patients r and omized to tadalafil 62 % and of the subgroup patients r and omized to tadalafil 71 % reported improved erections . Patients receiving tadalafil reported greater treatment satisfaction on the Erectile Dysfunction Inventory of Treatment Satisfaction than those receiving placebo . Headache ( 21 % ) , dyspepsia ( 13 % ) and myalgia ( 7 % ) were the most commonly reported adverse events . CONCLUSIONS Tadalafil 20 mg , taken on-dem and , was an efficacious and well tolerated treatment for erectile dysfunction following BNSRRP",
"Abstract Purpose . To determine the population dose-response relationship for tadalafil during on-dem and ( as-needed ) administration for treatment of erectile dysfunction ( ED ) . Methods . A total of 212 male patients with mild , moderate , or severe ED participated in a multicenter , r and omized , double-blind , placebo-controlled , parallel-group study . Patients were r and omized to receive placebo or 2 , 5 , 10 , or 25 mg tadalafil , taken on dem and over an 8-week period . Efficacy was assessed on the basis of questions 2 and 3 of the Sexual Encounter Profile ( SEP ) and questions 3 and 4 of the International Index of Erectile Function ( IIEF ) question aires . These scores were modeled using logistic regression . A fifth patient response , the IIEF EF ( erectile function ) domain score , was modeled as a continuous variable . Results . The dose-response relationship for each efficacy variable was best described with an Emax model , in which maximum effect increased with ED severity at baseline . Response scores increased substantially between 10 and 25 mg tadalafil doses , and the dose-response parameter estimates suggested possibly higher responses at even higher doses . Conclusions . Population dose-response modeling of all five oucome measures indicated that efficacy in all ED severity groups in the studied population generally increased across the 2 to 25 mg tadalafil dose range . Estimates of maximal improvement ( Emax ) in the IIEF EF domain score were 7.5 , 11.4 , and 16.3 points for patients with mild , moderate , and severe ED , respectively . Corresponding tadalafil doses to attain half-maximal improvement ( ED50 estimates ) were 4.7 mg , 7.1 mg , and 10.1 mg",
"OBJECTIVES To assess the efficacy and safety of Viagra ( sildenafil citrate ) in male out patients with erectile dysfunction and patient and partner satisfaction with treatment using the Erectile Dysfunction Inventory of Treatment Satisfaction ( EDITS ) . METHODS A total of 247 patients with erectile dysfunction of broad-spectrum etiology were treated in a r and omized , double-blind , parallel-group , multicenter study conducted at outpatient clinics . Patients receiving oral sildenafil ( 25 , 50 , and 100 mg ) were compared with patients receiving placebo during a 12-week period . The principal efficacy measures were responses to question 3 ( ability to achieve an erection ) and question 4 ( ability to maintain an erection ) on the International Index of Erectile Function and three global efficacy questions . Patient and partner satisfaction with treatment were assessed , for the first time , using the EDITS question naire . RESULTS Efficacy scores for the International Index of Erectile Function questions and the global efficacy questions were significantly higher for patients receiving sildenafil than for those receiving placebo ( P sildenafil also had significantly higher EDITS scores than those receiving placebo ( P Adverse events were chiefly mild or moderate . Two patients receiving sildenafil and none receiving placebo discontinued treatment because of adverse events . CONCLUSIONS Sildenafil was an effective , well-tolerated treatment for erectile dysfunction in an outpatient setting . Partner evaluations corroborated patient assessment s. The results from the EDITS question naire indicated that after 12 weeks of receiving sildenafil both patients and partners reported higher levels of treatment satisfaction relative to placebo",
"BACKGROUND Tadalafil is a phosphodiesterase 5 ( PDE5 ) inhibitor approved in > 30 countries for the treatment of erectile dysfunction ( ED ) . It has been shown to improve erectile function compared with placebo in Phase III studies , but clinical experience comparing tadalafil with the PDE5 inhibitor sildenafil citrate is lacking . OBJECTIVE This study compared patient preference for tadalafil 20 mg or sildenafil 50 mg during initial treatment for ED . It also compared the tolerability of the 2 agents at these doses . METHODS This r and omized , double-blind , fixed-dose , 2-period crossover trial took place at 13 sites in the United States and Germany . Patients were r and omized 1:1 to receive 4 weeks of treatment with tadalafil 20 mg or sildenafil 50 mg , followed by the alternative treatment , to be taken as needed up to once daily before sexual activity . RESULTS The study enrolled 215 men with ED , 109 r and omized to the tadalafil-sildenafil sequence and 106 to the sildenafil-tadalafil sequence . Their mean age was 49.8 years ; 84.7 % were sildenafil naive and 15.3 % had undergone a previous inadequate trial of sildenafil . Most patients had moderate ED ( 60.5 % ) of > or=1 year 's duration ( 74.9 % ) . Of 190 evaluable patients , 126 ( 66.3 % ) preferred to initiate treatment with tadalafil , compared with 64 ( 33.7 % ) with sildenafil ( P sildenafil exposure . Both medications were well tolerated , with no significant differences in the incidence of treatment-emergent adverse events . Headache ( 11.2 % tadalafil , 8.8 % sildenafil ) , dyspepsia ( 6.0 % and 4.2 % , respectively ) , nasopharyngitis ( 4.7 % and 2.8 % ) , and flushing ( 2.8 % and 4.7 % ) were the most common adverse events . The rate of ocular disturbances was low : 1 patient experienced intermittent bilateral reduction in visual acuity with tadalafil , and 2 exhibited conjunctival hyperemia or eyelid edema with sildenafil . CONCLUSIONS Tadalafil 20 mg was preferred to sildenafil 50 mg for the initiation of ED therapy in this study population . Both medications were well tolerated",
"A 12-week , double-blind , placebo-controlled , multicenter study evaluated the efficacy and safety of flexible-dose sildenafil citrate ( Viagra ® ) treatment ( 25 , 50 or 100 mg ) in Brazilian and Mexican men with erectile dysfunction ( ED ) of broad-spectrum etiology . Efficacy was assessed on the basis of responses to the 15-item International Index of Erectile Function ( IIEF ) question naire , completed at baseline and after 12 weeks of treatment . At end point , mean scores for all IIEF domains of sexual function ( erectile function , orgasmic function , sexual desire , intercourse satisfaction and overall satisfaction ) were significantly ( P increases in frequency of penetration and frequency of maintained erections reported previously . Sildenafil treatment was well tolerated . The most common adverse events were headache and flushing . In conclusion , sildenafil is a well-tolerated and effective treatment for ED of broad-spectrum etiology in Latin American men",
"PURPOSE To determine the efficacy and safety of oral sildenafil citrate in the treatment of erectile dysfunction ( ED ) in diabetic men . MATERIAL S AND METHODS In a r and omized , double-blind , placebo-controlled , and fixed-dose study , a total of 282 men ( mean age , 46.4 years ) with ED ( mean duration , 3.6 years ) and diabetes ( mean duration , 11 years ) were r and omly assigned to receive 100 mg sildenafil ( n=144 ) or placebo ( n=138 ) approximately 1 h before planned sexual activity , but not more than once daily , for 16 weeks . The efficacy of two treatments was assessed using responses to the International Index of Erectile Function ( IIEF ) question naire . RESULTS Two hundred sixty-two ( 93 % ) of men completed the study ( 134/144 in the sildenafil group , 128/138 in the placebo group ) . Positive clinical results were obtained in 68 ( 51 % ) of 134 patients in the sildenafil group compared with 14 ( 11 % ) of 128 patients in the placebo group ( P successful attempt at sexual intercourse in the sildenafil group as compared with 21 % successful attempts for the placebo group ( P Drug-related adverse effects occurred in 32 ( 22 % ) of 144 patients taking sildenafil and 4 ( 3 % ) of 138 patients receiving placebo . The most common adverse events were headache ( 20 % sildenafil , 2 % placebo ) , flushing ( 19 % sildenafil , 0 % placebo ) , dyspnea ( 9 % sildenafil , 2 % placebo ) , rhinitis ( 6 % sildenafil , 0 % placebo ) , and cardiovascular effects ( 7 % sildenafil , 0 % placebo ) . Of patients taking sildenafil , four ( 2.7 % ) developed new chest pains , with documented myocardial infa rct ion in two . CONCLUSION Oral sildenafil is a moderately effective treatment for ED in men with diabetes . The response rate was lower and cardiovascular events were higher than previously reported in nondiabetic patients",
"OBJECTIVES To evaluate the efficacy , safety , and tolerability of oral sildenafil in Asian men with erectile dysfunction of various causes ( organic , psychogenic , or mixed ) and of more than 6 months ' duration . METHODS In this double-blind , parallel-group trial conducted at eight centers in Malaysia , the Philippines , and Singapore , 254 men , 26 to 78 years old , were r and omized to 12 weeks of sildenafil or placebo taken as needed 1 hour before anticipated sexual activity . Initially , the sildenafil ( n = 127 ) or matching placebo ( n = 127 ) dose was 50 mg but could be increased to 100 mg or decreased to 25 mg because of a lack of efficacy or intolerance , respectively . Efficacy was assessed by the 15- question International Index of Erectile Function , patients ' event logs of sexual activity , and a global efficacy question about erections . RESULTS The two primary efficacy variables relating to achievement and maintenance of an erection sufficient for sexual intercourse , as assessed by the mean scores for International Index of Erectile Function question 3 ( 4.22 versus 2.59 ) and question 4 ( 4.15 versus 2.41 ) , were both significantly higher with sildenafil than with placebo ( P International Index of Erectile Function domains of sexual function , the percentage of successful intercourse attempts , and the global efficacy assessment of erections revealed significantly greater treatment effects in favor of sildenafil ( P Treatment-related adverse events occurred in 22.8 % of patients who received sildenafil and in 10.2 % of those who received placebo . CONCLUSIONS Sildenafil is an effective and well-tolerated treatment for Asian men with erectile dysfunction of broad-spectrum etiology",
"OBJECTIVE To evaluate the efficacy and safety of sildenafil citrate ( Viagra ) in a r and omized , double-blind , placebo-controlled , flexible-dose study in Thai men with erectile dysfunction of broad-spectrum etiology and more than 6 months ' duration . MATERIAL AND METHOD 125 patients aged 26 to 77 years were r and omized at 4 centers in Thail and to receive either sildenafil citrate ( 50 mg initially , increased if necessary up to 100 mg or decreased to 25 mg depending on efficacy and /or tolerability ) ( n = 63 ) or a matching placebo ( n = 62 ) taken on an ' as needed ' basis approximately 1 hour prior to anticipated sexual activity for a period of 12 weeks . Efficacy was assessed by the patients ' responses to the 15- question International Index of Erectile Function ( IIEF ) , to questions on the event log of sexual activity , and to the global efficacy assessment question concerning improvement in erections . RESULTS At the conclusion of the study , both the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse and the secondary efficacy variables , which included the 5 separate domains of sexual functioning of the IIEF , the percentage of successful attempts at sexual intercourse , and the global efficacy assessment question concerning improvement in erections , were all significantly improved statistically by sildenafil in comparison with placebo except in the sexual desire domain which showed no difference . The percentage of successful attempts at sexual intercourse in the sildenafil group was 66.16 per cent while in the placebo group it was 33.05 per cent . The percentage of global efficacy assessment was improved in the sildenafil group by 82.5 per cent compared to 36.1 per cent in the placebo group . Adverse events considered treatment-related occurred in 19 patients ( 30.2 % ) receiving sildenafil and 7 ( 11.3 % ) receiving placebo . The most common adverse events with sildenafil were vasodilatation ( flushing ) , headache , and dizziness , which occurred in 14.3 per cent , 6.3 per cent , and 6.3 per cent of patients respectively . All events were mild in nature . CONCLUSIONS Sildenafil is a safe and effective treatment for erectile dysfunction of broad-spectrum etiology in Thai men . Its efficacy appears similar to that reported in other studies in Western population",
"The efficacy and safety of sildenafil was evaluated in a r and omiSed , double-blind , placebo-controlled , flexible-dose study in Korean men aged 28–78 y with erectile dysfunction ( ED ) of broad-spectrum aetiology and more than 6 months duration . A total of 133 patients were r and omised at six centres in Korea to receive either sildenafil ( 50 mg initially , increased if necessary to l00 mg or decreased to 25 mg depending on efficacy and tolerance ) ( n=66 ) or matching placebo ( n=67 ) taken on an ‘ as needed ’ basis l h prior to anticipated sexual activity for a period of 8 weeks . At the end of this time , the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse , and the secondary efficacy variables , which included : ( 1 ) the five separate domains of sexual functioning of the International Index of Erectile Function ( IIEF ) scale , ( 2 ) the percentage of successful intercourse attempts , and ( 3 ) a global assessment of erections , were all statistically significantly improved by sildenafil in comparison with placebo ( P adverse events occurred in 56.1 % of patients receiving sildenafil and 20.9 % receiving placebo . The most common adverse events with sildenafil were vasodilatation ( flushing ) , headache and abnormalities in colour vision ( 31.8 , 22.7 and 6.1 % of patients , respectively ) , and most were mild in nature . The efficacy and safety of sildenafil in this population of Korean men appears similar to that reported in other studies in western population ",
"OBJECTIVES To determine the minimal time to successful intercourse after taking sildenafil citrate for erectile dysfunction ( ED ) . METHODS Male patients with ED ( mean age 60 years ; mean ED duration 7.0 years ) who were successfully treated with sildenafil ( 100 mg ) for 2 months or longer were r and omized to sildenafil ( n = 115 ) or placebo ( n = 113 ) for 4 weeks of double-blind treatment . Using a stopwatch , patients recorded the time needed to obtain an erection hard enough for sexual intercourse after taking the study drug at least 2 hours after eating . RESULTS Within 14 and 20 minutes of sildenafil dosing , 35 % and 51 % of sildenafil-treated patients , respectively , versus 22 % and 30 % of placebo-treated patients , respectively , had an erection that led to successful intercourse ( P median time to erection leading to successful intercourse after sildenafil dosing was 36 minutes compared with 141 minutes for placebo . CONCLUSIONS In this study , slightly more than one half of a population of prior sildenafil responders achieved an erection that led to successful sexual intercourse within 20 minutes of sildenafil administration , suggesting that the onset of action of sildenafil can be less than 30 minutes in men with ED",
"The objective of this study was to assess the efficacy and safety of sildenafil citrate ( Viagra ) in black American and Hispanic American men with erectile dysfunction ( ED ) of broad-spectrum etiology . A total of 246 black American and 197 Hispanic American men were r and omized to sildenafil ( 50 mg , adjustable to 25 mg or 100 mg , depending on efficacy and tolerability ; n = 124 and n = 99 , respectively ) or matching placebo ( n = 122 and n = 98 , respectively ) . After 6 weeks , patients were given the option of switching to the other blinded treatment for the following 6 weeks . The 12 weeks of double-blind treatment were followed by 12 weeks of open-label extension . Despite differences in prevalence of hypertension , diabetes mellitus , hyperlipidemia , and use of concomitant antihypertensive agents between the 2 study groups , sildenafil was efficacious and well tolerated . After 6 weeks , scores for questions 3 and 4 from the International Index of Erectile Function ( IIEF ) were significantly higher among sildenafil-treated black and Hispanic patients than in placebo-treated patients . In addition , compared with placebo , a significantly larger proportion of sildenafil patients reported improved erections and improved ability to have sexual intercourse . When efficacy results were stratified by ED severity or number of risk factors , scores for IIEF questions 3 and 4 were lower in men with severe ED versus mild-to-moderate ED . Similarly , the percentage of patients reporting improved erections decreased with ED severity and number of risk factors . The proportion of patients switching to the other treatment after 6 weeks was significantly higher in the placebo group ( 71 % to 85 % ) than in the sildenafil group ( 27 % to 28 % ) . The most common adverse events included headache and vasodilation , which were mild to moderate in nature and were comparable between groups . These data demonstrate that despite differences in prevalence rates of comorbidities , efficacy and safety of sildenafil is maintained across different ethnic groups",
"Sildenafil citrate ( Viagra ) has been shown to be an effective treatment for erectile dysfunction ( ED ) of organic aetiology . This study assessed the efficacy and tolerability of sildenafil for treating ED of psychogenic and mixed psychogenic/organic aetiology . Men with ED of psychogenic and mixed aetiology were r and omised in a double-blind , fixed-dose study to placebo ( n = 95 ) or sildenafil 10 mg ( n = 90 ) , 25 mg ( n = 85 ) , or 50 mg ( n = 81 ) once daily for 28 days . Efficacy was evaluated with two global efficacy questions , a patient log of erectile activity , a sexual function question naire and a partner question naire . Patients receiving sildenafil had significantly more grade 3 ( hard enough for penetration ) or grade 4 ( fully hard ) erections per week than patients receiving placebo , and a greater proportion of patients receiving sildenafil reported that treatment had improved their erections ( p sexual function question naire demonstrated significant improvement for patients with ED receiving sildenafil compared with patients receiving placebo for frequency , hardness and duration of erections ( p enjoyment of sexual intercourse and satisfaction with sex life ( p sildenafil was associated with significant improvement in the partners ' own sex lives ( p Adverse events were mostly mild to moderate in nature . The commonest adverse events were headache , dyspepsia , flushing , myalgia , arthralgia and flu syndrome . Discontinuations due to treatment-related adverse events were few , ranging from 1.1 % to 6.2 % for patients receiving different doses of sildenafil and 4.2 % for patients receiving placebo . Sildenafil is an effective and well-tolerated treatment for ED of psychogenic or mixed aetiology with once-daily dosing",
"This r and omised , double-blind study assessed the long-term efficacy and tolerability of vardenafil 10 and 20 mg in men with erectile dysfunction ( ED ) . A total of 566 men who completed an initial 12-month treatment period entered a 12-month extension . In these men , both doses of vardenafil produced improvement in scores for the ' erectile function ' Domain of the International Index of Erectile Function , evident from week 4 and maintained through 2 years . Sexual Encounter Profile diary responses indicated that following treatment , penetration was achieved on 92 - 94 % of attempts and erections that lasted long enough for successful intercourse were achieved on 87 - 89 % of attempts . In response to the General Assessment Question , 90 - 92 % of patients reported improved erections with vardenafil . Most treatment-emergent events were mild and transient with no cardiovascular safety concerns . These results support the long-term efficacy , reliability and tolerability of vardenafil 10 and 20 mg in men with ED",
"BACKGROUND Sildenafil is a potent inhibitor of cyclic guanosine monophosphate hydrolysis [ corrected ] in the corpus cavernosum and therefore increases the penile response to sexual stimulation . We evaluated the efficacy and safety of sildenafil , administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic , psychogenic , and mixed causes . METHODS In a 24-week dose-response study , 532 men were treated with oral sildenafil ( 25 , 50 , or 100 mg ) or placebo . In a 12-week , flexible dose-escalation study , 329 different men were treated with sildenafil or placebo , with dose escalation to 100 mg based on efficacy and tolerance . After this dose-escalation study , 225 of the 329 men entered a 32-week , open-label extension study . We assessed efficacy according to the International Index of Erectile Function , a patient log , and a global-efficacy question . RESULTS In the dose-response study , increasing doses of sildenafil were associated with improved erectile function ( P values for increases in scores for questions about achieving and maintaining erections were sildenafil , the mean score for the question about achieving erections was 100 percent higher after treatment than at base line ( 4.0 vs. 2.0 of a possible score of 5 ) . In the last four weeks of treatment in the dose-escalation study , 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil , as compared with 22 percent for those receiving placebo ( P mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo ( P Headache , flushing , and dyspepsia were the most common adverse effects in the dose-escalation study , occurring in 6 percent to 18 percent of the men . Ninety-two percent of the men completed the 32-week extension study . CONCLUSIONS Oral sildenafil is an effective , well-tolerated treatment for men with erectile dysfunction",
"BACKGROUND Erectile dysfunction is a common , multi-factorial disorder . AIMS To evaluate the efficacy , tolerability and frequency of use of sildenafil citrate in men with mild to moderate erectile dysfunction of no established organic cause . METHOD This double-blind , r and omised , placebo-controlled , flexible-dose , two-way crossover study was conducted at four centres in the UK in 44 men with mild to moderate erectile dysfunction of no clinical ly obvious organic cause . The study included two 28-day treatment periods , during which time sildenafil or placebo ( 25 - 75 mg , based on efficacy ) was taken as required . RESULTS Compared with placebo , sildenafil was associated with increases in frequency of use , erections adequate for sexual intercourse and level of sexual satisfaction ( P: sildenafil stated they would use the treatment again compared with those receiving placebo ( P: discontinuations due to sildenafil treatment . CONCLUSIONS Sildenafil is effective and well tolerated in men with mild to moderate erectile dysfunction of no clinical ly identifiable organic cause",
"Abstract . Aims /hypothesis : Ninety percent of all men with diabetes have Type II ( non-insulin-dependent ) diabetes mellitus , and erectile dysfunction ( ED ) is common in this patient group . This study evaluated the effects of sildenafil on men with erectile dysfunction and Type II diabetes and compared the results with glycated haemoglobin concentrations and chronic diabetic complications . Methods : Patients ( mean age , 59 years ) in this double-blind , placebo-controlled trial were r and omised to sildenafil ( 25–100 mg ; n = 110 ) or matching placebo ( n = 109 ) for 12 weeks . Primary criteria for efficacy included questions 3 ( achieving an erection ) and 4 ( maintaining an erection ) from the International Index of Erectile Function ( IIEF , score range , 0–5 ) . Secondary outcome measures included a global efficacy question ( GEQ ) , patient event logs , a life satisfaction checklist , and the remaining IIEF questions . Results : After 12 weeks , the mean scores for questions 3 and 4 had improved significantly in patients receiving sildenafil ( 3.42 ± 0.23 and 3.35 ± 0.24 ) compared with placebo ( 1.86 ± 0.22 and 1.84 ± 0.23 ; p the GEQ score was higher in the sildenafil ( 64.6 % ) than the placebo group ( 10.5 % ) . Even when correlating efficacy with glycated haemoglobin concentrations ( ≤ 8.3 % or > 8.3 % , the median concentration found in this study ) or the number of diabetic complications ( 0 or ≥ 1 ) , the mean scores for the GEQ and questions 3 and 4 from the IIEF remained higher for all the sildenafil groups compared with the placebo groups ( p improving erectile dysfunction in men with Type II diabetes , even in patients with poor glycaemic control and chronic complications . [ Diabetologia ( 2001 ) 44 : 1296–1301",
"OBJECTIVE Depressed men commonly have erectile dysfunction , and men with erectile dysfunction are frequently depressed . Since the etiologic and modulatory relationships between depression and erectile dysfunction have been poorly characterized , a 12-week , r and omized , double-blind , placebo-controlled trial was conducted at 20 urologic clinics to evaluate the effects of sildenafil treatment in men with erectile dysfunction and mild-to-moderate comorbid depressive illness . METHOD Men ( N=152 , mean age=56 years ) with erectile dysfunction for > or = 6 months ( mean=5.7 years ) , a DSM-IV diagnosis of depressive disorder not otherwise specified , and a Hamilton Depression Rating Scale score > or = 12 ( mean at baseline=16.9 ) were r and omly assigned to flexible-dose treatment with sildenafil citrate or matching placebo . Interviewer-rated and self-report instruments were used to assess changes in sexual function , depressive symptoms , and quality of life . Conservative criteria were used to classify erectile dysfunction treatment response and nonresponse . RESULTS Sildenafil was strongly associated with erectile dysfunction treatment response . Fifty-eight men met the conservative criteria for response ( 48 given sildenafil , 10 given placebo ) , and 78 men did not respond ( 18 given sildenafil , 60 given placebo ) . Mean decreases of 10.6 and 2.3 in Hamilton depression scale scores were seen in treatment responders and nonresponders , respectively ; 76 % of treatment responders showed a > or = 50 % decline in Hamilton depression scale score versus 14 % of nonresponders . Quality of life was similarly improved in treatment responders . CONCLUSIONS Sildenafil is efficacious for erectile dysfunction in men with mild-to-moderate depressive illness . Improvement of erectile dysfunction is associated with marked improvement in depressive symptoms and quality of life",
"BACKGROUND Three inhibitors of phosphodiesterase 5 ( PDE5 ) are now available for the treatment of erectile dysfunction ( ED ) : sildenafil citrate , vardenafil , and tadalafil . Pharmacologic differences between these compounds may result in patient preferences for one over another and may influence treatment decisions made by the physician and patient . Therefore , clinical research is needed to investigate whether individual properties of the PDE5 inhibitors play a role in shaping patient preference . OBJECTIVES The goal of this study was to determine what proportion of ED patients currently taking sildenafil would , after a period of treatment with tadalafil , elect to resume treatment with sildenafil at the customary dose and what proportion would elect a switch to tadalafil 20 mg for a longer period . The tolerability of both treatments was also investigated . METHODS This was a short-term , multicenter , open-label , 1-way crossover trial conducted in Sweden and Italy . Eligible patients included men aged > or=18 years with a minimum 3-month history of ED who had been taking sildenafil at stable fixed doses of 25 , 50 , or 100 mg as needed for at least 6 weeks and up to 24 weeks . The study consisted of 6 phases : a 1-week screening phase , a 3-week sildenafil assessment phase , a 1-week washout phase , a 6-week tadalafil initiation phase , a 3-week tadalafil assessment phase , and a 6-month extension phase , during which patients received their treatment of choice free of charge . The primary outcome measure was the proportion of patients electing to take sildenafil or tadalafil during the extension phase . RESULTS Of 155 men enrolled , 147 ( 97.8 % ) completed the assessment phases of the trial . Of these 147 men , 133 ( 90.5 % ) elected to receive tadalafil in the 6-month extension phase and 14 ( 9.5 % ) elected to receive sildenafil ( P proportions preferring tadalafil to sildenafil were similar irrespective of age group ( > or=50 years , 92 % ; severity of ED ( mild , 95 % ; moderate , 88 % ; severe , 96 % ) , etiology of ED ( psychogenic , 94 % ; organic , 91 % ; mixed , 87 % ) , and sildenafil dose at study entry ( 50 mg , 90 % ; 100 mg , 89 % ) . Both medications were well tolerated . The most common treatment-emergent adverse events occurring in > or=2 % of patients during the tadalafil assessment phase included headache ( 4.8 % ) , nasal congestion ( 4.1 % ) , dyspepsia ( 3.4 % ) , flushing ( 2.7 % ) , back pain ( 2.0 % ) , diarrhea ( 2.0 % ) , and nausea ( 2.0 % ) ; the most common treatment-emergent adverse events during the sildenafil assessment phase were flusing ( 7.1 % ) , nasal congestion ( 6.5 % ) , headache ( 4.5 % ) , and nasopharyngitis ( 3.2 % ) . CONCLUSIONS In this short-term , open-label study , patients who were currently taking sildenafil for ED and then received tadalafil preferred to continue oral therapy with tadalafil over sildenafil by a ratio of approximately 9:1 . Although the study sought to mimic the experience of actual patients receiving treatment for ED , the results are subject to potential limitations due to the design of the study , which included differences in dosing instructions and dosages for sildenafil and tadalafil . Both sildenafil and tadalafil were well tolerated",
"OBJECTIVES To evaluate the efficacy , safety , and tolerability of sildenafil in men with broad-spectrum erectile dysfunction ( ED ) , with reference to age-matched healthy control subjects . METHODS One hundred eleven patients were enrolled in a r and omized , double-blind , placebo-controlled , parallel-group , 12-week , flexible-dose study . Efficacy assessment s included the International Index of Erectile Function ( IIEF ) , a global assessment question , and patient event log data . In a separate , nontreatment study , 109 control subjects also completed the IIEF . RESULTS Mean IIEF scores at baseline were significantly lower for patients with ED than for control subjects without a history of ED . After treatment , mean IIEF scores for patients receiving sildenafil approached values observed in control subjects and were significantly higher than mean scores for patients receiving placebo ( P Sildenafil was well tolerated , with no discontinuations because of adverse events . CONCLUSIONS The results indicate that sildenafil , an effective oral therapy for the treatment of broad-spectrum ED , is associated with a near normalization of patient erectile function",
"OBJECTIVES To examine the therapeutic effects of tadalafil on erectile dysfunction ( ED ) at 24 and 36 hours after dosing . METHODS A multicenter , r and omized , double-blind , placebo-controlled , parallel-group study of 348 men ( mean age 57 years ) with ED was conducted in Europe and the United States . Patients were stratified by baseline severity of ED using the Erectile Function domain score of the International Index of Erectile Function and then r and omly allocated within the severity group to receive tadalafil 20 mg ( n = 175 ) or placebo ( n = 173 ) . Subsequently , participants were r and omly assigned to two 4-week treatment intervals , during which they were requested to attempt sexual intercourse approximately 24 or 36 hours after tadalafil or placebo dosing . The primary outcome measure was the proportion of successful sexual intercourse attempts ( completed to ejaculation ) according to patient self-report using the Sexual Encounter Profile diary . RESULTS Of the 348 patients , 327 ( 94 % ) completed the trial ( 163 of 175 in the tadalafil group and 164 of 173 in the placebo group ) . Thirty-six hours after tadalafil dosing , 59.2 % of intercourse attempts were successful versus 28.3 % in the placebo group ( P proportion of successful intercourse attempts at approximately 24 hours after treatment was also significantly greater with tadalafil ( 52.9 % ) than with placebo ( 29.1 % ; P Tadalafil was well tolerated . The incidences of four treatment-emergent adverse events were significantly greater in the tadalafil group than in the placebo group ( all P headache , flushing , dyspepsia , and myalgia . CONCLUSIONS Tadalafil 20 mg is an effective and well-tolerated treatment for ED that has a period of responsiveness of up to 36 hours",
"OBJECTIVE Tadalafil ( Cialis ) is an inhibitor of phosphodiesterase type 5 , which mediates relaxation of vascular smooth muscle in the corpus cavernosum thus facilitating erection . The purpose of this multicentre , r and omized , double-blind , parallel group , placebo-controlled study was to evaluate efficacy and treatment satisfaction of on-dem and Cialis in men with mild-to-severe erectile dysfunction ( ED ) . METHODS Following a 4-week treatment-free run in period , patients stratified into three severity groups by the International Index of Erectile Function ( IIEF ) Erectile Function ( EF ) domain score were r and omized to receive either placebo or Cialis 20 mg taken on dem and over a 12-week period . Efficacy endpoints were change from baseline in IIEF EF domain scores , responses to Sexual Encounter Profile diary ( SEP ) questions , and responses to the Global Assessment Questions ( GAQ ) . Treatment satisfaction was evaluated using the Erectile Dysfunction Inventory of Treatment Satisfaction ( EDITS ) question naire in two of seven participating countries where vali date d translations were available . RESULTS Of the 443 men who entered the trial , 409 ( mean age , 52 years ) formed the intent-to-treat population . Mean baseline demographics and ED severity measures were balanced between treatment groups except for a higher percentage of patients naïve to sildenafil in the tadalafil group compared to placebo ( 50 % versus 36 % ) . The percentage of patients in each IIEF EF severity class ( mild , moderate and severe ) was 47 % , 30 % and 23 % for placebo patients and 48 % , 29 % and 23 % for tadalafil patients , respectively . Tadalafil was significantly superior to placebo on all primary efficacy measures ( IIEF EF domain scores , SEP15 , GAQ1 ; p tadalafil patients achieved a normal IIEF EF domain score at endpoint compared to 16 % of placebo patients ( p 185 patients completing the EDITS question naire ( 137 receiving Cialis and 48 receiving placebo ) , tadalafil-treated patients had a median EDITS score of 84 ( 95%CI 80 , 86 ) , which was significantly higher than the median score for placebo-treated patients of 41 ( 95%CI 32 , 59 ; p proportion of patients satisfied with treatment ( defined as final EDITS score greater than 50 ) was 87 % for the tadalafil-treated group and 46 % for the placebo-treated group ( p . Adverse events were significantly more common with tadalafil than placebo ( p headache ( 7.2 % versus 1.9 % ) and flushing ( 4.6 % versus 0 % ) . One patient discontinued tadalafil treatment due to back pain . CONCLUSION In men with mild-to-severe ED , tadalafil 20 mg significantly improves erectile function , demonstrates superior treatment satisfaction relative to placebo , and is well tolerated . This is the first study to yield efficacy data on tadalafil in an Eastern European population of men with erectile dysfunction , and the first to measure satisfaction with the EDITS question naire in any study population of men with this condition using tadalafil",
"CONTEXT Sexual dysfunction is a common adverse effect of antidepressants that frequently results in treatment noncompliance . OBJECTIVE To assess the efficacy of sildenafil citrate in men with sexual dysfunction associated with the use of selective and nonselective serotonin reuptake inhibitor ( SRI ) antidepressants . DESIGN , SETTING , AND PATIENTS Prospect i ve , parallel-group , r and omized , double-blind , placebo-controlled trial conducted between November 1 , 2000 , and January 1 , 2001 , at 3 US university medical centers among 90 male out patients ( mean [ SD ] age , 45 [ 8 ] years ) with major depression in remission and sexual dysfunction associated with SRI antidepressant treatment . INTERVENTION Patients were r and omly assigned to take sildenafil ( n = 45 ) or placebo ( n = 45 ) at a flexible dose starting at 50 mg and adjustable to 100 mg before sexual activity for 6 weeks . MAIN OUTCOME MEASURES The primary outcome measure was score on the Clinical Global Impression-Sexual Function ( CGI-SF ) ; secondary measures were scores on the International Index of Erectile Function , Arizona Sexual Experience Scale , Massachusetts General Hospital-Sexual Functioning Question naire , and Hamilton Rating Scale for Depression ( HAM-D ) . RESULTS Among the 90 r and omized patients , 93 % ( 83/89 ) of patients treated per protocol took at least 1 dose of study drug and 85 % ( 76/89 ) completed week 6 end-point assessment s with last observation carried forward analyses . At a CGI-SF score of 2 or lower , 54.5 % ( 24/44 ) of sildenafil compared with 4.4 % ( 2/45 ) of placebo patients were much or very much improved ( P Erectile function , arousal , ejaculation , orgasm , and overall satisfaction domain measures improved significantly in sildenafil compared with placebo patients . Mean depression scores remained consistent with remission ( HAM-D score sildenafil effectively improved erectile function and other aspects of sexual function in men with sexual dysfunction associated with the use of SRI antidepressants . These improvements may allow patients to maintain adherence with effective antidepressant treatment",
"PURPOSE To determine the efficacy of sildenafil citrate ( Viagra ) in patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy ( 3D-CRT ) for prostate cancer . METHODS AND MATERIAL S 406 patients with complaints of erectile dysfunction and who completed radiation at least 6 months before the study were approached by mail . 3D-CRT had been delivered ( mean dose 68 Gy ) . Sixty patients were included and entered a double-blind , placebo-controlled , cross-over study lasting 12 weeks . They received during 2 weeks 50 mg of sildenafil or placebo ; at Week 2 the dose was increased to 100 mg in case of unsatisfactory erectile response . At Week 6 , patients crossed over to the alternative treatment . Data were collected using the International Index of Erectile Function ( IIEF ) question naire , and side effects were recorded . RESULTS Mean age was 68 years . All patients completed the study . For most questions of the IIEF question naire there was a significant increase in mean scores from baseline with sildenafil , but not with placebo . Ninety percent of the patients needed a dose adjustment to 100 mg sildenafil . Side effects were mild or moderate . CONCLUSION Sildenafil is well tolerated and effective in improving erectile function of patients with ED after 3D-CRT for prostate cancer",
" IC351 ( Cialis ™ ) is a selective inhibitor of PDE5 . The efficacy and safety of on-dem and dosing of IC351 in men with erectile dysfunction was assessed in a multicenter , double-blind , placebo-controlled study . One hundred seventy-nine men ( mean age : 56 y ) were r and omized to receive placebo or IC351 at doses of 2 , 5 , 10 or 25 mg , taken on dem and over a 3-week period . The primary endpoints were change from baseline in responses to Questions 3 ( Q3 ) and 4 ( Q4 ) of the International Index of Erectile Function ( IIEF ) . IC351 significantly improved IIEF Q3 scores at all doses vs placebo ( P≤0.003 ) . IC351 also significantly improved IIEF Q4 scores in all but the 2 mg group ( P≤0.0003 ) . No significant changes in laboratory values , ECGs , or blood pressure were observed . The most common adverse events were headache and dyspepsia . The conclusion of this study was that on-dem and IC351 at doses up to 25 mg was well tolerated and significantly improved erectile function ",
"The efficacy and safety of oral sildenafil citrate for the treatment of erectile dysfunction ( ED ) were assessed in a 12-week placebo-controlled study . Men with ED of organic , psychogenic , or mixed aetiology were r and omised to placebo ( n = 166 ) or 50 mg sildenafil ( n = 163 ) , with adjustment to 100 mg or 25 mg based on efficacy and tolerability . Efficacy assessment s included a global efficacy question , event log data , and an optional partner question naire . At the end of the study , improved erections were reported by 74 % of patients receiving sildenafil versus 16 % for placebo ( p attempts at sexual intercourse were successful for all patients ( responders and non-responders ) receiving sildenafil versus 20 % for placebo ( p mean number of successful attempts per month was 5.9 for patients receiving sildenafil versus 1.5 for those receiving placebo ( p adverse events -- headache , flushing , and dyspepsia -- were generally mild to moderate in nature and rarely ( sildenafil is an effective , reliable and well-tolerated treatment for ED of organic , psychogenic or mixed aetiology",
"OBJECTIVES To determine the efficacy and safety of fixed-dose oral sildenafil in patients with erectile dysfunction ( ED ) of various etiologies . METHODS In a 12-week , double-blind , r and omized , placebo-controlled , fixed-dose study , 514 men ( mean age 56 years ) with ED were r and omized to receive 25 , 50 , or 100 mg of sildenafil or placebo . The primary etiology of ED was determined to be organic in 32 % of men , psychogenic in 25 % , or mixed in 43 % . Sildenafil or placebo was taken in the home setting approximately 1 hour before sexual activity , not more than once daily . Efficacy was determined by responses to question 3 ( ability to achieve an erection ) and question 4 ( ability to maintain an erection ) of the 15-item International Index of Erectile Function ( IIEF ) . Other measures of efficacy included the five sexual function domains of the IIEF , a global efficacy question , event log data , and a partner question naire . RESULTS Sildenafil significantly increased patients ' ability to achieve and maintain erections ( P efficacy increasing with increasing dose . Significant improvements were also observed in the IIEF domains for erectile function , orgasmic function , intercourse satisfaction , and overall sexual satisfaction ( P sildenafil improved their erections was significantly greater ( 67 % to 86 % ) than that with placebo treatment ( 24 % , P proportion of successful attempts at sexual intercourse also increased significantly with sildenafil treatment ( P tolerated at the three doses studied . CONCLUSIONS Oral sildenafil is an effective , well-tolerated treatment for ED of various etiologies",
"PURPOSE We evaluate the efficacy and safety of tadalafil , taken as needed , in men with mild to severe erectile dysfunction ( ED ) and assess sexual intercourse attempt patterns . MATERIAL S AND METHODS In this multicenter , double-blind , placebo controlled , parallel study conducted in the United States and Puerto Rico 207 men with ED were r and omized to placebo or 20 mg tadalafil for 12 weeks . The primary efficacy variables were changes from baseline in the mean International Index of Erectile Function erectile function domain score and mean per patient percentage of \" yes \" responses to Sexual Encounter Profile ( SEP ) diary questions 2 ( successful penetration ) and 3 ( successful intercourse ) . The Global Assessment Question was a secondary end point and post hoc analyses on sexual intercourse attempt patterns were conducted . RESULTS Men treated with tadalafil compared with placebo reported greater mean changes from baseline on the erectile function domain score ( 9.3 vs 0.3 with placebo , p patient percentage of successful penetration ( SEP question 2 , 31.6 % vs 2.3 % with placebo , p successful intercourse attempts ( SEP question 3 , 43.6 % vs 3.5 % with placebo , p percentage of successful intercourse attempts during treatment was higher for tadalafil than placebo ( 67.6 % vs 24.1 % , respectively , p successful intercourse attempts occurred between 4 and 36 hours after taking tadalafil . Of the men treated with tadalafil 82.8 % reported improved erections versus 19.6 % taking placebo ( Global Assessment Question , p headache ( 15.7 % vs 6.3 % with placebo ) , back pain ( 8.8 % vs 0 % ) , and dyspepsia ( 7.5 % vs 0 % ) . CONCLUSIONS Tadalafil ( 20 mg ) significantly improved erectile function and patients did not closely temporally link sexual intercourse attempts with taking tadalafil . Tadalafil was also well tolerated in both groups of men with mild to severe ED",
"PURPOSE More than one-third of men may experience erectile dysfunction ( ED ) after nerve sparing radical retropubic prostatectomy . The efficacy and safety of vardenafil , a potent , selective , phosphodiesterase 5 inhibitor , was assessed for the treatment of ED after radical prostatectomy . MATERIAL S AND METHODS In this double-blind study 440 men with ED after nerve sparing radical prostatectomy were r and omized to take placebo , or 10 or 20 mg vardenafil . Efficacy was measured after 12 weeks using the erectile function domain of the International Index of Erectile Function , diary questions measuring vaginal penetration and intercourse success rates , and a global assessment question ( GAQ ) on erection . RESULTS Of the intent to treat population 70 % had severe ED ( erectile function less than 11 ) at baseline . After 12 weeks both vardenafil doses were significantly superior to placebo ( p Improved erections ( based on GAQ ) were reported by 65.2 % and 59.4 % of patients on 20 and 10 mg vardenafil , respectively , and by only 12.5 % of patients on placebo ( p positive GAQ responses were reported by 71.1 % and 59.7 % of patients on 20 and 10 mg vardenafil , respectively , versus 11.5 % of those on placebo ( p average intercourse success rate per patient receiving 20 mg vardenafil was 74 % in men with mild to moderate ED and 28 % in men with severe ED , compared to 49 % and 4 % for placebo , respectively . Few adverse events were observed . They were generally mild to moderate headache , flushing and rhinitis . CONCLUSIONS In men with severe ED after nerve sparing radical retropubic prostatectomy , vardenafil significantly improved key indices of erectile function",
"CONTEXT Erectile dysfunction is common in men with diabetes . OBJECTIVE To assess the efficacy and safety of oral sildenafil citrate in the treatment of erectile dysfunction in men with diabetes . DESIGN A multicenter , r and omized , double-blind , placebo-controlled , flexible dose-escalation study conducted May through November 1996 . SETTING Patients ' homes and 19 clinical practice centers in the United States . PATIENTS A total of 268 men ( mean age , 57 years ) with erectile dysfunction ( mean duration , 5.6 years ) and diabetes ( mean duration , 12 years ) . INTERVENTIONS Patients were r and omized to receive sildenafil ( n = 136 ) or placebo ( n = 132 ) as needed , but not more than once daily , for 12 weeks . Patients took the study drug or placebo 1 hour before anticipated sexual activity . The starting dose of sildenafil citrate was 50 mg , with the option to adjust the dose to 100 mg or 25 mg based on efficacy and tolerability , to be taken as needed . MAIN OUTCOME MEASURES Self-reported ability to achieve and maintain an erection for sexual intercourse according to the International Index of Erectile Function and adverse events . RESULTS Two hundred fifty-two patients ( 94 % ) completed the study ( 131/136 in the sildenafil group , 121/132 in the placebo group ) . By intention-to-treat analysis , at 12 weeks , 74 ( 56 % ) of 131 patients in the sildenafil group reported improved erections compared with 13 ( 10 % ) of 127 patients in the placebo group ( P proportion of men with at least 1 successful attempt at sexual intercourse was 61 % ( 71/ 117 ) for the sildenafil group vs 22 % ( 25/114 ) for the placebo group ( P Adverse events related to treatment were reported for 22 ( 16 % ) of 136 patients taking sildenafil and 1 ( 1 % ) of 132 patients receiving placebo . The most common adverse events were headache ( 11 % sildenafil , 2 % placebo ) , dyspepsia ( 9 % sildenafil , 0 % placebo ) , and respiratory tract disorder ( 6 % sildenafil , 2 % placebo ) , predominantly sinus congestion or drainage . The incidence of cardiovascular adverse events was comparable for both groups ( 3 % sildenafil , 5 % placebo ) . CONCLUSION Oral sildenafil is an effective and well-tolerated treatment for erectile dysfunction in men with diabetes",
"Objective : To evaluate the efficacy and safety of 50-mg doses of sildenafil during a 28-day period in patients with erectile dysfunction caused by spinal cord injury ( cord level range , T6 through L5 ) . Background : Sildenafil is an orally active , potent , and selective inhibitor of phosphodiesterase type 5 , an important regulator of cyclic guanosine monophosphate in the human corpus cavernosum . Methods : To be included in this double-blind , placebo-controlled study , all patients had to be able to achieve at least a partial reflexogenic erectile response to penile vibratory stimulation . The study utilized a single triangular sequential trial design . A total of 27 patients were r and omized to receive 50 mg of sildenafil or placebo , taken orally as required ( not more than once daily ) approximately 1 hour before sexual activity . Results : After 28 days of treatment , nine of 12 patients ( 75 % ) on sildenafil and one of 14 patients ( 7 % ) on placebo reported that treatment had improved their erections ( p = 0.0043 ) . Furthermore , eight of 12 patients ( 67 % ) on sildenafil and two of 13 patients ( 15 % ) on placebo indicated that they wished to continue treatment ( p = 0.018 ) . A significant improvement in satisfaction with their sex life was reported by patients taking sildenafil ( p = 0.012 ) . No patients discontinued treatment due to adverse events . Conclusion : Oral sildenafil , taken as required ( not more than once daily ) , significantly improves the quality of erections and satisfaction with sex life in men with erectile dysfunction caused by a spinal cord injury between T6 and L5"
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The aim of the present systematic review is to present an overview of the evidence linking atrial fibrillation ( AF ) , inflammation and oxidative stress , with emphasis on the potential of statins to decrease the incidence of different types of AF , including new-onset AF , after electrical cardioversion ( EC ) and after cardiac surgery . Observational and clinical trials have studied the impact of statin therapy on new-onset , post-EC or postoperative AF . Data from different observational trials have shown that treatment with statins significantly reduces the incidence of new-onset AF in the primary and secondary prevention . The data are insufficient to recommend the use of statins before EC . Finally , perioperative statin therapy may represent an important non-antiarrhythmic adjunctive therapeutic strategy for the prevention of postoperative AF
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"Background —We investigated whether serum concentration of carboxy-terminal propeptide of procollagen type I ( PIP ) , a marker of collagen type I synthesis , can be used to assess the ability of antihypertensive treatment to regress myocardial fibrosis in hypertensive patients . Methods and Results —The study was performed in 37 patients with essential hypertension and hypertensive heart disease . After r and omization , 21 patients were assigned to losartan and 16 patients to amlodipine treatment . At baseline and after 12 months , right septal endomyocardial biopsies were performed to quantify collagen volume fraction ( CVF ) on picrosirius red – stained sections with an automated image- analysis system . Serum PIP was measured by specific radioimmunoassay . Nineteen patients in the losartan group and 11 in the amlodipine group finished the study . Time-course changes in blood pressure during treatment were similar in the 2 groups of patients . In losartan-treated patients , CVF decreased from 5.65±2.03 % to 3.96±1.46 % ( P Neither CVF or PIP changed significantly in amlodipine-treated patients . CVF was directly correlated with PIP ( r = 0.44 , P regress fibrosis in hypertensives with biopsy-proven myocardial fibrosis is independent of its antihypertensive efficacy . Our data also suggest that blockade of the angiotensin II type 1 receptor is associated with inhibition of collagen type I synthesis and regression of myocardial fibrosis in hypertensives . Thus , determination of serum PIP may be useful to assess the cardioreparative properties of antihypertensive treatment in hypertensives",
"Epidemiologic studies have shown that hypercholesterolemia is associated with increased left ventricular ( LV ) mass . Free radicals have been shown to be increased in hyperlipidemic patients . This study sought to determine whether pravastatin administration can affect LV mass in patients with untreated total cholesterol ≥240 mg/dl by reducing 8-iso-prostagl and in F2&agr ; concentrations , a reliable marker of oxidant injury . Fifty patients were r and omly assigned to one of two groups , one with ( n = 25 ) and one without ( n = 25 ) treatment with pravastatin ( 10 or 20 mg/d ) . A group of normolipidemic control subjects was used for comparison . Echocardiograms were performed at baseline and after 6 months of therapy . Hyperlipidemic patients showed significant increases in LV mass index at baseline compared with the normolipidemic control group ( 125 ± 8 vs. 107 ± 5 g/m2 , p 0.0001 ) . Pravastatin treatment significantly reduced plasma total and low-density lipoprotein cholesterol levels , as well as increased high-density lipoprotein cholesterol . After 6 months of therapy with pravastatin , the magnitude of LV mass regression correlated with the magnitude of inhibition of free radical formation assessed by 8-iso-prostagl and in F2&agr ; formation ( r = 0.67 , p = 0.002 ) . Multivariate analysis revealed that regression of LV mass was significantly correlated only with the changes in 8-iso-prostagl and in F2&agr ; ( p , pravastatin may have an additional effect of reducing LV mass – independent lipid-lowering effects , possibly through attenuation of free radical formation",
"Background — Atrial fibrillation ( AF ) after cardiac surgery is associated with increased risk of complications , length of stay , and cost of care . Observational evidence suggests that patients who have undergone previous statin therapy have a lower incidence of postoperative AF . We tested this observation in a r and omized , controlled trial . Methods and Results — Two hundred patients undergoing elective cardiac surgery with cardiopulmonary bypass , without previous statin treatment or history of AF , were enrolled . Patients were r and omized to atorvastatin ( 40 mg/d , n=101 ) or placebo ( n=99 ) starting 7 days before operation . The primary end point was incidence of postoperative AF ; secondary end points were length of stay , 30-day major adverse cardiac and cerebrovascular events , and postoperative C-reactive protein ( CRP ) variations . Atorvastatin significantly reduced the incidence of AF versus placebo ( 35 % versus 57 % , P=0.003 ) . Accordingly , length of stay was longer in the placebo versus atorvastatin arm ( 6.9±1.4 versus 6.3±1.2 days , P=0.001 ) . Peak CRP levels were lower in patients without AF ( P=0.01 ) , irrespective of r and omization assignment . Multivariable analysis showed that atorvastatin treatment conferred a 61 % reduction in risk of AF ( odds ratio 0.39 , 95 % confidence interval 0.18 to 0.85 , P=0.017 ) , whereas high postoperative CRP levels were associated with increased risk ( odds ratio 2.0 , 95 % confidence interval 1.2 to 7.0 , P=0.01 ) . The incidence of major adverse cardiac and cerebrovascular events at 30 days was similar in the 2 arms . Conclusions — Treatment with atorvastatin 40 mg/d , initiated 7 days before surgery , significantly reduces the incidence of postoperative AF after elective cardiac surgery with cardiopulmonary bypass and shortens hospital stay . These results may influence practice patterns with regard to adjuvant pharmacological therapy before cardiac surgery",
"BACKGROUND Cholesterol lowering reduces coronary events . One mechanism could be improvement of endothelial function . In line with this hypothesis , this study investigates whether cholesterol reduction can result in rapid improvement of endothelial function after acute coronary syndromes . METHODS AND RESULTS Patients with acute myocardial infa rct ion or unstable angina and total cholesterol levels at admission > /=5.2 mmol/L or LDL > /=3.4 mmol/L were r and omized to placebo ( n=30 ) or pravastatin 40 mg daily ( n=30 ) for 6 weeks . Brachial ultrasound was used to measure endothelium-dependent flow-mediated dilatation ( FMD ) and response to endothelium-independent nitroglycerin . Changes in the levels of markers of platelet activation , coagulation factors , and plasma endothelin levels were also assessed . Total and LDL cholesterol levels were similar at admission and before r and omization in both groups . With pravastatin , but not with placebo , they decreased by 23 % ( P FMD was unchanged with placebo , 5.43+/-0.74 % ( mean+/-SEM ) to 5.84+/-0.81 % , but increased with pravastatin , 4.93+/-0.81 % to 7.0+/-0.79 % ( P=0.02 ) , representing a 42 % relative increase . Responses to nitroglycerin were similar during the time course of the study in the 2 groups . Markers of platelet activity , coagulation factors , and endothelin levels were not affected by pravastatin . CONCLUSIONS Cholesterol reduction with pravastatin initiated early after acute coronary syndromes rapidly improves endothelial function after 6 weeks of therapy",
"Background —Left ventricular hypertrophy ( LVH ) is a common risk factor for cardiovascular mortality . Causes other than hypertension have not previously been investigated longitudinally . The aim of the present study was to determine hemodynamic , metabolic , and psychosocial predictors at 50 years of age for the prevalence of echocardiographic LVH and geometric subtypes at age 70 by use of a large sample of men from the general population followed up for 20 years . Methods and Results —In 1970 to 1973 , all men born from 1920 to 1924 and residing in Uppsala County , Sweden , were invited to participate in a health survey aim ed at identifying risk factors for cardiovascular disease . At a reinvestigation 20 years later , echocardiographic left ventricular mass index was determined in 475 subjects . A 1-SD increase in body mass index , systolic or diastolic blood pressure , fasting LDL/HDL cholesterol , serum triglycerides , or the serum cholesterol ester proportion of several saturated fatty acids or oleic acid at age 50 significantly increased the odds of having LVH at age 70 by 27 % to 41 % , whereas an increase in linoleic acid proportion was protective . Almost all metabolic predictors were independent of ischemic heart disease , valvular disease , and use of antihypertensive medication at age 70 . Conclusions —Dyslipidemia and indices of a low dietary intake of linoleic acid and high intake of saturated and monounsaturated fats , as well as hypertension and obesity , at age 50 predicted the prevalence of LVH 20 years later in this prospect i ve longitudinal cohort study , thereby suggesting that lipids may be important in the origin of LVH",
"Atrial fibrillation ( AF ) , the most common chronic arrhythmia , increases the risk of stroke and is an independent predictor of mortality . Available pharmacological treatments have limited efficacy . Once initiated , AF tends to self-perpetuate , owing in part to electrophysiological remodeling in the atria ; however , the fundamental mechanisms underlying this process are still unclear . We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation ; we have now tested the hypothesis that these events participate in both pacing-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery . In chronically instrumented dogs , we found that rapid ( 400 min−1 ) atrial pacing was associated with attenuation of the atrial effective refractory period ( ERP ) . Treatment with ascorbate , an antioxidant and peroxynitrite decomposition catalyst , did not directly modify the ERP , but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing . Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration ( a biomarker of peroxynitrite formation ) . Oral ascorbate supplementation attenuated both of these changes . To evaluate the clinical significance of these observations , supplemental ascorbate was given to 43 patients before , and for 5 days following , cardiac bypass graft surgery . Patients receiving ascorbate had a 16.3 % incidence of postoperative AF , compared with 34.9 % in control subjects . In combination , these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia . The full text of this article is available at http://www.circresaha.org",
"OBJECTIVE It has been recently reported that AF is associated with tissue inflammation . Statins reduce C-reactive protein ( CRP ) levels . However , the effect of statin on atrial fibrillation ( AF ) is unclear . The purpose of the present study was to evaluate the effect of statin on AF in a canine sterile pericarditis model . METHODS Sterile pericarditis was created in 20 dogs r and omly assigned to two groups : a control group ( 10 dogs ) and an atorvastatin treatment group ( 10 dogs ) . Atorvastatin was administered orally ( 2 mg/kg/day ) beginning 1 week before the operation until the end of the study . Before and 2 days after the operation , CRP levels , the duration of induced AF , the atrial effective refractory period ( AERP ) , and intra-atrial conduction time were determined . RESULTS Before the operation , there were no significant differences in any of the parameters between the two groups . On the second postoperative day , the atorvastatin group had a lower CRP level ( 7.6+/-0.5 versus 11.7+/-1.3 mg/dl , P AF duration ( 177+/-57 versus 534+/-189 s , P longer AERP ( 138+/-6 versus 130+/-6 ms , P intra-atrial conduction time ( 46+/-3 versus 51+/-5 ms , P Atorvastatin can prevent maintenance of AF by inhibiting inflammation in the canine sterile pericarditis model . Atorvastatin may thus be a novel therapeutic agent for AF",
"Increased angiotensin II ( Ang II ) sensitivity predisposes to hypertension and plaque instability . Raised low-density lipoprotein cholesterol ( LDL-c ) may increase Ang II sensitivity , but evidence in humans for this effect of LDL-c is limited . In 28 , healthy , nonsmoking subjects , aged 30±8 years , with familial hypercholesterolemia , we determined the difference in infusion rate of Ang II and norepinephrine required to increase systolic blood pressure by 20 mm Hg ( Pd-20 ) after 4 weeks of placebo and fluvastatin 80 mg daily in a r and omized , double-blind , placebo-controlled , crossover study . Before infusions were started , fasting blood sample s were taken to measure lipids . After 4 weeks of placebo , the mean LDL-c concentration was 6.3±1.4 mmol/L. The average decrease of LDL-c was 1.7±0.7 mmol/L after 4 weeks of fluvastatin ( P The mean Pd-20 for Ang II increased by 1.28 ng/kg per minute ( 95 % CI , 2.05 to 0.50 ; P=0.002 ) on fluvastatin , corresponding with a 26 % decrease in Ang II sensitivity . Ang II sensitivity , however , remained increased compared with normocholesterolemic controls . The Pd-20 values for norepinephrine were unaffected by fluvastatin . The present study in healthy , young subjects with isolated hypercholesterolemia shows an increased sensitivity to Ang II that partly can be restored by LDL-c – lowering therapy . These findings indicate that LDL-c levels directly influence Ang II sensitivity",
"This study investigated the correlation between an elevated white blood cell ( WBC ) count as a marker of inflammation and the development of atrial fibrillation ( AF ) after cardiac surgery . WBC counts were prospect ively followed in 181 consecutive patients who underwent coronary bypass or cardiac valve surgery to determine if a baseline or postoperative WBC count elevation is an independent predictor of postoperative AF",
"BACKGROUND Atrial fibrillation ( AF ) after coronary artery bypass surgery ( CABG ) is the most common sustained arrhythmia . Its pathophysiology is unclear , and its prevention and management remain suboptimal . The aim of this prospect i ve study was to determine the current incidence of AF , identify its clinical predictors , and examine its impact on re source utilization . METHODS AND RESULTS Over a 12-month period ending July 31 , 1994 , a CABG procedure was performed on 570 consecutive patients ( age range , 32 to 87 years ; median age , 67 years ; 232 [ 41 % ] were > or = 70 years ; 175 [ 31 % ] were women ; 173 [ 30 % ] were diabetics ; 364 [ 65 % ] required nonelective surgery ; 86 [ 15 % ] had had a prior CABG ; and 86 [ 15 % ] had had prior percutaneous transluminal coronary angioplasty ) . AF occurred in 189 patients ( 33 % ) . The median age for patients with AF was 71 years compared with 66 for patients without ( P = .0001 ) . Multivariate logistic regression analysis ( odds ratio , + /- 95 % CI , P value ) was used to identify the following independent predictors of postoperative AF : increasing age ( age 70 to 80 years [ OR = 2 ; CI , 1.3 to 3 ; P = .002 ] , age > 80 years [ OR = 3 ; CI , 1.6 to 5.8 ; P = .0007 ] ) , male gender ( OR = 1.7 ; CI , 1.1 to 2.7 ; P = .01 ) , hypertension ( OR = 1.6 ; CI , 1.0 to 2.3 ; P = .03 ) , need for an intraoperative intraaortic balloon pump ( OR = 3.5 ; CI , 1.2 to 10.9 ; P = .03 ) , postoperative pneumonia ( OR = 3.9 ; CI , 1.3 to 11.5 ; P = .01 ) , ventilation for > 24 hours ( OR = 2 ; CI , 1.3 to 3.2 ; P = .003 ) , and return to the intensive care unit ( OR = 3.2 ; CI , 1.1 to 8.8 ; P = .03 ) . The mean length of hospital stay after surgery was 15.3 + /- 28.6 days for patients with AF compared with 9.3 + /- 19.6 days for patients without AF ( P = .001 ) . The adjusted length of hospital stay attributable to AF was 4.9 days , corresponding to > or = $ 10 055 in hospital charges . CONCLUSIONS AF remains the most common complication after CABG and consequently is a drain on hospital re sources . Concerted efforts to reduce the incidence of AF and the associated increased length of stay would result in substantial cost saving and decrease patient morbidity",
"OBJECTIVES The aim of this study was to assess the efficacy of preoperative and postoperative treatment with n-3 polyunsaturated fatty acids ( PUFAs ) in preventing the occurrence of atrial fibrillation ( AF ) after coronary artery bypass graft surgery ( CABG ) . BACKGROUND Postoperative AF is a common complication of CABG . There is growing clinical evidence that PUFAs have cardiac antiarrhythmic effects . METHODS A total of 160 patients were prospect ively r and omized to a control group ( 81 patients , 13 female , 64.9 + /- 9.1 years ) or PUFAs 2 g/day ( 79 patients , 11 female , 66.2 + /- 8.0 years ) for at least 5 days before elective CABG and until the day of discharge from the hospital . The primary end point was the development of AF in the postoperative period . The secondary end point was the hospital length of stay after surgery . All end points were independently adjudicated by two cardiologists blinded to treatment assignment . RESULTS The clinical and surgical characteristics of the patients in the two groups were similar . Postoperative AF developed in 27 patients of the control group ( 33.3 % ) and in 12 patients of the PUFA group ( 15.2 % ) ( p = 0.013 ) . There was no significant difference in the incidence of nonfatal postoperative complications , and postoperative mortality was similar in the PUFA-treated patients ( 1.3 % ) versus controls ( 2.5 % ) . After CABG , the PUFA patients were hospitalized for significantly fewer days than controls ( 7.3 + /- 2.1 days vs. 8.2 + /- 2.6 days , p = 0.017 ) . CONCLUSIONS This study first demonstrates that PUFA administration during hospitalization in patients undergoing CABG substantially reduced the incidence of postoperative AF ( 54.4 % ) and was associated with a shorter hospital stay",
"OBJECTIVES We sought to test the hypothesis that C-reactive protein ( CRP ) can predict the recurrence of atrial fibrillation ( AF ) after successful electrical cardioversion ( CV ) . BACKGROUND In patients with AF , CRP levels are predictive of immediate failure of CV . METHODS We prospect ively measured high-sensitivity CRP in 67 patients with AF or atrial flutter who underwent successful electrical CV . RESULTS At one-month follow-up , 22 patients ( 33 % ) had recurrence of their arrhythmia . Arrhythmia recurrence was associated with significantly higher pre-CV CRP levels ( odds ratio [ OR ] 1.84 ; 95 % confidence interval [ CI ] 1.14 to 2.98 ; p = 0.013 ) even after adjusting for age ( OR 2.22 ; 95 % CI 1.25 to 3.93 ; p = 0.006 ) , for gender ( OR 1.89 ; 95 % CI 1.16 to 3.09 ; p = 0.011 ) , or duration of arrhythmia ( OR 1.86 ; 95 % CI 1.13 to 3.07 ; p = 0.015 ) . On multivariate analysis , CRP was the only independent predictor of arrhythmia recurrence ( OR 2.19 ; 95 % CI 1.05 to 4.55 ; p = 0.036 ) . CONCLUSIONS Our data suggest that high levels of CRP are associated with an increased risk of recurrence of AF within one month . These data support the hypothesis that anti-inflammatory interventions may help in maintenance of normal sinus rhythm after CV . These data also may have implication s for the identification of patients who are most likely to experience substantial benefit from CV therapy for AF",
"This study was design ed to test whether nonsteroidal anti-inflammatory medications could reduce the frequency of atrial fibrillation after coronary artery bypass graft surgery . The study was design ed as an open-label , r and omized trial . Patients undergoing first-time coronary artery bypass graft surgery were considered eligible . Patients with a history of atrial fibrillation , serum creatinine > 2.0 mg/dL , on antiarrhythmic treatment , and those undergoing concomitant valvular surgery were excluded . The study was conducted in a single , university-affiliated community hospital . The research ers ' role in the study was restricted to r and omizing the patients and collecting data . The primary clinical care team made all decisions regarding patient care . One hundred patients were r and omized to two groups : one received 30 mg ketorolac intravenously every 6 hours until able to take oral medications , at which point the patients were switched to 600 mg ibuprofen orally three times a day ; the other group received conventional treatment . The primary end point of the study was incidence of atrial fibrillation in the immediate postoperative period . Atrial fibrillation occurred in 14 patients ( 28.6 % ) in the conventional treatment group vs. five patients ( 9.8 % ) in the ibuprofen group ( p Nonsteroidal anti-inflammatory medications were relatively safe and effective in significantly reducing the incidence of atrial fibrillation after coronary artery bypass graft surgery",
"Abstract Reactive cardiomyocyte hypertrophy after myocardial infa rct ion is an important risk factor for arrhythmias . Myocardial ATP-sensitive potassium ( KATP ) channels have been implicated in attenuating cardiac hypertrophy by inhibition of 70-kDa S6 kinase . We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after myocardial infa rct ion and whether the attenuated hypertrophic effect was via activation of myocardial KATP channels . Twenty-four hours after ligation of the anterior descending artery , male Wistar rats were r and omized to either vehicle , nicor and il ( an agonist of KATP channels ) , pravastatin , glibenclamide ( an antagonist of KATP channels ) , or a combination of nicor and il and glibenclamide or pravastatin and glibenclamide for 4 weeks . Infa rct size and mortality were similar among the infa rct ed groups . Cardiomyocyte sizes isolated by enzymatic dissociation after infa rct ion significantly increased at the border zone in vehicle-treated infa rct ed rats compared with sham-operated rats . Rats in the nicor and il- and pravastatin-treated groups significantly attenuated cardiomyocyte hypertrophy , as compared with the vehicle-treated group . Arrhythmic scores during programmed stimulation mirrored those of cardiomyocyte hypertrophy . Increased 70-kDa S6 kinase mRNA expression in cardiac remodeling was confirmed by reverse transcription-polymerase chain reaction , consistent with the results of immunohistochemistry and Western blot for the phosphorylation of 70-kDa S6 kinase . Nicor and il-induced effects were abolished by administering glibenclamide . Similarly , the beneficial effects of pravastatin were abolished by administering glibenclamide , implicating KATP channels as the relevant target . Activation of KATP channels by pravastatin administration can attenuate ventricular remodeling through a S6 kinase-dependent pathway after infa rct ion",
"BACKGROUND Little direct information is available on the effect of C-Reactive Protein ( CRP ) lowering on the reduction of recurrent atrial fibrillation ( AF ) . METHODS AND RESULTS We compared low-dose glucocorticoid therapy ( 16 mg methylprednisolone for 4 weeks tapered to 4 mg for 4 months ) and placebo in 104 patients who had experienced persistent AF with a median concentration of CRP 1.14 mg/dL ( min=0.01 , max=2.58 ) . Methylprednisolone reduced recurrent AF ( primary end-point ) from 50 % in the placebo group to 9.6 % in the glucocorticoid group and permanent AF ( exp and ed end-point ) from 29 % in the placebo group to 2 % in the glucocorticoid group . Survival distributions for methylprednisolone were significantly different ( for both primary and exp and ed end-point , P average CRP concentrations during follow-up were significant predictors of the primary end-point , with a relative risk 6.72 ( P = 0.006 ) and the exp and ed end-point , with a relative risk of 11.67 ( P = 0.0006 ) . CONCLUSIONS CRP concentration is a risk factor for recurrent and permanent AF . Methylprednisolone successfully prevents recurrent and permanent AF",
"Background —It has been suggested that inflammation can have a role in the development of atrial arrhythmias after cardiac surgery and that a genetic predisposition to develop postoperative complications exists . This study was conceived to verify if a potential genetic modulator of the systemic inflammatory reaction to cardiopulmonary bypass ( the −174 G/C polymorphism of the promoter of the Interleukin-6 gene ) has a role in the pathogenesis of postoperative atrial fibrillation ( AF ) . Patients and Results —In 110 primary isolated coronary artery bypass patients the −174G/C Interleukin-6 promoter gene variant was determined . Interleukin-6 , fibrinogen and C-reactive protein plasma levels were determined preoperatively , 24 , 48 , and 72 hours after surgery and at discharge . Heart rate and rhythm were continuously monitored for the first 36 to 48 hours ; daily 12-lead electrocardiograms were performed thereafter until discharge . GG , CT , and CC genotypes were found in 62 , 38 , and 10 patients , respectively . Multivariate analysis ( which included genotype , age , sex , and classical risk factors for AF ) identified the GG genotype as the only independent predictor of postoperative AF . The latter occurred in 33.9 % of GG versus 10.4 % of non-GG patients ( hazard ratio 3.25 , 95%CI 1.23 to 8.62 ) . AF patients had higher blood levels of Interleukin-6 and fibrinogen after surgery ( P the inflammatory response to surgery and to influence the development of postoperative AF . These data suggest an inflammatory component of postoperative atrial arrhythmias and a genetic predisposition to this complication",
"BACKGROUND C-reactive protein ( CRP ) lowering is associated with a reduction in recurrent and permanent atrial fibrillation . This study sought to determine whether CRP lowering also results in a reduction of paroxysmal atrial fibrillation ( PAF ) during daily life . METHODS AND RESULTS We enrolled 80 patients with proven PAF , CRP between 0.8 and 13 mg/L , and at least 1 episode of PAF on ambulatory electrocardiographic monitoring . Forty patients were r and omized to placebo ( placebo group ) and 40 to atorvastatin ( treatment group ) . Plasma CRP levels and ambulatory monitoring were repeated after 4 to 6 months of therapy . The 2 groups were comparable with respect to baseline characteristics , number of episodes of PAF , and baseline plasma CRP levels . The treatment group had lower median CRP levels at study end and experienced a significant reduction in the number of episodes of PAF compared with the placebo group . Paroxysmal atrial fibrillation was completely resolved in 26 ( 65 % ) of 40 patients in the treatment group versus 4 ( 10 % ) of 40 in the placebo group . The treatment group exhibited a highly significant reduction in PAF ( P atorvastatin was an independent predictor of PAF resolution . CONCLUSIONS C-reactive protein lowering with atorvastatin appears to be effective in eliminating PAF during daily life in a significant proportion of patients",
"BACKGROUND The purpose of this study was to prevent induction of sustained atrial fibrillation ( AF ) by radiofrequency catheter ablation ( RFCA ) of the atria in an open-chest canine model . METHODS AND RESULTS In dogs r and omized to acute studies , RFCA of the atria was performed after reproducible induction of sustained AF ( lasting > 30 minutes ) with burst stimulation or premature atrial pacing and perpetuation by low level cervical vagal stimulation or IV infusion of methacholine . Additionally , in four dogs , the long-term effectiveness of RFCA was assessed 7 to 21 days after ablation . Continuous discrete transmural lesions were produced with radiofrequency energy pulses ( 20 to 40 W for 60 seconds ) delivered to five atrial epicardial sites and endovascularly to the coronary sinus wall . RFCA electrically isolated regions of the atria that became dissociated from the nonisolated parts . Atrial RFCA markedly attenuated vagally induced shortening of effective refractory period ( ERP ) at both isolated and nonisolated test sites located in the left and right atria ( P sustained AF maintained by cervical vagal stimulation . The dose-response curve relating the dose of methacholine required to maintain AF was shifted down and to the right . AF was only inducible with high doses of methacholine . Atrial RFCA reduced the maximal sinus rate and prolonged the corrected sinus-node recovery time ( P atrial contractile function , AV-nodal ERP , or AV-nodal or His-Purkinje conduction times . In dogs in the chronic group , normal sinus rhythm and normal AV conduction were preserved and AF was only inducible with a high dose of methacholine . No atrial perforations result ed . CONCLUSIONS RFCA in open-chest dogs produces partial vagal denervation and reduces the inducibility of AF",
"STUDY OBJECTIVES The level of C-reactive protein ( CRP ) has been shown to be elevated in patients with atrial fibrillation/flutter ( AF ) unrelated to surgery , and statins are known to lower the CRP level . To determine whether an elevated CRP level predisposes the patient to postoperative AF and whether statin use is associated with a reduced AF incidence , we studied a consecutive group of patients who were at risk for AF after undergoing thoracic surgery ( age , > or = 60 years ) . DESIGN AND SETTING A prospect i ve study in a tertiary care cancer center of 131 patients ( mean [ + /- SD ] age , 73 + /- 6 years ) who had undergone major lung or esophageal resection . High-sensitivity CRP and interleukin (IL)-6 levels were measured before surgery , on arrival at the postanesthesia care unit , and on the first morning after surgery . Continuous telemetry was used for 72 to 96 h to detect AF . RESULTS AF occurred in 38 of 131 patients ( 29 % ) at a median time after surgery of 3 days . Although CRP and IL-6 levels increased significantly ( p AF did not differ in perioperative values . In a stepwise logistic regression , statin use was associated with a threefold decrease in the odds of developing AF ( odds ratio [ OR ] , 0.26 ; 95 % confidence interval [ CI ] , 0.08 to 0.82 ; p = 0.022 ) and a greater PR interval ( OR , 1.11 per 5-ms increments ; 95 % CI , 1.01 to 1.22 ; p = 0.027 ) predicted an increase in the risk of AF . CONCLUSIONS The preoperative use of statins was associated with a protective effect against postoperative AF independent of CRP levels . In contrast to AF in the general population , early markers of inflammation did not predict the postoperative occurrence of AF",
"Atrial fibrillation ( AF ) is prevalent in the elderly , in patients with hypertension , and in patients with coronary artery disease ( CAD ) . We hypothesized that statin therapy might be effective in preventing AF in patients with CAD and examined this hypothesis in a sample of patients with chronic stable CAD without AF , followed prospect ively at a large outpatient cardiology practice . The association between statin use and the risk of developing AF was examined univariately and then with adjustment for potential confounding factors . Four hundred forty-nine men and women between the ages of 40 and 87 years were followed for an average of 5 years . Fifty-two patients ( 12 % ) developed AF during follow-up . Statin therapy was used by 59 % of the patients during the study period and was associated with a significantly reduced risk of developing AF ( crude odds ratio , 0.48 , 95 % confidence interval 0.28 to 0.83 ) . This association remained significant after adjustment for potential confounders , including age , hypertension , left ventricular systolic function , occurrence of heart failure or acute ischemic events , and baseline cholesterol and changes in cholesterol levels ( adjusted odds ratio 0.37 , 95 % confidence interval 0.18 to 0.76 ) . Use of statins in patients with chronic stable CAD appears to be protective against AF . The underlying mechanism for this effect is unknown but appears to be independent of the reduction in serum cholesterol levels",
"To test the hypothesis that a statin could reduce the recurrence rate of atrial fibrillation after electrical cardioversion ( EC ) , we performed an open , controlled multicenter study . Patients ( n = 114 ) who had atrial fibrillation > 48 hours and who were scheduled for EC were r and omized to receive 40 mg of pravastatin once daily for 3 weeks before and 6 weeks after EC or no drug in addition to st and ard therapy . Pravastatin did not reduce the recurrence rate of atrial fibrillation after EC",
"OBJECTIVES This study sought to evaluate the antiarrhythmic effects of lipid-lowering drug therapy as assessed by ventricular tachyarrhythmia ( ventricular tachycardia [VT]/ventricular fibrillation [ VF ] ) recurrences recorded by an implantable cardioverter defibrillator ( ICD ) in patients with atherosclerotic heart disease ( ASHD ) . BACKGROUND R and omized trials of lipid-lowering drugs suggest reduction of sudden death ( SD ) in patients with ASHD . Because SD is usually secondary to VT/VF , this observation suggests that lipid-lowering therapy has antiarrhythmic effects . METHODS The probability of VT/VF recurrence in patients with ASHD treated with an ICD in the Antiarrhythmics Versus Implantable Defibrillators ( AVID ) trial who did not receive lipid-lowering drug therapy ( n = 279 ) was compared with that in patients who received early and consistent lipid-lowering therapy ( n = 83 ) . In addition , all-cause mortality and cardiac mortality of all patients in the AVID trial with ASHD who did not receive lipid-lowering therapy ( n = 564 ) were compared with that of those who received early and consistent lipid-lowering therapy ( n = 149 ) . RESULTS Using multivariate analyses , lipid-lowering therapy was associated with a reduction in the relative hazard for VT/VF recurrence of 0.40 ( 95 % confidence interval [ CI ] 0.15 to 0.58 ) ( adjusted p = 0.003 ) in the ICD subgroup . Lipid-lowering therapy was also associated with a reduction in the relative hazard for all-cause mortality of 0.36 ( 95 % CI 0.15 to 0.68 ) ( adjusted p = 0.03 ) and a reduction in the relative hazard for cardiac mortality of 0.39 ( 95 % CI 0.16 to 0.78 ) ( adjusted p = 0.04 ) in the larger study population . CONCLUSIONS In patients with ASHD who have received an ICD , lipid-lowering therapy is associated with reduction in the probability of VT/VF recurrence , suggesting that part of the benefit of lipid-lowering therapy may be due to an antiarrhythmic effect",
"To study the effect of atorvastatin on recurrence of atrial fibrillation ( AF ) after electrical cardioversion ( EC ) , 48 patients with AF lasting 48 hours who were scheduled for EC were r and omized to the atorvastatin ( group I ) and control ( group II ) groups . Six patients in group I ( 25 % ) and 2 patients in group II ( 8.3 % ) had spontaneous conversion before EC ( p > 0.05 ) . The end point was the recurrence of AF during 3 months of follow-up . Eighteen patients in group I ( 12.5 % ) and 11 patients in group II ( 45.8 % ) had recurrence ( p = 0.01 , log-rank test ) . With the Cox proportional model , the predictors of recurrence included a body mass index of 25 to 30 kg/m2 ( relative risk [ RR ] 0.07 , 95 % confidence interval [ CI ] 0.008 to 0.59 ) , body mass index > or = 30 kg/m2 ( RR 0.24 , 95 % CI 0.08 to 0.72 ) , AF duration of > or = 3 months ( RR 0.28 , 95 % CI 0.09 to 0.83 ) , diabetes mellitus ( RR 0.34 , 95 % CI 0.12 to 0.98 ) , and left atrial diameter of > or = 45 mm ( RR 0.23 , 95 % CI 0.07 to 0.74 ) . Atorvastatin was associated with a significantly reduced risk of developing AF ( unadjusted RR 0.23 , 95 % CI 0.064 to 0.82 , p = 0.024 ) . This association remained significant after adjustment for these predictors ( adjusted RR 0.19 , 95 % CI 0.052 to 0.72 , p = 0.01 ) . High-sensitivity C-reactive protein levels at baseline were not different between the 2 groups ( p = 0.92 ) . Although the high-sensitivity C-reactive protein levels decreased significantly 48 hours after EC compared with the baseline levels in group I ( 2.82 + /- 1.46 vs 2.56 + /- 1.3 mg/dl , p = 0.02 ) , no significant change occurred in group II ( 2.87 + /- 0.8 vs 2.84 + /- 0.8 mg/dl , p = 0.09 ) . In conclusion , atorvastatin decreased the recurrence rate of AF after EC",
"A retrospective review of 115 patients who underwent cardiac surgery demonstrated a marked reduction in postoperative atrial fibrillation ( 8 % vs 32 % , p patients who received carvedilol versus metoprolol or atenolol immediately after surgery . A prospect i ve study examining the possibility of carvedilol 's greater efficacy in preventing postoperative atrial fibrillation appears warranted",
"Objectives : Systemic inflammatory response occurs frequently after coronary artery bypass surgery , and it is strongly correlated with the risk of postoperative morbidity and mortality . Recent studies demonstrate that treatment with statin is associated with a significant and marked decrease in inflammation-associated variables such as the C-reactive protein , cytokines , and adhesion molecules . Therefore , we investigated the effects of preoperative atorvastatin treatment on systemic inflammatory response and perioperative morbidity after cardiopulmonary bypass . Design : Double-blinded , placebo-controlled , r and omized study . Setting : University hospital . Patients : Forty patients were r and omized to treatment with atorvastatin ( 20 mg/day , group A , n = 20 ) or placebo ( group B , n = 20 ) 3 wks before surgery . Interventions : Three-week treatment by atorvastatin 20 mg/day . Measurement and Main Results : Postoperative serum levels of both interleukin-6 and interleukin-8 increased significantly over baseline , but the peak levels observed 4 hrs postoperatively were significantly lower in the atorvastatin group . In the same fashion , CD11b expression on neutrophils was significantly lower in the statin group at 4 and 24 hrs postoperatively . Finally , neutrophil-endothelial adhesion was significantly reduced in the statin patients compared with controls . The operation time , blood loss , need for inotropic support , intubation time , and length of intensive care unit or hospital stay did not differ significantly between the two groups . The systemic inflammatory response syndrome score on postoperative days 1 and 2 was comparable in both groups . Conclusions : Pretreatment with atorvastatin significantly reduces cytokine release and neutrophil adhesion to the venous endothelium in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass",
"BACKGROUND Atrial fibrillation ( AF ) is associated to a high risk of systemic embolism . The mechanisms that contribute to thrombogenesis in these patients are still poorly understood . Systemic and /or local inflammation could be involved in the process of thrombogenesis and contribute to the perpetuation of the arrhythmia . The purpose of the study was to evaluate the role of inflammation and its relation to thrombogenesis and cardiac rhythm in AF . METHODS We prospect ively studied 130 patients with newly diagnosed non-valvular AF in absence of antithrombotic therapy . Determinations of C-reactive protein ( CRP ) and thrombin-antithrombin complex ( TAT ) plasma levels , along with a transesophageal echocardiogram were performed in all the patients at admission . RESULTS Mean age of the group was 67+/-14 years . CRP levels were significantly elevated in AF patients versus controls ( matched by age , gender and cardiovascular risk factors ) ( 1.0+/-1.8 versus 0.3+/-0.4 mg/dl , respectively , p Baseline TAT levels were also significantly elevated in AF patients but no correlation was found between CRP and TAT . At 1-year of follow-up , mean CRP levels were still elevated in patients that remained in AF compared to those who converted to sinus rhythm ( 1.2+/-1.8 compared to 0.5+/-1.5 mg/dl , p=0.03 ) . CRP was the only biochemical predictor of sinus rhythm maintenance at 1-year follow-up independently of clinical ( including adjustment for risk factors and antiarrhythmic drugs ) , biochemical and echo parameters . CONCLUSIONS There is evidence for the presence of inflammation in patients with non-valvular AF , which is not related to activation of the coagulation cascade . The persistence of inflammation is associated with chronic AF at 1-year follow up"
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INTRODUCTION Previous studies have suggested an association between vegetarian diets and improvements in glycemic control in diabetes , although this relationship is not well established . No meta- analysis of these studies has been performed . METHODS To conduct a systematic review and meta- analysis of controlled clinical trials examining the association between vegetarian diets and glycemic control in type 2 diabetes . DATA SOURCE The electronic data bases Medline , Web of Science , Excerpta Medica Data base ( EMBASE ) , and Cochrane Central Register of Controlled Trials were search ed for articles published in any language through December 9 , 2013 . STUDY SELECTION The following criteria were used for study inclusion : ( I ) age of participants > 20 years ; ( II ) vegetarian diet as intervention ; ( III ) mean difference in hemoglobin A1c ( HbA1c ) and /or fasting blood glucose levels used as outcomes ; and ( IV ) controlled trials , duration ≥4 weeks . Exclusion criteria were : ( I ) not an original investigation ; ( II ) duplicate sample s ; ( III ) diabetes other than type 2 ; ( IV ) multiple interventions ; and ( V ) uncontrolled studies . DATA EXTRACTION AND SYNTHESIS The data collected included study design , baseline population characteristics , dietary data , and outcomes . Data were pooled using a r and om-effects model . MAIN OUTCOMES AND MEASURES Differences in HbA1c and fasting blood glucose levels associated with vegetarian diets were assessed . RESULTS Of 477 studies identified , six met the inclusion criteria ( n=255 , mean age 42.5 years ) . Consumption of vegetarian diets was associated with a significant reduction in HbA1c [ -0.39 percentage point ; 95 % confidence interval ( CI ) , -0.62 to -0.15 ; P=0.001 ; I(2)=3.0 ; P for heterogeneity = 0.389 ] , and a non-significant reduction in fasting blood glucose concentration ( -0.36 mmol/L ; 95 % CI , -1.04 to 0.32 ; P=0.301 ; I(2)=0 ; P for heterogeneity = 0.710 ) , compared with consumption of comparator diets . CONCLUSIONS Consumption of vegetarian diets is associated with improved glycemic control in type 2 diabetes . PROSPERO registration number is CRD42013004370
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"OBJECTIVE To test whether a weight loss program promotes greater weight loss , glycemic control , and improved cardiovascular disease risk factors compared with control conditions and whether there is a differential response to higher versus lower carbohydrate intake . RESEARCH DESIGN AND METHODS This r and omized controlled trial at two university medical centers enrolled 227 overweight or obese adults with type 2 diabetes and assigned them to parallel in-person diet and exercise counseling , with prepackaged foods in a planned menu during the initial phase , or to usual care ( UC ; two weight loss counseling sessions and monthly contacts ) . RESULTS Relative weight loss was 7.4 % ( 95 % CI 5.7–9.2 % ) , 9.0 % ( 7.1–10.9 % ) , and 2.5 % ( 1.3–3.8 % ) for the lower fat , lower carbohydrate , and UC groups ( P . Glycemic control markers and triglyceride levels were lower in the intervention groups compared with UC group at 1 year ( fasting glucose 141 [ 95 % CI 133–149 ] vs. 159 [ 144–174 ] mg/dL , P = 0.023 ; hemoglobin A1c 6.9 % [ 6.6–7.1 % ] vs. 7.5 % [ 7.1–7.9 % ] or 52 [ 49–54 ] vs. 58 [ 54–63 ] mmol/mol , P = 0.001 ; triglycerides 148 [ 134–163 ] vs. 204 [ 173–234 ] mg/dL , P lower hemoglobin A1c ( 6.6 % [ 95 % CI 6.3–6.8 % ] vs. 7.2 % [ 6.8–7.5 % ] or 49 [ 45–51 ] vs. 55 [ 51–58 ] mmol/mol ) at 1 year ( P = 0.008 ) . CONCLUSIONS The weight loss program result ed in greater weight loss and improved glycemic control in type 2 diabetes",
"Disease risk factors identified in epidemiological studies serve as important public health tools , helping clinicians identify individuals who may benefit from more aggressive screening or risk-modification procedures , allowing policymakers to prioritize intervention programs , and encouraging at-risk individuals to modify behavior and improve their health . These factors have been based primarily on evidence from cross-sectional and prospect i ve studies , as most do not lend themselves to r and omized trials . While some risk factors are not modifiable , eating habits are subject to change through both individual action and broader policy initiatives . Meat consumption has been frequently investigated as a variable associated with diabetes risk , but it has not yet been described as a diabetes risk factor . In this article , we evaluate the evidence supporting the use of meat consumption as a clinical ly useful risk factor for type 2 diabetes , based on studies evaluating the risks associated with meat consumption as a categorical dietary characteristic ( i.e. , meat consumption versus no meat consumption ) , as a scalar variable ( i.e. , gradations of meat consumption ) , or as part of a broader dietary pattern",
"BACKGROUND Replacement of red meat in the diet with chicken has reduced the urinary albumin excretion rate ( UAER ) and serum cholesterol in microalbuminuric type 2 diabetes patients . The effects of withdrawing red meat are unknown in the more advanced stages of diabetic nephropathy . OBJECTIVE Our objective was to assess the effects of replacing red meat in the usual diet ( UD ) with chicken ( CD ) and of consuming a lactovegetarian low-protein diet ( LPD ) on renal function , fatty acid , and lipid profile in macroalbuminuric type 2 diabetes patients . DESIGN A crossover controlled trial was conducted in 17 type 2 diabetes patients with macroalbuminuria ( 24-h UAER > or = 200 microg/min ) . Each patient followed the UD , CD , and LPD in a r and om order for 4 wk . After each diet , glomerular filtration rate , UAER , serum fatty acid , lipid profile , glycemic control , anthropometric indexes , and blood pressure were measured . RESULTS UAER [ median CD : 269.4 ( range : 111 - 1128 ) microg/min ; LPD : 229.3 ( 76.6 - 999.3 ) microg/min ; UD : 312.8 ( 223.7 - 1223.7 ) microg/min ; P mean ( + /-SD ) non-HDL cholesterol ( CD : 3.92 + /- 0.99 mmol/L ; LPD : 3.92 + /- 0.93 mmol/L ; UD : 4.23 + /- 1.06 mmol/L ; P = 0.042 ) were lower after CD and LPD than after UD . Compared with the UD , an increase in serum total polyunsaturated fatty acids was also observed ( CD : 39.8 + /- 2.6 % ; LPD : 39.7 + /- 4.4 % ; UD : 37.3 + /- 3.1 % ; P = 0.029 ) . CONCLUSION In macroalbuminuric patients with type 2 diabetes , withdrawing red meat from the diet reduces the UAER",
"Aims The aim of this study was to compare the effects of calorie-restricted vegetarian and conventional diabetic diets alone and in combination with exercise on insulin resistance , visceral fat and oxidative stress markers in subjects with Type 2 diabetes . Methods A 24-week , r and omized , open , parallel design was used . Seventy-four patients with Type 2 diabetes were r and omly assigned to either the experimental group ( n = 37 ) , which received a vegetarian diet , or the control group ( n = 37 ) , which received a conventional diabetic diet . Both diets were isocaloric , calorie restricted ( -500 kcal/day ) . All meals during the study were provided . The second 12 weeks of the diet were combined with aerobic exercise . Participants were examined at baseline , 12 weeks and 24 weeks . Primary outcomes were : insulin sensitivity measured by hyperinsulinaemic isoglycaemic clamp ; volume of visceral and subcutaneous fat measured by magnetic resonance imaging ; and oxidative stress measured by thiobarbituric acid reactive substances . Analyses were by intention to treat . Results Forty-three per cent of participants in the experimental group and 5 % of participants in the control group reduced diabetes medication ( P decreased more in the experimental group than in the control group [ –6.2 kg ( 95 % CI –6.6 to –5.3 ) vs. –3.2 kg ( 95 % CI –3.7 to –2.5 ) ; interaction group × time P = 0.001 ] . An increase in insulin sensitivity was significantly greater in the experimental group than in the control group [ 30 % ( 95 % CI 24.5–39 ) vs. 20 % ( 95 % CI 14–25 ) , P = 0.04 ] . A reduction in both visceral and subcutaneous fat was greater in the experimental group than in the control group ( P = 0.007 and P = 0.02 , respectively ) . Plasma adiponectin increased ( P = 0.02 ) and leptin decreased ( P = 0.02 ) in the experimental group , with no change in the control group . Vitamin C , superoxide dismutase and reduced glutathione increased in the experimental group ( P = 0.002 , P exercise training . Changes in insulin sensitivity and enzymatic oxidative stress markers correlated with changes in visceral fat . Conclusions A calorie-restricted vegetarian diet had greater capacity to improve insulin sensitivity compared with a conventional diabetic diet over 24 weeks . The greater loss of visceral fat and improvements in plasma concentrations of adipokines and oxidative stress markers with this diet may be responsible for the reduction of insulin resistance . The addition of exercise training further augmented the improved outcomes with the vegetarian diet",
"Background / objectives : To determine the effects of a low-fat plant-based diet program on anthropometric and biochemical measures in a multicenter corporate setting .Subjects/ methods : Employees from 10 sites of a major US company with body mass index ⩾25 kg/m2 and /or previous diagnosis of type 2 diabetes were r and omized to either follow a low-fat vegan diet , with weekly group support and work cafeteria options available , or make no diet changes for 18 weeks . Dietary intake , body weight , plasma lipid concentrations , blood pressure and glycated hemoglobin ( HbA1C ) were determined at baseline and 18 weeks . Results : Mean body weight fell 2.9 kg and 0.06 kg in the intervention and control groups , respectively ( P fell 8.0 and 8.1 mg/dl in the intervention group and 0.01 and 0.9 mg/dl in the control group ( P HbA1C fell 0.6 percentage point and 0.08 percentage point in the intervention and control group , respectively (P , mean changes in body weight were −4.3 kg and −0.08 kg in the intervention and control groups , respectively ( P fell 13.7 and 13.0 mg/dl in the intervention group and 1.3 and 1.7 mg/dl in the control group ( P HbA1C levels decreased 0.7 percentage point and 0.1 percentage point in the intervention and control group , respectively ( P dietary intervention using a low-fat plant-based diet in a corporate setting improves body weight , plasma lipids , and , in individuals with diabetes , glycemic control",
"BACKGROUND Low-fat vegetarian and vegan diets are associated with weight loss , increased insulin sensitivity , and improved cardiovascular health . OBJECTIVE We compared the effects of a low-fat vegan diet and conventional diabetes diet recommendations on glycemia , weight , and plasma lipids . DESIGN Free-living individuals with type 2 diabetes were r and omly assigned to a low-fat vegan diet ( n = 49 ) or a diet following 2003 American Diabetes Association guidelines ( conventional , n = 50 ) for 74 wk . Glycated hemoglobin ( Hb A(1c ) ) and plasma lipids were assessed at weeks 0 , 11 , 22 , 35 , 48 , 61 , and 74 . Weight was measured at weeks 0 , 22 , and 74 . RESULTS Weight loss was significant within each diet group but not significantly different between groups ( -4.4 kg in the vegan group and -3.0 kg in the conventional diet group , P = 0.25 ) and related significantly to Hb A(1c ) changes ( r = 0.50 , P = 0.001 ) . Hb A(1c ) changes from baseline to 74 wk or last available values were -0.34 and -0.14 for vegan and conventional diets , respectively ( P = 0.43 ) . Hb A(1c ) changes from baseline to last available value or last value before any medication adjustment were -0.40 and 0.01 for vegan and conventional diets , respectively ( P = 0.03 ) . In analyses before alterations in lipid-lowering medications , total cholesterol decreased by 20.4 and 6.8 mg/dL in the vegan and conventional diet groups , respectively ( P = 0.01 ) ; LDL cholesterol decreased by 13.5 and 3.4 mg/dL in the vegan and conventional groups , respectively ( P = 0.03 ) . CONCLUSIONS Both diets were associated with sustained reductions in weight and plasma lipid concentrations . In an analysis controlling for medication changes , a low-fat vegan diet appeared to improve glycemia and plasma lipids more than did conventional diabetes diet recommendations . Whether the observed differences provide clinical benefit for the macro- or microvascular complications of diabetes remains to be established . This trial was registered at clinical trials.gov as NCT00276939",
"CONTEXT The Lifestyle Heart Trial demonstrated that intensive lifestyle changes may lead to regression of coronary atherosclerosis after 1 year . OBJECTIVES To determine the feasibility of patients to sustain intensive lifestyle changes for a total of 5 years and the effects of these lifestyle changes ( without lipid-lowering drugs ) on coronary heart disease . DESIGN R and omized controlled trial conducted from 1986 to 1992 using a r and omized invitational design . PATIENTS Forty-eight patients with moderate to severe coronary heart disease were r and omized to an intensive lifestyle change group or to a usual-care control group , and 35 completed the 5-year follow-up quantitative coronary arteriography . SETTING Two tertiary care university medical centers . INTERVENTION Intensive lifestyle changes ( 10 % fat whole foods vegetarian diet , aerobic exercise , stress management training , smoking cessation , group psychosocial support ) for 5 years . MAIN OUTCOME MEASURES Adherence to intensive lifestyle changes , changes in coronary artery percent diameter stenosis , and cardiac events . RESULTS Experimental group patients ( 20 [ 71 % ] of 28 patients completed 5-year follow-up ) made and maintained comprehensive lifestyle changes for 5 years , whereas control group patients ( 15 [ 75 % ] of 20 patients completed 5-year follow-up ) made more moderate changes . In the experimental group , the average percent diameter stenosis at baseline decreased 1.75 absolute percentage points after 1 year ( a 4.5 % relative improvement ) and by 3.1 absolute percentage points after 5 years ( a 7.9 % relative improvement ) . In contrast , the average percent diameter stenosis in the control group increased by 2.3 percentage points after 1 year ( a 5.4 % relative worsening ) and by 11.8 percentage points after 5 years ( a 27.7 % relative worsening ) ( P=.001 between groups . Twenty-five cardiac events occurred in 28 experimental group patients vs 45 events in 20 control group patients during the 5-year follow-up ( risk ratio for any event for the control group , 2.47 [ 95 % confidence interval , 1.48 - 4.20 ] ) . CONCLUSIONS More regression of coronary atherosclerosis occurred after 5 years than after 1 year in the experimental group . In contrast , in the control group , coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred",
"Purpose . To determine whether a multicomponent nutrition intervention program at a corporate site reduces body weight and improves other cardiovascular risk factors in overweight individuals . Design . Prospect i ve clinical intervention study . Subjects/ Setting . Employees of the Government Employees Insurance Company ( GEICO ) ( N = 113 ) , aged 21 to 65 years , with a body mass index ≥ 25 kg/m2 and /or previous diagnosis of type 2 diabetes . Intervention . A 22-week intervention including a low-fat , vegan diet . Measures . Changes in body weight , anthropometric measures , blood pressure , lipid profile , and dietary intake . Analysis . Multivariate analyses of variance were calculated for clinical and nutrient measures , followed by univariate analyses of variance , to determine the significance of differences between groups in changes over time . Results . Intervention-group participants experienced greater weight changes compared with control-group participants ( mean , – 5.1 [ SE , .6 ] kg vs. + .1 [ SE , .6 ] kg , p greater changes in waist circumference ( mean , – 4.7 [ SE , .6 ] cm vs. + .8 [ SE , .6 ] cm , p ( mean , – .006 [ SE , .003 ] vs. + .014 [ SE , .005 ] , p = .0007 ) . Weight loss of 5 % of body weight was more frequently observed in the intervention group ( 48.5 % ) compared with the control group ( 11.1 % ) ( χ2[1 , N= 113 ] = 16.99 , p individuals volunteering for a 22-week worksite research study , an intervention using a low-fat , vegan diet effectively reduced body weight and waist circumference ",
"BACKGROUND Although obesity is the most important risk factor for type 2 diabetes , evidence is emerging that certain foods and dietary factors may be associated with diabetes . To examine the association between major dietary patterns and risk of type 2 diabetes mellitus in a cohort of women . METHODS We prospect ively assessed the associations between major dietary patterns and risk of type 2 diabetes in women . Dietary information was collected in 1984 , 1986 , 1990 , and 1994 from 69,554 women aged 38 to 63 years without a history of diabetes , cardiovascular disease , or cancer in 1984 . We conducted factor analysis and identified 2 major dietary patterns : \" prudent \" and \" Western . \" We then calculated pattern scores for each participant and examined prospect ively the associations between dietary pattern scores and type 2 diabetes risks . RESULTS The prudent pattern was characterized by higher intakes of fruits , vegetables , legumes , fish , poultry , and whole grains , while the Western pattern included higher intakes of red and processed meats , sweets and desserts , french fries , and refined grains . During 14 years of follow-up , we identified 2699 incident cases of type 2 diabetes . After adjusting for potential confounders , we observed a relative risk for diabetes of 1.49 ( 95 % confidence interval [ CI ] , 1.26 - 1.76 , P for trend , type 2 diabetes and red meat and other processed meats . The relative risk for diabetes for every 1-serving increase in intake is 1.26 ( 95 % CI , 1.21 - 1.42 ) for red meat , 1.38 ( 95 % CI , 1.23 - 1.56 ) for total processed meats , 1.73 ( 95 % CI , 1.39 - 2.16 ) for bacon , 1.49 ( 95 % CI , 1.04 - 2.11 ) for hot dogs , and 1.43 ( 95 % CI , 1.22 - 1.69 ) for processed meats . CONCLUSION The Western pattern , especially a diet higher in processed meats , may increase the risk of type 2 diabetes in women",
"OBJECTIVE To investigate whether glycemic and lipid control in patients with non-insulin-dependent diabetes ( NIDDM ) can be significantly improved using a low-fat , vegetarian ( vegan ) diet in the absence of recommendations regarding exercise or other lifestyle changes . METHODS Eleven subjects with NIDDM recruited from the Georgetown University Medical Center or the local community were r and omly assigned to a low-fat vegan diet ( seven subjects ) or a conventional low-fat diet ( four subjects ) . Two additional subjects assigned to the control group failed to complete the study . The diets were not design ed to be isocaloric . Fasting serum glucose , body weight , medication use , and blood pressure were assessed at baseline and biweekly thereafter for 12 weeks . Serum lipids , glycosylated hemoglobin , urinary albumin , and dietary macronutrients were assessed at baseline and 12 weeks . RESULTS Although the sample was intentionally small in accordance with the pilot study design , the 28 % mean reduction in fasting serum glucose of the experimental group , from 10.7 to 7.75 mmol/L ( 195 to 141 mg/dl ) , was significantly greater than the 12 % decrease , from 9.86 to 8.64 mmol/L ( 179 to 157 mg/dl ) , for the control group ( P mean weight loss was 7.2 kg in the experimental group , compared to 3 . 8 kg for the control group ( P Insulin was reduced in both experimental group patients on insulin . No patient in the control group reduced medication use . Differences between the diet groups in the reductions of serum cholesterol and 24-h microalbuminuria did not reach statistical significance ; however , high-density lipoprotein concentration fell more sharply ( 0.20 mmol/L ) in the experimental group than in the control group ( 0.02 mmol/L ) ( P low-fat , vegetarian diet in patients with NIDDM was associated with significant reductions in fasting serum glucose concentration and body weight in the absence of recommendations for exercise . A larger study is needed for confirmation",
"Few controlled trials have studied cholesterol-lowering diets in premenopausal women . None has examined the cholesterol-lowering effect of a low-fat vegetarian diet , which , in other population groups , leads to marked reductions in serum cholesterol concentrations and , in combination with other life-style changes , a regression of atherosclerosis . We tested the hypothesis that a low-fat , vegetarian diet significantly reduces serum total and low-density lipoprotein ( LDL ) cholesterol concentrations in premenopausal women . In a crossover design , 35 women , aged 22 to 48 , followed a low-fat vegetarian diet deriving approximately 10 % of energy from fat for 2 menstrual cycles . For 2 additional cycles , they followed their customary diet while also taking a \" supplement \" ( placebo ) pill . Serum lipid concentrations were assessed at baseline and during each intervention phase . Mean serum LDL , high-density lipoprotein ( HDL ) , and total cholesterol concentrations decreased 16 . 9 % , 16.5 % , and 13.2 % , respectively , from baseline to the intervention diet phase ( p mean serum triacylglycerol concentration increased 18.7 % ( p LDL/HDL ratio remained unchanged . Thus , in healthy premenopausal women , a low-fat vegetarian diet led to rapid and sizable reductions in serum total , LDL , and HDL cholesterol concentrations",
"BACKGROUND The effect of increasing the intake of dietary fiber on glycemic control in patients with type 2 diabetes mellitus is controversial . METHODS In a r and omized , crossover study , we assigned 13 patients with type 2 diabetes mellitus to follow two diets , each for six weeks : a diet containing moderate amounts of fiber ( total , 24 g ; 8 g of soluble fiber and 16 g of insoluble fiber ) , as recommended by the American Diabetes Association ( ADA ) , and a high-fiber diet ( total , 50 g ; 25 g of soluble fiber and 25 g of insoluble fiber ) , containing foods not fortified with fiber ( unfortified foods ) . Both diets , prepared in a research kitchen , had the same macronutrient and energy content . We compared the effects of the two diets on glycemic control and plasma lipid concentrations . RESULTS Compliance with the diets was excellent . During the sixth week , the high-fiber diet , as compared with the the sixth week of the ADA diet , mean daily prepr and ial plasma glucose concentrations were 13 mg per deciliter [ 0.7 mmol per liter ] lower ( 95 percent confidence interval , 1 to 24 mg per deciliter [ 0.1 to 1.3 mmol per liter ] ; P=0.04 ) and mean median difference , daily urinary glucose excretion 1.3 g ( 0.23 ; 95 percent confidence interval , 0.03 to 1.83 g ; P= 0.008 ) . The high-fiber diet also lowered the area under the curve for 24-hour plasma glucose and insulin concentrations , which were measured every two hours , by 10 percent ( P=0.02 ) and 12 percent ( P=0.05 ) , respectively . The high-fiber diet reduced plasma total cholesterol concentrations by 6.7 percent ( P=0.02 ) , triglyceride concentrations by 10.2 percent ( P=0.02 ) , and very-low-density lipoprotein cholesterol concentrations by 12.5 percent ( P=0.01 ) . CONCLUSIONS A high intake of dietary fiber , particularly of the soluble type , above the level recommended by the ADA , improves glycemic control , decreases hyperinsulinemia , and lowers plasma lipid concentrations in patients with type 2 diabetes",
"Increasing protein intake and soy consumption appear to be promising approaches to prevent metabolic syndrome ( MetS ) . However , the effect of soy consumption on insulin resistance , glucose homeostasis , and other characteristics of MetS is not frequently studied in humans . We aim ed to investigate the effects of a 4-wk , strictly controlled , weight-maintaining , moderately high-protein diet rich in soy on insulin sensitivity and other cardiometabolic risk factors . We performed a r and omized crossover trial of 2 4-wk diet periods in 15 postmenopausal women with abdominal obesity to test diets with 22 energy percent ( En% ) protein , 27 En% fat , and 50 En% carbohydrate . One diet contained protein of mixed origin ( mainly meat , dairy , and bread ) , and the other diet partly replaced meat with soy meat analogues and soy nuts containing 30 g/d soy protein . For our primary outcome , a frequently sample d intravenous glucose tolerance test ( FSIGT ) was performed at the end of both periods . Plasma total , LDL , and HDL cholesterol , triglycerides , glucose , insulin , and C-reactive protein were assessed , and blood pressure , arterial stiffness , and intrahepatic lipid content were measured at the start and end of both periods . Compared with the mixed-protein diet , the soy-protein diet result ed in greater insulin sensitivity [ FSIGT : insulin sensitivity , 34 ± 29 vs. 22 ± 17 (mU/L)(-1 ) · min(-1 ) , P = 0.048 ; disposition index , 4974 ± 2543 vs. 2899 ± 1878 , P = 0.038 ; n = 11 ] . Total cholesterol was 4 % lower after the soy-protein diet than after the mixed-protein diet ( 4.9 ± 0.7 vs. 5.1 ± 0.6 mmol/L , P = 0.001 ) , and LDL cholesterol was 9 % lower ( 2.9 ± 0.7 vs. 3.2 ± 0.6 mmol/L , P = 0.004 ; n = 15 ) . Thus , partly replacing meat with soy in a moderately high-protein diet has clear advantages regarding insulin sensitivity and total and LDL cholesterol . Therefore , partly replacing meat products with soy products could be important in preventing MetS. This trial was registered at clinical trials.gov as NCT01694056"
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4117c49a-06ff-11f0-808a-c43d1ab1c353
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Hyperuricemia is linked to gout and features of metabolic syndrome . There is concern that dietary fructose may increase uric acid concentrations . To assess the effects of fructose on serum uric acid concentrations in people with and without diabetes , we conducted a systematic review and meta- analysis of controlled feeding trials . We search ed MEDLINE , EMBASE , and the Cochrane Library for relevant trials ( through August 19 , 2011 ) . Analyses included all controlled feeding trials ≥7 d investigating the effect of fructose feeding on uric acid under isocaloric conditions , where fructose was isocalorically exchanged with other carbohydrate , or hypercaloric conditions , and where a control diet was supplemented with excess energy from fructose . Data were aggregated by the generic inverse variance method using r and om effects models and expressed as mean difference ( MD ) with 95 % CI . Heterogeneity was assessed by the Q statistic and quantified by I2 . A total of 21 trials in 425 participants met the eligibility criteria . Isocaloric exchange of fructose for other carbohydrate did not affect serum uric acid in diabetic and nondiabetic participants [ MD = 0.56 μmol/L ( 95 % CI : −6.62 , 7.74 ) ] , with no evidence of inter- study heterogeneity . Hypercaloric supplementation of control diets with fructose ( + 35 % excess energy ) at extreme doses ( 213–219 g/d ) significantly increased serum uric acid compared with the control diets alone in nondiabetic participants [ MD = 31.0 mmol/L ( 95 % CI : 15.4 , 46.5 ) ] with no evidence of heterogeneity . Confounding from excess energy can not be ruled out in the hypercaloric trials . These analyses do not support a uric acid-increasing effect of isocaloric fructose intake in nondiabetic and diabetic participants . Hypercaloric fructose intake may , however , increase uric acid concentrations . The effect of the interaction of energy and fructose remains unclear . Larger , well- design ed trials of fructose feeding at “ real world ” doses are needed
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"Ten hyperinsulinemic and 11 nonhyperinsulinemic men consumed for 5 wk each in a cross-over design a diet , similar to one currently consumed in the United States , with 20 % of the kilocalories from either fructose or high-amylose cornstarch to determine the effects of the two diets on various blood metabolites considered to be risk factors associated with heart disease . In the hyperinsulinemic men the intake of fructose as compared with cornstarch significantly increased total triglycerides and their lipoprotein distribution ; total and very-low-density lipoprotein cholesterol ; apoproteins B-100 , C-II , C-III ; and uric acid . In the nonhyperinsulinemic men total triglycerides , total and low-density lipoprotein cholesterol and uric acid were significantly greater after the consumption of fructose than after cornstarch . The results indicate that in a diet high in saturated fatty acids and cholesterol , fructose increases the levels of risk factors associated with heart disease , especially in hyperinsulinemic men",
"Consumption of simple carbohydrates has markedly increased over the past decades , and may be involved in the increased prevalence in metabolic diseases . Whether an increased intake of fructose is specifically related to a dysregulation of glucose and lipid metabolism remains controversial . We therefore compared the effects of hypercaloric diets enriched with fructose ( HFrD ) or glucose ( HGlcD ) in healthy men . Eleven subjects were studied in a r and omised order after 7 d of the following diets : ( 1 ) weight maintenance , control diet ; ( 2 ) HFrD ( 3.5 g fructose/kg fat-free mass ( ffm ) per d , + 35 % energy intake ) ; ( 3 ) HGlcD ( 3.5 g glucose/kg ffm per d , + 35 % energy intake ) . Fasting hepatic glucose output ( HGO ) was measured with 6,6 - 2H2-glucose . Intrahepatocellular lipids ( IHCL ) and intramyocellular lipids ( IMCL ) were measured by 1H magnetic resonance spectroscopy . Both fructose and glucose increased fasting VLDL-TAG ( HFrD : + 59 % , P IHCL ( HFrD : + 52 % , P HGO increased after both diets ( HFrD : + 5 % , P fasting glycaemia , insulin and alanine aminotransferase concentrations . IMCL increased significantly only after the HGlcD ( HFrD : + 24 % , NS ; HGlcD : + 59 % , P IHCL and VLDL-TAG were not different between hypercaloric HFrD and HGlcD , but were increased compared to values observed with a weight maintenance diet . However , glucose led to a higher increase in IMCL than fructose",
"Objective To examine the relation between intake of sugar sweetened soft drinks and fructose and the risk of incident gout in men . Design Prospect i ve cohort over 12 years . Setting Health professionals follow-up study . Participants 46 393 men with no history of gout at baseline who provided information on intake of soft drinks and fructose through vali date d food frequency question naires . Main outcome measure Incident cases of gout meeting the American College of Rheumatology survey criteria for gout . Results During the 12 years of follow-up 755 confirmed incident cases of gout were reported . Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout . Compared with consumption of less than one serving of sugar sweetened soft drinks a month the multivariate relative risk of gout for 5 - 6 servings a week was 1.29 ( 95 % confidence interval 1.00 to 1.68 ) , for one serving a day was 1.45 ( 1.02 to 2.08 ) , and for two or more servings a day was 1.85 ( 1.08 to 3.16 ; P for trend=0.002 ) . Diet soft drinks were not associated with risk of gout ( P for trend=0.99 ) . The multivariate relative risk of gout according to increasing fifths of fructose intake were 1.00 , 1.29 , 1.41 , 1.84 , and 2.02 ( 1.49 to 2.75 ; P for trend risk of gout ( P values for trend sugar sweetened soft drinks and fructose is strongly associated with an increased risk of gout in men . Furthermore , fructose rich fruits and fruit juices may also increase the risk . Diet soft drinks were not associated with the risk of gout",
"BACKGROUND Both nutritional and genetic factors are involved in the pathogenesis of nonalcoholic fatty liver disease and insulin resistance . OBJECTIVE The aim was to assess the effects of fructose , a potent stimulator of hepatic de novo lipogenesis , on intrahepatocellular lipids ( IHCLs ) and insulin sensitivity in healthy offspring of patients with type 2 diabetes (OffT2D)--a subgroup of individuals prone to metabolic disorders . DESIGN Sixteen male OffT2D and 8 control subjects were studied in a crossover design after either a 7-d isocaloric diet or a hypercaloric high-fructose diet ( 3.5 g x kg FFM(-1 ) x d(-1 ) , + 35 % energy intake ) . Hepatic and whole-body insulin sensitivity were assessed with a 2-step hyperinsulinemic euglycemic clamp ( 0.3 and 1.0 mU x kg(-1 ) x min(-1 ) ) , together with 6,6-[2H2]glucose . IHCLs and intramyocellular lipids ( IMCLs ) were measured by 1H-magnetic resonance spectroscopy . RESULTS The OffT2D group had significantly ( P IHCLs ( + 94 % ) , total triacylglycerols ( + 35 % ) , and lower whole-body insulin sensitivity ( -27 % ) than did the control group . The high-fructose diet significantly increased IHCLs ( control : + 76 % ; OffT2D : + 79 % ) , IMCLs ( control : + 47 % ; OffT2D : + 24 % ) , VLDL-triacylglycerols ( control : + 51 % ; OffT2D : + 110 % ) , and fasting hepatic glucose output ( control : + 4 % ; OffT2D : + 5 % ) . Furthermore , the effects of fructose on VLDL-triacylglycerols were higher in the OffT2D group ( group x diet interaction : P 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity . Fructose-induced alterations in VLDL-triacylglycerols appeared to be of greater magnitude in the OffT2D group , which suggests that these individuals may be more prone to developing dyslipidemia when challenged by high fructose intakes . This trial was registered at clinical trials.gov as NCT00523562",
"The published literature contains numerous reports of clinical studies . A problem in their interpretation is that studies in which the observed efficacy of the treatment is high are much more likely to be reported than those in which the observed efficacy is average or poor . This phenomenon has had the consequence of generally discrediting the reliability of the literature , especially that of non-r and omized studies . In this paper a model is developed which permits estimation of the potential magnitude by which the reported efficacy of a treatment might be inflated . This quantity is termed the publication bias . The magnitude of the bias depends on the sample size of the study and the number of similar studies conducted concurrently . Tabulated values of the bias are presented , permitting easy computation . The new measure may have potential use for physicians in clinical decision making in that it characterizes the reliability of results from a specific published study , especially when there are no definitive r and omized studies . However , correction of publication bias in this manner is not a substitute for a well controlled or a r and omized study . The technique merely assists in the interpretation of available evidence from the literature . Moreover , it must be used with due caution in recognition of the assumptions and approximations involved in the calculation"
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4117c4d6-06ff-11f0-808a-c43d1ab1c353
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Objective The purpose of this study was to systematic ally review and critically analyze the published data of in vitro studies testing the effect of root canal sealers on the fracture resistance of endodontically treated teeth . Methods A comprehensive literature search was performed by using the Medline , Scopus , Web of Science , Cochrane , and Open Grey data bases . A h and search of the reference lists of identified articles was also performed . Two review ers critically assessed the studies for eligibility against inclusion and exclusion criteria and performed data extraction . Evaluation of the risk of bias of the studies was performed . Results A total of 48 studies were assessed for eligibility . Of these , 20 met the inclusion criteria and were included in the systematic review . All studies had a medium or high risk of bias . Although the majority of the studies reported that the use of root canal sealers increased the fracture resistance of endodontically treated teeth , conflicting evidence was found for the reinforcing effect of resin , glass ionomer , and calcium silicate-based sealers while there was moderate evidence for zinc oxide eugenol-based sealers in favor of no reinforcing effect . Conclusion On the basis of available evidence , the use of root canal sealer increases the fracture resistance of endodontically treated teeth . However , included studies presented considerable risk of bias . Regarding the comparisons among the sealers , no conclusions could be drawn for the superiority of one sealer type to another . Clinical relevance A considerable heterogeneity was found in the method ologies of included studies . Therefore , this review strongly suggests the development of st and ardized methods to test the reinforcement effect of root canal filling material s in in vitro studies
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"Objective : Bacterial leakage and root fractures are the most important reasons of root canal treatment failure . Due to the lack of adhesion of gutta percha to the canal walls , Resilon has been introduced as a root-filling material able to bond to the root walls . Metal posts may predispose the tooth walls to oblique and vertical fracture which usually leads to tooth loss ; whereas , fiber posts may reinforce the remaining tooth structure . The purpose of this study was to compare the effect of Resilon and gutta-percha on the fracture resistance of root canal following restoring with quartz fiber posts . Material s and Methods : Forty-four maxillary incisor root canals were chemo-mechanically prepared , then r and omly divided into three groups : 1-Control group ( n=20 ) , 2-Experimental group ( n=20 ) and a negative control group ( n=4 ) . Root filled teeth were restored with quartz fiber posts and composite resin cores . Four teeth with a conservative prepared access cavities and without any further post preparation were used as a negative control group . After simulating the clinical situation , specimens were loaded in the Universal Testing Machine for compressive strength test . All data were statistically analyzed by the T-test . Results : The mean compressive strengths for group 1 was 535.8 ± 155.23 N and 645.93 ± 182.98N for group 2 , which were statistically significant ( p-value= 0.047 ) . Conclusion : Root canals filled with Resilon were significantly more resistant than that of gutta-percha , following restoration with quartz fiber posts",
"Background : As per many studies endodontically treated teeth are widely considered to be more susceptible to fracture than vital teeth . Obturation strains and post placement have been a major cause of vertical root fracture . Present study was conducted to compare in vitro fracture resistance after filling with either Gutta-percha or Resilon by lateral condensation techniques in root canals . This study evaluated a new thermoplastic synthetic polymer based on polyester , which contains bioactive and radiopaque filler , Resilon performs every way as Gutta-percha except that it allows the bonding agent to attach to the resin core and the dentin wall thus forming a monoblock . Material s and Methods : In the present study 90 freshly extracted single-rooted human m and ibular premolar teeth endodontically treated , were cut at the cemento-enamel junction , and were r and omly divided into three groups of 30 each as teeth of Group A ( Control ) received no obturation , Group B teeth were obturated using Gutta-percha/AH26 , and Group C teeth were obturated using Resilon/Epiphany obturating kit . Each specimen were mounted in acrylic in a polyvinyl ring and then tested for fracture resistance with the help of an universal testing machine . A compressive force was applied until the root is fractured . The data were subjected to analysis of variance for comparing mean difference of fracture resistance among three groups . Multiple comparisons among these groups were carried out by non-parametric Kruskal – Wallis analysis . A p value of fracture resistance between the two tested groups of endodontic sealers . Conclusion : Within the limitation of the present in-vitro study , Resilon/Epiphany sealer performs better than Gutta-percha/AH 26 sealer with lateral condensation technique",
"Aim : Comparative assessment of fracture resistance of roots obturated with three hydrophilic systems — novel CPoint system , Resilon/Epiphany system , and EndoSequence BC sealer ; and one hydrophobic gold st and ard gutta-percha/AHPlus system . Material s and Methods : Ninety freshly extracted , human , single-rooted m and ibular premolars were selected . The specimens were decoronated and st and ardized to a working length of 13 mm . The teeth were r and omly divided into six groups ( n = 15 ) . In Group A , teeth were left unprepared and unfilled ( negative control ) . Rest of the groups were prepared by using ProTaper system up to a master apical file F3 ; followed by which Group B was left unobturated ( positive control ) ; Group C , novel CPoint System ; group D , Resilon/Epiphany system , Group E EndoSequence BC sealer , and Group F gutta-percha and AH Plus . Specimens were stored for 2 weeks at 100 % humidity . Each group was then subjected to fracture testing by using a universal testing machine . The force required to fracture each specimen was recorded and the data was analyzed statistically using analysis of variance ( ANOVA ) test and Tukey 's post-hoc test . Results : The hydrophilic obturation systems have shown to exhibit significantly higher fracture resistance as shown by the values in Groups C , D , and E ( P 0.05 ) . Conclusion : In contrast to hydrophobic systems , hydrophilic systems showed higher fracture resistance in a single-rooted premolar",
"AIM The aim of this study was to compare in vitro root fracture resistance following root canal filling with either Ketac-Endo or Roth 's root canal sealer . METHODOLOGY The roots of 40 teeth with single canals were instrumented and placed r and omly into four groups of 10 teeth . The prepared canals were obturated with lateral compaction using gutta-percha and Roth 's 801 sealer , lateral compaction and Ketac-Endo sealer or with a single cone and Ketac-Endo sealer ; the fourth group acted as unfilled controls . The roots were stored for 2 weeks in 100 % humidity prior to being mounted in acrylic resin blocks . A steel tipped rod attached to an Instron testing machine was positioned against the canal opening and a slowly increasing force was applied until root fracture occurred . The results were subjected to statistical analysis using Kruskal-Wallis one-way ANOVA . RESULTS There were no significant differences between the groups in terms of force required to vertically fracture the roots . CONCLUSIONS Under the conditions of this study , the use of Ketac-Endo sealer in conjunction with lateral compaction or single-cone obturation techniques does not increase the fracture resistance of root-filled teeth ",
" The aim of this study was to compare the fracture resistance of roots filled with gutta percha ( GP ) and different root canal sealers . Fifty-five human maxillary central incisors were selected and r and omly divided into three experimental groups ( Groups 1 - 3 ) and two control groups ( Groups 4 and 5 ) . They were Group 1 - 15 root canals filled with an epoxy resin-based sealer ( AH Plus ) and GP , Group 2 -15 root canals filled with a calcium silicate-based sealer ( iRoot SP ) and GP , Group 3 : 15 root canals filled with another calcium silicate-based sealer ( MTA Fillapex ) and GP , Group 4 : five roots were instrumented but not filled , and Group 5 : five roots were neither instrumented nor filled . Compressive loading was carried out using a universal testing machine until fracture occurred . Force applied at time of fracture was recorded as fracture strength of specimen in Newtons . There were no significant differences in fracture strength among the three experimental groups ( p>0.05 ) , whose results were significantly superior to that of Group 4 ( p root canal sealers used in the present study increased the fracture resistance of instrumented root canals",
"Background : Reinforcement of root canals obturated with Resilon was reported by several investigators , but no studies reported the reinforcement of overtly flared root canals obturated with Resilon material . The aim of this study was to investigate the fracture resistance of overtly flared root canals filled with Resilon as compared to similar root canals filled with gutta-percha ( GP ) . Material s and Methods : Sixty single-rooted premolars were divided r and omly into six groups . Group 1 served as control group . The control group was sub-divided into two groups , a negative group and a positive group . The negative group consisted of root canals that were only cleaned from residual pulpal tissues , however , the positive group had prepared and overtly flared root canals without obturation . Groups 2 and 4 were shaped using 0.04 taper rotary files , while groups 3 and 5 were shaped using 0.06 taper rotary files . Before obturation , the last four groups were further flared coronally with a reverse cone diamond bur . Groups 2 and 3 were obturated with GP and a resin-based sealer , while groups 4 and 5 were obturated with Resilon and Epiphany self-etching primer and Epiphany sealer . Roots were then fixed into a universal testing machine and vertically loaded until fracture . SPSS software ( Release 9.0 for Windows , SPSS , Chicago , USA ) was used to perform the statistical analysis . Results : Fracture resistance measurements showed that there were differences in resistance to fracture among the experimental groups ( ANOVA , P Mean values of the loading force applied to the negative control group were the highest at 1.81 KN , whereas the mean values for the Resilon groups ( Groups 4 and 5 ) at 1.13 KN and 1.54 KN were found to be higher than the GP groups ( Groups 2 and 3 ) at 0.45 KN and 0.88 KN , respectively . Tukey 's post hoc test showed that there was no statistical difference between the mean values of the negative control group and Group 5 ( P = 0.69 ) . Conclusion : Obturation of overtly flared roots with Resilon material increased the resistance of these teeth to vertical root fracture",
"OBJECTIVE The objective of this study is to evaluate the vertical root fracture resistance of endodontically treated teeth obturated with - Tubli-Seal EWT/Gutta-percha , AH Plus/Gutta-percha , Epiphany SE sealer/Epiphany point . STUDY DESIGN Sixty-five single rooted premolars were decoronated and root length was 14 mm for each specimen . Fifty five teeth were enlarged up to ISO size 40 master apical file with stainless steel K-files using st and ardized preparation and remaining ten teeth were served as negative control . Then teeth were r and omly assigned into different groups depending on sealer used for obturation as follows : Group 1 : Negative control-no instrumentation was performed . Group 2 : Positive control-gutta-percha with out the use of any sealer . Group 3 : Experimental group-gutta-percha and Tubli-Seal EWT root canal sealer . Group 4 : Experimental group-gutta-percha and AH Plus . Group 5 : Experimental group-epiphany SE sealer and epiphany points . After 72 hours , the specimens were embedded in autopolymerizing resin leaving 7 mm of each root exposed and were subjected to fracture testing under universal testing machine at a crosshead speed of 1.0 mm per minute until the root fractured . Results were statistically analyzed using one-way ANOVA and independent t-test . RESULTS Showed that Epiphany SE sealer/Epiphany points showed highest mean fracture resistance and Tubli-Seal EWT group showed the least fracture resistance of all the material s tested . There was no statistically significant difference among experimental groups . CONCLUSION Epiphany SE sealer/Epiphany points demonstrated highest fracture resistance values than the other material s tested and intact tooth had highest resistance against vertical root fracture . CLINICAL SIGNIFICANCE Epiphany SE sealer/Epiphany points may be one of the material s of choice in the endodontic treatment of teeth",
"The aim of this study was to evaluate the influence of the embedment material and periodontal ligament simulation on fracture resistance of bovine teeth . Eighty bovine incisor teeth were r and omized into 8 groups ( n = 10 ) , embedded in acrylic or polystyrene resin using 4 types of periodontal ligament simulation : 1 - -absence of the ligament ; 2 - -polyether impression material ; 3 - -polysulfide impression material ; 4 - -polyurethane elastomeric material . The specimens were stored at 370C and 100 % humidity for 24 hours . Specimens were su bmi tted to tangential load on the palatal surface at 0.5 mm/minute crosshead speed until fracture . The fracture modes were analyzed as follows : 1 - -coronal fracture ; 2 - -cemento-enamel junction fracture ; 3 - -partial root fracture ; 4 - -total root fracture . Statistical analyses by two-way ANOVA and Tukey 's test were applied ( p root embedment method and periodontal ligament simulation have a significant effect on fracture resistance . Artificial periodontal ligament modified the fracture modes ",
"OBJECTIVE To investigate the role of dentinal tubules in the fracture properties of human root dentin and whether resin-filled dentinal tubules can enhance fracture resistance . MATERIAL S AND METHODS Crack propagation in human root dentin was investigated in 200 microm thick longitudinal sample s and examined by light and scanning electron microscopy . 30 maxillary premolar teeth were prepared for work of fracture ( Wf ) test at different tubule orientations , one perpendicular and two parallel to dentinal tubules . Another 40 single canal premolars were r and omly divided into four groups of 10 each : intact dentin , prepared but unobturated canal , canal obturated with epoxy rein ( AH Plus/gutta percha ) , or with UDMA resin sealer ( Resilon/RealSeal . The sample s were prepared for Wf test parallel to dentinal tubules . Wf was compared under ANOVA with statistical significance set at p tubules influenced the path of cracks through dentin , with micro-cracks initiated in peritubular dentin of individual tubules ahead of the main crack tip . A significant difference ( p epoxy- or UDMA-based resins as sealer cements substantially influenced fracture properties of root dentin , despite extensive infiltration of dentinal tubules by both sealer cements",
"AIM To determine whether resin-based sealer cements are able to strengthen root dentine , as measured by work of fracture ( Wf ) , micro-punch shear strength ( MPSS ) and resistance to vertical root fracture ( VRF ) . METHODOLOGY One hundred and twenty extracted premolar teeth were r and omly assigned amongst four treatments before testing : intact , root canals prepared but unfilled , or root filled using epoxy- or urethane dimethacrylate (UDMA)-based sealer ( plus core material ) . Sample s were then prepared for measuring Wf , MPSS or VRF using st and ard test procedures . Data were analyzed using one-way anova with significance set at P epoxy resin-based sealer were not statistically significantly different compared with UDMA resin ( P = 1 for Wf , P = 0.7 for MPSS and P = 0.12 for VRF ) , or different from both sound and prepared dentine ( P > 0.05 ) . There was also no significant difference between sound dentine and prepared dentine for both Wf ( P = 0.92 ) and resistance to VRF ( P = 1 ) . CONCLUSIONS Neither epoxy nor UDMA resins used as sealer cements enhanced fracture resistance of root dentine when placed within root canals of extracted teeth",
"Objective Considering that periodontal ligament simulation may influence the stress distribution over teeth restored with intraradicular retainers , this study aim ed to assess the combined effect of mechanical cycling and periodontal ligament simulation on both the bond strength between fiber posts and root dentin and the fracture resistance of teeth restored using glass fiber posts . Material and Methods Ninety roots were r and omly distributed into 3 groups ( n=10 ) ( C-MC : control ; P-MC : polyether ; AS-MC : addition silicone ) to test bond strength and 6 groups ( n=10 ) ( C : control ; P : polyether ; AS : addition silicone , without mechanical cycling , and C-MC , P-MC and AS-MC with mechanical cycling ) to test fracture strength , according to the material used to simulate the periodontal ligament . For the bond strength test , fiber posts were cemented , cores were built , mechanical cycling was applied ( 2 × 106 cycles , 88 N , 2.2 Hz , and 45º incline ) , and the teeth cut into 3 slices ( 2 mm ) , which were then subjected to the push-out test at 1 mm/min . For the fracture strength test , fiber posts were cemented , cores were built , and half of the groups received mechanical cycling , followed by the compressive strength ( 45 ° to the long axis and 1 mm/min ) performed on all groups . Results Periodontal ligament simulation did not affect the bond strength ( p=0.244 ) between post and dentin . Simulation of periodontal ligament ( p=0.153 ) and application of mechanical cycling ( p=0.97 ) did not affect fracture resistance . Conclusions The material s used to simulate the periodontal ligament did not affect fracture or bond strength , therefore periodontal ligament simulation using the tested material s could be considered optional in the conditions of the study",
"The aim of this study was to compare the vertical fracture resistance of roots obturated with different root canal filling material s and sealers . Crowns of 55 extracted m and ibular premolar teeth were removed to provide root lengths of 13 mm . Five roots were saved as negative control group ( canals unprepared and unfilled ) . Fifty root canals were instrumented and then five roots were saved as positive control group ( canals prepared but unfilled ) . The remaining 45 roots were r and omly divided into three experimental groups ( n = 15 root/group ) and obturated with the following procedures : in group 1 , glass ionomer-based sealer and cone ( ActiV GP obturation system ) ; in group 2 , bioceramic sealer and cone ( EndoSequence BC obturation system ) ; and in group 3 , roots were filled with bioceramic sealer and cone ( Smartpaste bio obturation system ) . All specimens were tested in a universal testing machine for measuring fracture resistance . For each root , the force at the time of fracture was recorded in Newtons . The statistical analysis was performed by using Kruskal-Wallis and post hoc test . There were no significant differences between the three experimental groups . The fracture values of three experimental and negative control groups were significantly higher than the positive control group . Within the limitations of this study , all material s increased the fracture resistance of instrumented roots",
"AIM To evaluate the effect of chlorhexidine ( CHX ) on fracture resistance of roots treated with different concentrations of ethylenediaminetetraacetic acid ( EDTA ) . METHODOLOGY One hundred and twenty intact single-rooted premolar teeth were sectioned below the cementum-enamel junction to st and ardize the length of the teeth to 12 mm . The canals of one hundred specimens were instrumented with ProTaper Universal rotary instruments up to size F4 and were r and omly divided into five groups ( n = 20 ) according to the final irrigating solutions : Group 1 : distilled water ( DW ) ; Group 2 : 5 % EDTA and 2.5 % NaOCl ; Group 3 : 17 % EDTA and 2.5 % NaOCl ; Group 4 : 5 % EDTA , 2.5 % NaOCl , DW and 2 % CHX ; Group 5 : 17 % EDTA and 2.5 % NaOCl , DW and 2 % CHX . Root canals were filled with gutta-percha and epoxy resin-based root canal sealer using a single-cone technique . Twenty teeth served as negative controls and were not instrumented nor root filled ( Group 6 ) . All specimens were embedded in self-curing acrylic resin and loaded vertically at 0.5 mm min-1 until fracture occurred . The data were evaluated statistically using one-way anova test followed by Holm-Sidak 's multiple comparison test ( P vertical fracture strength , followed by Group 3 ( 17 % EDTA and 2.5 % NaOCl ; P fracture resistance . Final irrigation with CHX following irrigation with 17 % EDTA or 5 % EDTA and 2.5 % NaOCl ( groups 4 and 5 ) significantly increased the fracture resistance of roots ( P 0.05 ) . CONCLUSIONS Intracanal CHX rinse of EDTA/NaOCl-treated root dentine enhanced the fracture resistance of roots filled with AH Plus",
"BACKGROUND The authors evaluated the fracture resistance of endodontically treated teeth filled with either gutta-percha or a new resin-based obturation material . METHODS The authors prepared and r and omly divided 80 single-canal extracted teeth into five groups : lateral and vertical condensation with gutta-percha , lateral and vertical condensation with the new resin-based obturation material , and a control group with no filling material . The specimens were stored in 100 percent humidity for two weeks , mounted in polyester resin and loaded to failure . RESULTS The authors found statistically significant differences among the experimental groups ( P mean fracture loads and the gutta-percha groups lower mean fracture load values than the control unfilled group . However , the differences were not significant . The groups with the new material displayed significantly higher mean fracture loads than gutta-percha groups independent of the filling technique used . CONCLUSIONS Filling the canals with the new resin-based obturation material increased the in vitro resistance to fracture of endodontically treated single-canal extracted teeth when compared with st and ard gutta-percha techniques . CLINICAL IMPLICATION S ; If other properties of the new resin-based obturation material compare favorably with those of gutta-percha for filling the root canal , it should be considered as a replacement for gutta-percha , as the results of this study indicate that it could provide enhanced resistance to tooth fracture",
"INTRODUCTION The aim of this study was to evaluate the fracture resistance of teeth filled with 3 different endodontic sealers . METHODS Seventy-five single-rooted extracted m and ibular premolars were decoronated to a length of 13 mm . The teeth were r and omly divided into 5 groups ( n = 15 for each group ) . In group 1 , the teeth were left unprepared and unfilled ( negative control ) , and in group 2 , the teeth were left unobturated ( positive control ) . The rest of the roots were prepared by using the ProTaper System up to a master apical file size of F3 : group 3 , bioceramic sealer ( Endosequence BC sealer ) + gutta-percha ; group 4 , mineral trioxide aggregate-based sealer ( Tech Biosealer Endo ) + gutta-percha ; and group 5 , epoxy resin-based sealer ( AH Plus Jet ) + gutta-percha . All root specimens were stored for 2 weeks at 100 % humidity to allow the complete setting of the sealers . Each specimen was then subjected to fracture testing by using a universal testing machine at a crosshead speed of 1.0 mm/min(-1 ) until the root fractured . The force required to fracture each specimen was recorded , and the data were analyzed statistically . RESULTS The fracture values of groups 3 and 5 were significantly higher than those of group 4 ( P .05 ) . CONCLUSIONS In contrast to Tech Biosealer Endo , Endosequence BC and AH Plus Jet sealer increased the force to fracture in root-filled single-rooted premolar teeth",
"OBJECTIVE The aim of this study was to evaluate and compare the fracture resistance of endodontically treated teeth filled with gutta percha and Resilon using lateral and vertical condensation methods . MATERIAL S AND METHODS A total of 75 freshly extracted single-rooted teeth were selected . All sample s were instrumented with profile 4 % Ni-Ti rotary instruments . Sample s were r and omly divided into five groups of 15 sample s each : Group 1 was obturated using lateral condensation with gutta percha and AH -26 sealer . Group 2 was obturated using vertical condensation with gutta-percha and AH-26 . Group 3 was obturated with Resilon and epiphany using lateral condensation technique . Group 4 was obturated with Resilon and epiphany using vertical condensation method . Group 5 received no filling . Restored teeth were subjected to compressive loading in a universal testing machine . RESULTS One-way ANOVA test showed significant difference among the groups ( P highest fracture resistance followed by Group 4 , Group 1 , and Group 2 . Group 5 showed the least fracture resistance . CONCLUSION Resilon-epiphany obturated roots using lateral condensation method showed higher fracture resistance compared with gutta percha-AH 26 groups on vertical loading",
" AIM To evaluate the vertical root fracture resistance of maxillary central incisors filled with different root filling material s and sealers . METHODOLOGY Forty maxillary central incisor root canals were instrumented and divided r and omly into four groups . Each group was filled using lateral compaction , with gutta-percha and AH Plus , gutta-percha and RealSeal ( ® ) sealer , RealSeal ( ® ) cone and RealSeal ( ® ) sealer , or RealSeal ( ® ) cone and AH Plus , respectively . The roots were loaded vertically by a conical spreader tip inserted into the canal and attached to an Instron testing machine until root fracture occurred . The load at fracture and the pattern of fracture were recorded . Mechanical properties of both core material s were tested under compressive loading . Results were analysed statistically by two-way analysis of variance and post hoc Tukey 's tests . An independent sample t-test was used to compare the mechanical properties of the filling material s. RESULTS Load at fracture of roots filled with gutta-percha and AH Plus ( 255 ± 74 N ) and gutta-percha and RealSeal ( ® ) sealer ( 237 ± 38 N ) was significantly greater than those filled using the RealSeal ( ® ) system ( 163 ± 29 N ) and RealSeal ( ® ) cone with AH Plus sealer ( 134 ± 17 N ) . Most fracture lines were in a bucco-lingual direction . In compressive tests of the core material s , RealSeal ( ® ) had greater flow in response to load than gutta-percha , suggesting more efficient transmission of forces to the canal wall in the fracture tests . CONCLUSIONS The lower fracture resistance of roots filled using RealSeal ( ® ) is probably the result of more efficient transmission of forces within the canal , rather than a direct effect of the material itself",
"The purpose of this in vitro study was to test the effect of Ketac-Endo ( KE ) and AH 26 on resistance to root fracture and also to evaluate the effect of smear layer . Seventy-two human maxillary canine teeth were r and omly divided into six groups ( n = 12 ) and were prepared using six different methods : group 1 : KE , without smear layer ( smear - ) ; group 2 : KE , with smear layer ( smear + ) ; group 3 : AH 26 , smear ( - ) ; group 4 : AH 26 , smear ( + ) ; group 5 ( negative control ) : nonprepared ; group 6 ( positive control ) : prepared but unfilled . After storing 1 week in 100 % humidity at 37 degrees C , the coronal lingual walls and root canal spaces were lowered 2 mm below the buccal walls of the roots . The sample s were placed into acrylic resin blocks so that 10 mm of buccal roots were exposed and were placed in a specially design ed steel pad at an angle of 15 degrees to the long axis of the root . A slowly increasing force was applied at the junction of the buccal wall and root canal space until fracture occurred . The force required to fracture each tooth was recorded as kg and statistically analyzed using one-way analysis of variance and Duncan tests . The results indicated that instrumentation of the root canals significantly weakened the tooth structure to fracture ( p stronger than roots whose canals were instrumented but not obturated ( p root fracture resistance of the teeth ( p > 0.05 )",
"The purpose of this research was to determine if the use of Endocal 10 ( previously called Biocalex 6.9 ) is associated with root fracture and to assess its sealability . Thirty-six freshly extracted , single canal human m and ibular incisors were instrumented and r and omly divided into two equal groups ( n = 15 ) . Canals in group A were obturated with vertically compacted gutta-percha and Sealapex , and those in group B were filled with Endocal 10 placed with a # 25 Lentulo spiral per manufacturer 's instructions . Two blinded investigators evaluated the teeth for fractures using transillumination and an operating microscope at 12 x magnification . Three of the fifteen sample s filled with Endocal 10 had vertically fractured in half , whereas none of the teeth filled with gutta-percha had any evident fracture lines . The remaining teeth were tested for leakage via a fluid filtration model at 1 wk and 30 days postobturation . No leakage was found among any of the sample s whether filled with gutta-percha or with Endocal 10 at either time interval . Statistical analyses were completed using Fisher 's exact test ( p = 0.023 ) , which showed that there was a significant increase in chance of fracture when using Endocal 10 versus gutta-percha . The results indicate that , although Endocal 10 is able to seal the tooth as well as gutta-percha and sealer , there is a significant potential risk of root fracture",
"OBJECTIVE The aim of this study was to compare the fracture resistance of roots obturated with different material s. STUDY DESIGN Sixty root canals were instrumented and divided into 4 equal groups ( n = 15 each ) . The root canals in group 1 were filled with AH26 sealer and gutta-percha , in group 2 with Resilon and Epiphany , and in group 3 with Ketac-Endo Aplicap and gutta-percha . Fifteen root canals had no obturation . The force required to fracture was recorded . The data was analyzed with analysis of variance and Duncan test . RESULTS The mean force of fracture for group 1 was significantly higher than for the other 3 groups ( P .05 ) . CONCLUSION The use of AH26 + gutta-percha increased the fracture resistance of instrumented root canals compared with Resilon + Epiphany and Ketac-Endo Aplicap + gutta-percha",
"This study aim ed to evaluate the effect of final irrigation protocol s on microhardness reduction and erosion of root canal dentin . Sixty root canals from m and ibular incisors were instrumented and r and omly divided into six groups ( n = 10 ) according to the irrigant used : QMiX , 17 % EDTA , 10 % citric acid ( CA ) , 1 % peracetic acid ( PA ) , 2.5 % NaOCl ( solution control ) , and distilled water ( negative control ) . The chelating solutions were used to irrigate the canal followed by 2.5 % NaOCl as a final flush . After the irrigation protocol s , all specimens were rinsed with 10 mL of distilled water to remove any residue of the chemical solutions . Before and after the final irrigation protocol s , dentin microhardness was measured with a Knoop indenter . Three indentations were made at 100 µm and 500 µm from the root canal lumen . Afterwards , the specimens were prepared for scanning electron microscopic analysis and the amount of dentin erosion was examined . Wilcoxon and Kruskal-Wallis tests were used to analyze the results with a significance level set at 5 % . At 100 µm , all protocol s significantly reduced dentin microhardness ( p .05 ) . CA was the irrigant that caused more extensive erosion in dentinal tubules , followed by PA and EDTA . QMiX opened dentinal tubules , but did not cause dentin erosion . Results suggest that QMiX and 17 % EDTA reduced dentin microhardness at a greater depth . Additionally , QMiX did not cause dentin erosion ",
"This study compared the microshear bond strength of three resin-based sealers to root dentin and assessed whether sealer cements behave differently in thin and thick films . Extracted maxillary premolars were sectioned buccolingually , and 45 root halves were r and omly allocated for microshear bond testing with the three resin sealers in thin and thick films . The microshear bond strength was then calculated in MPa . Failure modes were examined under light and scanning electron microscopy . Data were analyzed by using analysis of variance , with significance set at p epoxy resin-based sealers had the highest microshear bond strength to root dentin compared with urethane dimethacrylate-based sealers ( p Bond strengths for the thick sealer group were significantly higher than the thin sealer group ( p < 0.001 ) and may reflect different patterns of behavior when the sealer is present as a thin layer",
"INTRODUCTION The purpose of this study was to compare the effect of different final irrigation solutions on fracture resistance values ( FRVs ) of endodontically treated teeth . METHODS Eighty extracted decoronated human incisors were used . Ten r and omly selected roots were used as the negative control group . The remaining roots were prepared by the ProTaper system ( Dentsply Maillefer , Ballaigues , Switzerl and ) up to F2 . Ten prepared roots were selected as the positive control . The other prepared roots were divided into 6 ( n = 10 ) groups according to the final irrigation solution used : 5 mL saline , 17 % EDTA , EDTA with a surfactant ( REDTA ) , chlorhexidine , QMix ( Dentsply Tulsa Dental Specialties , Tulsa , OK ) , and BioPure MTAD ( Dentsply Tulsa Dental Specialties ) . In all groups , the final irrigation was performed for 1 minute except for the BioPure MTAD group ; in this group , it was applied for 5 minutes according to the manufacturer 's instructions . The specimens were filled with a single gutta-percha cone and AH 26 sealer ( Dentsply , De Trey , Konstanz , Germany ) . After being stored under 37 ° C and 100 % humidity for a week , the specimens were loaded in a vertical direction at 1 mm/min speed until they were vertically fractured . The results were analyzed by the Kruskal-Wallis and Siegel Castellan tests . RESULTS The negative control group showed the highest FRV . There were statistically significant differences between the negative and positive control groups ( P higher FRV compared with the positive control group ( P chlorhexidine and BioPure MTAD showed a lower FRV compared with the negative control group ( P FRV . A short time exposure to irrigation solutions ( REDTA and QMix ) that include surfactants probably contributed to the higher FRV , instead of a long time exposure as done with BioPure MTAD",
"PURPOSE The aim of this study was to assess the role of obturating systems , dowel material s , and adhesive techniques on the resistance to fracture of endodontically treated teeth . MATERIAL AND METHODS Eighty maxillary central incisors were selected and r and omly divided into two groups according to the obturating system ( n = 40 ) ; group I : gutta-percha and Roeko sealer ; group II : RealSeal . Both groups were further subdivided into two subgroups ; subgroup A : using ceramic dowels ( Cosmopost ) ; subgroup B using fiber dowels ( Easy Post ) . Each subgroup was assigned to two divisions according to the adhesive luting technique ; division V ( total-etch ) Variolink II resin cement ; division U ( self-adhesive ) RelyX Unicem . Composite core build-up was made using a core former . Each specimen was loaded 2 mm from its incisal edge on the palatal side at a 135 ° angle with the long axis of the tooth using a universal testing machine with a load cell of 5 KN at a crosshead speed of 0.5 mm/min until fracture . Failure loads were recorded in N. Scanning electron microscopic examination at the dentin/resin interface ( 1000x ) was performed . Three-way ANOVA was used to test the effect of obturating system , dowel material , adhesive technique , and their interactions ( obturating system * dowel material , obturating system * adhesive , dowel material * adhesive , obturating system * dowel material * adhesive ) . Duncan 's test was used for pairwise comparison . The significance level was set at p≤ 0.05 . Statistical analysis was performed with SPSS 16.0 . RESULTS The mean resistance to fracture ( 617.4 N ) was statistically significantly higher in the ceramic dowel with gutta-percha and Variolink ( GP/C/V ) group than in the other groups . The RealSeal and RelyX fiber dowel group 's mean resistance was the lowest and was significantly lower than the other groups . CONCLUSIONS In this study , three factors played a part in enhancing the resistance to fracture of endodontically treated teeth . High resistance to fracture was achieved when ceramic dowels were luted with total-etch technique in gutta-percha-obturated teeth",
"INTRODUCTION This study aim ed to evaluate the effects of root canal irrigants on the microhardness of root canal dentin in the presence and absence of surface-modifying agents . METHODS Forty-eight root halves were prepared by longitudinal splitting of the distal roots of 24 freshly extracted m and ibular human third molars and embedded in autopolymerizing acrylic resin , leaving the dentin surface exposed . After polishing , the microhardness values of the untreated dentin surfaces were recorded by using Vickers tester at the mid-root level . The root halves were r and omly assigned to 6 groups composed of 8 sample s each and treated for 5 minutes with one of the following irrigants : 17 % EDTA , REDTA , 2 % chlorhexidine gluconate ( CHX ) , 2 % CHX with surface modifiers ( CHX-Plus ) , 6 % NaOCl , or 6 % NaOCl with surface modifiers ( Chlor-XTRA ) . After surface treatment , dentin microhardness values were recorded at close proximity to the initial indentation areas . Experimental data were statistically analyzed by using the t test and one-way analysis of variance , followed by Tukey honestly significant difference test at α = 0.05 . RESULTS EDTA , REDTA , NaOCl , and Chlor-XTRA significantly decreased the microhardness of root dentin compared with intact controls ( P the microhardness of the sample"
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Aim and background Reducing inflammation by nutritional supplements may help to reduce the risk of many chronic diseases . Our aim in this meta- analysis was to determine the effect of L-carnitine on inflammatory mediators including C-reactive protein ( CRP ) , tumor necrosis factor-α ( TNF-α ) , and interleukin-6 ( IL-6 ) . Methods Our systematic search to find relevant r and omized clinical trials ( RCTs ) was performed up to October 2018 using ISI Web of Science , Google Scholar , PubMed / Medline , and SCOPUS . In this meta- analysis , the weighted mean differences ( WMD ) with st and ard errors ( SE ) were used to pool the data . WMD was calculated by subtracting change-from-baseline mean values in the control group from change-from-baseline mean values in the intervention group in each study . To identify heterogeneity among studies , the I2 statistic was employed . The protocol was registered with PROSPERO ( No. CRD42019116695 ) . Results Thirteen articles were included in our systematic review and meta- analysis . The results of the meta- analysis indicated that L-carnitine supplementation was significantly associated with lower levels of CRP in comparison to controls ( WMD = −1.23 mg/L ; 95 % CI : −1.73 , −0.72 mg/dL ; P observed in IL-6 and TNF-α levels ( WMD = −0.85 pg/dL ; 95 % CI : −1.38 , −0.32 pg/dL ; P = 0.002 and WMD = −0.37 pg/dL ; 95 % CI : −0.68 , −0.06 pg/dL ; P = 0.018 , respectively ) . Conclusion Our results indicate that L-carnitine reduced inflammatory mediators , especially in studies with a duration of more than 12 weeks . Further studies with different doses and intervention duration s and separately in men and women are necessary
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"BACKGROUND Interleukin-6 ( IL-6 ) plays a central role in inflammation and tissue injury . However , epidemiological data evaluating the role of IL-6 in atherogenesis are sparse . METHODS AND RESULTS In a prospect i ve study involving 14 916 apparently healthy men , we measured baseline plasma concentration of IL-6 in 202 participants who subsequently developed myocardial infa rct ion ( MI ) and in 202 study participants matched for age and smoking status who did not report vascular disease during a 6-year follow-up . Median concentrations of IL-6 at baseline were higher among men who subsequently had an MI than among those who did not ( 1.81 versus 1 . 46 pg/mL ; P=0.002 ) . The risk of future MI increased with increasing quartiles of baseline IL-6 concentration ( P for trend C-reactive protein ( r=0.43 , P IL-6 with subsequent risk remained after control for this factor ( P apparently healthy men , elevated levels of IL-6 are associated with increased risk of future MI . These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis",
"OBJECTIVE Inflammation mediators have been recognized as risk factors for the pathogenesis of coronary artery disease ( CAD ) . The purpose of this study was to investigate the effect of L-carnitine supplementation ( LC , 1000 mg/d ) on inflammation markers in patients with CAD . METHODS We enrolled 47 patients with CAD in the study . The patients with CAD were identified by cardiac catheterization as having The patients were r and omly assigned to the placebo ( n = 24 ) and LC ( n = 23 ) groups and the intervention was administered for 12 wk . The levels of LC , antioxidant status ( malondialdehyde and antioxidant enzymes activities ) , and inflammation markers ( C-reactive protein [ CRP ] , interleukin [IL]-6 , and tumor necrosis factor [TNF]-α ) were measured . RESULTS Thirty-nine participants completed the study ( 19 placebo ; 20 LC ) . After LC supplementation , the levels of inflammation markers were significantly reduced compared with the baseline ( CRP , P the placebo group ( CRP , P P = 0.03 ) . The levels of inflammation markers were significantly negatively correlated with the levels of LC and antioxidant enzymes activities ( P that LC supplementation , due to its antioxidant effects , may have potential utility to reduce inflammation in CAD",
"Background Resting and postpr and ial oxidative stress is elevated in those with metabolic disorders such as diabetes . Antioxidant supplementation may attenuate the rise in oxidative stress following feeding . Therefore we sought to determine the effects of acetyl L-carnitine arginate ( ALCA ) on resting and postpr and ial biomarkers of glucose and lipid metabolism , as well as oxidative stress . Methods Twenty-nine pre-diabetic men and women were r and omly assigned to either 3 g·day-1 of ALCA ( n = 14 ; 31 ± 3 yrs ) or placebo ( n = 15 ; 35 ± 3 yrs ) in a double-blind design , to consume for eight weeks . Fasting blood sample s were taken from subjects both pre and post intervention . After each fasting sample was obtained , subjects consumed a high fat , high carbohydrate meal and additional blood sample s were taken at 1 , 2 , 4 , and 6 hours post meal . Sample s were analyzed for a variety of metabolic variables ( e.g. , glucose , HbA1c , lipid panel , C-reactive protein , nitrate/nitrite , and several markers of oxidative stress ) . Area under the curve ( AUC ) was calculated for each variable measured post meal , both pre and post intervention . Results ALCA , but not placebo , result ed in an increase in nitrate/nitrite ( 25.4 ± 1.9 to 30.1 ± 2.8 μmol·L-1 ) from pre to post intervention , with post intervention values greater compared to placebo ( p = 0.01 ) . No other changes of statistical significance were noted ( p > 0.05 ) , although ALCA result ed in slight improvements in glucose ( 109 ± 5 to 103 ± 5 mg·dL-1 ) , HbA1c ( 6.6 ± 1.1 to 6.2 ± 1.2 % ) , and HOMA-IR ( 3.3 ± 1.3 to 2.9 ± 1.2 ) . AUC postpr and ial data were not statistically different between ALCA and placebo for any variable ( p > 0.05 ) . However , nitrate/nitrite demonstrated a moderate effect size ( r = 0.35 ) for increase from pre ( 139.50 ± 18.35 μmol·L-1·6 hr-1 ) to post ( 172.40 ± 21.75 μmol·L-1·6 hr-1 ) intervention with ALCA , and the magnitude of decrease following feeding was not as pronounced as with placebo . ConclusionS upplementation with ALCA results in an increase in resting nitrate/nitrite in pre-diabetics , without any statistically significant change in other metabolic or oxidative stress variables measured at rest or post meal",
"Background Frailty is a biological syndrome of decreased reserve and resistance to stressors due to decline in multiple physiological systems . Amino acid deficiency , including L-carnitine , has been proposed to be associated with its pathophysiology . Nevertheless , the efficacy of L-carnitine supplementation on frailty status has not been documented . Thus , this study aim ed to determine the effect of 10-week L-carnitine supplement ( 1.5 g/day ) on frailty status and its biomarkers and also physical function , cognition , and nutritional status among prefrail older adults in Klang Valley , Malaysia . Methodology This study is a r and omized , double-blind , placebo-controlled clinical trial conducted among 50 prefrail subjects r and omized into two groups ( 26 in L-carnitine group and 24 in placebo group ) . Outcome measures include frailty status using Fried criteria and Frailty Index accumulation of deficit , selected frailty biomarkers ( interleukin-6 , tumor necrosis factor-alpha , and insulin-like growth factor-1 ) , physical function , cognitive function , nutritional status and biochemical profile . Results The results indicated that the mean scores of Frailty Index score and h and grip test were significantly improved in subjects supplemented with L-carnitine ( P placebo group . Based on Fried criteria , four subjects ( three from the L-carnitine group and one from the control group ) transited from prefrail status to robust after the intervention . Conclusion L-carnitine supplementation has a favorable effect on the functional status and fatigue in prefrail older adults",
"The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight , glycemic control , insulin resistance , and inflammatory state in type 2 diabetes mellitus patients . Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus ( glycated hemoglobin [ HbA(1c ) ] > 8.0 % ) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and r and omized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy . We evaluated at baseline and after 3 , 6 , 9 , and 12 months these parameters : body weight , body mass index , HbA(1c ) , fasting plasma glucose , postpr and ial plasma glucose , fasting plasma insulin , homeostasis model assessment of insulin resistance index , total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triglycerides , leptin , tumor necrosis factor-α , adiponectin , vaspin , and high-sensitivity C-reactive protein . Sibutramine plus L-carnitine gave a faster improvement of fasting plasma glucose , postpr and ial plasma glucose , lipid profile , leptin , tumor necrosis factor-α , and high-sensitivity C-reactive protein compared with sibutramine alone . Furthermore , there was a better improvement of body weight , HbA(1c ) , fasting plasma insulin , homeostasis model assessment of insulin resistance index , vaspin , and adiponectin with sibutramine plus L-carnitine compared with sibutramine alone . Sibutramine plus L-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect",
" OBJECTIVES : Nonalcoholic steatohepatitis ( NASH ) is a known metabolic disorder of the liver . No treatment has been conclusively shown to improve NASH or prevent disease progression . The function of L-carnitine to modulate lipid profile , glucose metabolism , oxidative stress , and inflammatory responses has been shown . The aim of this study was to evaluate the effects of L-carnitine 's supplementation on regression of NASH . METHODS : In patients with NASH and control subjects , we r and omly dispensed one 1-g L-carnitine tablet after breakfast plus diet and one 1 g tablet after dinner plus diet for 24 weeks or diet alone at the same dosage and regimen . We evaluated liver enzymes , lipid profile , fasting plasma glucose , C-reactive protein ( CRP ) , tumor necrosis factor (TNF)-α , homeostasis model assessment (HOMA)-IR , body mass index , and histological scores . RESULTS : At the end of the study , L-carnitine-treated patients showed significant improvements in the following parameters : aspartate aminotransferase ( P=0.000 ) , alanine aminotransferase ( ALT ) ( P=0.000 ) , γ-glutamyl-transpeptidase ( γ-GT ) ( P=0.000 ) , total cholesterol ( P=0.000 ) , low-density lipoprotein ( LDL ) ( P=0.000 ) , high-density lipoprotein ( HDL ) ( P=0.000 ) , triglycerides ( P=0.000 ) , glucose ( P=0.000 ) , HOMA-IR ( P=0.000 ) , CRP ( P=0.000 ) , TNF-α ( P=0.000 ) , and histological scores ( P=0.000 ) . CONCLUSIONS : L-carnitine supplementation to diet is useful for reducing TNF-α and CRP , and for improving liver function , glucose plasma level , lipid profile , HOMA-IR , and histological manifestations of NASH ",
"To evaluate the effects of 1-year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight , glycemic and lipid control , and inflammatory parameters in obese type 2 diabetic patients . Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus ( T2DM ) [ glycated hemoglobin ( HbA(1c ) ) > 8.0 % ] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and r and omized to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day . We evaluated the following parameters at baseline and after 3 , 6 , 9 , and 12 months : body weight , body mass index ( BMI ) , glycated hemoglobin ( HbA(1c ) ) , fasting plasma glucose ( FPG ) , postpr and ial plasma glucose ( PPG ) , fasting plasma insulin ( FPI ) , homeostasis model assessment insulin resistance index ( HOMA-IR ) , total cholesterol ( TC ) , low-density lipoprotein cholesterol ( LDL-C ) , high-density lipoprotein cholesterol ( HDL-C ) , triglycerides ( Tg ) , adiponectin ( ADN ) , leptin , tumor necrosis factor-α ( TNF-α ) , vaspin , and high-sensitivity C-reactive protein ( Hs-CRP ) . We observed a better decrease in body weight , glycemic profile , HOMA-IR , LDL-C , and ADN and a faster improvement in FPI , TC , Tg , leptin , TNF-α , Hs-CRP with orlistat plus L-carnitine compared to orlistat alone . We also recorded an improvement in vaspin with orlistat plus l-carnitine not reached with orlistat alone . Orlistat plus L-carnitine gave a better improvement in body weight , glycemic and lipid profile compared to orlistat alone ; furthermore , a faster and better improvement in inflammatory parameters was observed with orlistat plus L-carnitine compared to orlistat alone",
"Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists",
"AIM Obesity is an important worldwide public health problem and considered a disease of chronic low- grade inflammation . The aim of this study was to evaluate the effect of L-carnitine supplementation in comparison with moderate aerobic exercise training on serum inflammatory parameters in healthy obese women . METHODS In this double-blind r and omized controlled clinical trial , 44 obese women were r and omly assigned to 4 groups ( N.=11 ) as follows : 1 : L-carnitine supplementation ( 2 g/day ) ( CAR ) , 2 : aerobic training + placebo ( EXR+PLA ) , 3 : L-carnitine supplementation + aerobic training ( CAR+EXR ) and 4 : placebo ( PLA ) . All intervention periods were eight weeks and subjects of aerobic training groups underwent 8-week aerobic training protocol ( 3 sessions a week [ 24 sessions ] ) . Body Mass Index , daily dietary intake and serum free L-carnitine , IL-6 , high-sensitivity C-reactive protein ( Hs-CRP ) and IL-10 levels of subjects were measured before and after interventions . RESULTS Interventions had no significant effects on body weight , BMI , daily dietary intake and serum IL-10 levels of subjects in all groups . Serum free L-carnitine concentration increased significantly after interventions in CAR and CAR+EXR groups . Significant decreases of IL-6 were observed in EXR+PLA and CAR+EXR groups compared with placebo group . L-carnitine supplementation plus aerobic training led to significant decrease of serum Hs-CRP levels in CAR+EXR group compared with baseline values . CONCLUSION L-carnitine supplementation did not affect serum IL-6 , Hs-CRP and IL-10 levels in obese women . Aerobic training alone or in combination with L-carnitine had favorable effect on serum Il-6 and Hs-CRP levels as markers of inflammation in studied subjects",
"OBJECTIVE To evaluate the effects of one year of treatment with sibutramine plus L-carnitine compared to sibutramine on body weight , glycemic control , and insulin resistance state in type 2 diabetic patients . METHODS Two hundred and fifty-four patients with uncontrolled type 2 diabetes mellitus ( T2DM ) [ glycated hemoglobin ( HbA(1c ) ) > 8.0 % ] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and r and omised to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy . We evaluated at baseline , and after 3 , 6 , 9 , and 12 months these parameters : body weight , body mass index ( BMI ) , glycated hemoglobin ( HbA(1c ) ) , fasting plasma glucose ( FPG ) , post-pr and ial plasma glucose ( PPG ) , fasting plasma insulin ( FPI ) , homeostasis model assessment insulin resistance index ( HOMA-IR ) , total cholesterol ( TC ) , low density lipoprotein-cholesterol ( LDL-C ) , high density lipoprotein-cholesterol ( HDL-C ) , triglycerides ( Tg ) , retinol binding protein-4 ( RBP-4 ) , resistin , visfatin , high sensitivity-C reactive protein ( Hs-CRP ) . RESULTS There was a decrease in body weight , BMI , HbA(1c ) , FPI , HOMA-IR , and RBP-4 in both groups , even when the values obtained with sibutramine plus L-carnitine were lower than the values obtained in sibutramine group . There was a faster decrease of FPG , PPG , TC , LDL-C , resistin and Hs-CRP with sibutramine plus L-carnitine even when no differences between the two groups were obtained . Furthermore , only sibutramine plus L-carnitine improved Tg , and visfatin . CONCLUSION Sibutramine plus L-carnitine gave a faster improvement of lipid profile , insulin resistance parameters , glycemic control , and body weight compared to sibutramine",
"Probiotic therapies are going to be an effective alternative therapeutic strategy in the treatment and management of diabetes . The mechanism behind the essential effects of probiotic therapies in diabetic patients was not fully understood . The objective of this study was to evaluate the effects of probiotic soy milk containing Lactobacillus planetarum A7 on inflammation , lipid profile , fasting blood glucose , and serum adiponectin among patients with type 2 diabetes mellitus . Forty patients with type 2 diabetes , at the age of 35–68 years old , were assigned to two groups in this r and omized , double-blind , controlled clinical trial . The patients in the intervention group consumed 200 ml/day of probiotic soy milk containing L. planetarum A7 and those in control group consumed 200 ml/day of pure soy milk for 8 weeks . Serum TNF-α , C reactive protein , adiponectin , lipid profile , and fasting blood glucose were determined before and after intervention . In intervention group , serum adiponectin in pre- and post-treatment did not show any significant changes ( 2.52 ± 0.74 vs 2.84 ± 0.61 , P = 0.658 ) , as well as changes in serum TNF-α and C reactive protein ( 172.44 ± 5.7 vs 172.83 ± 7.6 , P = 0.278 , 4.2 ± 1.4 vs 4.5 ± 1.9 , P = 0.765 , respectively ) . Low-density cholesterol and high-density cholesterol changed significantly ( P = 0.023 , P = 0.017 , respectively ) , but fasting blood glucose did not show any significant changes . The results of this study showed that consumption of probiotic soy milk and soy milk has no effect on serum adiponectin and inflammation , but it can change lipid profile among type 2 diabetic patients",
"Our study wants to evaluate the effects of one year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight , glycemic and lipid control , and insulin resistance state in type 2 diabetic patients . Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus ( T2DM ) [ glycated hemoglobin ( HbA(1c ) ) > 8.0 % ] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and r and omised to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day . We evaluated at baseline , and after 3 , 6 , 9 , and 12 months these parameters : body weight , body mass index ( BMI ) , HbA(1c ) , fasting plasma glucose ( FPG ) , post-pr and ial plasma glucose ( PPG ) , fasting plasma insulin ( FPI ) , homeostasis model assessment insulin resistance index ( HOMA-IR ) , total cholesterol ( TC ) , low density lipoprotein-cholesterol ( LDL-C ) , high density lipoprotein-cholesterol ( HDL-C ) , triglycerides ( Tg ) , retinol binding protein-4 ( RBP-4 ) , resistin , visfatin , high sensitivity-C reactive protein ( Hs-CRP ) . We observed a faster , and better decrease of body weight , HbA(1c ) , FPG , PPG , LDL-C , HOMA-IR with orlistat plus L-carnitine compared to orlistat . A faster improvement of TC , Tg , FPI , resistin , RBP-4 , visfatin , and Hs-CRP was reached with orlistat plus L-carnitine compared to orlistat . We can safely conclude that the association of orlistat plus L-carnitine was better than orlistat in improving body weight , glycemic and lipid profile , insulin resistance , and inflammatory parameters and no significant adverse events were recorded",
"Abstract Herbal medicines with high amounts of phytochemicals have been shown to have beneficial effects on blood pressure ( BP ) , endothelial function and anthropometric measures . This study aim ed to determine the effect of herbal treatment on BP , endothelial function and anthropometric measures in patients with type 2 diabetes mellitus ( T2DM ) . This clinical trial included 204 T2DM patients r and omly assigned to four intervention groups receiving 3 g cinnamon , 3 g cardamom , 1 g saffron or 3 g ginger with three glasses of black tea , and one control group consuming only three glasses of tea without any herbals , for 8 weeks . Intercellular adhesion molecule-1 ( ICAM-1 ) , systolic and diastolic BP and anthropometric measures were collected at baseline and after 8 weeks . No significant difference was found between various medicinal plants in terms of influencing BP , serum soluble (s)ICAM-1 concentrations and anthropometric measures . However , in within-group comparison saffron and ginger intakes significantly reduced sICAM-1 concentrations ( 340.9 ± 14.4 vs 339.69 ± 14.4 ng/ml , p = 0.01 , and 391.78 ± 16.0 vs 390.97 ± 15.8 ng/ml , p = 0.009 , respectively ) and ginger intake affected systolic BP ( 143.06 ± 0.2 vs 142.07 ± 0.2 mmHg , p = 0.02 ) . Although administration of these herbal medicines as supplementary remedies could affect BP and sICAM-1 concentrations , there was no significant difference between the plants in terms of influencing anthropometric measures , BP and endothelial function ",
"Background : Hypercoagulability is an important risk factor for thrombosis and its complications in hemodialysis patients . This study was design ed to investigate the effects of l-carnitine supplement on plasma coagulation and anticoagulation factors in hemodialysis patients . Methods : Thirty-six hemodialysis patients were r and omly assigned to either a carnitine or a placebo group . Patients in the carnitine group received 1000 mg/day oral l-carnitine for 12 weeks , whereas patients in the placebo group received a corresponding placebo . At baseline and the end of week 12 , 5 mL blood was collected after a 12- to 14-hour fast and plasma fibrinogen concentration , activity of plasma protein C , coagulation factors V , VII , IX , and serum concentrations of tissue plasminogen activator ( tPA ) , plasminogen activator inhibitor type-1 ( PAI-1 ) , free carnitine , and C-reactive protein ( CRP ) were measured . Results : In the carnitine group , mean serum free carnitine concentration increased significantly to 150 % of baseline ( p plasma fibrinogen and serum CRP had 98 mg/dL ( p activity of plasma protein C , coagulation factors V , VII , IX , and serum PAI-1 to tPA ratio . Conclusion : l-Carnitine supplement reduces serum CRP , a marker of systemic inflammation , and plasma fibrinogen , an inflammation-related coagulation factor , in hemodialysis patients . Therefore , l-carnitine may play an effective role in preventing cardiovascular diseases in these patients",
"Atrial fibrillation ( AF ) is one of the most common complications in patients who undergo coronary artery bypass graft surgery ( CABG ) . The aim of this study was to evaluate the effect of L-carnitine administration on postoperative AF and the levels of C-reactive protein ( CRP ) following CABG . The effects of L-carnitine on the incidence of acute kidney injury after CABG were also assessed . One hundred thirty-four patients undergoing elective CABG , without a history of AF or previous L-carnitine treatment , were r and omly assigned to an L-carnitine group ( 3000 mg/d L-carnitine ) or a control group . CRP levels , as a biomarker of inflammation , were assessed in all the patients before surgery as baseline levels and 48 hours postoperatively . Neutrophil gelatinase-associated lipocalin , as a kidney biomarker , was also measured in the patients before surgery and 2 hours thereafter . The incidence of AF was 13.4 % in our population . The incidence of AF was decreased in the L-carnitine group ( 7.5 % in the L-carnitine group vs 19.4 % in the control group ; P = 0.043 ) and the postoperative CRP level ( 8.79 ± 6.9 in the L-carnitine group , and 10.83 ± 5.7 in the control group ; P = 0.021 ) . The postoperative neutrophil gelatinase-associated lipocalin concentration demonstrated no significant rise after surgery compared with the preoperative concentration ( 72.54 ± 20.30 in the L-carnitine group vs 67.68 ± 22.71 in the placebo group ; P = 0.19 ) . Our study showed that L-carnitine administration before CABG might inhibit and reduce the incidence of AF after CABG . It seems that a rise in the CRP level , as an inflammation marker , may be associated with the incidence of AF . Inflammation as measured by CRP was also reduced in the carnitine group , compared with the control group",
"Acetyl-L-carnitine ( ALC ) , a drug for the treatment of ageing-related neuroendocrine dysfunctions , was orally administered--2 gm/day for 30 days -- to 10 patients with active pulmonary tuberculosis ( TBC ) . Lymphocyte-mediated antibacterial activity and serum levels of tumor necrosis factor (TNF)-alpha were evaluated before and after treatment , comparing the values with those of 10 TBC patients receiving placebo . Results show that by day 30 , antibacterial activity remained unmodified or increased in ALC-treated subjects , while decreased in the placebo group . No influence of ALC on TNF-alpha levels was detectable . These data suggest that the host 's immune responses to M. tuberculosis infection can be selectively modulated by drugs acting on the neuroendocrine axis",
"Inflammation , oxidative stress , and high concentration of serum lipoprotein ( a ) [ Lp ( a ) ] are common complications in hemodialysis patients . The present study was design ed to investigate the effects of L-carnitine supplement on serum inflammatory cytokines , C-reactive protein ( CRP ) , Lp ( a ) , and oxidative stress in hemodialysis patients with Lp ( a ) hyperlipoproteinemia [ hyper Lp ( a ) ] . This was an unblinded , r and omized clinical trial . Thirty-six hyper Lp ( a ) hemodialysis patients ( 23 men and 13 women ) were r and omly assigned to either a carnitine or control group . Patients in the carnitine group received 1000 mg/d oral L-carnitine for 12 weeks , whereas patients in the control group did not receive any L-carnitine supplement . At baseline and the end of week 12 , 5 mL of blood were collected after a 12- to 14-hours fast and serum free carnitine , CRP , interleukin-1β , interleukin-6 ( IL-6 ) , tumor necrosis factor-α , Lp ( a ) , and oxidized low-density lipoprotein were measured . Serum free carnitine concentration increased significantly by 86 % in the carnitine group at the end of week 12 compared with baseline ( P while serum CRP and IL-6 showed a significant decrease of 29 % ( P in serum free carnitine , CRP , and IL-6 in the control group . There were no significant differences between the two groups in mean changes of serum interleukin-1β , tumor necrosis factor-α , Lp ( a ) , and oxidized low-density lipoprotein concentrations . L-carnitine supplement reduces inflammation in hemodialysis patients , but has no effect on hyper Lp ( a ) and oxidative stress "
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[ Purpose ] This study investigated whether the Canadian Occupational Performance Measure is a suitable outcome measure for assessing patients with stroke in research and clinical setting s. [ Subjects and Methods ] The study included into two parts : ( 1 ) an investigation of the reliability and validity of the Canadian Occupational Performance Measure for patients with stroke and ( 2 ) an exploration of Canadian Occupational Performance Measure results in r and omized controlled trials of patients with stroke . For this review , the study search ed the MEDLINE , PubMed , and CINAHL Plus with Full Text data bases for articles published before September 2015 . [ Results ] Finally , three eligible articles were collected in part 1 , and ten r and omized controlled trials studies were collected in part 2 . The findings of part 1 revealed that the Canadian Occupational Performance Measure had efficient test – retest reliability , however , the Canadian Occupational Performance Measure revealed weak associations with other assessment tools such as Barthel Index used for patients with stroke . Six of the r and omized controlled trials studies used the Canadian Occupational Performance Measure as a primary outcome and two as a secondary outcome , while the other two as a goal - setting instrument . [ Conclusion ] This review indicates that the Canadian Occupational Performance Measure is appropriate for clinicians , including physiotherapists , in assessing outcome for patients with stroke . The Canadian Occupational Performance Measure can assist patients in identifying their outcome performance and provide therapists with directions on interventions
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"Abstract Background : Efforts have been made to apply motor learning theories to the rehabilitation of individuals following stroke . Motor learning poststroke has not been well investigated in the literature . This research attempted to fill the gap regarding motor learning applied to practice . Purpose : This two-group research study attempted to determine the effectiveness of an experimental therapy combining videotape feedback with occupational therapy compared to only occupational therapy in learning the motor skill of donning socks and shoes after stroke . Method : Ten participants were r and omly assigned to one of the two groups and all participants were videotaped during pretest and up to 10 treatment sessions aim ed at donning socks and shoes . Only one group viewed their videotape replay . The acquisition of donning socks and shoes was measured using the socks and shoes subtests of the Klein-Bell Activities of Daily Living Scale and their scores on the Canadian Occupational Performance Measure . Results : There was no significant difference between the two groups and both groups improved . However , the group that received videotape feedback thought they performed better and were more satisfied with their ability to don shoes , lending support for the use of videotape feedback poststroke to improve satisfaction with performance",
"Study Design . In a prospect i ve interventional study , problems with performance were evaluated in 101 consecutive patients with chronic low-back pain for more than 12 months , before and after participation in an outpatient-based multidisciplinary pain management program in Mansfield , United Kingdom . Objectives . To describe problems identified as most important by patients with chronic low-back pain and to evaluate the Canadian Occupational Performance Measure ( COPM ) as a tool for measuring problem-specific outcomes . Summary of Background Data . Patients with chronic low-back pain report difficulties with a variety of activities . The COPM permits the identification and measurement of problems of particular concern to the patient . Material s and Methods . COPM , likert-modified Rol and and Morris Disability Question naire , Pain Self-Efficacy Question naire , and 5-minute walk test were administered at baseline , immediately after , and 9 months after intervention . Differences and statistical interactions were determined by nonparametric tests . Results . Participants identified 60 different types of problem activity , 45 of which were identified by nine or fewer participants . Decreased walking tolerance was the most frequently identified problem ( 56 % of participants ) . Improvements were observed in all outcomes following intervention . Approximately one third of participants reported improvements two or more COPM units in overall performance and satisfaction with their performance at 9 months . Higher reported performance and satisfaction were associated with greater self-efficacy . Increased reported walking performance was associated with increased observed 5-minute walk distance ( R = 0.35 , P = 0.02 ) . Conclusions . Patients with chronic low-back pain report problems with diverse activities . The COPM provides a patient-centered outcome measure that displays good external validity and responsiveness to change when addressing the individual ’s goals",
"Routines-based early intervention ( RBEI ) for children with or at risk for developmental delay encourages collaboration between professionals and families to enhance children 's participation in family routines with family-selected goals . We conducted the first single-blinded r and omized control trial to examine the effectiveness of a 6-month RBEI vs. traditional home visiting ( THV ) , which uses a curriculum focused on children 's developmental domains . Thirty-one families with children aged 5 - 30 months ( mean age 17.4 months ) with or at risk for developmental delay were r and omly assigned to an RBEI group ( n=15 ) or a THV group ( n=16 ) . The enrolled children were evaluated using the Chinese version of Pediatric Evaluation of Disability Inventory ( PEDI-C ) and the Comprehensive Development Inventory for Infants and Toddlers ( CDIIT ) at 5 time points . Two-way mixed analysis of variance ( ANOVA ) was used to examine the group by stage interactions . Goal Attainment Scaling ( GAS ) and the Canadian Occupational Performance Measure ( COPM ) were applied to explore between-group differences on individualized goal achievement . PEDI-C showed that the RBEI group had a faster progress rate in self-care functions and independence in social functions in the first 3 months of intervention and at the 6-month follow-up . The RBEI group also scored higher on the GAS in the first 3 months of intervention . However , between-group differences in changes in the developmental domains on the CDIIT were not significant . Thus , RBEI was more effective than THV in promoting functional outcomes and reaching family-selected goals , while both interventions allowed equal improvement in developmental domains",
"Objective : To determine the feasibility , the cluster design effect and the variance and minimal clinical importance difference in the primary outcome in a pilot study of a structured approach to goal - setting . Design : A cluster r and omized controlled trial . Setting : Inpatient rehabilitation facilities . Subjects : People who were admitted to inpatient rehabilitation following stroke who had sufficient cognition to engage in structured goal - setting and complete the primary outcome measure . Interventions : Structured goal elicitation using the Canadian Occupational Performance Measure . Main measures : Quality of life at 12 weeks using the Schedule for Individualised Quality of Life ( SEIQOL-DW ) , Functional Independence Measure , Short Form 36 and Patient Perception of Rehabilitation ( measuring satisfaction with rehabilitation ) . Assessors were blinded to the intervention . Results : Four rehabilitation services and 41 patients were r and omized . We found high values of the intraclass correlation for the outcome measures ( ranging from 0.03 to 0.40 ) and high variance of the SEIQOL-DW ( SD 19.6 ) in relation to the minimally importance difference of 2.1 , leading to impractically large sample size requirements for a cluster r and omized design . Conclusions : A cluster r and omized design is not a practical means of avoiding contamination effects in studies of inpatient rehabilitation goal - setting . Other techniques for coping with contamination effects are necessary",
"OBJECTIVE The Canadian Occupational Performance Measure ( COPM ) is a client-centered measure , design ed to detect changes in occupational performance over time . The main aim of our study was to examine the test-retest reliability of the Norwegian version of the COPM in patients with ankylosing spondylitis ( AS ) in 3 different retest modes of data collection . METHODS A total of 119 patients with AS completed the baseline COPM interview before r and omization into one of 3 modes of retest data collection performed 2 weeks later : by personal interview , telephone interview , or mailed question naire . Scores were computed for Performance and Satisfaction , and the 2 sets of scores were examined for reliability by intraclass correlations ( ICC ) , and by the Bl and -Altman procedure for calculation of smallest detectable difference ( SDD ) . RESULTS The ICC coefficients for Performance and Satisfaction were as follows : 0.92 and 0.93 ( rescoring by personal interview ) , 0.73 and 0.73 ( rescoring by telephone interview ) , and 0.90 and 0.90 ( rescoring by mail ) . SDD for the Performance and Satisfaction scores were 1.47 and 1.80 , respectively , for rescoring by personal interview ; 3.14 and 4.00 for rescoring by telephone interview ; and 2.20 and 2.41 for rescoring by mailed survey . CONCLUSION The results confirm that the COPM is a reliable instrument for use in clinical practice in patients with AS , and may serve as an instrument to promote a patient-centered approach in the planning and evaluation of rehabilitation programs . Mailed question naires may replace personal interview in followup examinations , while rescoring by telephone interview is less reliable",
"Objective : To evaluate a day service for people aged 18–55 years who had a stroke . Design : A r and omized cross-over study design was used , r and omly allocating individuals to attend the service for six months followed by a period of no attendance for six months . Setting : A day service pilot project was launched in Cardiff in July 1995 for people who were aged between 18 and 55 years and had a stroke . It met one day a week . Subjects : Twenty-six participants were recruited to the study between June 1998 and February 2000 . Their mean age was 48 years ( SD = 7 ) . Interventions : The service aim ed to offer participants the opportunity to identify and pursue meaningful and realistic opportunities within the community . A range of activities occurred at the service including creative activities and social outings . Main outcome measures : The Barthel ADL Index , Extended ADL Scale , Nottingham Leisure Question naire , Short Form 36 , the Hospital Anxiety and Depression Scale , the Canadian Occupational Performance Measure , the Role Checklist and the Semantic Differential Self Concept Scale were used to assess the outcomes from the service . Results : Attending the service increased occupational performance and satisfaction with performance but there was no evidence that depression and anxiety were reduced or that quality of life and self-concept were improved . Conclusion : Although there were some gains from attending the service there were also many unmet needs . Further research is required to continue to identify how best to meet the needs of individuals post stroke under retirement age",
"OBJECTIVE The authors compared changes in client performance on three goals poststroke after the Cognitive Orientation to daily Occupational Performance ( CO-OP ) intervention or st and ard occupational therapy ( SOT ) to determine the magnitude and direction of change . METHOD Eight people living in the community following a stroke were r and omly assigned to receive CO-OP ( n = 4 ) or SOT ( n = 4 ) . CO-OP is a 10-session , cognitive-oriented approach to improving performance that uses client-driven cognitive strategies . SOT was therapist driven and combined task-specific and component-based training . Goal performance was measured by the therapist-rated Performance Quality Rating Scale ( PQRS ) and the participant-rated Canadian Occupational Performance Measure ( COPM ) . RESULTS Using Mann-Whitney U test , we found that CO-OP participants showed significantly greater improvement in performance ( PQRS , p = .02 ; COPM Performance , p = .02 ) compared with SOT but no improvement in satisfaction ( COPM Satisfaction , p = .38 ) . CONCLUSION The CO-OP group demonstrated larger performance improvements than the SOT group . Because of the promising results , an investigation using a larger sample is warranted",
"OBJECTIVE We compared the effectiveness of constraint-induced movement therapy ( CIMT ) with bilateral treatment of equal intensity for chronic upper-extremity ( UE ) dysfunction caused by cerebrovascular accident ( CVA ) . DESIGN We conducted a 2-group , r and omized intervention trial with stratification by severity of UE dysfunction . Twelve community-dwelling adults were provided with 6 hr of occupational therapy for 10 days plus additional home practice . Six participants wore a mitt on the unimpaired UE , and 6 participants were intrusively and repetitively cued to use both UEs . The Wolf Motor Function Test ( WMFT ) and the Canadian Occupational Performance Measure ( COPM ) were administered before and after treatment and at 6-mo follow-up . RESULTS Significant improvements were found in WMFT and COPM scores across time in both groups . No significant between-group differences were found on the WMFT . CONCLUSION High-intensity occupational therapy using a CIMT or a bilateral approach can improve UE function in people with chronic UE dysfunction after CVA . Treatment intensity rather than restraint may be the critical therapeutic factor",
"PURPOSE To determine the effect of an intense physical therapy intervention on gross motor function , community walking and participation in children with cerebral palsy ( CP ) . METHODS A single group design was used with two pre-test and two post-test measures . Subjects were 17 ambulatory children with CP who participated in an intense intervention ( i.e. , four hours per day , five days per week , three weeks ) , a modified version of the TheraSuit protocol . Gross motor function measure ( GMFM-66 ) , Step watch activity monitor ( SAM ) , Canadian occupational performance measure ( COPM ) and pediatric outcomes data collection instrument ( PODCI ) were tested twice at baseline , immediately following the intervention , and three months later . RESULTS Immediately following the intervention , GMFM-66 , COPM and PODCI scores improved significantly ( p GMFM-66 and COPM ( p Walking amount or intensity ( SAM ) did not improve . CONCLUSIONS Participants improved gross motor skills and participation but not community ambulation following this intense physical therapy intervention",
"Objective : To research test – retest reliability and discriminant validity of the Canadian Occupational Performance Measure ( COPM ) , a client-centred outcome measure , in stroke patients . Design : The COPM was administered twice with a mean interval of eight days ( SD 2.5 , range 5–16 ) . On both occasions the patient identified a maximum of five problems in daily activities . The problems of both interviews were compared . The problems identified during the first COPM were rated by the patient on a performance and satisfaction rating scale on both occasions . The individually identified items with use of the client-centred COPM were compared with the fixed items of st and ardized measures ( Barthel Index , Frenchay Activities Index , Stroke Adapted Sickness Impact Profile-30 , Euroqol 5D and Rankin Scale ) . Setting : Patients were interviewed at their place of residence . Subjects : Twenty-six stroke patients participated , 11 men and 15 women , aged from 26 to 83 years ( mean 68 , SD 15 ) . Twenty-four patients were six months , two patients were two months post stroke . Results : Of the 115 problems identified during the first COPM , 64 ( 56 % ) were also identified the second time . Correlation coefficients for the scores were 0.89 ( p performance and 0.88 ( p satisfaction . Of the individual problems identified with the COPM , 25 % or less were present in the st and ardized measures . Correlations between the scores on the COPM and the st and ardized measures were low and nonsignificant , while all st and ardized measures correlated significantly with each other . Conclusions : Test – retest reliability of the COPM was moderate for the item pool but was good for the performance and satisfaction scores . Discriminant validity was confirmed . Many patient-unique problems identified with the COPM were not evaluated by st and ardized measures",
"Objective : To compare the efficacy of a repetitive task-specific practice regimen integrating a portable , electromyography-controlled brace called the ‘ Myomo ’ versus usual care repetitive task-specific practice in subjects with chronic , moderate upper extremity impairment . Subjects : Sixteen subjects ( 7 males ; mean age 57.0 ± 11.02 years ; mean time post stroke 75.0 ± 87.63 months ; 5 left-sided strokes ) exhibiting chronic , stable , moderate upper extremity impairment . Interventions : Subjects were administered repetitive task-specific practice in which they participated in valued , functional tasks using their paretic upper extremities . Both groups were supervised by a therapist and were administered therapy targeting their paretic upper extremities that was 30 minutes in duration , occurring 3 days/week for eight weeks . One group participated in repetitive task-specific practice entirely while wearing the portable robotic , while the other performed the same activity regimen manually . Main outcome measures : The upper extremity Fugl-Meyer , Canadian Occupational Performance Measure and Stroke Impact Scale were administered on two occasions before intervention and once after intervention . Results : After intervention , groups exhibited nearly identical Fugl-Meyer score increases of ≈2.1 points ; the group using robotics exhibited larger score changes on all but one of the Canadian Occupational Performance Measure and Stroke Impact Scale subscales , including a 12.5-point increase on the Stroke Impact Scale recovery subscale . Conclusions : Findings suggest that therapist-supervised repetitive task-specific practice integrating robotics is as efficacious as manual practice in subjects with moderate upper extremity impairment",
"OBJECTIVE This preliminary study sought to determine whether the imagery perspective used during mental practice ( MP ) differentially influenced performance outcomes after stroke . METHOD Nineteen participants with unilateral subacute stroke ( 9 men and 10 women , ages 28 - 77 ) were r and omly allocated to one of three groups . All groups received 30-min occupational therapy sessions 2 × /wk for 6 wk . Experimental groups received MP training in functional tasks using either an internal or an external perspective ; the control group received relaxation imagery training . Participants were pre- and posttested using the Fugl-Meyer Motor Assessment ( FMA ) , the Jebsen-Taylor Test of H and Function ( JTTHF ) , and the Canadian Occupational Performance Measure ( COPM ) . RESULTS At posttest , the internal and external experimental groups showed statistically similar improvements on the FMA and JTTHF ( p the COPM ( p CONCLUSION MP combined with occupational therapy improves upper-extremity recovery after stroke . MP does not appear to enhance self-perception of performance . This preliminary study suggests that imagery perspective may not be an important variable in MP interventions"
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BACKGROUND Cardiovascular disease , which includes coronary artery disease , stroke and peripheral vascular disease , is a leading cause of death worldwide . Homocysteine is an amino acid with biological functions in methionine metabolism . A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level . The impact of homocysteine-lowering interventions , given to patients in the form of vitamins B6 , B9 or B12 supplements , on cardiovascular events has been investigated . This is an up date of a review previously published in 2009 , 2013 , and 2015 . OBJECTIVES To determine whether homocysteine-lowering interventions , provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events , as well as reducing all-cause mortality , and to evaluate their safety . SEARCH METHODS We search ed the Cochrane Central Register of Controlled Trials ( CENTRAL 2017 , Issue 5 ) , MEDLINE ( 1946 to 1 June 2017 ) , Embase ( 1980 to 2017 week 22 ) and LILACS ( 1986 to 1 June 2017 ) . We also search ed Web of Science ( 1970 to 1 June 2017 ) . We h and search ed the reference lists of included papers . We also contacted research ers in the field . There was no language restriction in the search . SELECTION CRITERIA We included r and omised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer . We considered myocardial infa rct ion and stroke as the primary outcomes . We excluded studies in patients with end-stage renal disease . DATA COLLECTION AND ANALYSIS We performed study selection , ' Risk of bias ' assessment and data extraction in duplicate . We estimated risk ratios ( RR ) for dichotomous outcomes . We calculated the number needed to treat for an additional beneficial outcome ( NNTB ) . We measured statistical heterogeneity using the I2 statistic . We used a r and om-effects model . We conducted trial sequential analyses , Bayes factor , and fragility indices where appropriate . MAIN RESULTS In this third up date , we identified three new r and omised controlled trials , for a total of 15 r and omised controlled trials involving 71,422 participants . Nine trials ( 60 % ) had low risk of bias , length of follow-up ranged from one to 7.3 years . Compared with placebo , there were no differences in effects of homocysteine-lowering interventions on myocardial infa rct ion ( homocysteine-lowering = 7.1 % versus placebo = 6.0 % ; RR 1.02 , 95 % confidence interval ( CI ) 0.95 to 1.10 , I2 = 0 % , 12 trials ; N = 46,699 ; Bayes factor 1.04 , high- quality evidence ) , death from any cause ( homocysteine-lowering = 11.7 % versus placebo = 12.3 % , RR 1.01 , 95 % CI 0.96 to 1.06 , I2 = 0 % , 11 trials , N = 44,817 ; Bayes factor = 1.05 , high- quality evidence ) , or serious adverse events ( homocysteine-lowering = 8.3 % versus comparator = 8.5 % , RR 1.07 , 95 % CI 1.00 to 1.14 , I2 = 0 % , eight trials , N = 35,788 ; high- quality evidence ) . Compared with placebo , homocysteine-lowering interventions were associated with reduced stroke outcome ( homocysteine-lowering = 4.3 % versus comparator = 5.1 % , RR 0.90 , 95 % CI 0.82 to 0.99 , I2 = 8 % , 10 trials , N = 44,224 ; high- quality evidence ) . Compared with low doses , there were uncertain effects of high doses of homocysteine-lowering interventions on stroke ( high = 10.8 % versus low = 11.2 % , RR 0.90 , 95 % CI 0.66 to 1.22 , I2 = 72 % , two trials , N = 3929 ; very low- quality evidence ) .We found no evidence of publication bias . AUTHORS ' CONCLUSIONS In this third up date of the Cochrane review , there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6 , B9 or B12 given alone or in combination comparing with placebo on myocardial infa rct ion , death from any cause or adverse events . In terms of stroke , this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6 , B9 or B12 given alone or in combination comparing with placebo . There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke ; approximately 143 ( 95 % CI 85 to 428 ) people would need to be treated for 5.4 years to prevent 1 stroke , this evidence emerged from one mega-trial . Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo . There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication , and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses . Potential trials should be large and co-operative
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"Certain epidemiological and experimental studies suggest that n-3 fatty acids and folate can reduce blood pressure ( BP ) . We investigated the effect of a daily supplementation with dietary doses of B-vitamins or n-3 fatty acids for 5 years on BP in patients with a history of CVD who participated in the Supplémentation en Folates et Omega-3 trial . The patients ( n 2501 ; 1987 men and 514 women ) were r and omly assigned in a 2 × 2 factorial design to one of four groups : B-vitamins ( 5-methyl-THF ( 560 μg ) ; vitamin B₆ ( 3 mg ) and vitamin B₁₂ ( 20 μg ) ) and a placebo capsule for n-3 fatty acids ; n-3 fatty acids ( 600 mg of EPA and DHA at a ratio of 2:1 ) and a placebo capsule for B-vitamins ; both B-vitamins and n-3 fatty acids ; or placebo capsules for both treatments . The patients took two capsules daily in a double-blind manner for a median duration of 4·7 years . At baseline and annual examination for 5 years , the patients underwent a clinical examination where BP and clinical and biological parameters were assessed . No effect of supplementation with either n-3 PUFA or B-vitamins on BP was observed in crude and adjusted multivariate models . Change in BP was not associated with change in homocysteine . In conclusion , the present results do not support the routine use of dietary supplements containing B-vitamins , or of n-3 fatty acids , to reduce BP in people with prior CVD",
"During the past 25 years , 24 r and omized trials of intravenous ( IV ) fibrinolytic treatment have been reported , involving a total of some 6000 patients in the acute phase of myocardial infa rct ion . Most tested IV streptokinase ( SK ) , but a few tested IV urokinase ( UK ) . In the past 2 or 3 years numerous small r and omized trials of intracoronary ( IC ) SK have been started , 9 of which , involving a total of about 1000 such patients , have been reported . Because all of these IV and IC trials were small ( the largest including only 747 patients ) , their separate results appear contradictory and unreliable . But , an overview of the data from these trials indicates that IV treatment produces a highly significant ( 22 % + /- 5 % , P less than 0.001 ) reduction in the odds of death , an even larger reduction in the odds of reinfa rct ion , and an absolute frequency of serious adverse effects to set against this that is much smaller than the absolute mortality reduction . The apparent size of the mortality reduction in the IV trials was similar whether anticoagulants were compulsory or optional , whether treatment was in a coronary care unit or an ordinary ward and , surprisingly , whether treatment began early ( less than 6 h from onset of symptoms ) or late ( generally 12 - 24 h ) . In addition , there was no evidence that UK was more effective than the less expensive SK , or that , despite their technical complexity , the new IC regimes were more effective than the old IV regimes . Even the IV schedules that have been studied in r and omized trials were , however , quite complex , and the IC schedules were far more so . Perhaps partly because of this , none of them is widely used . If so , then some much simpler , and hence more widely practicable , IV SK regimes should be developed and tested . For example , a simple one hour high-dose IV SK infusion , without anticoagulation , will successfully convert virtually all of the available plasminogen into plasmin . But , it may be several years before the net effects on mortality of any more widely practicable IV SK regimes can be agreed unless many of the hospitals that do not wish routinely to use IC regimes or the complex previous IV regimes will collaborate in multicentre r and omized trials that can , if necessary , continue rapid intake until some tens of thous and s of patients have been r and omized , and some thous and s of deaths have been observed among the control and treated patients . The same , of course , may be true for any other fibrinolytic regimes ( e.g. infusion of tissue plasminogen activator ) if their net effects on mortality are comparable to those of IV SK",
"Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures",
"Total plasma homocysteine ( tHcy ) is an independent risk factor for coronary artery disease , and tHcy is lowered by B vitamins . To assess the effect of homocysteine-lowering B-vitamin treatment on angiographic progression of coronary artery disease , this sub study of the Western Norway B Vitamin Intervention Trial ( WENBIT ) included patients who had undergone percutaneous coronary intervention . The patients were r and omized to daily oral treatment with folic acid , vitamin B(12 ) , and vitamin B(6 ) or placebo in a 2 x 2 factorial design . The coronary angiograms obtained at baseline and follow-up were evaluated . The primary angiographic end points were the changes in minimum lumen diameter and diameter stenosis . A total of 348 subjects ( 288 men ) with a mean + /- SD age of 60 + /- 10.2 years were followed up for a median of 10.5 months ( twenty-fifth , seventy-fifth percentile 9.2 , 11.8 ) . The baseline median plasma tHcy level was 10.0 mumol/L ( twenty-fifth , seventy-fifth percentile 8.1 , 11.0 ) , and treatment with folic acid/vitamin B(12 ) lowered the tHcy levels by 22 % . At follow-up , we found 309 lesions with a significant decrease from baseline in the minimum lumen diameter of a mean of -0.16 + /- 0.4 mm and an increase in the diameter stenosis of 4.4 + /- 0.7 % . Treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) was not associated with a change in diameter stenosis or minimum lumen diameter . In a post hoc analysis , folic acid/vitamin B(12 ) treatment was significantly associated with rapid progression ( odds ratio 1.84 , 95 % confidence interval 1.07 to 3.18 ) . In conclusion , vitamin B treatment showed no beneficial effect on the angiographic progression of coronary artery disease , and the post hoc analyses suggested that folic acid/vitamin B(12 ) treatment might promote more rapid progression",
"Background and Purpose — Elevated concentrations of homocysteine are associated with cerebral small vessel disease ( CSVD ) . b-vitamin supplementation with folate and vitamins b12 and b6 reduces homocysteine concentrations . In a sub study of the VITAmins TO Prevent Stroke ( VITATOPS ) trial , we assessed the hypothesis that the addition of once-daily supplements of b vitamins would reduce the progression of CSVD-related brain lesions . Methods — A total of 359 patients with recent stroke or transient ischemic attack , who were r and omly allocated to double-blind treatment with placebo or b vitamins , underwent brain MRI at r and omization and after 2 years of b-vitamin supplementation . MR images were analyzed blinded to treatment allocation . Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes . We also explored the effect of b-vitamin supplementation on the incidence of other ischemic abnormalities . Results — After 2 years of treatment with b vitamins or placebo , there was no significant difference in white matter hyperintensities volume change ( 0.08 vs 0.13cm3 ; P=0.419 ) and incidence of lacunes ( 8.0 % vs 5.9 % , P=0.434 ; odds ratio=1.38 ) . In a sub analysis of patients with MRI evidence of severe CSVD at baseline , b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change ( 0.3 vs 1.7cm3 ; P=0.039 ) . Conclusions — Daily b-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions result ing from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD . Clinical Trial Registration — http://vitatops.highway1.com.au/. Unique identifier : NCT00097669 and IS RCT N74743444",
"CONTEXT Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease . Oral administration of folic acid and vitamin B(12 ) can lower plasma total homocysteine levels . OBJECTIVE To assess the effect of treatment with folic acid and vitamin B(12 ) and the effect of treatment with vitamin B(6 ) as secondary prevention in patients with coronary artery disease or aortic valve stenosis . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999 - 2006 . A total of 3096 adult participants undergoing coronary angiography ( 20.5 % female ; mean age , 61.7 years ) were r and omized . At baseline , 59.3 % had double- or triple-vessel disease , 83.7 % had stable angina pectoris , and 14.9 % had acute coronary syndromes . INTERVENTIONS Using a 2 x 2 factorial design , participants were r and omly assigned to 1 of 4 groups receiving daily oral treatment with folic acid , 0.8 mg , plus vitamin B(12 ) , 0.4 mg , plus vitamin B(6 ) , 40 mg ( n = 772 ) ; folic acid plus vitamin B(12 ) ( n = 772 ) ; vitamin B(6 ) alone ( n = 772 ) ; or placebo ( n = 780 ) . MAIN OUTCOME MEASURES The primary end point was a composite of all-cause death , nonfatal acute myocardial infa rct ion , acute hospitalization for unstable angina pectoris , and nonfatal thromboembolic stroke . RESULTS Mean plasma total homocysteine concentration was reduced by 30 % after 1 year of treatment in the groups receiving folic acid and vitamin B(12 ) . The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention . During a median 38 months of follow-up , the primary end point was experienced by a total of 422 participants ( 13.7 % ) : 219 participants ( 14.2 % ) receiving folic acid/vitamin B(12 ) vs 203 ( 13.1 % ) not receiving such treatment ( hazard ratio , 1.09 ; 95 % confidence interval , 0.90 - 1.32 ; P = .36 ) and 200 participants ( 13.0 % ) receiving vitamin B(6 ) vs 222 ( 14.3 % ) not receiving vitamin B(6 ) ( hazard ratio , 0.90 ; 95 % confidence interval , 0.74 - 1.09 ; P = .28 ) . CONCLUSIONS This trial did not find an effect of treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) on total mortality or cardiovascular events . Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00354081",
"IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data . OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension . DESIGN , SETTING , AND PARTICIPANTS The China Stroke Primary Prevention Trial , a r and omized , double-blind clinical trial conducted from May 19 , 2008 , to August 24 , 2013 , in 32 communities in Jiangsu and Anhui provinces in China . A total of 20,702 adults with hypertension without history of stroke or myocardial infa rct ion ( MI ) participated in the study . INTERVENTIONS Eligible participants , stratified by MTHFR C677 T genotypes ( CC , CT , and TT ) , were r and omly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril , 10 mg , and folic acid , 0.8 mg ( n = 10,348 ) or a tablet containing enalapril , 10 mg , alone ( n = 10,354 ) . MAIN OUTCOMES AND MEASURES The primary outcome was first stroke . Secondary outcomes included first ischemic stroke ; first hemorrhagic stroke ; MI ; a composite of cardiovascular events consisting of cardiovascular death , MI , and stroke ; and all-cause death . RESULTS During a median treatment duration of 4.5 years , compared with the enalapril alone group , the enalapril-folic acid group had a significant risk reduction in first stroke ( 2.7 % of participants in the enalapril-folic acid group vs 3.4 % in the enalapril alone group ; hazard ratio [ HR ] , 0.79 ; 95 % CI , 0.68 - 0.93 ) , first ischemic stroke ( 2.2 % with enalapril-folic acid vs 2.8 % with enalapril alone ; HR , 0.76 ; 95 % CI , 0.64 - 0.91 ) , and composite cardiovascular events consisting of cardiovascular death , MI , and stroke ( 3.1 % with enalapril-folic acid vs 3.9 % with enalapril alone ; HR , 0.80 ; 95 % CI , 0.69 - 0.92 ) . The risks of hemorrhagic stroke ( HR , 0.93 ; 95 % CI , 0.65 - 1.34 ) , MI ( HR , 1.04 ; 95 % CI , 0.60 - 1.82 ) , and all-cause deaths ( HR , 0.94 ; 95 % CI , 0.81 - 1.10 ) did not differ significantly between the 2 treatment groups . There were no significant differences between the 2 treatment groups in the frequencies of adverse events . CONCLUSIONS AND RELEVANCE Among adults with hypertension in China without a history of stroke or MI , the combined use of enalapril and folic acid , compared with enalapril alone , significantly reduced the risk of first stroke . These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00794885",
"CONTEXT Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine . OBJECTIVE To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas . DESIGN , SETTING , AND PARTICIPANTS A double-blind , placebo-controlled , 2-factor , phase 3 , r and omized clinical trial conducted at 9 clinical centers between July 6 , 1994 , and October 1 , 2004 . Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma . INTERVENTION Participants were r and omly assigned in a 1:1 ratio to receive 1 mg/d of folic acid ( n = 516 ) or placebo ( n = 505 ) , and were separately r and omized to receive aspirin ( 81 or 325 mg/d ) or placebo . Follow-up consisted of 2 colonoscopic surveillance cycles ( the first interval was at 3 years and the second at 3 or 5 years later ) . MAIN OUTCOME MEASURES The primary outcome measure was occurrence of at least 1 colorectal adenoma . Secondary outcomes were the occurrence of advanced lesions ( > or = 25 % villous features , high- grade dysplasia , size > or = 1 cm , or invasive cancer ) and adenoma multiplicity ( 0 , 1 - 2 , or > or =3 adenomas ) . RESULTS During the first 3 years , 987 participants ( 96.7 % ) underwent colonoscopic follow-up , and the incidence of at least 1 colorectal adenoma was 44.1 % for folic acid ( n = 221 ) and 42.4 % for placebo ( n = 206 ) ( unadjusted risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.90 - 1.20 ; P = .58 ) . Incidence of at least 1 advanced lesion was 11.4 % for folic acid ( n = 57 ) and 8.6 % for placebo ( n = 42 ) ( unadjusted RR , 1.32 ; 95 % CI , 0.90 - 1.92 ; P = .15 ) . A total of 607 participants ( 59.5 % ) underwent a second follow-up , and the incidence of at least 1 colorectal adenoma was 41.9 % for folic acid ( n = 127 ) and 37.2 % for placebo ( n = 113 ) ( unadjusted RR , 1.13 ; 95 % CI , 0.93 - 1.37 ; P = .23 ) ; and incidence of at least 1 advanced lesion was 11.6 % for folic acid ( n = 35 ) and 6.9 % for placebo ( n = 21 ) ( unadjusted RR , 1.67 ; 95 % CI , 1.00 - 2.80 ; P = .05 ) . Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers . There was no significant effect modification by sex , age , smoking , alcohol use , body mass index , baseline plasma folate , or aspirin allocation . CONCLUSIONS Folic acid at 1 mg/d does not reduce colorectal adenoma risk . Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00272324",
"Background and Purpose — We sought to determine whether folic acid supplementation can independently reduce the risk of first stroke associated with elevated total cholesterol levels in a sub analysis using data from the CSPPT ( China Stroke Primary Prevention Trial ) , a double-blind , r and omized controlled trial . Methods — A total of 20 702 hypertensive adults without a history of major cardiovascular disease were r and omly assigned to a double-blind daily treatment of an enalapril 10-mg and a folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone . The primary outcome was first stroke . Results — The median treatment duration was 4.5 years . For participants not receiving folic acid treatment ( enalapril-only group ) , high total cholesterol ( ≥200 mg/dL ) was an independent predictor of first stroke when compared with low total cholesterol ( . Folic acid supplementation significantly reduced the risk of first stroke among participants with high total cholesterol ( 4.0 % in the enalapril-only group versus 2.7 % in the enalapril – folic acid group ; hazard ratio , 0.69 ; 95 % confidence interval , 0.56–0.84 ; P low total cholesterol , the risk of stroke was 2.6 % in the enalapril-only group versus 2.5 % in the enalapril – folic acid group ( hazard ratio , 1.00 ; 95 % confidence interval , 0.75–1.30 ; P=0.982 ) . The effect was greater among participants with elevated total cholesterol ( P for interaction=0.024 ) . Conclusions — Elevated total cholesterol levels may modify the benefits of folic acid therapy on first stroke . Folic acid supplementation reduced the risk of first stroke associated with elevated total cholesterol by 31 % among hypertensive adults without a history of major cardiovascular diseases . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00794885",
"BACKGROUND M and atory fortification of flour with folic acid has reduced the number of neural tube defects in North America . Concerns that high intakes of folic acid might mask vitamin B-12 deficiency in older persons have delayed the introduction of fortification in many European countries . Cofortification of flour with folic acid and vitamin B-12 could simultaneously improve folate and vitamin B-12 status . OBJECTIVE The objective was to estimate the effect of the consumption of bread fortified with modest amounts of folic acid and vitamin B-12 on folate and vitamin B-12 status in healthy older persons living in the Netherl and s , where folic acid fortification is not taking place . DESIGN Men and women aged 50 - 75 y were r and omly assigned in this 12-wk double-blind , placebo-controlled trial to consume bread fortified with 138 mug folic acid and 9.6 mug vitamin B-12 daily ( n = 72 ) or unfortified bread ( n = 70 ) . RESULTS The consumption of fortified bread increased serum folate concentrations by 45 % ( mean : 6.3 nmol/L ; 95 % CI : 4.5 , 8.1 nmol/L ) and serum vitamin B-12 concentrations by 49 % ( mean : 102 pmol/L ; 95 % CI : 82 , 122 pmol/L ) relative to the placebo group . Fortified bread increased erythrocyte folate concentrations by 22 % and holotranscobalamin concentrations by 35 % ; it decreased homocysteine concentrations by 13 % and methylmalonic acid concentrations by 10 % . Consumption of fortified bread decreased the proportion of individuals with marginal serum vitamin B-12 concentrations ( fortified with modest amounts of folic acid and vitamin B-12 will improve folate and vitamin B-12 status and a considerable proportion of vitamin B-12 deficiency in older people . This trial was registered at clinical trials.gov as NCT00353353",
"National Institutes of Health ( NIH ) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1 ) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality ( AHRQ ) , 2 ) presentations by investigators working in areas relevant to the conference questions during a 2-day public session , 3 ) questions and statements from conference attendees during open discussion periods that are part of the public session , and 4 ) closed deliberations by the panel during the remainder of the second day and the morning of the third . This statement is an independent report of the panel and is not a policy statement of the NIH or the federal government . The statement reflects the panel 's assessment of medical knowledge available at the time the statement was written . Thus , it provides a snapshot in time of the state of knowledge on the conference topic . When reading the statement , keep in mind that new knowledge is inevitably accumulating through medical research . At least half of American adults take a dietary supplement , the majority of which are multivitamin/multimineral ( MVM ) supplements . As more and more Americans seek strategies for maintaining good health and preventing disease , and as the marketplace offers an increasing number of products to fulfill that desire , it is important that consumers have the best possible information to make their choices . Assessing the available scientific evidence on the benefits of MVM supplement use for chronic disease prevention , identifying the gaps in the evidence , and recommending an appropriate research agenda to meet the shortfalls are subjects considered in this report . The word vitamine was coined in 1912 , as an abbreviated term meant to capture the notion of important factors in the diet , or vital amines . This was preceded more than 150 years earlier by British navy physician James Lind 's discoveryin the first recorded controlled trialthat citrus juice , a good source of what was found 2 centuries later to be vitamin C , could prevent scurvy in sailors . In 1913 , the first vitamin was isolated : thiamin , the deficiency of which caused beriberi . Thirteen vitamins and 15 essential minerals have now been identified as important to human nutrition . Large-scale fortification of diets began in the United States with the addition of iodine to table salt in 1924 to prevent goiter , followed by the addition of vitamin D to milk in 1933 to prevent rickets and the addition of thiamin , riboflavin , niacin , and iron to flour in 1941 . Multivitamin/multimineral products providing more than vitamins A and D became available in pharmacies and grocery stores in the mid-1930s . In the early 1940s , the first MVM tablet was introduced . Although clinical deficiency of vitamins or minerals , other than iron , is now uncommon in the United States , growth in supplement use has accelerated rapidly with marketing spurred by cl aims some based on scientific studies that chronic conditions could be prevented or treated by supplement use . Annual sales of supplements to Americans are now reported at about $ 23 billion , a substantial share of which is spent on vitamins and minerals . Because of such widespread use of MVM , increasing public and medical confusion over apparently contradictory results from studies , and reports of possible adverse effects from overuse in certain circumstances , the Office of Dietary Supplements and the Office of Medical Applications of Research of the NIH convened a State-of-the-Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention , held on 1517 May 2006 , in Bethesda , Maryl and . The goal of the conference was to assess the evidence available on MVM use and outcomes for chronic disease prevention in the generally healthy population of adults and to make recommendations for future research . The conference focused on vitamins and minerals and did not deal with botanicals , hormones , or other supplements . It also did not address the treatment of vitamin or mineral deficiencies . Except for considerations of safety , the conference also did not review issues of primary relevance to pregnant women or children . Specifically , the conference explored the following key questions : 1 ) What are the current patterns and prevalence of the public 's use of MVM supplements ? 2 ) What is known about the dietary nutrient intake of MVM users versus nonusers ? 3 ) What is the efficacy of single vitamin/mineral supplement use in chronic disease prevention ? 4 ) What is the efficacy of MVM in chronic disease prevention in the general population of adults ? 5 ) What is known about the safety of MVM for the generally healthy population ? and 6 ) What are the major knowledge gaps and research opportunities regarding MVM use ? During the first 2 days of the conference , experts presented information on each of the key questions . After weighing the scientific evidence , including the data presented by the speakers and a formal evidence report commissioned through AHRQ , an independent panel prepared and presented a draft of this state-of-the-science statement addressing the conference questions . The evidence report prepared for the conference is available at www.ahrq.gov/clinic/tp/multivittp.htm . For the purpose of this statement , the term MVM refers to any supplement containing 3 or more vitamins and minerals but no herbs , hormones , or drugs , with each component at a dose less than the tolerable upper level determined by the Food and Nutrition Boardthe maximum daily intake likely to pose no risk for adverse health effects . Our review also included studies of the relationship of single-nutrient supplements and 2-nutrient supplements to certain disease outcomes . The term primary prevention refers to preventing the development of disease in a person who does not have the disease in question . The chronic conditions assessed include cancer ; age-related sensory loss ; and cardiovascular , endocrine , neurologic , musculoskeletal , gastroenterologic , renal , and pulmonary diseases . A word is warranted about the nature of the evidence base considered by the panel . The range of vitamins and minerals of possible interest was so broad that the conference planning committee chose to focus the evidence report on nutrients for which the potential for impact had been most strongly suggested and on conditions for which supplements were thought to have the most potential influence . The planning committee also limited the scope of the evidence report to consideration of r and omized , controlled trials ( RCTs ) , which are generally considered the gold st and ard for evidence -based decision making . These are studies in which participants are allocated by chance alone to receive or not to receive 1 of 2 or more clinical interventions . For example , while folate supplementation was initially shown to decrease the risk for neural tube defects in animal studies , outcome data in nonhuman models were not considered sufficient evidence on which to base policy recommendations . At the next level of evidence , observational studies in humans suggested efficacy of folate supplementation to prevent such defects . However , these were criticized because they were not r and omized and were potentially subject to bias . Not until these findings were confirmed by RCTs in humans was public policy implemented , including fortification of cereal grains with folate . An observational study is one in which the exposure or treatment of interest is not assigned to the participant by the investigator . Such studies suggested that -carotene intake might protect against the development of some types of cancer . However , RCTs of -carotene supplementation not only showed no benefit , they also found an increased risk for lung cancer in persons who smoked cigarettes or who were exposed to asbestos . These examples illustrate both the risk of relying only on observational studies and the advantage of RCTs in identifying both benefits and risks of MVM supplementation . Limiting the focus of our statement to RCTs has some inherent limitations , given the potential of other types of studies to provide important insights . Observational studies , for example , are particularly useful for generating hypotheses , defining adverse effects , and documenting long-term treatment consequences . They are often essential precursors to the well-conducted RCTs important for policy formation . Our principal recommendations focus on the compelling research activities that must be supported to better inform the decisions that millions of Americans are making each day to use or not to use MVM supplements to prevent chronic disease . At the same time , mindful of the constraints of the available evidence base , we have also taken care not to make premature recommendations about whether generally healthy Americans should or should not take MVM supplements . Because of the need for more reliable information on MVMs , we have made strong recommendations for research and for increased U.S. Food and Drug Administration ( FDA ) oversight of the MVM industry . 1 . What Are the Current Patterns and Prevalence of the Public 's Use of MVM Supplements ? More than half of American adults take dietary supplements in the belief that they will make them feel better , give them greater energy , improve their health , and prevent and treat disease . The use of supplements has been steadily increasing , and growth appears likely to continue . Currently , users spend more than $ 23 billion per year on supplements , and among this supplement-using population , MVM is the major category of supplements , used by about one third of Americans . Uncertainty remains in estimating prevalence of use because of problems defining these products ; increasing complexity in the formulation of supplements , including more non-MVM components and specialized formulas ; and varying frequency of use . It appears that use is higher",
"BACKGROUND Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures . Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk . OBJECTIVE This study [ B-vitamins for the PRevention Of Osteoporotic Fractures ( B-PROOF ) ] aim ed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals . DESIGN This was a double-blind , r and omized , placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations ( 12 - 50 μmol/L ) . Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3 . The primary endpoint was time to first osteoporotic fracture . Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per- protocol principles . RESULTS Osteoporotic fractures occurred in 61 persons ( 4.2 % ) in the intervention group and 75 persons ( 5.1 % ) in the placebo group . Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses ( HR : 0.84 ; 95 % CI : 0.58 , 1.21 ) or per- protocol analyses ( HR : 0.81 ; 95 % CI : 0.54 , 1.21 ) . For persons aged > 80 y , in per- protocol analyses , osteoporotic fracture risk was lower in the intervention group than in the placebo group ( HR : 0.27 ; 95 % CI : 0.10 , 0.74 ) . The total number of adverse events ( including mortality ) did not differ between groups . However , 63 and 42 participants in the intervention and placebo groups , respectively , reported incident cancer ( HR : 1.56 ; 95 % CI : 1.04 , 2.31 ) . CONCLUSIONS These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population . Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged > 80 y. However , treatment was also associated with increased incidence of cancer , although the study was not design ed for assessing cancer outcomes . Therefore , vitamin B-12 plus folic acid supplementation can not be recommended at present for fracture prevention in elderly people . The B-PROOF study was registered with the Netherl and s Trial Register ( trialregister.nl ) as NTR1333 and at clinical trials.gov as NCT00696414",
"INTRODUCTION Observational studies have suggested a causal relationship between hyperhomocysteinemia and cardiovascular complications such as stroke and ischemic heart disease . The Homocysteine Lowering Trialists ' Collaboration has shown that daily administration of folic acid can significantly decrease homocysteine levels up to 25 % . Aim of this study was to investigate the effect of daily supplementation of folic acid ( 5 mg ) on IMT after 18 months of treatment in patients with at least one cardiovascular risk factor . METHODS We enrolled 103 patients with at least one cardiovascular risk factor who were r and omized to receive either a daily dose of 5 mg folic acid ( group I , n=53 ) or placebo ( group II , n=50 ) for 18 months . RESULTS After 18 months of folic acid supplementation , homocysteine levels were significantly reduced in the active treatment group compared to a non-significant increase in the placebo group . Folic acid levels were markedly increased in the former group and non-significantly reduced in the latter . Significant regression of carotid IMT was observed ( 0.961+/-0.092 to 0.933+/-0.077 mm , p IMT progression in the placebo group ( 0.964+/-0.099 to 0.984+/-0.094 mm ) . CONCLUSION Folic acid supplementation results in significant IMT reduction after 18 months in patients with at least one cardiovascular risk",
"Background Osteoporosis is a major health problem , and the economic burden is expected to rise due to an increase in life expectancy throughout the world . Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk . As vitamin B12 and folate intake and status play a large role in homocysteine metabolism , it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration . Methods / Design The B-PROOF ( B-Vitamins for the PRevention Of Osteoporotic Fractures ) study is a r and omized double-blind placebo-controlled trial . The intervention comprises a period of two years , and includes 2919 subjects , aged 65 years and older , independently living or institutionalized , with an elevated homocysteine concentration ( ≥ 12 μmol/L ) . One group receives daily a tablet with 500 μg vitamin B12 and 400 μg folic acid and the other group receives a placebo tablet . In both tablets 15 μg ( 600 IU ) vitamin D is included . The primary outcome of the study is osteoporotic fractures . Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers , physical performance and physical activity including falls , nutritional intake and status , cognitive function , depression , genetics and quality of life . This large multi-center project is carried out by a consortium from the Erasmus MC ( Rotterdam , the Netherl and s ) , VUmc ( Amsterdam , the Netherl and s ) and Wageningen University , ( Wageningen , the Netherl and s ) , the latter acting as coordinator . Discussion To our best knowledge , the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population . We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013 . The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures . Trial Registration The B-PROOF study is registered with the Netherl and s Trial ( NTR NTR1333 ) and with Clinical Trials.gov ( NCT00696514 )",
"Objective To determine if use of paracetamol in early life is an independent risk factor for childhood asthma . Design Prospect i ve birth cohort study . Setting Melbourne Atopy Cohort Study . Participants 620 children with a family history of allergic disease , with paracetamol use prospect ively documented on 18 occasions from birth to 2 years of age , followed until age 7 years . Main outcome measures The primary outcome was childhood asthma , ascertained by question naire at 6 and 7 years . Secondary outcomes were infantile wheeze , allergic rhinitis , eczema , and skin prick test positivity . Results Paracetamol had been used in 51 % ( 295/575 ) of children by 12 weeks of age and in 97 % ( 556/575 ) by 2 years . Between 6 and 7 years , 80 % ( 495/620 ) were followed up ; 30 % ( 148 ) had current asthma . Increasing frequency of paracetamol use was weakly associated with increased risk of childhood asthma ( crude odds ratio 1.18 , 95 % confidence interval 1.00 to 1.39 , per doubling of days of use ) . However , after adjustment for frequency of respiratory infections , this association essentially disappeared ( odds ratio 1.08 , 0.91 to 1.29 ) . Paracetamol use for non-respiratory causes was not associated with asthma ( crude odds ratio 0.95 , 0.81 to 1.12 ) . Conclusions In children with a family history of allergic diseases , no association was found between early paracetamol use and risk of subsequent allergic disease after adjustment for respiratory infections or when paracetamol use was restricted to non-respiratory tract infections . These findings suggest that early paracetamol use does not increase the risk of asthma",
"BACKGROUND Multivitamin-mineral ( MVM ) products are the most commonly used supplements in the United States , followed by multivitamin ( MV ) products . Two r and omized clinical trials ( RCTs ) did not show an effect of MVMs or MVs on cardiovascular disease ( CVD ) mortality ; however , no clinical trial data are available for women with MVM supplement use and CVD mortality . OBJECTIVE The objective of this research was to examine the association between MVM and MV use and CVD-specific mortality among US adults without CVD . METHODS A nationally representative sample of adults from the restricted data NHANES III ( 1988 - 1994 ; n = 8678 ; age ≥40 y ) were matched with mortality data reported by the National Death Index through 2011 to examine associations between MVM and MV use and CVD mortality by using Cox proportional hazards models , adjusting for multiple potential confounders . RESULTS We observed no significant association between CVD mortality and users of MVMs or MVs compared with nonusers ; however , when users were classified by the reported length of time products were used , a significant association was found with MVM use of > 3 y compared with nonusers ( HR : 0.65 ; 95 % CI : 0.49 , 0.85 ) . This finding was largely driven by the significant association among women ( HR : 0.56 ; 95 % CI : 0.37 , 0.85 ) but not men ( HR : 0.79 ; 95 % CI : 0.44 , 1.42 ) . No significant association was observed for MV products and CVD mortality in fully adjusted models . CONCLUSIONS In this nationally representative data set with detailed information on supplement use and CVD mortality data ∼20 y later , we found an association between MVM use of > 3 y and reduced CVD mortality risk for women when models controlled for age , race , education , body mass index , alcohol , aspirin use , serum lipids , blood pressure , and blood glucose/glycated hemoglobin . Our results are consistent with the 1 available RCT in men , indicating no relation with MVM use and CVD mortality ",
"Background and Purpose — Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine ( total homocysteine [ tHcy ] ) accelerate cardiovascular disease by promoting vascular inflammation , endothelial dysfunction , and hypercoagulability . Methods — We conducted a r and omized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg , vitamin B12 0.5 mg , and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation , endothelial dysfunction , and hypercoagulability . Results — At 6 months after r and omization , there was no significant difference in blood concentrations of markers of vascular inflammation ( high-sensitivity C-reactive protein [ P=0.32 ] ; soluble CD40L [ P=0.33 ] ; IL-6 [ P=0.77 ] ) , endothelial dysfunction ( vascular cell adhesion molecule-1 [ P=0.27 ] ; intercellular adhesion molecule-1 [ P=0.08 ] ; von Willebr and factor [ P=0.92 ] ) , and hypercoagulability ( P-selectin [ P=0.33 ] ; prothrombin fragment 1 and 2 [ P=0.81 ] ; D-dimer [ P=0.88 ] ) among patients assigned vitamin therapy compared with placebo despite a 3.7-&mgr;mol/L ( 95 % CI , 2.7 to 4.7 ) reduction in total homocysteine ( tHcy ) . Conclusions — Lowering tHcy by 3.7 & mgr;mol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation , endothelial dysfunction , or hypercoagulability measured in our study . The possible explanations for our findings are : ( 1 ) these biomarkers are not sensitive to the effects of lowering tHcy ( eg , multiple risk factor interventions may be required ) ; ( 2 ) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured ; or ( 3 ) elevated tHcy is a noncausal marker of increased vascular risk",
"Objective The efficacy of combined treatment consisting of enalapril and folic acid ( FA ) was compared to that of enalapril alone in reducing the serum uric acid ( UA ) levels in adult hypertensive patients in China . Methods Patients with mild to moderate hypertension ( n=480 ) were r and omly assigned to one of three treatment groups : ( 1 ) 10 mg enalapril ( control group ) , ( 2 ) 10 mg enalapril plus 0.4 mg FA ( low-FA group ) or ( 3 ) 10 mg enalapril plus 0.8 mg FA ( high-FA group ) daily for eight weeks . The primary outcome was the UA ratio ( week 8 UA : baseline UA ) . Results The final analysis included 450 patients ( 43.1 % men , 27 - 75 years of age ) . An adjusted multivariable regression analysis revealed no significant differences in the UA ratio between the three groups after eight weeks of treatment . In the subgroup analysis stratified according to the baseline UA level , the high-FA group demonstrated a significantly greater UA-lowering response among the patients with an elevated baseline UA concentration ( UA ≥310 μmol/L ) [ median UA ratio ( 25th percentile , 75th percentile ) : 0.94 ( 0.83 , 1.01 ) ] , compared with that observed in the control group [ 0.97 ( 0.90 , 1.00 ) , p=0.025 ] . Similar results were found in the participants with baseline hyperuricemia ( HUA ; UA : men > 420 μmol/L , women > 350 μmol/L ) . Conclusion In this sample of adult hypertensive patients , the administration of a daily dose of 10 mg of enalapril combined with 0.8 mg of FA had a greater beneficial effect on the serum UA levels than did that of 10 mg of enalapril alone in patients with either an elevated UA concentration or HUA",
"In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias",
"AIMS To determine the effects on homocysteine levels of two doses of folic acid compared to placebo , where the high dose is typical of that provided by pharmacological intervention and the low dose approximates that provided by dietary supplementation . METHODS AND RESULTS The PACIFIC study was a double-blind , placebo-controlled , factorial r and omized trial . Seven hundred and twenty-three individuals with a history of myocardial infa rct ion or unstable angina were recruited from 28 clinical cardiology centres in Australia and New Zeal and and r and omized to folic acid 2.0 mg daily , folic acid 0.2 mg daily or placebo . The primary outcome , homocysteine , was measured using a fluorescence polarization immunoassay . Compared to placebo , 2.0 mg folic acid reduced homo-cysteine by 1.8 micromol x 1(-1 ) [ 95 % confidence interval ( CI ) 1.3 - 2.3 ] and 0.2 mg reduced homocysteine by 1.2 micromol x 1(-1 ) [ 95 % CI 0.8 - 1.7 ) . The higher dose reduced homocysteine significantly more than the lower dose ( P=001 ) . CONCLUSIONS Both doses of folic acid reduced homocysteine , but the effects of the 2.0 mg dose were about one third greater than the 0.2 mg dose . Fortification of foods with folic acid should result in population -wide lower levels of homocysteine but high-dose pharmacological supplementation would produce greater reductions for high-risk individuals",
"Background Despite growing attention to nutrition and quality of life in cardiovascular disease survivors , the impact of dietary factors according to disease type or to quality of life domain is poorly understood . We investigated the effects of B vitamin and /or n-3 fatty acid supplementation on health-related quality of life among survivors of stroke , myocardial infa rct ion , or unstable angina . Methods We performed ancillary analyses of the SU.FOL.OM3 trial ( 2003–2009 ; France ) . In total , 2,501 men ( mean age = 61 y ) and women ( mean age = 63 y ) were r and omized in a 2 × 2 factorial design to : 1 ) 0.56 mg 5-methyl-tetrahydrofolate , 3 mg vitamin B6 , 0.02 mg vitamin B12 ; 2 ) 600 mg eicosapentaenoic and docosahexaenoic acids in a 2∶1 ratio ; 3 ) B vitamins and n-3 fatty acids combined ; or 4 ) placebo . Health-related quality of life was evaluated at follow-up with the Medical Outcomes Study 36-Item Short Form Health Survey . Data from 2,029 individuals were used in this analysis . Results After 3.1±0.4 y , no effects of supplementation with either B vitamins or n-3 fatty acids on quality of life ( physical or mental health domains ) were found . However , participants receiving B vitamins had slightly more activity limitations due to emotional problems compared with those not receiving B vitamins ( mean difference = 3.8 ; 95 % CI : 0.4 , 7.1 ) . A significant interaction of treatment by prior disease revealed an inverse association between n-3 fatty acids and vitality among myocardial infa rct ion survivors ( mean difference = 2.9 ; 95 % CI : 0.5 , 5.2 ) . Conclusions There were no beneficial effects of supplementation with relatively low doses of B vitamins or n-3 fatty acids on health-related quality of life in cardiovascular disease survivors . The adverse effects of B vitamins on activity limitations and of n-3 fatty acids on vitality among individuals with prior myocardial infa rct ion merit confirmation",
"High plasma homocysteine ( Hcy ) levels are associated with increased osteoporotic fracture incidence . However , the mechanism remains unclear . We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density ( BMD ) and calcaneal quantitative ultrasound ( QUS ) parameters . This r and omized , double-blind , placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12 , 400 µg folic acid , and 600 IU vitamin D or placebo with 600 IU vitamin D only . In total , 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS . Femoral neck ( FN ) BMD , lumbar spine ( LS ) BMD , calcaneal broadb and ultrasound attenuation ( BUA ) , and calcaneal speed of sound ( SOS ) were assessed . After 2 years , FN-BMD and BUA had significantly decreased , while LS-BMD significantly increased ( all p for FN-BMD ( p = 0.24 ) , LS-BMD ( p = 0.16 ) , SOS ( p = 0.67 ) , and BUA ( p = 0.96 ) . However , exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons > 80 years ( estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group , p = 0.04 for difference ) . In conclusion , this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly , mildly hyperhomocysteinemic persons , but suggests a small beneficial effect on BUA in persons > 80 years who were compliant in taking the supplement ",
"BACKGROUND Homocysteine is a risk factor for cardiovascular disease . We evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infa rct ion . METHODS The trial included 3749 men and women who had had an acute myocardial infa rct ion within seven days before r and omization . Patients were r and omly assigned , in a two-by-two factorial design , to receive one of the following four daily treatments : 0.8 mg of folic acid , 0.4 mg of vitamin B12 , and 40 mg of vitamin B6 ; 0.8 mg of folic acid and 0.4 mg of vitamin B12 ; 40 mg of vitamin B6 ; or placebo . The primary end point during a median follow-up of 40 months was a composite of recurrent myocardial infa rct ion , stroke , and sudden death attributed to coronary artery disease . RESULTS The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12 , but such treatment had no significant effect on the primary end point ( risk ratio , 1.08 ; 95 percent confidence interval , 0.93 to 1.25 ; P=0.31 ) . Also , treatment with vitamin B6 was not associated with any significant benefit with regard to the primary end point ( relative risk of the primary end point , 1.14 ; 95 percent confidence interval , 0.98 to 1.32 ; P=0.09 ) . In the group given folic acid , vitamin B12 , and vitamin B6 , there was a trend toward an increased risk ( relative risk , 1.22 ; 95 percent confidence interval , 1.00 to 1.50 ; P=0.05 ) . CONCLUSIONS Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infa rct ion . A harmful effect from combined B vitamin treatment was suggested . Such treatment should therefore not be recommended . ( Clinical Trials.gov number , NCT00266487 . )",
"Homocysteinemia is a risk factor for cardiovascular diseases . Folic acid combined with vitamins B6 and B12 is effective in lowering homocysteine levels . This r and omized placebo-controlled study was design ed to determine the effect of a folic acid-based supplement on secondary prevention of clinical events in non-ST-segment elevation acute coronary syndromes . The study comprised 240 patients with either unstable angina or non-ST-elevation myocardial infa rct ion in the previous 2 weeks who were r and omized to a folate group ( n = 116 ) or a placebo group ( n = 124 ) . The folate group received 1 mg folic acid , 400 μg vitamin B12 , and 10 mg vitamin B6 daily . Clinical outcomes within 6 months were assessed . The composite endpoint of death , nonfatal acute coronary syndrome , and serious re-hospitalization was significantly higher in the folate group ; serious re-hospitalization alone was significantly higher in this group . Advanced age and diabetes increased susceptibility to the composite outcome . Folic acid-based supplementation is not beneficial and may even be harmful in the secondary prevention of cardiovascular events in patients with unstable angina and non-ST-elevation myocardial infa rct ion . Further studies on the safety of such supplements are suggested . Controlled Clinical Trials Registry no. IS RCT N30249553",
"Background and Purpose — Elevated total homocysteine is associated with a higher risk of cerebrovascular disease . It is not known whether lowering homocysteine impacts on stroke risk , both in terms of severity and ischemic vs hemorrhagic stroke subtypes . Our aim was to determine whether vitamin therapy reduces the risk of ischemic and hemorrhagic stroke , as well as stroke-related disability . Methods — We analyzed stroke outcomes among participants of the Heart Outcomes Prevention Evaluation 2 ( HOPE 2 ) trial that r and omized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 , or matching placebo , for 5 years . Results — Among 5522 participants , stroke occurred in 258 ( 4.7 % ) individuals during a mean of 5 years of follow-up . The geometric mean homocysteine concentration decreased by 2.2 & mgr;mol/L in the vitamin therapy group and increased by 0.80 & mgr;mol/L in the placebo group . The incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group ( hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59–0.97 ) . Vitamin therapy also reduced the risk of nonfatal stroke ( HR , 0.72 ; 95 % CI , 0.54–0.95 ) but did not impact on neurological deficit at 24 hours ( P=0.45 ) or functional dependence at discharge or at 7 days ( OR , 0.95 ; 95 % CI , 0.57–1.56 ) . In subgroup analysis , patients aged younger than 69 years , from regions without folic acid food fortification , with higher baseline cholesterol and homocysteine levels , and those not receiving antiplatelet or lipid-lowering drugs at enrollment had a larger treatment benefit . Conclusions — Lowering of homocysteine with folic acid and vitamins B6 and B12 did reduce the risk of overall stroke , but not stroke severity or disability",
"OBJECTIVE To assess prospect ively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine . DESIGN Nested case-control study using prospect ively collected blood sample s. SETTING Participants in the Physicians ' Health Study . PARTICIPANTS A total of 14,916 male physicians , aged 40 to 84 years , with no prior myocardial infa rct ion ( MI ) or stroke provided plasma sample s at baseline and were followed up for 5 years . Sample s from 271 men who subsequently developed MI were analyzed for homocyst(e)ine levels together with paired controls , matched by age and smoking . MAIN OUTCOME MEASURE Acute MI or death due to coronary disease . RESULTS Levels of homocyst(e)ine were higher in cases than in controls ( 11.1 + /- 4.0 [ SD ] vs 10.5 + /- 2.8 nmol/mL ; P = .03 ) . The difference was attributable to an excess of high values among men who later had MIs . The relative risk for the highest 5 % vs the bottom 90 % of homocyst(e)ine levels was 3.1 ( 95 % confidence interval , 1.4 to 6.9 ; P = .005 ) . After additional adjustment for diabetes , hypertension , aspirin assignment , Quetelet 's Index , and total/high-density lipoprotein cholesterol , this relative risk was 3.4 ( 95 % confidence interval , 1.3 to 8.8 ) ( P = .01 ) . Thirteen controls and 31 cases ( 11 % ) had values above the 95th percentile of the controls . CONCLUSIONS Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of MI independent of other coronary risk factors . Because high levels can often be easily treated with vitamin supplements , homocyst(e)ine may be an independent , modifiable risk factor",
"Background and Purpose — The Vitamin Intervention for Stroke Prevention trial ( VISP ) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke . Reasons for lack of efficacy may have included folate fortification of grain products , inclusion of the recommended daily intake for B12 in the low-dose arm , treatment with parenteral B12 in patients with low B12 levels in both study arms , a dose of B12 too low for patients with malabsorption , supplementation with non study vitamins , and failure of patients with significant renal impairment to respond to vitamin therapy . We conducted an efficacy analysis limited to patients most likely to benefit from the treatment , based on hypotheses arising from evidence developed since VISP was initiated . The criteria for this subgroup were defined before any data analysis . Methods — For this analysis , we excluded patients with low and very high B12 levels at baseline ( 637 pmol/L , representing the 25th and 95th percentiles ) , to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment ( glomerular filtration rate Results — This subgroup represents 2155 patients ( 37 % female ) , with a mean age of 66±10.7 years . For the combined end point of ischemic stroke , coronary disease , or death , there was a 21 % reduction in the risk of events in the high-dose group compared with the low-dose group ( unadjusted P=0.049 ; adjusted for age , sex , blood pressure , smoking , and B12 level P=0.056 ) . In Kaplan – Meier survival analysis comparing 4 groups , patients with a baseline B12 level at the median or higher r and omized to high-dose vitamin had the best overall outcome , and those with B12 less than the median assigned to low-dose vitamin had the worst ( P=0.02 for combined stroke , death , and coronary events ; P=0.03 for stroke and coronary events ) . Conclusions — In the era of folate fortification , B12 plays a key role in vitamin therapy for total homocysteine . Higher doses of B12 , and other treatments to lower total homocysteine may be needed for some patients",
"In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies , most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted",
"Background and Purpose — To determine the effect of B vitamin treatment on the incidence of cancer among patients with stroke or transient ischemic attack . Methods — A total of 8164 patients with recent stroke or transient ischemic attack were r and omly allocated to double-blind treatment with 1 tablet daily of placebo or B vitamins ( 2 mg folic acid , 25 mg vitamin B6 , 500 & mgr;g vitamin B12 ) and followed for a median of 3.4 years for any cancer as an adverse event . Results — There was no significant difference in the incidence of any cancer among participants assigned B vitamins compared with placebo ( 4.04 % versus 4.59 % ; risk ratio , 0.86 ; 95 % CI , 0.70–1.07 ) and no difference in cancer mortality ( 2.35 % versus 2.09 % ; risk ratio , 1.09 ; 0.81–1.46 ) . Among 1899 patients with diabetes , the incidence of cancer was higher among participants assigned B vitamins compared with placebo ( 5.35 % versus 3.28 % ; adjusted risk ratio , 2.21 ; 1.31–3.73 ) , whereas among 6168 patients without diabetes , the incidence of cancer was lower among participants assigned B vitamins compared with placebo ( 3.66 % versus 5.03 % ; adjusted risk ratio , 0.67 ; 0.51–0.87 ; P for interaction=0.0001 ) . Conclusions — Daily administration of folic acid , vitamin B6 , and vitamin B12 to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect , compared with placebo , on cancer incidence or mortality . However , a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack . Clinical Trial Registration — URL : www . clinical trials.gov . Unique identifier : NCT00097669 . URL : www.controlled-trials.com . Unique identifier : IS RCT N74743444",
"The aim of this study was to test the influence of high-dose folic acid ( 10 mg/d ) on endothelial function in patients referred for coronary intervention after an acute myocardial infa rct ion ( AMI ) and determine its relation to homocysteine levels . Flow-mediated dilation ( FMD ) of the brachial artery was performed in 40 patients after AMI ( 16 with normal homocysteine levels and 24 patients with elevated levels [ > 11 micromol/L ] ) . Subjects were r and omized to receive first folic acid ( 10 mg/day ; group A ) or placebo ( group B ) for 6 weeks in a double-blind crossover trial with a 2-week washout . Plasma folate , total homocysteine and its subtypes ( oxidized , reduced , and protein-bound ) , FMD , and nitroglycerin-mediated dilation were assessed at baseline and at 6 and 14 weeks . In group A , folic acid improved FMD from 3.98 + /- 0.35 % to 6.44 + /- 0.56 % ( p placebo did not increase FMD ( 4.01 + /- 0.34 % vs 4.46 + /- 0.38 , p = 0.38 ) ; however , a significant increase was observed in the second active treatment period ( 6.49 + /- 0.56 % , p = 0.005 ) . In both groups , improved FMD neither correlated with basal levels of homocysteine and its subtypes nor with changes induced during the folate treatment . Nitroglycerin-mediated dilation did not change significantly in either group . Folic acid increased FMD in both normo- and hyperhomocysteinanemic groups ( p = 0.006 and p folic acid improves endothelial function in post-AMI patients , independent from homocysteine status . Folic acid can be recommended to improve postinfa rct ion endothelial dysfunction in patients with normo- and hyperhomocysteinemia",
"BACKGROUND Elevated plasma total homocysteine ( tHcy ) , low B-vitamin intake , and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease ( CHD ) . More prospect i ve studies are needed . METHODS AND RESULTS We used a prospect i ve case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women . Age- , race- , and field center-adjusted CHD incidence was associated positively ( P tHcy in women but not men , and CHD was associated negatively ( P vitamin supplementation ( women only ) . However , after accounting for other risk factors , only plasma pyridoxal 5'-phosphate was associated with CHD incidence ; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 ( 95 % CI=0.1 to 0.7 ) . There was no association of CHD with the C677 T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene . CONCLUSIONS Our prospect i ve findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major , independent , causative risk factor for CHD . Our findings point more strongly to the possibility that vitamin B6 offers independent protection . R and omized trials , some of which are under way , are needed to better clarify the interrelationships of tHcy , B vitamins , and cardiovascular disease",
"Background / Objectives : To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocol s in subjects with “ moderate ” hyperhomocysteinemia , also taking into account C677 T polymorphism of 5,10-methylenetetrahydrofolate reductase ( MTHFR ) gene . Subjects/ Methods : We performed a 13 week open , r and omized , double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia , with daily 200 μg from a natural folate-rich diet , 200 μg [6S]5-methyltetrahydrofolate ( 5-MTHF ) , 200 μg folic acid or placebo . Participants were stratified according to their MTHFR genotype . Results : Homocysteine ( Hcy ) levels were reduced after folate enriched diet , 5-MTHF or folic acid supplementation respectively by 20.1 % ( p supplementation , Hcy in both genotype groups decreased approximately to the same level , with higher percentage decreases observed for the TT group because of their higher pre-treatment value . Similar results were not seen by genotype for 5-MTHF . A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations , as compared to placebo . Conclusions : Supplementation with natural folate-rich foods , folic acid and 5-MTHF reached a similar reduction in Hcy concentrations ",
"Background During the last decades , many basic and clinical research have pointed to the role of B vitamins ( folate , vitamins B6 and B12 ) and n-3 fatty acids as nutritional factors that might have a protective effect on the development of cardiovascular diseases ( CVD ) . Methods / design The SU.FOL.OM3 ( SUpplementation with FOlate , vitamin B6 and B12 and /or OMega-3 fatty acids ) trial is a r and omized double-blind , placebo-controlled , secondary -prevention trial design ed to test the efficacy of 5-methyl tetra-hydro-folates ( 5-MTHF ) supplementation , in combination with vitamin B6 and B12 and /or n-3 fatty acids , at nutritional doses , on fatal and non fatal ischemic CVD in a 2 × 2 factorial design . A total of 2501 patients aged between 45 and 80 years who had a past history , in the previous year , of myocardial infa rct ion ( n = 1151 ) or instable angina pectoris ( n = 711 ) or an ischemic stroke ( n = 639 ) were included . Subjects have to be supplemented and followed up for five years . Daily supplementation comprised nutritional doses of 5-MTHF ( 560 μg ) , vitamin B6 ( 3 mg ) and B12 ( 20 μg ) and /or n-3 fatty acids ( 600 mg with an EPA : DHA ratio of 2:1 ) . A factorial design 2 × 2 has been applied to investigate the separate effects of the B-vitamins , and the n-3 fatty acids , as well as their interaction as compared to the placebo . The primary endpoint is a combination of myocardial infa rct ion , ischemic stroke and cardiovascular death . Secondary endpoints are events of the composite endpoint taken separately , total mortality , and other cardiovascular events such as acute coronary syndromes , coronary revascularization , cardiac failure , arrhythmia ... Conclusion Baseline socio-demographic and medical characteristics of participants are totally comparable in the four r and omized groups . Trial registration Current Controlled Trials IS RCT",
" A total of 3,318 men and women from a region in rural China were r and omized to receive daily either a multiple vitamin/mineral supplement or a placebo . Deaths that occurred in the participants were ascertained and classified according to cause over the 6-year period from 1985 to 1991 . At the end of supplementation , blood pressure readings were taken , and the prevalence of hypertension was determined . There was a slight reduction in overall mortality in the supplement group ( relative risk ( RR ) = 0.93 , 95 percent confidence interval ( CI ) 0.75 - 1.16 ) , with the decreased relative risk most pronounced for cerebrovascular disease deaths ( RR = 0.63 , 95 percent CI 0.37 - 1.07 ) . This benefit was greater for men ( RR = 0.42 , 95 percent CI 0.19 - 0.93 ) than for women ( RR = 0.93 , 95 percent CI 0.44 - 1.98 ) . Among the survivors , the presence of elevations in both systolic and diastolic blood pressures was less common in those who received the supplement ( RR for men = 0.43 , 95 % CI 0.28 - 0.65 ; RR for women = 0.92 , 95 percent CI 0.68 - 1.24 ) . This study indicates that supplementation with a multivitamin/mineral combination may have reduced mortality from cerebrovascular disease and the prevalence of hypertension in this rural population with a micronutrient-poor diet",
"OBJECTIVE Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress , systemic inflammation , and endothelial dysfunction . We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes . RESEARCH DESIGN AND METHODS The Women 's Antioxidant and Folic Acid Cardiovascular Study ( WAFACS ) , a r and omized , double-blind , placebo-controlled trial of 5,442 female health professionals aged ≥40 years with a history of cardiovascular disease ( CVD ) or three or more CVD risk factors , included 4,252 women free of diabetes at baseline . Participants were r and omly assigned to either an active treatment group ( daily intake of a combination pill of 2.5 mg folic acid , 50 mg vitamin B6 , and 1 mg vitamin B12 ) or to the placebo group . RESULTS During a median follow-up of 7.3 years , 504 women had an incident diagnosis of type 2 diabetes . Overall , there was no significant difference between the active treatment group and the placebo group in diabetes risk ( relative risk 0.94 [ 95 % CI 0.79–1.11 ] ; P = 0.46 ) , despite significant lowering of homocysteine levels . Also , there was no evidence for effect modifications by baseline intakes of dietary folate , vitamin B6 , and vitamin B12 . In a sensitivity analysis , the None result remained for women compliant with their study pills ( 0.92 [ 0.76–1.10 ] ; P = 0.36 ) . CONCLUSIONS Lowering homocysteine levels by daily supplementation with folic acid and vitamins B6 and B12 did not reduce the risk of developing type 2 diabetes among women at high risk for CVD",
"BACKGROUND Epidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events . Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown . We aim ed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke , non-fatal myocardial infa rct ion , and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye . METHODS In this r and omised , double-blind , parallel , placebo-controlled trial , we assigned patients with recent stroke or transient ischaemic attack ( within the past 7 months ) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins ( 2 mg folic acid , 25 mg vitamin B6 , and 0.5 mg vitamin B12 ) . Patients were r and omly allocated by means of a central 24-h telephone service or an interactive website , and allocation was by use of r and om permuted blocks stratified by hospital . Participants , clinicians , carers , and investigators who assessed outcomes were masked to the assigned intervention . The primary endpoint was the composite of stroke , myocardial infa rct ion , or vascular death . All patients r and omly allocated to a group were included in the analysis of the primary endpoint . This trial is registered with Clinical Trials.gov , NCT00097669 , and Current Controlled Trials , IS RCT N74743444 . FINDINGS Between Nov 19 , 1998 , and Dec 31 , 2008 , 8164 patients were r and omly assigned to receive B vitamins ( n=4089 ) or placebo ( n=4075 ) . Patients were followed up for a median duration of 3.4 years ( IQR 2.0 - 5.5 ) . 616 ( 15 % ) patients assigned to B vitamins and 678 ( 17 % ) assigned to placebo reached the primary endpoint ( risk ratio [ RR ] 0.91 , 95 % CI 0.82 to 1.00 , p=0.05 ; absolute risk reduction 1.56 % , -0.01 to 3.16 ) . There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups . INTERPRETATION Daily administration of folic acid , vitamin B6 , and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events . These results do not support the use of B vitamins to prevent recurrent stroke . The results of ongoing trials and an individual patient data meta- analysis will add statistical power and precision to present estimates of the effect of B vitamins . FUNDING Australia National Health and Medical Research Council , UK Medical Research Council , Singapore Biomedical Research Council , Singapore National Medical Research Council , Australia National Heart Foundation , Royal Perth Hospital Medical Research Foundation , and Health Department of Western Australia",
"Objective To investigate whether dietary supplementation with B vitamins or omega 3 fatty acids , or both , could prevent major cardiovascular events in patients with a history of ischaemic heart disease or stroke . Design Double blind , r and omised , placebo controlled trial ; factorial design . Setting Recruitment throughout France via a network of 417 cardiologists , neurologists , and other physicians . Participants 2501 patients with a history of myocardial infa rct ion , unstable angina , or ischaemic stroke . Intervention Daily dietary supplement containing 5-methyltetrahydrofolate ( 560 μg ) , vitamin B-6 ( 3 mg ) , and vitamin B-12 ( 20 μg ) or placebo ; and containing omega 3 fatty acids ( 600 mg of eicosapentanoic acid and docosahexaenoic acid at a ratio of 2:1 ) or placebo . Median duration of supplementation was 4.7 years . Main outcome measures Major cardiovascular events , defined as a composite of non-fatal myocardial infa rct ion , stroke , or death from cardiovascular disease . Results Allocation to B vitamins lowered plasma homocysteine concentrations by 19 % compared with placebo , but had no significant effects on major vascular events ( 75 v 82 patients , hazard ratio , 0.90 ( 95 % confidence interval 0.66 to 1.23 , P=0.50 ) ) . Allocation to omega 3 fatty acids increased plasma concentrations of omega 3 fatty acids by 37 % compared with placebo , but also had no significant effect on major vascular events ( 81 v 76 patients , hazard ratio 1.08 ( 0.79 to 1.47 , P=0.64 ) ) . Conclusion This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke , at least when supplementation is introduced after the acute phase of the initial event . Trial registration Current Controlled Trials IS RCT N41926726",
"Background / Objectives : Vitamin B12 ( B12 ) deficiency is common in Indians and a major contributor to hyperhomocysteinemia , which may influence fetal growth , risk of type II diabetes and cardiovascular disease . The purpose of this paper was to study the effect of physiological doses of B12 and folic acid on plasma total homocysteine ( tHcy ) concentration . Subjects/ Methods : A cluster r and omized , placebo-controlled , double-blind , 2 × 3 factorial trial , using the family as the r and omization unit . B12 was given as 2 or 10 μg capsules , with or without 200 μg folic acid , forming six groups ( B0F0 , B2F0 , B10F0 , B0F200 , B2F200 and B10F200 ) . Plasma tHcy concentration was measured before and after 4 and 12 months of supplementation . Results : From 119 families in the Pune Maternal Nutrition Study , 300 individuals were r and omized . There was no interaction between B12 and folic acid ( P=0.14 ) in relation to tHcy concentration change and their effects were analyzed separately : B0 vs. B2 vs. B10 ; and F0 vs. F200 . At 12 months , tHcy concentration reduced by a mean 5.9 ( 95 % CI : −7.8 , −4.1 ) μmol/l in B2 , and by 7.1 ( 95 % CI : −8.9 , −5.4 ) μmol/l in B10 , compared to nonsignificant rise of 1.2 ( 95 % CI : −0.5 , 2.9 ) μmol/l in B0 . B2 and B10 did not differ significantly . In F200 , tHcy concentration decreased by 4.8 ( 95 % CI : −6.3 , −3.3 ) μmol/l compared to 2.8 ( 95 % CI : −4.3 , −1.2 ) μmol/l in F0 . Conclusion : Daily oral supplementation with physiological doses of B12 is an effective community intervention to reduce tHcy . Folic acid ( 200 μg per day ) showed no additional benefit , neither had any unfavorable effects ",
"BACKGROUND Observational studies have shown that low folate and elevated homocysteine concentrations are risk factors for vascular disease in the general population . R and omized controlled trials in vascular patients have failed to show that folic acid reduces the risk of recurrent vascular disease , whereas such trials are lacking in the general population . OBJECTIVE The objective was to determine whether folic acid supplementation reduces the progression of atherosclerosis as measured by common carotid intima-media thickness (CIMT)-a vali date d marker of atherosclerosis and predictor of vascular disease risk . DESIGN A r and omized , double-blind , placebo-controlled study in 819 men and postmenopausal women aged 50 - 70 y , free-living in the Netherl and s , and with a total homocysteine concentration ≥13 μmol/L at screening was conducted . Participants received either 800 μg folic acid or placebo daily for 3 y. Rate of change in CIMT and arterial distensibility were the primary and secondary outcomes , respectively . RESULTS Compared with placebo , serum folate increased by 577 % and plasma total homocysteine concentrations decreased by 26 % after 3 y of folic acid supplementation . The mean ( ±SE ) rate of change in CIMT was 1.9 ± 0.9 μm/y in the folic acid arm and 1.3 ± 0.8 μm/y in the placebo arm ( mean difference : 0.7 μm/y ; 95 % CI : -1.8 , 3.1 μm/y ; P = 0.59 ) . No difference was observed ( P = 0.23 ) between the rates of change in distensibility in the folic acid arm ( -0.53 ± 0.06 × 10(-3 ) kPa(-1 ) ) and in the placebo arm ( -0.62 ± 0.06 × 10(-3 ) kPa(-1 ) ) . CONCLUSION Despite a considerable increase in folate concentrations and a reduction in total homocysteine concentrations , 3-y folic acid supplementation did not slow down atherosclerotic progression or arterial stiffening . This trial was registered at clinical trials.gov as NCT00110604",
"Rationale Epidemiological studies suggest that elevated homocysteine is linked to stroke and heart disease . However , the results of lowering homocysteine levels in reducing the risk of stroke recurrence are controversial . Aims The study aims to evaluate whether homocysteine-lowering therapy with folic acid and vitamins B6 and B12 reduces recurrent stroke events and other combined incidence of recurrent vascular events and vascular death in ischemic stroke patients of low folate regions . Design This is a multicenter , r and omized , double-blinded , placebo-controlled trial . Patients ( n = 8000 , α = 0·05 , β = 0·10 ) within one-month of ischemic stroke ( large-artery atherosclerosis or small-vessel occlusion ) or hypertensive intracerebral haemorrhage with plasma homocysteine level ⩾15 μmol/l will be enrolled . Eligible patients will be r and omized by a web-based , r and om allocation system to receive multivitamins ( folic acid 0·8 mg , vitamin B610 mg , and vitamin B12 500 μg ) or matching placebo daily with a median follow-up of three-years . Study Outcomes Patients will be evaluated at six monthly intervals . The primary outcome event is the composite event ‘ stroke , myocardial infa rct ion , or death from any vascular cause ’ , whichever occurs first . Secondary outcome measures include nonvascular death , transient ischemic attack , depression , dementia , unstable angina , revascularization procedures of the coronary , and cerebral and peripheral circulations . Discussion This is the first multicenter r and omized trial of secondary prevention for ischemic stroke in a Chinese population with a higher homocysteine level but without folate food fortification",
"BACKGROUND To advance knowledge about the cancer-chemopreventive potential of individual nutrients , we investigated the effects of B vitamin and /or ω-3 fatty acid supplements on cancer outcomes among survivors of cardiovascular disease . METHODS This was an ancillary study of the Supplementation With Folate , Vitamins B(6 ) and B(12 ) and /or Omega-3 Fatty Acids ( SU.FOL.OM3 ) secondary prevention trial ( 2003 - 2009 ) . In all , 2501 individuals aged 45 to 80 years were r and omized in a 2 × 2 factorial design to one of the following 4 daily supplementation groups : ( 1 ) 5-methyltetrahydrofolate ( 0.56 mg ) , pyridoxine hydrochloride ( vitamin B(6 ) ; 3 mg ) and cyanocobalamin ( vitamin B(12 ) ; 0.02 mg ) ; ( 2 ) eicosapentaenoic and docosahexaenoic acid ( 600 mg ) in a 2:1 ratio ; ( 3 ) B vitamins and ω-3 fatty acids ; or ( 4 ) placebo . Overall and sex-specific hazard ratios ( HRs ) and 95 % CIs regarding the cancer outcomes were estimated with Cox proportional hazards models . RESULTS After 5 years of supplementation , incident cancer was vali date d in 7.0 % of the sample ( 145 events in men and 29 in women ) , and death from cancer occurred in 2.3 % of the sample . There was no association between cancer outcomes and supplementation with B vitamins ( HR , 1.15 [ 95 % CI , 0.85 - 1.55 ] ) and /or ω-3 fatty acids ( HR , 1.17 [ 95 % CI , 0.87 - 1.58 ] ) . There was a statistically significant interaction of treatment by sex , with no effect of treatment on cancer risk among men and increased cancer risk among women for ω-3 fatty acid supplementation ( HR , 3.02 [ 95 % CI , 1.33 - 6.89 ] ) . CONCLUSION We found no beneficial effects of supplementation with relatively low doses of B vitamins and /or ω-3 fatty acids on cancer outcomes in individuals with prior cardiovascular disease . Trial Registration is rct n.org Identifier : IS RCT N41926726",
"BACKGROUND In observational studies , lower homocysteine levels are associated with lower rates of coronary heart disease and stroke . Folic acid and vitamins B6 and B12 lower homocysteine levels . We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease . METHODS We r and omly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 or with placebo for an average of five years . The primary outcome was a composite of death from cardiovascular causes , myocardial infa rct ion , and stroke . RESULTS Mean plasma homocysteine levels decreased by 2.4 micromol per liter ( 0.3 mg per liter ) in the active-treatment group and increased by 0.8 micromol per liter ( 0.1 mg per liter ) in the placebo group . Primary outcome events occurred in 519 patients ( 18.8 percent ) assigned to active therapy and 547 ( 19.8 percent ) assigned to placebo ( relative risk , 0.95 ; 95 percent confidence interval , 0.84 to 1.07 ; P=0.41 ) . As compared with placebo , active treatment did not significantly decrease the risk of death from cardiovascular causes ( relative risk , 0.96 ; 95 percent confidence interval , 0.81 to 1.13 ) , myocardial infa rct ion ( relative risk , 0.98 ; 95 percent confidence interval , 0.85 to 1.14 ) , or any of the secondary outcomes . Fewer patients assigned to active treatment than to placebo had a stroke ( relative risk , 0.75 ; 95 percent confidence interval , 0.59 to 0.97 ) . More patients in the active-treatment group were hospitalized for unstable angina ( relative risk , 1.24 ; 95 percent confidence interval , 1.04 to 1.49 ) . CONCLUSIONS Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease . ( Clinical Trials.gov number , NCT00106886 ; Current Controlled Trials number , IS RCT N14017017 . )",
"BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure",
"Importance The efficacy of folic acid therapy on renal outcomes has not been previously investigated in population s without folic acid fortification . Objective To test whether treatment with enalapril and folic acid is more effective in slowing renal function decline than enalapril alone across a spectrum of renal function at baseline from normal to moderate chronic kidney disease ( CKD ) among Chinese adults with hypertension . Design , Setting , and Participants In this sub study of eligible China Stroke Primary Prevention Trial ( CSPPT ) , 15 104 participants with an estimated glomerular filtration rate ( eGFR ) 30 mL/min/1.73 m2 or greater , including 1671 patients with CKD , were recruited from 20 communities in Jiangsu province in China . Interventions Participants were r and omized to receive a single tablet daily containing 10 mg enalapril and 0.8 mg folic acid ( n = 7545 ) or 10 mg enalapril alone ( n = 7559 ) . Main Outcomes and Measures The primary outcome was the progression of CKD , defined as a decrease in eGFR of 30 % or more and to a level of less than 60 mL/min/1.73 m2 if the baseline eGFR was 60 mL/min/1.73 m2 or more , or a decrease in eGFR of 50 % or more if the baseline eGFR was less than 60 mL/min/1.73 m2 ; or end-stage renal disease . Secondary outcomes included a composite of the primary outcome and all-cause death , rapid decline in renal function , and rate of eGFR decline . Results Overall , 15 104 Chinese adults with a mean ( range ) age of 60 ( 45 - 75 ) years were recruited ; median follow-up was 4.4 years . There were 164 and 132 primary events in the enalapril group and the enalapril-folic acid group , respectively . Compared with the enalapril group , the enalapril-folic acid group had a 21 % reduction in the odds of the primary event ( odds ratio [ OR ] , 0.79 ; 95 % CI , 0.62 - 1.00 ) and a slower rate of eGFR decline ( 1.28 % vs 1.42 % per year ; P = .02 ) . Among the participants with CKD at baseline , folic acid therapy result ed in a significant reduction in the risks for the primary event ( OR , 0.44 ; 95 % CI , 0.26 - 0.75 ) , rapid decline in renal function ( OR , 0.67 ; 95 % CI , 0.47 - 0.96 ) and the composite event ( OR , 0.62 ; 95 % CI , 0.43 - 0.90 ) , and a 44 % slower decline in renal function ( 0.96 % vs 1.72 % per year , P Conclusions and Relevance Enalapril-folic acid therapy , compared with enalapril alone , can significantly delay the progression of CKD among patients with mild-to-moderate CKD . Trial Registration clinical trials.gov Identifier : NCT00794885",
"Abstract Purpose We investigated whether daily supplementation with low-dose B vitamins in the healthy elderly population improves the Framingham risk score ( FRS ) , a predictor of cardiovascular disease risk . Methods Between 2007 and 2012 , a double-blind r and omized controlled trial was conducted in a rural area of North China . In all , 390 healthy participants aged 60–74 were r and omly allocated to receive daily vitamin C ( 50 mg ; control group ) or vitamin C plus B vitamins ( 400 µg folic acid , 2 mg B6 , and 10 µg B12 ; treatment group ) for 12 months . FRSs were calculated for all 390 subjects . Results Folate and vitamin B12 plasma concentrations in the treatment group increased by 253 and 80 % , respectively , after 6 months , stopped increasing with continued supplementation after 12 months and returned to baseline levels 6 months after supplementation cessation . Compared with the control group , there was no significant effect of B vitamin supplementation on FRSs after 6 months ( mean difference −0.38 ; 95 % CI −1.06 , 0.31 ; p = 0.279 ) , whereas a significant effect of supplementation was evident after 12 months ( reduced magnitude 7.6 % ; −0.77 ; 95 % CI −1.47 , −0.06 ; p = 0.033 ) . However , this reduction disappeared 6 months after supplementation stopped ( −0.07 ; 95 % CI −0.80 , 0.66 ; p = 0.855 ) . The reduction in FRS 12 months after supplementation was more pronounced in individuals with a folate deficiency ( 10.4 % ; −1.30 ; 95 % CI −2.54 , −0.07 ; p = 0.039 ) than in those without ( 4.1 % ; −0.38 ; 95 % CI −1.12 , 0.36 ; p = 0.313 ) . B vitamins increased high-density lipoprotein cholesterol by 3.4 % after 6 months ( 0.04 ; 95 % CI −0.02 , 0.10 ; p = 0.155 ) and by 9.2 % after 12 months ( 0.11 ; 95 % CI 0.04 , 0.18 ; p = 0.003 ) . Compared with the control group , this change in magnitude decreased to 3.3 % ( 0.04 ; 95 % CI −0.02 , 0.10 ; p = 0.194 ) 6 months after supplementation cessation . Conclusions Daily supplementation with a low-dose of B vitamins for 12 months reduced FRS , particularly in healthy elderly subjects with a folate deficiency . These reduced effects declined after supplementation cessation , indicating a need for persistent supplementation to maintain the associated benefits",
"BACKGROUND The lowest dose of folic acid required to achieve effective reductions in homocysteine is controversial but important for food fortification policy given recent concerns about the potential adverse effects of overexposure to this vitamin . OBJECTIVE We compared the effectiveness of 0.2 mg folic acid/d with that of 0.4 and 0.8 mg/d at lowering homocysteine concentrations over a 6-mo period . DESIGN A r and omized dose-finding trial with folic acid was conducted . Of 203 participants screened , 101 patients with ischemic heart disease and 71 healthy volunteers completed the study . Participants were r and omly assigned to receive placebo or folic acid at doses of 0.2 , 0.4 , or 0.8 mg/d for 26 wk ; sub sample s of patients with ischemic heart disease were also examined at 6 or 12 wk . RESULTS Participants with higher baseline homocysteine concentrations had the greatest reductions in homocysteine in response to folic acid doses of 0.2 mg ( -20.6 % ) , 0.4 mg ( -20.7 % ) , and 0.8 mg ( -27.8 % ) ; in those with lower baseline homocysteine concentrations , the responses were -8.2 % , -8.9 % , and -8.3 % , respectively . No significant differences in homocysteine responses to the different doses were observed . In the patient group sample d at intervals during the intervention , the maximal homocysteine response appeared to be achieved by 6 wk in the 0.8-mg/d group and by 12 wk in the 0.4-mg/d group . However , the homocysteine response was suboptimal in the 0.2-mg/d group at both 6 and 12 wk compared with that at 26 wk . CONCLUSIONS A folic acid dose as low as 0.2 mg/d can , if administered for 6 mo , effectively lower homocysteine concentrations . Higher doses may not be necessary because they result in no further significant lowering , whereas doses even lower than 0.2 mg/d may be effective in the longer term . Previous trials probably overestimated the folic acid dose required because of a treatment duration that was too short . This trial was registered at clinical trials.gov as IS RCT N45296887",
"Abstract Objectives : Homocysteine , folate , and some group B vitamins have been proposed as a cause of Cerebro-Vascular Accidents ( CVA ) . We conducted a case-control study to compare the plasma levels of folate , vitamin B12 and homocysteine in Iranian subjects with and without cerebro-vascular accident . Methods : We recruited 82 patients with ischemic stroke as cases and 60 subjects as controls ( using simple nonr and om sampling ) . Homocysteine was measured by fluorimetric high-performance liquid chromatography . Plasma folate and vitamin B12 levels were measured by an ion-capture method . Results : Mean plasma level of vitamin B12 in cases and controls were 358.4±290.3 Pg/ml and 369.8±110.4 Pg/ml , respectively which did not show any significant difference . Mean plasma level of folate in cases was significantly lower than the controls ( 6.8±4.5 ng/ml vs. 12.2±3.0 ng/ml , p=0.001 ) . It was also shown that mean plasma level of total homocysteine in cases was significantly higher than the controls ( 21.1±9.8 μM/L vs. 13.5±3.2 μM/L , P=0.001 ) . Homocysteine and folate but not plasma B12 had linear relation with age . Male cases had significantly lower Folate and B12 in contrast to women . In addition , male cases had significantly higher Homocysteine level in contrast to women . Conclusions : Our data shows that the level of homocysteine was higher and the level of folate was significantly lower in patients with ischemic stroke in contrast to controls . Effectiveness of supplementary folate and B 12 in such patients needs further well-structured prospect i ve placebo controlled studies",
"BACKGROUND Folic acid is assumed to have favourable effects on vascular endothelium , directly as well as indirectly through its effect on homocysteine metabolism . However , the clinical value of folic acid in secondary prevention after acute myocardial infa rct ion ( MI ) has never been tested . Thus , a r and omised , open-label , multicentre trial was performed in order to study the effect of folic acid 5 mg o.d . when added to statin therapy on the incidence of recurrent major clinical events up to 1 year post-MI . METHODS A total of 283 patients with a total cholesterol > 6.5 mmol/l ( 251 mg/dl ) ( mean 7.3 mmol/l ) were included . All patients received 40 fluvastatin . In 140 of the 283 patients , folic acid ( 5 mg o.d . ) was instituted at discharge , and the remaining 143 patients served as controls . Other secondary prevention measures for both groups were advocated . The primary endpoint was a composite consisting of all vascular events , including death , recurrent MI , strokes , and unplanned invasive coronary interventions . RESULTS At baseline , the two groups were well-matched for all clinical and demographic parameters . After 1 year of treatment , no difference was noticed in the primary endpoint between the two groups . These endpoints occurred in 43 patients ( 31 % ) in the folic acid group , as opposed to 45 patients ( 31 % ) in the control group . All separate cardiovascular events were also equally distributed between both groups . Total cholesterol levels decreased to a similar extent in the two groups ( to 5.5 and 5.7 mmol/l , in folic acid and control groups , respectively ) . CONCLUSIONS In this medium-size pilot study , folic acid did not demonstrate any beneficial additive effects on cardiovascular mortality or morbidity in post-MI patients with hypercholesterolemia who were treated with statin therapy . Larger trials , possibly targeting at selected population s , must be awaited before definitive conclusions regarding the potentially favourable effects of folic acid supplementation in secondary prevention can be drawn",
"CONTEXT Folate , vitamin B(6 ) , and vitamin B(12 ) are thought to play an important role in cancer prevention . OBJECTIVE To evaluate the effect of combined folic acid , vitamin B(6 ) , and vitamin B(12 ) treatment on cancer risk in women at high risk for cardiovascular disease . DESIGN , SETTING , AND PARTICIPANTS In the Women 's Antioxidant and Folic Acid Cardiovascular Study , 5442 US female health professionals aged 42 years or older , with preexisting cardiovascular disease or 3 or more coronary risk factors , were r and omly assigned to receive either a daily combination of folic acid , vitamin B(6 ) , and vitamin B(12 ) or a matching placebo . They were treated for 7.3 years from April 1998 through July 31 , 2005 . INTERVENTION Daily supplementation of a combination of 2.5 mg of folic acid , 50 mg of vitamin B(6 ) , and 1 mg of vitamin B(12 ) ( n = 2721 ) or placebo ( n = 2721 ) . MAIN OUTCOME MEASURES Confirmed newly diagnosed total invasive cancer or breast cancer . RESULTS A total of 379 women developed invasive cancer ( 187 in the active treatment group and 192 in the placebo group ) . Compared with placebo , women receiving the active treatment had similar risk of developing total invasive cancer ( 101.1/10,000 person-years for the active treatment group vs 104.3/10,000 person-years for placebo group ; hazard ratio [ HR ] , 0.97 ; 95 % confidence interval [ CI ] , 0.79 - 1.18 ; P = .75 ) , breast cancer ( 37.8/10,000 person-years vs 45.6/10,000 person-years , respectively ; HR , 0.83 ; 95 % CI , 0.60 - 1.14 ; P = .24 ) , or any cancer death ( 24.6/10,000 person-years vs 30.1/10,000 person-years , respectively ; HR , 0.82 ; 95 % CI , 0.56 - 1.21 ; P = .32 ) . CONCLUSION Combined folic acid , vitamin B(6 ) , and vitamin B(12 ) treatment had no significant effect on overall risk of total invasive cancer or breast cancer among women during the folic acid fortification era . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000541",
"CONTEXT Recently , concern has been raised about the safety of folic acid , particularly in relation to cancer risk . OBJECTIVE To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 r and omized controlled trials . DESIGN , SETTING , AND PARTICIPANTS Combined analysis and extended follow-up of participants from 2 r and omized , double-blind , placebo-controlled clinical trials ( Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial ) . A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005 , and were followed up through December 31 , 2007 . INTERVENTIONS Oral treatment with folic acid ( 0.8 mg/d ) plus vitamin B(12 ) ( 0.4 mg/d ) and vitamin B(6 ) ( 40 mg/d ) ( n = 1708 ) ; folic acid ( 0.8 mg/d ) plus vitamin B(12 ) ( 0.4 mg/d ) ( n = 1703 ) ; vitamin B(6 ) alone ( 40 mg/d ) ( n = 1705 ) ; or placebo ( n = 1721 ) . MAIN OUTCOME MEASURES Cancer incidence , cancer mortality , and all-cause mortality . RESULTS During study treatment , median serum folate concentration increased more than 6-fold among participants given folic acid . After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up , 341 participants ( 10.0 % ) who received folic acid plus vitamin B(12 ) vs 288 participants ( 8.4 % ) who did not receive such treatment were diagnosed with cancer ( hazard ratio [ HR ] , 1.21 ; 95 % confidence interval [ CI ] , 1.03 - 1.41 ; P = .02 ) . A total of 136 ( 4.0 % ) who received folic acid plus vitamin B(12 ) vs 100 ( 2.9 % ) who did not receive such treatment died from cancer ( HR , 1.38 ; 95 % CI , 1.07 - 1.79 ; P = .01 ) . A total of 548 patients ( 16.1 % ) who received folic acid plus vitamin B(12 ) vs 473 ( 13.8 % ) who did not receive such treatment died from any cause ( HR , 1.18 ; 95 % CI , 1.04 - 1.33 ; P = .01 ) . Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12 ) . Vitamin B(6 ) treatment was not associated with any significant effects . CONCLUSION Treatment with folic acid plus vitamin B(12 ) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway , where there is no folic acid fortification of foods . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00671346",
"Elevated plasma total homocysteine ( tHcy ) is a risk factor for vascular disease but lowering tHcy with B-vitamins , including folate , has generally not reduced vascular events in secondary prevention trials . Elevated plasma S-adenosylhomocysteine ( AdoHcy ) concentration may be a more sensitive indicator of vascular disease than plasma tHcy . However , unlike tHcy , plasma AdoHcy did not correlate with folate concentration in one study indicating that folate supplementation may not lower AdoHcy . Our aim was to determine whether providing B-vitamin supplements to healthy older people with elevated tHcy ( > 13 micromol/l ) affects plasma AdoHcy and S-adenosylmethionine ( AdoMet ) concentrations . Healthy older participants ( n 276 ; > or = 65 years ) were r and omised to receive a daily supplement containing folate ( 1 mg ) , vitamin B12 ( 500 microg ) and vitamin B6 ( 10 mg ) , or placebo , for 2 years . Of these participants , we selected the first fifty participants in each treatment group and measured plasma AdoHcy and AdoMet . Plasma tHcy was 4.4 ( 95 % CI 3.2 , 5.6 ; P plasma AdoMet ( + 4 % ( 95 % CI - 2 , 11 ) ; P = 0.19 ) , AdoHcy ( - 1 % ( 95 % CI - 10 , 8) ; P = 0.61 ) or the AdoMet : AdoHcy ratio ( 0.22 ( 95 % CI - 0.04 , 0.49 ) ; P = 0.10 ) between the two groups . In conclusion , B-vitamin supplementation of older people lowered plasma tHcy but had no effect on plasma AdoMet or AdoHcy concentration . If elevated plasma AdoHcy is detrimental , this may explain why B-vitamins have generally failed to reduce vascular events in clinical trials",
"CONTEXT Recent r and omized trials among patients with preexisting cardiovascular disease ( CVD ) have failed to support benefits of B-vitamin supplementation on cardiovascular risk . Observational data suggest benefits may be greater among women , yet women have been underrepresented in published r and omized trials . OBJECTIVE To test whether a combination of folic acid , vitamin B6 , and vitamin B12 lowers risk of CVD among high-risk women with and without CVD . DESIGN , SETTING , AND PARTICIPANTS Within an ongoing r and omized trial of antioxidant vitamins , 5442 women who were US health professionals aged 42 years or older , with either a history of CVD or 3 or more coronary risk factors , were enrolled in a r and omized , double-blind , placebo-controlled trial to receive a combination pill containing folic acid , vitamin B6 , and vitamin B12 or a matching placebo , and were treated for 7.3 years from April 1998 through July 2005 . INTERVENTION Daily intake of a combination pill of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 . MAIN OUTCOME MEASURES A composite outcome of myocardial infa rct ion , stroke , coronary revascularization , or CVD mortality . RESULTS Compared with placebo , a total of 796 women experienced a confirmed CVD event ( 406 in the active group and 390 in the placebo group ) . Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point ( 226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group ; relative risk [ RR ] , 1.03 ; 95 % confidence interval [ CI ] , 0.90 - 1.19 ; P = .65 ) , as well as for the secondary outcomes including myocardial infa rct ion ( 34.5/10,000 person-years vs 39.5/10,000 person-years ; RR , 0.87 ; 95 % CI , 0.63 - 1.22 ; P = .42 ) , stroke ( 41.9/10,000 person-years vs 36.8/10,000 person-years ; RR , 1.14 ; 95 % CI , 0.82 - 1.57 ; P = .44 ) , and CVD mortality ( 50.3/10,000 person-years vs 49.6/10,000 person-years ; RR , 1.01 ; 95 % CI , 0.76 - 1.35 ; P = .93 ) . In a blood sub study , geometric mean plasma homocysteine level was decreased by 18.5 % ( 95 % CI , 12.5%-24.1 % ; P of folic acid , vitamin B6 , and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women , despite significant homocysteine lowering . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000541",
"Introduction : Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old , and is associated with elevated arterial stiffness in this age group . Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes , we aim ed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients . Methods : The B-PROOF study is a double-blind , r and omized controlled trial , including 2919 elderly aged at least 65 years , with hyperhomocysteinemia ( 12–50 & mgr;mol/l ) , treated with B-vitamins ( 500 & mgr;g vitamin B12 and 400 & mgr;g folic acid ) or placebo for 2 years . In a subgroup ( n = 569 ) , the effect of B-vitamins on pulse wave velocity ( PWV ) was investigated as a measurement of arterial stiffness . To measure atherosclerosis , carotid intima – media thickness ( IMT ) measures had been used . Incidents of cardiovascular and cerebrovascular events were determined via structured question naires , and blood pressure was also measured . Results : Compared to placebo , B-vitamin supplementation lowered serum homocysteine by 3.6 & mgr;mol/l ( P supplementation on PWV levels , and this was not different for patients without increased arterial stiffness at baseline . Furthermore , no effect on carotid IMT was observed . Discussion : Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT . Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes",
"Background Epidemiological studies suggest that raised plasma concentrations of total homocysteine ( tHcy ) may be a common , causal and treatable risk factor for atherothromboembolic ischaemic stroke , dementia and depression . Although tHcy can be lowered effectively with small doses of folic acid , vitamin B12 and vitamin B6 , it is not known whether lowering tHcy , by means of B vitamin therapy , can prevent stroke and other major atherothromboembolic vascular events . Aim To determine whether the addition of B-vitamin supplements ( folic acid 2 mg , B6 25 mg , B12 500 μg ) to best medical and surgical management will reduce the combined incidence of stroke , myocardial infa rct ion ( MI ) and vascular death in patients with recent stroke or transient ischaemic attack ( TIA ) of the brain or eye . Design A prospect i ve , international , multicentre , r and omised , double blind , placebo-controlled clinical trial . Setting One hundred and four medical centres in 20 countries on five continents . Subjects Eight thous and ( 6600 recruited as of 5 January , 2006 ) patients with recent ( 7 months ) stroke ( ischaemic or haemorrhagic ) or TIA ( brain or eye ) . R and omisation R and omisation and data collection are performed by means of a central telephone service or secure internet site . Intervention One tablet daily of either placebo or B vitamins ( folic acid 2 mg , B6 25 mg , B12 500 μg ) . Primary outcome The composite of stroke , MI or death from any vascular cause , whichever occurs first . Outcome and serious adverse events are adjudicated blinded to treatment allocation . Secondary outcomes TIA , unstable angina , revascularisation procedures , dementia , depression . Statistical power With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8 % among patients assigned placebo , the study will have at least 80 % power to detect a relative reduction of 15 % in the incidence of the primary outcome among patients assigned B vitamins ( to 6·8%/year ) , applying a two-tailed level of significance of 5 % . Conclusion VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008 , and provide a reliable estimate of the safety and effectiveness of folic acid , vitamin B12 , and vitamin B6 supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world",
"Elevated plasma total homocysteine is independently associated with atherosclerosis . Recent r and omized trials show that vitamins lower total homocysteine but do not prevent cardiovascular events , suggesting the need for nonvitamin therapies to evaluate whether a causative relationship exists . Mesna ( sodium 2-mercaptoethanesulfonate ) is a thiol-containing drug capable of liberating homocysteine bound by disulfide bonds to proteins , facilitating its excretion . The effect of oral mesna on total homocysteine has not been evaluated and was the objective of this study . Eleven healthy volunteers received vehicle or 10 mg/kg mesna in r and om order , after which serial blood and urine sample s were collected over 4 hours . Plasma total homocysteine decreased by 24.2 % ( P mesna . Urinary homocysteine excretion was significantly greater with mesna ( 3.9 + /- 2.4 mumol ) compared to vehicle ( 0.4 + /- 0.1 mumol ) , P mesna decreases plasma total homocysteine and is a potential nonvitamin treatment for assessing the homocysteine theory of atherosclerosis",
"OBJECTIVES Vitamin B-12 and n-3 polyunsaturated fatty acids ( PUFA ) decrease blood homocysteine ( Hcy ) concentrations . However , the combined effect of these nutrients on Hcy and ferritin , and C-reactive protein is limited and inconclusive . The objective was to examine the synergistic effect of vitamin B-12 in combination of n-3 PUFA on plasma Hcy , ferritin , and other biochemical markers . METHODS In a r and omized controlled trial , thirty eligible subjects were r and omly divided into three groups , and assigned to receive 1000 μg of vitamin B-12 , 2 g fish oil , or 1000 μg vitamin B-12 and 2 g fish oil , respectively , for 8 weeks . Plasma phospholipids ( PL ) fatty acids and biochemical markers were determined . This study was registered under Clinical Trials.gov Identifier : NCT01762072 . RESULTS Plasma PL 20:5n-3 , 22:6n-3 and n-3 PUFA was increased after 4 and 8 week supplementation of fish oil , and vitamin B-12+fish oil . Plasma concentrations of triacylglycerol , uric acid , C-reactive protein , and ferritin were significantly decreased after 4 and 8 week supplementation of fish oil , and vitamin B-12+fish oil . In all groups , significant changes in plasma Hcy were observed during the study period . Vitamin B-12 , fish oil , and vitamin B-12+fish oil supplementation lowered plasma Hcy concentrations by 22 % , 19 % , and 39 % , respectively . CONCLUSIONS The combination of vitamin B-12 and fish oil has a synergistic effect on lowering plasma concentrations of Hcy",
"BACKGROUND Mechanisms involved in coronary stenosis evolution are different than those involved in clinical events . Because of differential vascular effects , N-3 polyunsatured fatty acids ( PUFA ) and B vitamins could have differential effects on different types of cardiovascular clinical events in high-risk patients . METHODS We analyzed the effects of n-3 PUFA and of B vitamins on both coronary revascularization and on hard coronary events risks in a subgroup of the SU.FOL.OM3 trial , a r and omized , double-blind , placebo-controlled secondary prevention trial . Data were analyzed according to the intention-to-treat principle , with the use of Cox proportional-hazards models . RESULTS After a mean follow-up of 4.2 ± 1.0 years among the 1,863 participants with coronary heart disease , 163 coronary revascularizations were performed , and 95 patients experienced a hard coronary event . Neither treatment with n-3 PUFA , nor treatment with B vitamins was associated with any significant effect on the occurrence of hard coronary events . Allocation to n-3 PUFA was not associated with any significant effect on coronary revascularization . However , treatment with B vitamins was associated with a statistically significant 52 % increase in the risk of coronary revascularization ( multivariate HR : 1.52 ; 95 % CI : [ 1.11 - 2.10 ] ; p=0.01 ) . CONCLUSIONS Neither n-3 PUFA , nor B vitamins reduced the rates of hard coronary events and of coronary revascularization . Furthermore , B vitamins significantly increased the rate of coronary revascularization . Consistent with the findings of previous trials , our results do not support the routine use of dietary supplements containing n-3 PUFA and argue against using dietary supplements containing B-vitamins in coronary patients in secondary cardiovascular prevention",
"Homocysteine is a risk factor for atherosclerosis in the general population , and serum homocysteine levels are almost universally elevated in chronic renal failure patients . When such patients are treated with dialysis , cardiovascular disease accounts for more than 50 % of their mortality , which , in some proportion , may be pathophysiologically related to the elevated serum homocysteine levels . From April 2003 to March 2005 , we conducted a 2-year , double-blind , r and omized , placebo-controlled trial of 186 patients with end-stage kidney disease due to any cause , who were older than 18 years and stable on hemodialysis . Patients were assigned to receive either oral folic acid 10 mg 3 times a week immediately after every dialysis session under nurse supervision or an identical-appearing placebo for the entire study . On admission , plasma total homocysteine ( tHcy ) levels were above 13.9 micromol/L in 96.7 % of patients ( median 25.0 micromol/L , range 9.3 - 104.0 micromol/L ) . In the placebo group , tHcy levels remained elevated at 6 , 12 , and 24 months , while oral folate significantly decreased tHcy to a median value of 10.5 ( 2.8 - 20.3 ) micromol/L , ( p ( folic acid group 17 vs. placebo group 21 ; p=0.47 ) died from cardiovascular disease . Kaplan-Meier life table analysis dealing with the incidence of cardiovascular events , both fatal and nonfatal ( myocardial infa rct ion , arrhythmias , angina , heart failure , cerebrovascular accident ) , showed that 2 years of folic acid treatment and the lowering of the homocysteine blood levels had no effect on cardiovascular events ( p=0.41 ; hazard ratio 1.24 , 95 % CI 0.74 - 2.10 ) . However , the carotid artery intima-media wall thickness measured in a blinded fashion decreased from 1.94 + /- 0.59 mm to 1.67 + /- 0.38 mm ( p folate therapy . In this short-term study of uremic patients , 2 years of folic acid supplementation normalized the tHcy blood levels in 92.3 % of patients but did not change the incidence of cardiovascular events compared with the control group . However , ultrasonography of the common carotid arteries performed at entry and 24 months later showed a significant decrease in intima-media thickness with folate supplementation . This suggests that early folate supplementation may benefit patients with chronic renal failure by preventing cardiovascular deterioration",
"OBJECTIVES We sought to conduct a r and omized trial with folic acid 0.5 mg/day in a patient population with stable coronary artery disease ( CAD ) . BACKGROUND Folic acid has favorable effects on vascular endothelium and lowers plasma homocysteine levels . In addition , homocysteine appears to be an independent risk factor for atherosclerotic disease . However , the value of folic acid in secondary prevention had seldom been tested . METHODS In this open-label study , 593 patients were included ; 300 were r and omized to folic acid and 293 served as controls . Mean follow-up time was 24 months . At baseline all patients had been on statin therapy for a mean of 3.2 years . RESULTS In patients treated with folic acid , plasma homocysteine levels decreased by 18 % , from 12.0 + /- 4.8 to 9.4 + /- 3.5 micromol/l , whereas these levels remained unaffected in the control group ( p ( all-cause mortality and a composite of vascular events ) was encountered in 31 ( 10.3 % ) patients in the folic acid group and in 28 ( 9.6 % ) patients in the control group ( relative risk 1.05 ; 95 % confidence interval : 0.63 to 1.75 ) . In a multifactorial survival model with adjustments for clinical factors , the most predictive laboratory parameters were , in order of significance , levels of creatinine clearance , plasma fibrinogen , and homocysteine . CONCLUSIONS Within two years , folic acid does not seem to reduce clinical end points in patients with stable coronary artery disease ( CAD ) while on statin treatment . Homocysteine might therefore merely be a modifiable marker of disease . Thus , low-dose folic acid supplementation should be treated with reservation , until more trial outcomes become available",
"OBJECTIVES A high level of total homocysteine ( tHcy ) is a risk marker for cardiovascular disease ( CVD ) , and is related to inflammation . We wanted to test the effect of homocysteine-lowering B-vitamin therapy , as used in the Western Norway B-vitamin Intervention Trial ( WENBIT ) , on inflammatory markers associated with atherosclerosis . DESIGN Single centre , prospect i ve double-blind clinical interventional study , r and omised in a 2 x 2 factorial design . SUBJECTS AND METHODS Ninety patients ( 21 female ) with suspected coronary artery disease ( CAD ) , aged 38 - 80 years , were blindly r and omised into one of four groups of daily oral treatment with ( A ) folic acid ( 0.8 mg)/vitamin B12 ( 0.4 mg)/vitamin B6 ( 40 mg ) , ( B ) folic acid/vitamin B12 , ( C ) vitamin B6 alone or ( D ) placebo . Blood sample s were collected before and after 6 months of treatment . RESULTS Before intervention , median levels of the analytes were : tHcy 11.0 micromol L(-1 ) , neopterin 8.1 nmol L(-1 ) , soluble CD40 lig and ( sCD40L ) 3.9 ng mL(-1 ) , interleukin (IL)-6 1.9 pg mL(-1 ) , C-reactive protein ( CRP ) 1.9 mg L(-1 ) and low-density lipoprotein ( LDL ) cholesterol 3.3 mmol L(-1 ) . tHcy was significantly associated with neopterin ( r = 0.49 , P IL-6 ( r = 0.29 , P = 0.01 ) , but not with CRP or sCD40L . Neither treatment with folic acid/B12 nor with B6 induced significant changes in any of these inflammatory biomarkers ( P > or= 0.14 ) . In patients receiving folic acid/B12 ( groups A and B ) , tHcy was reduced with 33 % ( P patients with stable CAD , homocysteine-lowering therapy with B-vitamins does not affect levels of inflammatory markers associated with atherogenesis . Failure to reverse inflammatory processes , may partly explain the negative results in clinical secondary B-vitamin intervention trials",
"BACKGROUND Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular ( CV ) disease . Simple , inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25 % to 30 % and may reduce CV events . Therefore , a large , r and omized clinical trial -- the Heart Outcomes Prevention Evaluation (HOPE)-2 study --is being conducted to evaluate this therapy in patients at high risk for CV events . OBJECTIVES To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population . The primary study outcome is the composite of death from CV causes , myocardial infa rct ion and stroke . METHODS A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s ) at 145 centres in 13 countries were r and omly assigned to daily therapy with combined folic acid 2.5 mg , vitamin B6 50 mg and vitamin B12 1 mg , or to placebo . Follow-up will average five years , to be completed by the end of 2005 . RESULTS The patients ' baseline characteristics confirmed their high-risk status . Baseline homocysteine levels varied between countries and regions . HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention",
"CONTEXT Plasma homocysteine level has been recognized as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis and influences restenosis rate after percutaneous coronary intervention . OBJECTIVE To evaluate the effect of homocysteine-lowering therapy on clinical outcome after percutaneous coronary intervention . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind placebo-controlled trial involving 553 patients referred to the University Hospital in Bern , Switzerl and , from May 1998 to April 1999 and enrolled after successful angioplasty of at least 1 significant coronary stenosis ( > or = 50 % ) . INTERVENTION Participants were r and omly assigned to receive a combination of folic acid ( 1 mg/d ) , vitamin B12 ( cyanocobalamin , 400 micro g/d ) , and vitamin B6 ( pyridoxine hydrochloride , 10 mg/d ) ( n = 272 ) or placebo ( n = 281 ) for 6 months . MAIN OUTCOME MEASURE Composite end point of major adverse events defined as death , nonfatal myocardial infa rct ion , and need for repeat revascularization , evaluated at 6 months and 1 year . RESULTS After a mean ( SD ) follow-up of 11 ( 3 ) months , the composite end point was significantly lower at 1 year in patients treated with homocysteine-lowering therapy ( 15.4 % vs 22.8 % ; relative risk [ RR ] , 0.68 ; 95 % confidence interval [ CI ] , 0.48 - 0.96 ; P = .03 ) , primarily due to a reduced rate of target lesion revascularization ( 9.9 % vs 16.0 % ; RR , 0.62 ; 95 % CI , 0.40 - 0.97 ; P = .03 ) . A nonsignificant trend was seen toward fewer deaths ( 1.5 % vs 2.8 % ; RR , 0.54 ; 95 % CI , 0.16 - 1.70 ; P = .27 ) and nonfatal myocardial infa rct ions ( 2.6 % vs 4.3 % ; RR , 0.60 ; 95 % CI , 0.24 - 1.51 ; P = .27 ) with homocysteine-lowering therapy . These findings remained unchanged after adjustment for potential confounders . CONCLUSION Homocysteine-lowering therapy with folic acid , vitamin B12 , and vitamin B6 significantly decreases the incidence of major adverse events after percutaneous coronary intervention",
"CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue",
"BACKGROUND Cholesterol lowering with statins reduces the risk of vascular disease , but uncertainty remains as to whether more intensive statin therapy produces worthwhile benefits safely . Blood homocysteine level is an independent marker of vascular risk , but it is unknown whether this association is causal . METHODS AND RESULTS 12,064 myocardial infa rct ion survivors have been r and omized to more versus less intensive cholesterol-lowering treatment using simvastatin 80 mg versus 20 mg daily . Allocation to more intensive treatment has yielded average further low-density lipoprotein cholesterol reductions of 0.5 mmol/L at 2 months and 0.4 mmol/L at 5 years . In addition , using a factorial design , these patients have been r and omized to homocysteine lowering with folic acid 2 mg plus vitamin B12 1 mg daily versus matching placebo , yielding an average 3 to 4 mumol/L reduction in homocysteine . After 6 years of median follow-up , the annual overall rate of major vascular events is approximately 3 % . Follow-up is scheduled to continue for a median of 7 years . CONCLUSION SEARCH should provide reliable evidence about the efficacy and safety of prolonged use of more intensive cholesterol-lowering therapy and , separately , of folate-based homocysteine-lowering therapy in a high-risk population",
"BACKGROUND Dietary supplements are widely used in industrialized countries . OBJECTIVE The objective was to examine the association between multivitamin use and myocardial infa rct ion ( MI ) in a prospect i ve , population -based cohort of women . DESIGN The study included 31,671 women with no history of cardiovascular disease ( CVD ) and 2262 women with a history of CVD aged 49 - 83 y from Sweden . Women completed a self-administered question naire in 1997 regarding dietary supplement use , diet , and lifestyle factors . Multivitamins were estimated to contain nutrients close to recommended daily allowances : vitamin A ( 0.9 mg ) , vitamin C ( 60 mg ) , vitamin D ( 5 μg ) , vitamin E ( 9 mg ) , thiamine ( 1.2 mg ) , riboflavin ( 1.4 mg ) , vitamin B-6 ( 1.8 mg ) , vitamin B-12 ( 3 μg ) , and folic acid ( 400 μg ) . RESULTS During an average of 10.2 y of follow-up , 932 MI cases were identified in the CVD-free group and 269 cases in the CVD group . In the CVD-free group , use of multivitamins only , compared with no use of supplements , was associated with a multivariable-adjusted hazard ratio ( HR ) of 0.73 ( 95 % CI : 0.57 , 0.93 ) . The HR for multivitamin use together with other supplements was 0.70 ( 95 % CI : 0.57 , 0.87 ) . The HR for use of supplements other than multivitamins was 0.93 ( 95 % CI : 0.81 , 1.08 ) . The use of multivitamins for ≥5 y was associated with an HR of 0.59 ( 95 % CI : 0.44 , 0.80 ) . In the CVD group , use of multivitamins alone or together with other supplements was not associated with MI . CONCLUSIONS The use of multivitamins was inversely associated with MI , especially long-term use among women with no CVD . Further prospect i ve studies with detailed information on the content of preparations and the duration of use are needed to confirm or refute our findings",
"Hyperhomocysteinemia is considered to be a risk factor for vascular diseases including ischemic stroke . It has been shown that plasma homocysteine level can be lowered by folic acid supplementation . Vitamin B(12 ) may be also beneficial when included in the supplement regimen with folic acid . We have examined in Japanese patients with ischemic stroke the homocysteine-lowering potential of a combination therapy with folic acid and vitamin B(12 ) . Patients with ischemic stroke were r and omized into three groups and each group received vitamin B(12 ) ( 1500 microg/day , n = 63 ) , folic acid ( 5 mg/day , n = 64 ) , or both vitamin B(12 ) and folic acid ( n = 64 ) for 8 weeks . Plasma levels of homocysteine and these vitamins were followed . Significant reduction in plasma homocysteine was observed in all three groups , and the combination therapy yielded the most remarkable result , i.e. , plasma total homocysteine was reduced by 38.5 % and this was significantly larger than the reduction in other two groups ( 22.4 % and 10.9 % in the groups received folic acid and vitamin B(12 ) , respectively ) . Vitamin B(12 ) synergizes with folic acid in reducing plasma homocysteine in Japanese patients with ischemic stroke and the combined therapy may be particularly effective in the secondary prevention",
"CONTEXT High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease . Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown . OBJECTIVE To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind r and omized controlled trial ( 2001 - 2006 ) in 36 US Department of Veterans Affairs medical centers . Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease ( estimated creatinine clearance or = 15 micromol/L ) . INTERVENTION Participants received a daily capsule containing 40 mg of folic acid , 100 mg of pyridoxine hydrochloride ( vitamin B6 ) , and 2 mg of cyanocobalamin ( vitamin B12 ) or a placebo . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality . Secondary outcomes included myocardial infa rct ion ( MI ) , stroke , amputation of all or part of a lower extremity , a composite of these 3 plus all-cause mortality , time to initiation of dialysis , and time to thrombosis of arteriovenous access in hemodialysis patients . RESULTS Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group . It was lowered 6.3 micromol/L ( 25.8 % ; P mortality ( 448 vitamin group deaths vs 436 placebo group deaths ) ( hazard ratio [ HR ] , 1.04 ; 95 % CI , 0.91 - 1.18 ) . No significant effects were demonstrated for secondary outcomes or adverse events : there were 129 MIs in the vitamin group vs 150 for placebo ( HR , 0.86 ; 95 % CI , 0.67 - 1.08 ) , 37 strokes in the vitamin group vs 41 for placebo ( HR , 0.90 ; 95 % CI , 0.58 - 1.40 ) , and 60 amputations in the vitamin group vs 53 for placebo ( HR , 1.14 ; 95 % CI , 0.79 - 1.64 ) . In addition , the composite of MI , stroke , and amputations plus mortality ( P = .85 ) , time to dialysis ( P = .38 ) , and time to thrombosis in hemodialysis patients ( P = .97 ) did not differ between the vitamin and placebo groups . CONCLUSION Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00032435",
"BACKGROUND Methylenetetrahydrofolate dehydrogenase ( MTHFD1 ) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate ( THF ) in folate-dependent one-carbon metabolism . Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress . However , limited information is available on its relation to the development of atherothrombotic cardiovascular disease . METHODS AND RESULTS We explored the association between a MTHFD1 polymorphism ( rs1076991 C > T ) and acute myocardial infa rct ion ( AMI ) , and potential effect modifications by folic acid/B12 and /or vitamin B6 treatment in suspected stable angina pectoris patients ( n = 2381 ) participating in the r and omized Western Norway B Vitamin Intervention Trial ( WENBIT ) . During the median follow-up of 4.9 years 204 participants ( 8.6 % ) suffered an AMI . After adjusting for established CVD risk factors , the MTHFD1 polymorphism was significantly associated with AMI ( HR : 1.49 ; 95 % CI , 1.23 - 1.81 ) . A similar association was observed among patients allocated to treatment with vitamin B6 alone ( HR : 1.53 ; 95 % CI , 1.01 - 2.31 ) , and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 ( HR : 2.35 ; 95 % CI , 1.55 - 3.57 ) . However , no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo ( HR : 1.29 ; 95 % CI , 0.86 - 1.93 ) or folic acid/B12 ( 1.17 ; 95 % CI , 0.83 - 1.65 ) . CONCLUSION A common and functional MTHFD1 polymorphism is associated with increased risk of AMI , although the risk seems to be dependent on specific B vitamin treatment . Further studies are warranted to eluci date the possible mechanisms , also in order to explore potential effect modifications by nutritional factors",
"Abstract Cardiovascular disease ( CVD ) is a major cause of morbidity and mortality in developed countries . However , traditional risk factors can not fully account for this . In the last 20 years , there has been an explosion of interest in plasma total homocysteine ( tHcy ) as a potential modifiable risk factor for CVD . Recent meta-analyses of epidemiological studies support the concept that increased tHcy concentrations are associated with CVD . This has led to the ‘ homocysteine hypothesis ’ , which states that lowering plasma tHcy using folic acid and other B-vitamins will reduce the risk of CVD . In experimental studies , homocysteine has been shown to cause oxidative stress , endothelial cell dysfunction and promote thrombogenesis . However , data from recent large r and omized controlled trials have shown that there is no clinical benefit to lowering plasma tHcy concentrations with folic acid and other B-vitamins . This lack of effect of tHcy lowering strongly suggests that homocysteine is not an instigator but merely an indicator of CVD",
"Background Plasma concentration of total homocysteine is associated with risk of cardiovascular disease in epidemiological studies . We wanted to examine the effects of B-vitamin therapy , which may lower total homocysteine , on coronary flow and vascular function in patients with established coronary artery disease ( CAD ) . Methods Forty patients with stable CAD , mean ( st and ard deviation ) aged 57.8 ( 9.0 ) years , recruited into the Western Norway B-Vitamin Intervention Trial , were r and omly assigned to daily oral treatment with 0.8 mg of folic acid and 0.4 mg of vitamin B12 or placebo , and 40 mg of vitamin B6 or placebo , using a 2 × 2 factorial design . At baseline , and after 9 and 24 months , coronary blood flow was assessed by coronary angiography and Doppler flow-wire measurements during intracoronary infusion of saline ( basal ) , incremental doses of acetylcholine , adenosine , and nitroglycerin . Results We found a significant increase in basal ( P ) and adenosine-induced ( P in patients who received folic acid/vitamin B12 for 24 months , compared with placebo or vitamin B6 alone . Folic acid/vitamin B12 or vitamin B6 treatment did not change endothelial-dependent response after acetylcholine infusion or flow-dependent proximal dilatation in response to adenosine-induced maximal hyperemia ( P≥0.45 ) . Conclusion Long-term treatment with a combination of folic acid and vitamin B12 increase basal and adenosine-induced maximal coronary blood flow . This may reflect improved microvascular function in patients with stable CAD",
"BACKGROUND Elevated plasma homocysteine levels are a risk factor for coronary heart disease , but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined . METHODS We prospect ively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease . At the time of angiography in 1991 or 1992 , risk factors for coronary disease , including homocysteine levels , were evaluated . The majority of the patients subsequently underwent coronary-artery bypass grafting ( 318 patients ) or percutaneous transluminal coronary angioplasty ( 120 patients ) ; the remaining 149 were treated medically . RESULTS After a median follow-up of 4.6 years , 64 patients ( 10.9 percent ) had died . We found a strong , grade d relation between plasma homocysteine levels and overall mortality . After four years , 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died , as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher . Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infa rct ion , the left ventricular ejection fraction , and the serum creatinine level . The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders . In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group , the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter , 2.8 for those with levels of 15.0 to 19.9 micromol per liter , and 4.5 for those with levels of 20.0 micromol per liter or higher ( P for trend=0.02 ) . When death due to cardiovascular disease ( which occurred in 50 patients ) was used as the end point in the analysis , the relation between homocysteine levels and mortality was slightly strengthened . CONCLUSIONS Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease",
"BACKGROUND AND AIMS Hypercholesterolemia is one of the predisposing factors of cardiovascular diseases . A positive correlation of homocysteine ( Hcy ) concentration with total cholesterol is described . Lovastatin , one of the most administered agents in hypercholesterolemia , is not effective in lowering the level of serum Hcy and increasing serum total antioxidant capacity ( TAC ) . This study was performed to evaluate the effects of folate supplementation on lowering Hcy level and changes of TAC in asymptomatic hypercholesterolemic adults under lovastatin treatment . METHODS This was a double-blind r and omized controlled clinical trial . Forty asymptomatic newly diagnosed hypercholesterolemic individuals were recruited . Patients were r and omized into two groups : group A--20 patients supplemented for 8 weeks with folate ( 5 mg daily ) and group B--20 patients receiving placebo . Lovastatin was administered to both groups . Laboratory lipid profiles , serum Hcy and folate concentration , and TAC were measured at the beginning and after the 8(th ) week of the study period . RESULTS After folate supplementation in group A subjects , serum Hcy was significantly decreased ( 13.35+/-5.01 micromol/L to 8.43+/-2.52 micromol/L , p=0.001 ) , whereas no significant changes occurred in group B ( p>0.05 ) . A significant increase in TAC was only observed in group A ( 1.54+/-0.24 micromol/L to 1.96+/-0.42 micromol/L , p Folate supplementation decreases the serum level of Hcy and increases TAC . It seems that a pharmacological dose of folate supplementation could potentially decrease the risk of cardiovascular diseases by reducing serum level of Hcy in adults with hypercholesterolemia",
"Homocysteine ( HCY ) , C-reactive protein ( hsCRP ) , and triglycerides ( TG ) are risk factors for cardiovascular disease ( CVD ) . While multivitamins ( MVit ) may reduce HCY and hsCRP , omega-3 fatty acids ( N3 ) reduce TG ; yet , they are seldom studied simultaneously . We r and omly assigned 100 participants with baseline HCY ( > 8.0 umol/L ) to the daily ingestion of : ( 1 ) placebo , ( 2 ) MVit ( VitC : 200 mg ; VitE : 400 IU ; VitB6 : 25 mg ; Folic Acid : 400 ug ; VitB12 : 400 ug ) + placebo , ( 3 ) N3 ( 2 g N3 , 760 mg EPA , 440 mg DHA)+placebo , or ( 4 ) MVit + N3 for 12 weeks . At follow-up , we observed significant reductions in HCY ( umol/L ) for the MVit ( - 1.43 , 95 % CI , - 2.39 , - 0.47 ) and MVit + N3 groups ( - 1.01 , 95 % CI , - 1.98 , - 0.04 ) groups , both being significant ( p hsCRP ( nmol/L ) was significantly reduced in the MVit ( - 6.00 , 95 % CI , - 1.04 , - 0.15 ) and MVit + N3 ( - 0.98 , 95 % CI , - 1.51 , - 0.46 ) groups , but not vs. placebo ( - 0.15 , 95 % CI , - 0.74 , 0.43 ) or N3 ( - 0.53 , 95 % CI , - 1.18 , 0.12 ) . Lastly , we observed significant reductions in TG for the N3 ( - 0.41 , 95 % CI , - 0.69 , - 0.13 ) and MVit + N3 ( - 0.71 , 95 % CI , - 0.93 , - 0.46 ) groups , both significant vs. placebo ( - 0.10 , 95 % CI , - 0.36 , 0.17 ) and MVit groups ( 0.15 , 95 % CI , - 12 , 0.42 ) . The co-ingestion of MVit + N3 provides synergistic affects on HCY , hsCRP , and plasma TG",
"Background : Previous studies support an association between elevated total homocysteine ( tHcy ) levels and increased all-cause mortality . However , few prospect i ve studies have examined this association in hypertensive patients , and /or tested any effect modification by the methylene tetrahydrofolate reductase ( MTHFR ) C677 T genotype . Methods : This was a post hoc analysis of the China Stroke Primary Prevention Trial . Serum tHcy and folate were measured at baseline . Individual MTHFR C677 T genotype ( CC , CT , and TT ) was determined . Evidence for death included death certificates or home visits . Cumulative hazards of all-cause mortality by tHcy quartiles were estimated using the Kaplan – Meier method , and group differences were compared by log-rank tests . Hazard ratios ( HRs ) and 95 % confidence intervals were estimated by Cox proportional-hazard regression models , adjusting for age , sex , baseline folate , vitamin B12 , blood pressure , body mass index , smoking and alcohol drinking status , study center , total cholesterol , triglycerides , high-density lipoprotein cholesterol , fasting glucose , creatinine , and treatment group . Potential effect modification by the MTHFR genotype on the relationship between tHcy and all-cause mortality was tested . Results : The analyses included 20,424 hypertensive patients ( 41 % males ) without a history of myocardial infa rct ion or stroke . Baseline mean age ( SD ) was 60 ± 7.5 years and mean ( SD ) serum tHcy was 14.5 ± 8.4 & mgr;mol/L. After a mean follow-up period of 4.5 years , there were 612 ( 3 % ) all-cause deaths . Kaplan – Meier survival curves revealed a grade d relationship between tHcy quartiles and all-cause mortality . The HRs , using the lowest quartile as the reference , were 1.2 , 1.2 , and 1.5 in Q2 , Q3 , and Q4 , respectively . A linear trend test , using natural log-transformed tHcy , result ed in an HR of 1.5 ( 95 % confidence interval 1.2–1.9 , P on mortality , it significantly modified the tHcy – mortality association , which was much stronger in the CC/CT genotype than in the TT genotype ( P for interaction Chinese hypertensive patients without cardiovascular comorbidities , elevated tHcy was a significant risk marker for death from all causes , and the association was subject to effect modification by MTHFR genotypes . If confirmed that tHcy and MTHFR genotypes may serve as useful biomarkers for mortality risk assessment and targeted intervention",
"Background : Homocysteine may promote atherosclerosis by exacerbating inflammatory processes within the arterial wall . B-vitamin supplements reduce total plasma homocysteine concentrations ( tHcy ) , but it is not known whether the treatment also reduces arterial wall inflammation . We used 18F-fluorodeoxygluose positron emission tomography ( 18F-FDG PET ) to investigate whether long-term homocysteine-lowering treatment alters arterial wall inflammation in patients with a history of ischemic stroke . Methods : 30 stroke patients were r and omly assigned to B-vitamin therapy ( folic acid 2 mg , vitamin B6 25 mg and vitamin B12 0.5 mg ) or placebo in a double-blind clinical trial . After a mean treatment period of 4.0 ± 0.7 years , all subjects had tHcy , carotid intima-medial thickness ( CIMT ) and flow-mediated dilation ( FMD ) of the brachial artery measured and underwent an 18F-FDG PET scan . St and ardised uptake values ( SUV ) were measured at six sites in the carotid , femoral and aortic arteries . Areas of locally increased tracer uptake in the arterial wall ( ‘ hot spots ’ ) were also identified and counted . Results : Long-term B-vitamin treatment significantly reduced tHcy compared with placebo ( 8.4 μmol/l , 95 % confidence interval , CI , 7.2–9.6 vs. 11.6 μmol/l , 95 % CI 10.0–13.4 , p = 0.002 ) . The treatment did not affect mean arterial SUV ( 2.0 ± 0.3 vitamins vs. 2.1 ± 0.3 placebo , p = 0.65 ) or the number of hot spots ( n = 1.1 ± 1.0 vitamins vs. n = 1.2 ± 1.0 placebo , p = 0.65 ) . There was no significant correlation between mean arterial SUV and CIMT or FMD . Conclusions : These results suggest that a long-term Hcy reduction with B vitamins does not affect arterial wall inflammation assessed by 18F-FDG PET",
"The relationship of folic acid supplementation with the risk of cancer remains inconclusive . We aim ed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infa rct ion ( MI ) in the China Stroke Primary Prevention Trial ( CSPPT ) . A total of 20,702 hypertensive adults without history of stroke or MI , stratified by MTHFR C677 T genotypes(CC , CT and TT ) , were r and omly assigned to receive double‐blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348 ) or a pill containing 10 mg enalapril alone(n = 10,354 ) . During a median treatment duration of 4.5 years , cancer occurred in 116 participants ( 1.12 % ) in the enalapril‐folic acid group versus 116 participants ( 1.12 % ) in the enalapril group ( HR , 1.00 ; 95%CI , 0.77–1.29 ) . There was also no significant difference in the HRs for specific types of cancer(esophageal , gastric , breast , lung , colorectal , head and neck , liver and gynecologic cancer or lymphoma ) or cancer mortality(HR , 1.05 ; 95%CI , 0.69–1.58 ) . For participants not receiving folic acid treatment ( enalapril only group ) , MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype ( HR , 1.86 ; 95%CI , 1.07–3.22 ) . Consistently , a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels ( mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China . Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels",
"CONTEXT Blood homocysteine levels are positively associated with cardiovascular disease , but it is uncertain whether the association is causal . OBJECTIVE To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12 ) on vascular and nonvascular outcomes . DESIGN , SETTING , AND PATIENTS Double-blind r and omized controlled trial of 12,064 survivors of myocardial infa rct ion in secondary care hospitals in the United Kingdom between 1998 and 2008 . INTERVENTIONS 2 mg folic acid plus 1 mg vitamin B(12 ) daily vs matching placebo . MAIN OUTCOME MEASURES First major vascular event , defined as major coronary event ( coronary death , myocardial infa rct ion , or coronary revascularization ) , fatal or nonfatal stroke , or noncoronary revascularization . RESULTS Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L ( 28 % ) . During 6.7 years of follow-up , major vascular events occurred in 1537 of 6033 participants ( 25.5 % ) allocated folic acid plus vitamin B(12 ) vs 1493 of 6031 participants ( 24.8 % ) allocated placebo ( risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.97 - 1.12 ; P = .28 ) . There were no apparent effects on major coronary events ( vitamins , 1229 [ 20.4 % ] , vs placebo , 1185 [ 19.6 % ] ; RR , 1.05 ; 95 % CI , 0.97 - 1.13 ) , stroke ( vitamins , 269 [ 4.5 % ] , vs placebo , 265 [ 4.4 % ] ; RR , 1.02 ; 95 % CI , 0.86 - 1.21 ) , or noncoronary revascularizations ( vitamins , 178 [ 3.0 % ] , vs placebo , 152 [ 2.5 % ] ; RR , 1.18 ; 95 % CI , 0.95 - 1.46 ) . Nor were there significant differences in the numbers of deaths attributed to vascular causes ( vitamins , 578 [ 9.6 % ] , vs placebo , 559 [ 9.3 % ] ) or nonvascular causes ( vitamins , 405 [ 6.7 % ] , vs placebo , 392 [ 6.5 % ] ) or in the incidence of any cancer ( vitamins , 678 [ 11.2 % ] , vs placebo , 639 [ 10.6 % ] ) . CONCLUSION Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12 ) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N74348595"
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[ 1 ] Immonen H , Hannukainen JC , Iozzo P , Soinio M , Salminen P , Saunavaara V , et al. Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients . J Hepatol 2014;60:377–383 . [ 2 ] Mingrone G , Panunzi S , De Gaetano A , Guidone C , Iaconelli A , Leccesi L , et al. Bariatric surgery vs. conventional medical therapy for type 2 diabetes . N Engl J Med 2012;366:1577–1585 . [ 3 ] Schauer PR , Bhatt DL , Kirwan JP , Wolski K , Brethauer SA , Navaneethan SD , et al. Bariatric surgery vs. intensive medical therapy for diabetes – 3-year outcomes . N Engl J Med 2014;370:2002–2013 . [ 4 ] Schauer PR , Kashyap SR , Wolski K , Brethauer SA , Kirwan JP , Pothier CE , et al. Bariatric surgery vs. intensive medical therapy in obese patients with diabetes . N Engl J Med 2012;366:1567–1576 . [ 5 ] Kashyap SR , Bhatt DL , Wolski K , Watanabe RM , Abdul-Ghani M , Abood B , et al. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes : analysis of a r and omized control trial comparing surgery with intensive medical treatment . Diabetes Care 2013;36 : 2175–2182 . [ 6 ] Parikh M , Issa R , Vieira D , McMacken M , Saunders JK , Ude-Welcome A , et al. Role of bariatric surgery as treatment for type 2 diabetes in patients who do not meet current NIH criteria : a systematic review and meta- analysis . J Am Coll Surg 2013;217:527–532 . [ 7 ] Maggard-Gibbons M , Maglione M , Livhits M , Ewing B , Maher AR , Hu J , et al. Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes : a systematic review . JAMA 2013;309:2250–2261 . [ 8 ] Courcoulas AP , Goodpaster BH , Eagleton JK , Belle SH , Kalarchian MA , Lang W , et al. Surgical vs. medical treatments for type 2 diabetes mellitus : a r and omized clinical trial . JAMA Surg 2014;149:707–715
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"IMPORTANCE Many questions remain unanswered about the role of bariatric surgery for people with type 2 diabetes mellitus ( T2DM ) . OBJECTIVE To determine feasibility of a r and omized clinical trial ( RCT ) and compare initial outcomes of bariatric surgery and a structured weight loss program for treating T2DM in participants with grade s I and II obesity . DESIGN , SETTING , AND PARTICIPANTS A 12-month , 3-arm RCT at a single center including 69 participants aged 25 to 55 years with a body mass index ( calculated as weight in kilograms divided by height in meters squared ) of 30 to 40 and T2DM . INTERVENTIONS Roux-en-Y gastric bypass ( RYGB ) , laparoscopic adjustable gastric b and ing ( LAGB ) , and an intensive lifestyle weight loss intervention ( LWLI ) . MAIN OUTCOMES AND MEASURES Primary outcomes in the intention-to-treat cohort were feasibility and effectiveness measured by weight loss and improvements in glycemic control . RESULTS Of 667 potential participants who underwent screening , 69 ( 10.3 % ) were r and omized . Among the r and omized participants , 30 ( 43 % ) had grade I obesity , and 56 ( 81 % ) were women . Mean ( SD ) age was 47.3 ( 6.4 ) years and hemoglobin A1c level , 7.9 % ( 2.0 % ) . After r and omization , 7 participants ( 10 % ) refused to undergo their allocated intervention ( 3 RYGB , 1 LAGB , and 3 LWLI ) , and 1 RYGB participant was excluded for current smoking . Twenty participants underwent RYGB ; 21 , LAGB ; and 20 , LWLI , with 12-month retention rates of 90 % , 86 % , and 70 % , respectively . In the intention-to-treat cohort with multiple imputation for missing data , RYGB participants had the greatest mean weight loss from baseline ( 27.0 % ; 95 % CI , 30.8 - 23.3 ) compared with LAGB ( 17.3 % ; 95 % CI , 21.1 - 13.5 ) and LWLI ( 10.2 % ; 95 % CI , 14.8 - 5.61 ) ( P Partial and complete remission of T2DM were 50 % and 17 % , respectively , in the RYGB group and 27 % and 23 % , respectively , in the LAGB group ( P remission in the LWLI group . Significant reductions in use of antidiabetics occurred in both surgical groups . No deaths were noted . The 3 serious adverse events included 1 ulcer treated medically in the RYGB group and 2 rehospitalizations for dehydration in the LAGB group . CONCLUSIONS AND RELEVANCE This study highlights several potential challenges to successful completion of a larger RCT for treatment of T2DM and obesity in patients with a body mass index of 30 to 40 , including the difficulties associated with recruiting and r and omizing patients to surgical vs nonsurgical interventions . Preliminary results show that RYGB was the most effective treatment , followed by LAGB for weight loss and T2DM outcomes at 1 year . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01047735",
"BACKGROUND In short-term r and omized trials ( duration , 1 to 2 years ) , bariatric surgery has been associated with improvement in type 2 diabetes mellitus . METHODS We assessed outcomes 3 years after the r and omization of 150 obese patients with uncontrolled type 2 diabetes to receive either intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy . The primary end point was a glycated hemoglobin level of 6.0 % or less . RESULTS The mean ( ±SD ) age of the patients at baseline was 48±8 years , 68 % were women , the mean baseline glycated hemoglobin level was 9.3±1.5 % , and the mean baseline body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 36.0±3.5 . A total of 91 % of the patients completed 36 months of follow-up . At 3 years , the criterion for the primary end point was met by 5 % of the patients in the medical-therapy group , as compared with 38 % of those in the gastric-bypass group ( P The use of glucose-lowering medications , including insulin , was lower in the surgical groups than in the medical-therapy group . Patients in the surgical groups had greater mean percentage reductions in weight from baseline , with reductions of 24.5±9.1 % in the gastric-bypass group and 21.1±8.9 % in the sleeve-gastrectomy group , as compared with a reduction of 4.2±8.3 % in the medical-therapy group ( P for both comparisons ) . Quality -of-life measures were significantly better in the two surgical groups than in the medical-therapy group . There were no major late surgical complications . CONCLUSIONS Among obese patients with uncontrolled type 2 diabetes , 3 years of intensive medical therapy plus bariatric surgery result ed in glycemic control in significantly more patients than did medical therapy alone . Analyses of secondary end points , including body weight , use of glucose-lowering medications , and quality of life , also showed favorable results at 3 years in the surgical groups , as compared with the group receiving medical therapy alone . ( Funded by Ethicon and others ; STAMPEDE Clinical Trials.gov number , NCT00432809 . )"
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PURPOSE We performed two parallel systematic review s and meta-analyses to determine the association between early migration of tibial components and late aseptic revision . METHODS One review comprised early migration data from radiostereometric analysis ( RSA ) studies , while the other focused on revision rates for aseptic loosening from long-term survival studies . Thresholds for acceptable and unacceptable migration were determined according to that of several national joint registries : 50 studies ( involving 847 total knee prostheses ( TKPs ) ) were included in the RSA review and 56 studies ( 20,599 TKPs ) were included in the survival review . The results showed that for every mm increase in migration there was an 8 % increase in revision rate , which remained after correction for age , sex , diagnosis , hospital type , continent , and study quality . Consequently , migration up to 0.5 mm was considered acceptable during the first postoperative year , while migration of 1.6 mm or more was unacceptable . TKPs with migration of between 0.5 and 1.6 mm were considered to be at risk of having revision rates higher than 5 % at 10 years . INTERPRETATION There was a clinical ly relevant association between early migration of TKPs and late revision for loosening . The proposed migration thresholds can be implemented in a phased , evidence -based introduction of new types of knee prostheses , since they allow early detection of high-risk TKPs while exposing only a small number of patients
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"BACKGROUND In total knee replacement , sound early fixation of the prosthesis is crucial for achieving a good long-term result and for minimising the risk of loosening . Various types of prosthetic material , different surface textures and shapes and the incorporation of screws or pegs have been used to achieve good fixation , particularly in the uncemented knee . Hydroxyapatite ( HA ) coating of prosthetic joint components is another technique used to enhance early stability and so to improve the longevity of the prosthesis-bone fixation . HA ceramic coatings are mostly plasma sprayed onto the fixation surface of the implant . Plasma spraying is largely a ' line of sight ' technique and as such there are difficulties involved when covering three-dimensional planes , such as porous beaded fixation surfaces typically found on several knee prostheses . The objective of this study was to assess the clinical performance of the solution-deposited HA coating , Peri-Apatite , with regard to its ability to stimulate an endurable and stable implant fixation . PATIENTS AND METHODS We r and omised 60 patients into two groups ; one group received the porous coated prosthesis with solution-deposited HA , and the other group received a prosthesis without HA . Radiostereometric examination was used as the primary tool for measuring migration in the prosthetic components . RESULTS There was a lower incidence of early subsidence in the Peri-Apatite group . At 24 months there were no differences in clinical scorings or maximal total point motion . CONCLUSION Addition of solution-deposited HA coating appears to provide better early stable fixation in a porous coated knee prosthesis",
"Background We have previously reported that 6 months of oral treatment with clodronate reduced the migration of the NexGen total knee prosthesis during the first postoperative year , as measured by radiostereometry ( RSA ) . We now report the 4-year results . Methods This was a double-blind r and omized study , using RSA with maximal total point motion ( MTPM ) . Results With analysis according to the “ intention to treat ” principle , the only remaining difference between the groups at 4 years was reduced rotation around the transverse axis ( a secondary variable ) in the clodronate group . However , 3 patients ( all clodronate ) did not take any tablet after surgery . If they are excluded , there was an almost statistically significant difference between the groups at 4 years regarding MTPM from baseline , with the clodronate group showing 25 % less migration . From 1 to 4 years , there was no difference in migration rate by MTPM , but there was a continuous increase in rotation around the transverse axis in the controls , which differed from the clodronate group . There were no cases of aseptic loosening . 2 patients had migration of more than 1.3 mm from baseline to 4 years ; neither of them had taken clodronate . The others had migration of less than 0.9 mm . Interpretation Because migration was clearly reduced by clodronate during the first postoperative year , and there was still a difference at 4 years when analyzed per protocol , it appears likely that this treatment can diminish the risk of loosening . The difference in the number of outliers also points in this direction , and may be more relevant than mean migration values",
"In a single-blind , r and omised series of knee replacements in 116 patients , we used radiostereometric analysis ( RSA ) to measure micromotion in three types of tibial implant fixation for two years after knee replacement . We compared hydroxyapatite-augmented porous coating , porous coating , and cemented fixation of the same design of tibial component . At one to two years , porous-coated implants migrated at a statistically significantly higher rate than hydroxyapatite-augmented or cemented implants . There was no significant difference between hydroxyapatite-coated and cemented implants . We conclude that hydroxyapatite augmentation may offer a clinical ly relevant advantage over a simple porous coating for tibial component fixation , but is no better than cemented fixation",
"Sixty-two knees ( 60 patients ) were r and omized to four noncemented groups . In Groups 1 , 3 , and 4 , the bone cuts were made with a cooled saw blade . In Group 1 , 15 patients were operated on with the porous coated Osteonic 7000 tibial component . In Group 2 , 15 patients were operated on with the same tibial component as in Group 1 but with the use of a st and ard saw blade . In Group 3 , 16 patients were operated on with the hydroxyapatite-coated Osteonic tibial component , and in Group 4 , 16 patients were operated on with the hydroxyapatite Duracon tibial component . All patients were followed up clinical ly and with roentgenstereometric analysis . There were no differences among the groups regarding clinical outcome . One knee was revised ( Group 2 ) after 1 year because of loosening of the tibial component . The maximum migration at 1 year was 1.7 mm in Group 1 , 1.9 mm in Group 2 , 1.3 mm in Group 3 , and 1 mm in Group 4 . At the 2-year followup , the migrations were 1.8 mm , 1.5 mm , 1.4 mm , and 1 mm in Groups 1 , 2 , 3 , and 4 , respectively . The inducible displacement that occurred at 1 year was 0.6 mm in Group 1 , 0.5 mm in Group 2 , 0.4 mm in Group 3 , and 0.4 mm in Group 4 . The hydroxyapatite coating had a strong positive effect on the tibial component fixation . No prosthesis in the hydroxyapatite groups showed continuous migration",
"Abstract Objective : Migration of the tibial component in total knee arthroplasty ( TKA ) is subject of many studies using roentgen stereophotogrammetric analysis ( RSA ) . In previous studies of cemented and uncemented tibial components , high migration values were found . Improvements in cementing technique , prosthetic design and pre-coating techniques reduced these values as shown in more recent studies . Material and subjects : A total of 35 patients were initially included in the study and operated on between 12/1999 and 10/2000 . All patients received a NexGen ® TKA cemented into the proximal tibia using Palamed ® G bone cement . The implants and the tibial metaphysis were marked with st and ard tantalum markers . Radiostereometric analysis was performed post-operatively and after 3 , 6 and 12 months using a st and ard digital radiostereometric analysis . Functional parameters were assessed using the Knee Society Score ( KSS ) clinical rating system . Results : There were no complications and failures within the first year . After 1 year radiostereometric measurements of the translational parameters along and the rotational parameters around the x- , y- and z-axis revealed : X-Trans –0.19 mm , Y-Trans + 0.02 mm , Z-Trans + 0.08 mm , X-Rot + 0.26 ° , Y-Rot –0.35 ° , Z-Rot + 0.09 ° . The maximum total point motion was + 0.96 mm and the mean maximum subsidence was –0.23 mm . Except for anterior-posterior , medio-lateral stability and extension leg all endpoints of the KSS clinical rating system showed a significant improvement . Conclusions : After 12 months , the use of Palamed ® G bone cement in total knee arthroplasty was demonstrated to be safe . Both the clinical and radiostereometric results were good and comparable to the results reported in other RSA studies in cemented total knee arthroplasty",
"Prosthesis migration in bone inevitably occurs in cemented and uncemented total knee arthroplasty tibial components . Cemented design s as the gold st and ard give immediate fixation whereas cementless design s need a period of bone ingrowth onto the surface irregularities of the implants . The addition of bioactive coatings may enhance this process of ingrowth . A controlled r and omized prospect i ve RSA study was carried out on 26 Duracon implants in a rheumatoid arthritis patient group to evaluate the effect of a periapatite coating on the fixation of the tibial tray . The coated and the noncoated groups were matched for sex , age , body mass index , and HSS Knee Score . Stage of preoperative joint destruction and preoperative and postoperative mechanical leg axis showed no differences . We saw no differences in migration between the two groups , but a trend for lesser translations along and rotations about all three axes in the periapatite group . The periapatite-coated components showed a lower variance in subsidence than did the uncoated components . Both groups also showed a high variance in anterior tilting of the components . The cementless PA-coated Duracon prosthesis used in patients with RA may provide improved fixation of tibial components although we could not demonstrate improvement in this small controlled series . Level of Evidence : Therapeutic Level II . See the Guidelines for Authors for a complete description of levels of evidence",
"Surgery and other invasive therapies are complex interventions , the assessment of which is challenged by factors that depend on operator , team , and setting , such as learning curves , quality variations , and perception of equipoise . We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process . We also encourage the widespread use of prospect i ve data bases and registries . Reports of new techniques should be registered as a professional duty , anonymously if necessary when outcomes are adverse . Case series studies should be replaced by prospect i ve development studies for early technical modifications and by prospect i ve research data bases for later pre-trial evaluation . Protocol s for these studies should be registered publicly . Statistical process control techniques can be useful in both early and late assessment . R and omised trials should be used whenever possible to investigate efficacy , but adequate pre-trial data are essential to allow power calculations , clarify the definition and indications of the intervention , and develop quality measures . Difficulties in doing r and omised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems . Alternative prospect i ve design s , such as interrupted time series studies , should be used when r and omised trials are not feasible . Established procedures should be monitored with prospect i ve data bases to analyse outcome variations and to identify late and rare events . Achievement of improved design , conduct , and reporting of surgical research will need concerted action by editors , funders of health care and research , regulatory bodies , and professional societies",
"Fixation of the tibial component in total knee arthroplasty in younger patients remains controversial . We evaluate the results of three different types of fixation of the Profix total knee arthroplasty in a r and omized controlled trial of 97 consecutive knees ( 85 patients ) with osteoarthrosis or inflammatory arthritis with 2-year followup of all patients . We r and omized patients to three different types of fixation of the tibial component : cemented , uncemented ( HA coated ) with screws , or uncemented ( HA coated ) without screws . We performed clinical evaluations and radiostereometric analysis at 6 weeks , and 3 , 6 , 12 and 24 months postoperatively . The knees in the uncemented groups migrated more than those in the cemented group during the first 3 months , but at 2 years we observed no differences . The uncemented implants displayed all migration within the first 3 months . The cemented implants did not stabilize but had continuously increasing migration during the followup . Cementless implants without screws did not migrate more than implants with screws and displayed similar pattern of migration , indicating screws do not improve fixation . Uncemented fixation using hydroxyapatite-coated implants without screws seems to be the best solution for the younger patient . Level of Evidence : Therapeutic Level I. See the Guidelines for Authors for a complete description of levels of evidence",
"Background Bioactive coating of uncemented total knee arthroplasty ( TKA ) is believed to increase bone ingrowth and enhance early fixation of the TKA . In a prospect i ve r and omized study using radiostereometric analysis ( RSA ) we examined migrations of the tibial implant , in an uncemented TKA with and without bioactive coating . The study was performed according to new RSA guidelines , and focus was put on some important method ological issues . Material s and methods Twenty-three patients with osteoarthrosis of the knee received an uncemented Duracon TKA either with bioactive ( hydroxyapatite or periapatite ) coating ( + HA ) or without bioactive coating ( −HA ) . Patients had RSA examinations postoperatively and at 3 , 6 and 12 months . Nine patients were excluded during the study result ing in 14 knees for final analysis . Results At 12 months follow-up we found no significant differences in migrations between the two groups . However , in general the −HA group migrated more than the + HA group , and we found a significant larger variation in migration pattern in the −HA group . In the + HA group the tibia component stabilized after 6 months , whereas the −HA group showed continuous migration . Subsidence and posterior tilt were the main migration patterns in both groups . Conclusions Bioactive coating of TKA seems to enhance early stabilization of the tibia component . Similar results are found in previous studies",
"We report prospect i ve clinical and radiographic outcomes of a series of 219 hydroxyapatite-coated Duracon ( Stryker Howmedica Osteonics Corporation , Kalamazoo , Mich ) total knee arthroplasties with a follow-up of 5 to 8 years . Knee Society Score , Western Ontario and McMaster Universities Osteoarthritis index ( WOMAC ) , and SF-12 Health Status Question naire were used . Analysis of fluoroscopic radiographs was performed with the American Knee Society Score . All living patients ( 186 knees ) were followed up . Twenty-eight patients ( 30 knees ) had died . The preoperative Knee Society Score of 43.8 increased to 77.1 and the preoperative Function score of 20.3 increased to 63.4 . WOMAC scores showed marked improvement ( pain , 250 preoperatively to 157 ; stiffness , 115 preoperatively to 56 ; and function , 910 preoperatively to 588 ) . There was no radiographic evidence of loosening or migration . Gaps visible at the bone-implant interface healed over the first year . Three prostheses were revised , 2 for deep infection and 1 for tibial tray subsidence . A survivorship of 98.6 % has been achieved at 8 years . This intermediate-term study with 100 % follow-up at 8 years demonstrates excellent clinical and radiographic outcomes . It is our opinion that these are comparable to the gold st and ard cemented total knee arthroplasties and may have advantages over other uncoated cementless design",
"Background Postoperative migration of a joint prosthesis is related to the risk of late loosening . We have previously reported that oral treatment with clodronate reduced migration of the cemented NexGen total knee prosthesis during the first postoperative year , as measured by radiostereometry ( RSA ) . Oral bisphosphonate treatment is sometimes unpleasant , and local treatment will enable higher local concentrations . We now report the results of local peroperative treatment with another bisphosphonate , ib and ronate , with the same prosthesis . Methods This is a double-blind , r and omized study of 50 patients using RSA with maximal total point motion ( MTPM ) as primary effect variable . 1 mg ib and ronate ( 1 mL ) or 1 mL saline was applied to the tibial bone surface 1 min before cementation . RSA examination was done on the first postoperative day , and at 6 , 12 , and 24 months . Results One ib and ronate-treated patient died of unrelated causes , and 1 control patient refused to come for follow-up , leaving 24 patients in each group for analysis . There were no cases of aseptic loosening . By repeated measures ANOVA , migration ( MTPM ) was reduced by local application of ib and ronate ( p = 0.006 ) . The effect was most pronounced at 6 months , with a reduction from 0.45 to 0.32 mm ( 95 % CI for reduction : 0.04–0.21 mm ) . At 12 months , the migration from the postoperative examination was reduced from 0.47 to 0.36 mm ( 95 % CI for reduction : 0.02–0.20 mm ) . At 24 months , the reduction was from 0.47 to 0.40 mm ( 95 % CI : -0.01–0.16 mm ) . Interpretation This is the first study to show improvement of prosthesis fixation by local pharmacological treatment in humans . The treatment appears to be safe , cheap , and easy to perform . However , the improvement in postoperative stability was not greater than with systemic clodronate treatment",
"40 patients with non-inflammatory arthrosis and minor preoperative deformity ( / 5 ° ) were operated on with an AMK type ( DePuy , Johnson & Johnson ) total knee arthroplasty ( TKA ) . The posterior cruciate ligament was retained . The patients were divided into those with a flat ( terminology of the manufacturer : st and ard ) or a concave ( terminology of the manufacturer : constrained ) polyethylene insert ( 20 in each group ) . Radiostereometric ( RSA ) examinations were done postoperatively and after 3 , 12 and 24 months . The median absolute rotations of the tibial inserts varied between 0.12 and 0.24 ( range 0.00 - 1.54 ) degrees , with no differences between the 2 groups . The median maximum totalpoint motions ( flat/concave = 0.41/0.42 mm ) , the maximum subsidence or lift-off did not differ . The Hospital for Special Surgery knee score and the patients ' opinion about the operation , based on their preoperative expectations , showed little , if any , differences . At 2 years , 10 of 20 patients with flat and 13 of 19 with concave inserts regarded their knee function as normal or almost so",
"We compared Boneloc bone cement with conventional cement ( Palacos ) in fixating the tibial component during 2 - 5 years in 19 patients with gonarthrosis undergoing total knee arthroplasty in a prospect i ve r and omized study . Boneloc displayed significantly larger migration , subsidence and lift-off than Palacos . The difference was identifiable already within 3 months postoperatively , but became significant at 12 months . In the Boneloc group , all components showed subsidence of the posterior part and lift-off of the anterior part of the tibial component , whereas in the Palacos group , the locations of subsidence and lift-off were evenly distributed about the edge of the implant . At 5 years , both Boneloc knees so far investigated were clinical failures with high migration rates . We conclude that , even in total knee arthroplasty , there is a substantial risk that Boneloc leads to inferior clinical results , but later than in hip replacements",
"A prospect i ve , r and omized , double-blind study was performed to evaluate three different means of fixing tibial components during total knee arthroplasty . Eleven components fixed with cement , ten hydroxyapatite-coated components fixed without cement , and ten noncoated components fixed without cement were studied . A posterior cruciate ligament-retaining total condylar implant was used . Micromotion of the components was assessed with roentgen stereophotogrammetric analysis during the two-year follow-up period . There were no significant differences among the patients with regard to age ( mean [ and st and ard deviation ] , 68 ± 11.6 years ) , body-mass index ( mean , 23 ± 2.8 kilograms per square meter ) , or stage of osteoarthrosis ( mean , 4 ± 2.4 according to the classification system of Ahlbäck and 5 ± 0.6 according to that of Larsen et al. ) . The diagnosis was osteoarthrosis in five knees , and it was rheumatoid arthritis in twenty-six . The clinical scores were similar among the study groups . According to the system of the Knee Society , the mean preoperative functional score was 10 ± 2.9 points and the mean preoperative knee score was 24 ± 3.2 points . At the two-year follow-up evaluation , these scores were 41 ± 8.3 and 79 ± 3.2 points , respectively . A significant difference with regard to micromotion was found between the noncoated components fixed without cement and the hydroxyapatite-coated components fixed without cement as well as between the noncoated components fixed without cement and the components fixed with cement ( p The hydroxyapatite-coated components fixed without cement and the components fixed with cement both had far less micromotion along the longitudinal axis ( subsidence ) throughout the follow-up period than did the noncoated components fixed without cement . At the two-year follow-up evaluation , the subsidence of the noncoated components was -0.73 ± 0.924 millimeter , the subsidence of the cemented components was -0.05 ± 0.109 millimeter , and the subsidence of the hydroxyapatite-coated components was -0.06 ± 0.169 millimeter . The cemented components as well as the hydroxyapatite-coated components also had less translation along the transverse axis ( p micromotion of hydroxyapatite-coated tibial components fixed without cement was similar to that of tibial components fixed with cement . Therefore , hydroxyapatite , a biological mediator , may be necessary for the adequate fixation of tibial components when cement is not used",
"One hundred two patients with 131 consecutive cementless total knee arthroplasties that retained the posterior cruciate ligament were followed up prospect ively . The average age of the patients was 58 years ( range , 32–75 years ) . The mean followup on the surviving knee arthroplasties was 11 years ( range , 7–16 years ) . The patellar component was metal-backed in the first 112 ( 85 % ) knees , cementless all-polyethylene in the last 17 ( 13 % ) knees , and two knees had a prior patellectomy . Forty-four metal-backed patellar components ( 48 % ) were revised ; nine were loose , and 35 had polyethylene wear through . Thirteen femoral components ( 12 % ) were revised because of femoral abrasion from a failed metal-backed patellar component . No other femoral component was revised , loose , or had osteolysis develop . Nine ( 8 % ) tibial components had failure of ingrowth ; eight have been revised . Partial radiolucencies occurred in 53 % of the tibias . Thirteen ( 12 % ) small osteolytic lesions developed , all around screws or screw holes in the tibial components . At an average of 11 years followup , cementless fixation yielded mixed results : cementless femoral fixation was excellent and metal-backed patellar components had a 48 % patellar revision rate . Cementless tibial components had an 8 % aseptic loosening rate and a 12 % incidence of small osteolytic lesions . Based on these results , the authors have ab and oned cementless fixation in total knee arthroplasty",
"Patellar resurfacing in total knee arthroplasty is a topic debated in the literature . Concerns include fracture , dislocation , loosening , and extensor mechanism injury . Residual anterior knee pain has been reported when the patella is not resurfaced . One hundred patients with osteoarthritic knees were prospect ively r and omized to either have their patella resurfaced or left not resurfaced . All patients were treated with a single prosthesis that featured an anatomically design ed patellofemoral articulation ( Anatomic Medullary Knee , DePuy , Warsaw , IN ) Two patients in the unresurfaced group and one in the resurfaced group required repeat surgery for patellofemoral complications . At 8- to 10-year follow-up evaluations , Knee Society Clinical Ratings scores were not different between the 2 groups . Rates of anterior knee pain with walking and stair climbing were significantly less in the resurfaced group . Eighty percent of patients with a resurfaced patella were extremely satisfied with their total knee arthroplasty versus 48 % without patellar resurfacing . When satisfied and extremely satisfied patients were grouped together , there was no difference between the 2 groups",
"The DePuy Sigma total knee arthroplasty ( TKA ) was introduced in 1997 as a modification of the Press Fit Condylar Knee ( PFC ) TKA and has been used extensively in the United Kingdom and worldwide . It is the most commonly used TKA in Engl and and Wales , where it accounts for 36 % of all primary TKA . The PFC was well established , with reported 10-year survival rates of 93 - 97 % , but this study reports the first 5-year clinical and radiographic follow-up data for the Sigma TKA . Over a 10-month period , 212 Sigma TKAs were performed in 180 patients . Patients were seen at a specialist nurse-led clinic 7 to 10 days before admission and at 6 months , 18 months , 3 years and 5 years after surgery . Data were recorded prospect ively at each visit . Radiographs were obtained at the 5-year follow-up appointment . Of 212 knees , 178 ( 151 patients ) were alive at 5 years . Three were lost to follow up . Six knees ( 3.0 % ) were revised , five for infection and one underwent change of polyethylene insert at 4.9 years . Five-year survival with an endpoint of revision for any reason was 97.0 % ; with an endpoint of revision for aseptic failure it was 99.5 % . The median American Knee Society knee rating score was 93 out of 100 at 5 years compared with 25 out of 100 at admission . Of 147 radiographs , none showed radiographic loosening of either component . Seventeen ( 11.6 % ) showed radiolucent lines . Twenty-eight ( 19.0 % ) had alignment outside the range of 7+/-3 degrees valgus . These results suggest that the Sigma TKA gives acceptable clinical results after 5 years . Further follow-up studies are required to see if this performance is maintained in the long term",
"A series of 100 consecutive osteoarthritic patients was r and omised to undergo total knee replacement using a Miller-Galante II prosthesis , with or without a cemented polyethylene patellar component . Knee function was evaluated using the American Knee Society score , Western Ontario and McMaster University Osteoarthritis index , specific patellofemoral-related questions and radiographic evaluation until the fourth post-operative year , then via question naire until ten years post-operatively . A ten-point difference in the American Knee Society score between the two groups was considered a significant change in knee performance , with alpha and beta levels of 0.05 . The mean age of the patients in the resurfaced group was 71 years ( 53 to 88 ) and in the non-resurfaced group was 73 years ( 54 to 86 ) . After ten years 22 patients had died , seven were suffering from dementia , three declined further participation and ten were lost to follow-up . Two patients in the non-resurfaced group subsequently had their patellae resurfaced . In the resurfaced group one patient had an arthroscopic lateral release . There was no significant difference between the two treatment groups : both had a similar deterioration of scores with time , and no further patellofemoral complications were observed in either group . We are unable to recommend routine patellar resurfacing in osteoarthritic patients undergoing total knee replacement on the basis of our findings",
"The long term survival of the Miller-Galante I cementless total knee arthroplasty was evaluated by study ing prospect ively for a minimum of 14 years ( range , 14–17 years ) , 124 consecutive cementless total knee arthroplasties using a Miller-Galante I prosthesis in 99 patients with a mean age of 62 years who had primary or secondary osteoarthritis . Knee function and roentgenograms were evaluated using the Knee Society criteria . Kaplan-Meier survivorship analysis was conducted . Five patients ( five knees ) were lost to followup ; six patients died with six knees in place . Fifteen knees ( 15 patients ) failed and were revised . Thirteen metal-backed patellas were revised . Eight of these revisions also required exchange of the femoral component , but only one tibial tray was revised . One knee ( one patient ) was revised for an infection . Of the 98 knees not revised ( 73 patients ) observed throughout this study , the average preoperative knee score was 31 ( range , 0–47 ) ; postoperatively , the average knee score was 91 ( range , 72–100 ) . The average function score improved from 28 ( range , 10–45 ) to 84 ( range , 50–100 ) . Twenty-four tibial trays ( 21 % ) and twenty femoral components ( 17 % ) of the 113 knees studied showed osteolysis . This study indicates that osteointegration of cementless tibial components can be successful with screw fixation , although there is a worrisome incidence of tibial and femoral osteolysis . The overall knee survival rate was 87 % ; however , the tibial component had a survival of 99 %",
"To underst and better the type and incidence of long-term complications in total knee replacement , 306 primary Kinematic total knee arthroplasties performed between June 1978 and December 1982 were prospect ively review ed in detail . The Kinematic knee is a nonconstrained , posterior cruciate-retaining prosthesis that has right and left femoral components to afford anatomic tracking of the patella . The overall revision rate was 6.5 % . The most common cause for revision surgery was patellar complications . Ten revisions ( 3.06 % ) were for patellar component loosening . Two knees were revised for patella subluxation ( 0.65 % ) ; 1 was in a resurfaced rheumatoid patella , and 1 in an unsurfaced osteoarthritic patella . Stair climbing was better with an unsurfaced patella . Anterior knee pain was 21.8 % in the unsurfaced patella and 11.2 % in the replaced patella . These data suggest patella replacement is not appropriate with this design",
"The role of modular tibial implants in total knee replacement is not fully defined . We performed a prospect i ve r and omised controlled clinical trial using radiostereophotogrammetric analysis to compare the performance of an all-polyethylene tibia with a metal-backed cruciate-retaining condylar design , PFC-Sigma total knee replacement for up to 24 months . There were 51 patients who were r and omised into two treatment groups . There were 10 subsequent withdrawals , leaving 21 all-polyethylene and 20 metal-backed tibial implants . No patient was lost to follow-up . There were no significant demographic differences between the groups . At two years one metal-backed implant showed migration > 1 mm , but no polyethylene implant reached this level . There was a significant increase in the SF-12 and Oxford knee scores after operation in both groups . In an uncomplicated primary total knee replacement the all-polyethylene PFC-Sigma tibial prosthesis showed no statistical difference in migration from that of the metal-backed counterpart . There was no difference in the clinical results as assessed by the SF-12 , the Oxford knee score , alignment or range of movement at 24 months , although these assessment measures were not statistically powered in this study",
"We studied the effect of a layer of cement placed under the tibial component of Freeman-Samuelson total knee prostheses with a metal back and an 80 mm intramedullary stem , using roentgen stereophotogrammetry to measure the migration of the tibial component during one year in 13 uncemented and 16 cemented knees . The addition of cement produced a significant reduction in migration at one year , from a mean of 1.5 mm to one of 0.5 mm ( p less than 0.01 ) , including a significant reduction in pure subsidence . One year postoperatively the clinical results were similar between the groups , but , at three years , one uncemented knee had required revision",
"Twenty-four patients ( 25 knees ) with osteoarthrosis ( OA ) and 19 patients ( 20 knees ) with rheumatoid arthritis ( RA ) were operated with bi-tricompartmental knee arthroplasty . The patients were r and omized to cemented or cementless fixation of the tibial component . The fixation of the tibial components was examined with roentgen stereophotogrammetric analysis ( RSA ) up to 24 months after operation . The following parameters representing tibial component micromotion were measured : ( 1 ) maximum migration of the prosthetic edge ( maximum total point motion , MTPM ) ; ( 2 ) distal migration of the prosthetic center ( subsidence ) ; ( 3 ) maximum proximal movements of the prosthetic edge ( \" lift-off \" ) ; and ( 4 ) prosthetic rotations , corresponding to internal/external rotation , adduction/abduction , and forward/backward tilt of the tibial component . All prostheses displayed significant micromotions , which tended to decrease 3 - 6 months after the operation . The average migration after 2 years , when measured as maximum single axis rotation , and MTPM were about 0.9 degrees-1.5 degrees and 1.0 - 1.5 mm , respectively , in all four groups . There were no statistically significant differences between cemented and cementless prostheses in either the OA or the RA group . The fixation in the RA patients did not significantly differ from that of the OA patients , perhaps because the RA patients had lower weight and were living a more sedentary life",
"The fixation of tibial components r and omized to insertion with or without cement in twenty-six knees was examined for inducible displacement at six weeks and one year postoperatively with use of roentgen stereophotogrammetric analysis . Furthermore , migration was studied during the first two postoperative years . Inducible displacement was found in all knees at both the six-week and the one-year follow-up examination , but no differences were detected with respect to the type of fixation ( p > 0.05 ) . All tibial components migrated for as long as one year postoperatively , after which most stabilized . No difference was found between the groups with respect to migration during the first two years postoperatively ( p > 0.05 ) , with the exception of subsidence of the component , which was found to be 0.0 ± 0.1 millimeter ( mean and st and ard error of the mean ) for the components inserted with cement and 0.5 ± 0.1 millimeter for the components inserted without cement ( p . Migration after one year was the same for both groups . We found a relationship between inducible displacement at six weeks and at one year as well as one between inducible displacement and migration at one year . To our knowledge , the present study is the first in which the micromotion of an interference-fit prosthesis was found to be similar to that of a device inserted with cement . The results of the present study emphasize the importance of the initial prosthetic fixation",
"The goal of this study was to compare the migration of noncemented diffusion sintered titanium fibermesh-coated tibial components with ( HA group ) and without ( non-HA group ) additional hydroxyapatite coating . For this purpose digital radiostereometry ( DIRSA ) was used to compare the migration after 2 and 9 years for the two groups . After 2 years the mean maximum subsidence of the HA-coated components ( 0.24+/-0.18 mm ) was about one-half of the mean maximum subsidence of the non-HA-coated group ( 0.55+/-0.55 mm ) . After 9 years the maximum subsidence of the HA-coated components was still smaller , but not as pronounced as before . The same trend was also found for the endpoint maximum total point motion ( MTPM ) . After 2 years the mean MTPM of the HA-coated components was 0.66+/-0.38 mm and of the non-HA group 0.73+/-0.50 mm . After 9 years the mean MTPM for the HA-coated components was 0.54+/-0.15 mm and for the non-HA-coated components 0.74+/-0.20 mm . None of the HA-coated tibial components but one of the non-HA group had to be revised and exchanged due to aseptic loosening",
"We have examined the differences in clinical outcome of total knee replacement ( TKR ) with and without patellar resurfacing in a prospect i ve , r and omised study of 181 osteoarthritic knees in 142 patients using the Profix total knee system which has a femoral component with features considered to be anatomical and a domed patellar implant . The procedures were carried out between February 1998 and November 2002 . A total of 159 TKRs in 142 patients were available for review at a mean of four years ( 3 to 7 ) . The patients and the clinical evaluator were blinded in this prospect i ve study . Evaluation was undertaken annually by an independent observer using the knee pain scale and the Knee Society clinical rating system . Specific evaluation of anterior knee pain , stair-climbing and rising from a seated to a st and ing position was also undertaken . No benefit was shown of TKR with patellar resurfacing over that without resurfacing with respect to any of the measured outcomes . In 22 of 73 knees ( 30.1 % ) with and 18 of 86 knees ( 20.9 % ) without patellar resurfacing there was some degree of anterior knee pain ( p = 0.183 ) . No revisions related to the patellofemoral joint were performed in either group . Only one TKR in each group underwent a re-operation related to the patellofemoral joint . A significant association between knee flexion contracture and anterior knee pain was observed in those knees with patellar resurfacing ( p = 0.006 )",
"This study reports the 14-year survivorship for 106 consecutive total condylar knee arthroplasties implanted using modern technique . All were performed by a single surgeon and have been observed prospect ively since 1979 . Failure was defined as revision for any reason , or radiographic evidence of loosening of the components . Life-table analysis reveals a 95.6 % clinical survival rate at 14 years , with no radiographically loose components . Confidence interval is + /- 4.2 % . There were 4 revisions , but none for aseptic loosening , and there are no impending revisions . Thirty-seven patients ( 49 knees ) were known to be deceased as of April 1993 , and 8 other patients are lost to followup . Clinical results for patients with pre- and postoperative Hospital For Special Surgery knee scores show 72 knees rated excellent and 11 good ( mean score , 90 points ) . The 4 failures were rated poor . Mean flexion was 100 degrees . Radiographs of 93 knees were evaluated using the criteria of the Knee Society . Average overall alignment was 5 degrees valgus . Radiolucencies were present in 29 of 78 femoral components with adequate radiographs , and averaged 1 mm in 1 zone . Tibial radiolucency was present in 42 of 93 tibiae , again averaging 1 mm in 1 zone , with no loose pegs . In comparison with the first series of total condylar prostheses , this series showed comparable clinical results , with improved radiographic results , and no radiographic failures",
"Our study examines the clinical , radiographic , and patient satisfaction outcome of the cemented Modular Porous-Coated Anatomic ( PCA ) total knee arthroplasty with a minimum 5-year follow up . All data were gathered prospect ively and consecutively . Patient satisfaction was assessed with a self-administered survey . Statistical analysis examined the effect of 17 patient factors , 19 surgical factors , and postoperative continuous passive motion use on range of motion ( ROM ) and HSS scores at 2 years . Seventy-eight Modular PCA arthroplasties performed by 9 orthopedic surgeons on 71 patients between January 1988 and November 1989 are reported in this study . Preoperative HSS scores averaged 51.2 and improved to an average of 89 at 1 and 2 years , and 86 at 5 years after surgery ( 90 % good or excellent ) . ROM changed after surgery through improvement in preoperative knee flexion contracture , but not in increased knee flexion . One patient underwent reoperation for patellar instability , and one patient 's arthroplasty was revised at 53 months for late instability . The total reoperation rate for any reason was 7.7 % . Zonal analysis for progressive radiolucency at the bone-cement interface showed increasing frequency of narrow ( radiolucencies concentrated on the anterior and medial aspect of the tibial tray . Ninety-eight percent of patients responded to an outcome question naire , and 96 % rated themselves improved . The Kaplan-Meier probability of an implant surviving without loosening at 5 years was 100 % . The Modular PCA TKA has a low incidence of patellofemoral problems , is clinical ly successful , and results are stable at a minimum 5-year follow-up examination",
"We studied CMW-1 bone cement with gentamicin in the laboratory and in a r and omized clinical study . Palacos bone cement containing gentamicin was used as the control . In the pre clinical evaluation , the CMW cement had slightly less mechanical strength . In the clinical study , 51 patients ( 51 knees ) operated on with total knee arthroplasty were studied for 2 years . We used radiostereometric analysis to measure migration of the tibial components , r and omized to fixation with either of the two types of cement . The extent and pattern of migration were similar in both groups , and we found no differences in the number , size and extent of radiolucent lines or clinical outcome . No complications occurred . Our findings suggest a need for more studies of CMW-1 bone cement containing gentamicin in a larger cohort of patients",
"Mobile bearings were introduced to improve wear and knee kinematics . By uncoupling the forces generated at the articulation from the implant-bone interface this would , theoretically , also improve the fixation of the implant to bone . We did this study to evaluate whether mobile bearings improve the fixation of the tibial component to bone . Fifty-two consecutive knees in 47 patients ( average age , 72 years ; range , 62 - 84 years ) with primary osteoarthrosis were r and omized into two groups to receive a cemented total knee arthroplasty with either a fixed-bearing or mobile-bearing tibial component . The quality of fixation was analyzed with radiostereometric analysis for up to 2 years . Mobile bearings did not improve fixation . Both magnitudes and directions of component rotations were similar , and the number of implants with continuous migration was almost identical . Both implant types had a combination of subsidence and lift-off , but where the mobile bearing implants displayed more of subsidence , the fixed bearing knees showed more lift-off . It might be that the somewhat stiffer cobalt-chromium baseplate or the different joint conformity used in the mobile-bearing knees counteracts any potential effects of the mobile bearing . Level of Evidence : Therapeutic Level I. See the Guidelines for Authors for a complete description of levels of evidence",
"Twenty-six women and three men ( 34 knees ) with osteoarthrosis were operated with the Miller-Galante I ( Zimmer , Warsaw , IN ) knee prosthesis . The patients were r and omized to either cemented or uncemented fixation of the tibial component . All patients received a TiVaAl alloy tibial plate with four pegs and titanium fiber-mesh undersurface . In the uncemented knees four screws were added . The fixation of the tibial component was determined by roentgen stereophotogrammetric analysis during the first 2 postoperative years . Rotations of the entire tibial component were recorded , as well as proximal or distal translation of various parts of the prosthetic edge corresponding to subsidence and lift-off . The uncemented components displayed almost all rotation and translation during the first 6 weeks , whereas the cemented ones displayed a more gradually increasing migration during the 2 years . Tibial component rotation about the sagittal axis was significantly increased in the uncemented knees throughout the investigation period . This corresponded to increased subsidence medially or laterally in the uncemented knees , whereas lift-off was equal in the two groups . Thin ( 8.5 mm ) uncemented tibial components displayed more subsidence than the thicker ones at the medial or lateral edge 3 months after surgery",
"We have found poor mid-term results in a multisurgeon series of 94 Johnson-Elloy ( Accord ) total knee replacements . A total of 27 knees ( 29 % ) has required revision , in 26 for aseptic loosening . Only 18 ( 19 % ) remain in situ , and these give poor function , are painful and most show radiological evidence of early failure . At 12 to 13 years the survival rate is 43 % ( confidence interval 29 to 57 ) with failure requiring revision as the endpoint . Proximal migration of the femoral component is associated with considerable loss of bone stock . We believe that all patients who have this implant should be recalled for regular review in order to anticipate this problem",
" We performed a survival analysis on 354 cemented primary Press-Fit Condylar ( PFC ) total knee arthroplasties ( TKA ) in 277 patients with prospect i ve follow-up ( mean , 6 years ; range , 2 - 11.7 years ) . No patient was lost to follow-up . Using revision for all causes as the endpoint , the cumulative survival rate at 10 years was 95.5 % ( 95 % confidence interval , 90.1%-98.1 % ) . The 10-year clinical outcome available on 41 patients was good , with significant improvement in pain and mobility assessment s using the Nottingham data collection system . Our results indicate that the cemented PFC TKA has good long-term survival based on revision as the endpoint . Revision for implant failure is rare and brings to question modifications to this prosthesis",
"In this issue of Spine , a novel method for managing chronic discogenic low back pain with a thermal intradiscal catheter is reported . This study raises some general questions regarding the introduction of new treatment techniques and devices . Decisions about medical treatment should be based on a careful appraisal of the best evidence available . A step-wise introduction is necessary to increase the use of evidence -based decision making in the implementation of new surgical techniques and implants while exposing as few patients as possible to the potential risk of failure . The development of the total hip arthroplasty procedure , for example , could have been different if the introduction of new devices and techniques had been done more carefully and performed in a step-wise manner . Inferior properties could have been revealed earlier , thus reducing the number of failures and allowing for necessary improvements . It is also desirable , therefore , that members of this profession agree on a st and ardized way to introduce new surgical techniques and implants in the field of spinal disorders . Based on the results of Swedish reports and practice , the following schedule for step-wise clinical introduction of new implants is suggested ( Figure 1 ) : The initial step is a pre clinical testing and is beyond the scope of this discussion . The first clinical step is the open prospect i ve and preferably r and omized trial that includes a minimum of patients but yields a relevant evaluation . The strict rules of prospect i ve , r and omized trials should be adhered to . In this first clinical phase , methods associated with high accuracy , such as radiostereometric analysis ( RSA ) , are required . Within 6 to 24 months , this method has the potential to identify implants/ methods that provide inferior fixation and increased polyethylene wear . Results from this first step determine whether further clinical evaluation is worthwhile . It should be noted and stressed that all types of complications can not be predicted and that further follow-up study is necessary . If favorable results are obtained in the first step , the second step , a multicenter trial exposing the new procedure to a broader aspect in the orthopedic community , can be initiated . In the first step , there is a risk for susceptibility and performance bias because the inventors themselves often perform this introductory investigation . The protocol in the multicenter trial must be prepared carefully and agreed on by all participating inventors . A sufficient number of patients should be included to allow adequate statistical analysis . The ultimate goal for step two is to make even the multicenter trial r and omized by using well-documented methods /implants as the gold st and ard . The final step in the evaluation , step three , is to include a continuous control group by using register studies based on large cohorts to reveal early or unusual and potential clinical catastrophic complications . In a rather small and closed community such as Sweden , the register should be nationwide and include all units in a specific field . When applying the principles for step-wise introduction to the investigation of chronic discogenic low back pain with a thermal intradiscalcatheterbySaal and Saal , oneobserves that the current study falls between the pre clinical step and step one . The lack of r and omization toward either conservative or surgical intervention is a definite limitation of the study , and before this method is introduced to a larger study group , a r and omized trial must be considered . A multicenter trial exposing the new procedure to a broader aspect of the orthopedic community is recommended before using it in general orthopedic practice . The length of the follow-up period was very short in this study , and no long-term clinical conclusions can be drawn based on the results",
"We conducted a prospect i ve , r and omized study of 45 patients to evaluate 3 different uncemented tibial component design s in total knee arthroplasty . The stability of the components was assessed by radiostereometry ( RSA ) , both as migration during 2 years and as inducible displacement at 2 years . The PCA resurfacing , the Tricon stem and the Tricon-M prosthesis groups showed a similar level of migration at 2 years , about 1.4 mm . In response to externally applied rotatory forces , the Tricon groups rotated more than the PCA group , interpreted as a consequence of the more conforming articular surface in the Tricon design . The series was divided into one group of continuously migrating prostheses with a poor prognosis ( unstable , one third ) and another group of prostheses in which migration stopped after 1 year ( stable , two thirds ) . With this classification , no differences between the prostheses design groups were revealed . However , the unstable group showed a larger inducible displacement by provocation , an association hitherto not established",
"Roentgen stereophotogrammetry was used to measure the migration of the centre of the femoral head in 84 cemented Lubinus SP I hip arthroplasties ( 58 primary operations , 26 revisions ) . Four to seven years later , seven femoral components had been revised because of painful loosening . These implants showed greater subsidence , medial migration and posterior migration during the first two postoperative years than did the hips which had not been revised . Six months after operation , subsidence of more than 0.33 mm combined with a total migration of more than 0.85 mm predicted an increased risk of subsequent revision ; the amount of subsidence at two years was an even better predictor . The probability of revision was greater than 50 % if the subsidence at two years was 1.2 mm or more",
"VersaBond is a newly developed bone cement . To investigate its clinical performance , VersaBond was compared to Palacos R in a prospect i ve r and omized study in total knee replacement . Fifty-nine patients ( 61 knees ) undergoing total knee replacement were r and omized to either VersaBond or Palacos R bone cement and followed for 24 months using radiostereometric analysis ( RSA ) . Up to 2 years there were no significant differences in clinical performance between the two cements . The mean/median values for implant migration were very similar for the two bone cements , as were the dispersion , and distribution of outliers . Also the proportion \" stable \" and \" continuously migrating \" implants was similar between the two cements . The result of this study indicates that VersaBond bone cement will perform at least equally as well as Palacos R in total knee replacement as regards as aseptic loosening",
"We present the long-term results of the Kinematic Condylar Knee Arthroplasty followed in a prospect i ve fashion . Between October 1982 and March 1988 , 404 consecutive replacement arthroplasties were carried out on 335 patients . Of these , 354 knees had osteoarthritis , 45 rheumatoid arthritis and five other diagnoses . At the time of final follow-up 158 patients ( 188 knees ) had died . No patient was lost to follow-up . The minimum follow-up for all living patients was ten years ( 10 to 17 ) . The mean age at surgery was 68 years ( 30 to 92 ) . There were seven complications ( 1.7 % ) . Sixteen knees ( 3.9 % ) were revised , four because of infection . Survivorship was 99.4 % ( CI 97.9 to 99.8 ) at five years , 98.2 % ( CI 96.1 to 99.2 ) at ten years and 92.6 % ( CI 87.6 to 95.6 ) at 17 years"
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4117c63e-06ff-11f0-808a-c43d1ab1c353
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Purpose This guideline is structured to provide a clinical framework stratified by cancer severity to facilitate care decisions and guide the specifics of implementing the selected management options . The summary presented represents Part I of the two‐part series dedicated to Clinical ly Localized Prostate Cancer : AUA/ASTRO/SUO Guideline discussing risk stratification and care options by cancer severity . Material s and Methods The systematic review utilized in the creation of this guideline was completed by the Agency for Healthcare Research and Quality and through additional supplementation by ECRI Institute . This review included articles published between January 2007 and March 2014 with an up date search conducted through August 2016 . When sufficient evidence existed , the body of evidence for a particular treatment was assigned a strength rating of A ( high ) , B ( moderate ) , or C ( low ) for support of Strong , Moderate , or Conditional Recommendations . Additional information is provided as Clinical Principles and Expert Opinions ( table 2 in supplementary unabridged guideline , http://jurology.com/ ) . Results The AUA ( American Urological Association ) , ASTRO , and SUO ( Society of Urologic Oncology ) formulated an evidence ‐based guideline based on a risk stratified clinical framework for the management of localized prostate cancer . Conclusions This guideline attempts to improve a clinician ’s ability to treat patients diagnosed with localized prostate cancer , but higher quality evidence in future trials will be essential to improve the level of care for these patients . In all cases , patient preferences should be considered when choosing a management strategy
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[
"BACKGROUND The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen ( PSA ) testing remains uncertain . METHODS We compared active monitoring , radical prostatectomy , and external-beam radiotherapy for the treatment of clinical ly localized prostate cancer . Between 1999 and 2009 , a total of 82,429 men 50 to 69 years of age received a PSA test ; 2664 received a diagnosis of localized prostate cancer , and 1643 agreed to undergo r and omization to active monitoring ( 545 men ) , surgery ( 553 ) , or radiotherapy ( 545 ) . The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up . Secondary outcomes included the rates of disease progression , metastases , and all-cause deaths . RESULTS There were 17 prostate-cancer-specific deaths overall : 8 in the active-monitoring group ( 1.5 deaths per 1000 person-years ; 95 % confidence interval [ CI ] , 0.7 to 3.0 ) , 5 in the surgery group ( 0.9 per 1000 person-years ; 95 % CI , 0.4 to 2.2 ) , and 4 in the radiotherapy group ( 0.7 per 1000 person-years ; 95 % CI , 0.3 to 2.0 ) ; the difference among the groups was not significant ( P=0.48 for the overall comparison ) . In addition , no significant difference was seen among the groups in the number of deaths from any cause ( 169 deaths overall ; P=0.87 for the comparison among the three groups ) . Metastases developed in more men in the active-monitoring group ( 33 men ; 6.3 events per 1000 person-years ; 95 % CI , 4.5 to 8.8 ) than in the surgery group ( 13 men ; 2.4 per 1000 person-years ; 95 % CI , 1.4 to 4.2 ) or the radiotherapy group ( 16 men ; 3.0 per 1000 person-years ; 95 % CI , 1.9 to 4.9 ) ( P=0.004 for the overall comparison ) . Higher rates of disease progression were seen in the active-monitoring group ( 112 men ; 22.9 events per 1000 person-years ; 95 % CI , 19.0 to 27.5 ) than in the surgery group ( 46 men ; 8.9 events per 1000 person-years ; 95 % CI , 6.7 to 11.9 ) or the radiotherapy group ( 46 men ; 9.0 events per 1000 person-years ; 95 % CI , 6.7 to 12.0 ) ( P , prostate-cancer-specific mortality was low irrespective of the treatment assigned , with no significant difference among treatments . Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring . ( Funded by the National Institute for Health Research ; ProtecT Current Controlled Trials number , IS RCT N20141297 ; Clinical Trials.gov number , NCT02044172 . )",
"BACKGROUND No r and omized trials have compared survival outcomes for men with localized prostate cancer ( PC ) being treated with radical prostatectomy ( RP ) or external beam radiotherapy ( EBRT ) . The goal of the study , therefore , was to estimate the association of RP ( compared with EBRT ) with overall and PC mortality . METHODS We analyzed an observational cohort from the population -based Prostate Cancer Outcomes Study , which included men aged 55 to 74 years diagnosed with localized PC between October 1994 and October 1995 who underwent either RP ( n = 1164 ) or EBRT ( n = 491 ) within 1 year of diagnosis . Patients were followed until death or study end ( December 31 , 2010 ) . Overall and disease-specific mortality were assessed with multivariable survival analysis , with propensity scores to adjust for potential treatment selection confounders ( demographics , comorbidities , and tumor characteristics ) . All statistical tests were two-sided . RESULTS After 15 years of follow-up , there were 568 deaths , including 104 from PC . RP was associated with statistically significant advantages for overall ( hazard ratio [ HR ] = 0.60 , 95 % confidence interval [ CI ] = 0.53 to 0.70 , P disease-specific mortality ( HR = 0.35 , 95 % CI = 0.26 to 0.49 , P Mortality benefits for RP were also observed within treatment propensity quintiles , when subjects were pair-matched on propensity scores , and in subgroup analyses based on age , tumor characteristics , and comorbidity . CONCLUSIONS Population -based observational data on men diagnosed with localized PC in the mid-1990s suggest a mortality benefit associated with RP vs EBRT . Possible explanations include residual selection bias or a true survival advantage . Results might be less applicable for men facing treatment decisions today",
"PURPOSE To assess long-term outcomes of men with favorable-risk prostate cancer in a prospect i ve , active-surveillance program . METHODS Curative intervention was recommended for disease reclassification to higher cancer grade or volume on prostate biopsy . Primary outcomes were overall , cancer-specific , and metastasis-free survival . Secondary outcomes were the cumulative incidence of reclassification and curative intervention . Factors associated with grade reclassification and curative intervention were evaluated in a Cox proportional hazards model . RESULTS A total of 1,298 men ( median age , 66 years ) with a median follow-up of 5 years ( range , 0.01 to 18.00 years ) contributed 6,766 person-years of follow-up since 1995 . Overall , cancer-specific , and metastasis-free survival rates were 93 % , 99.9 % , and 99.4 % , respectively , at 10 years and 69 % , 99.9 % , and 99.4 % , respectively , at 15 years . The cumulative incidence of grade reclassification was 26 % at 10 years and was 31 % at 15 years ; cumulative incidence of curative intervention was 50 % at 10 years and was 57 % at 15 years . The median treatment-free survival was 8.5 years ( range , 0.01 to 18 years ) . Factors associated with grade reclassification were older age ( hazard ratio [ HR ] , 1.03 for each additional year ; 95 % CI , 1.01 to 1.06 ) , prostate-specific antigen density ( HR , 1.21 per 0.1 unit increase ; 95 % CI , 1.12 to 1.46 ) , and greater number of positive biopsy cores ( HR , 1.47 for each additional positive core ; 95 % CI , 1.26 to 1.69 ) . Factors associated with intervention were prostate-specific antigen density ( HR , 1.38 per 0.1 unit increase ; 95 % CI , 1.22 to 1.56 ) and a greater number of positive biopsy cores ( HR , 1.35 for one additional positive core ; 95 % CI , 1.19 to 1.53 ) . CONCLUSION Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention",
"Summary Background Whether the addition of radiation therapy ( RT ) improves overall survival in men with locally advanced prostate cancer managed with and rogen deprivation therapy ( ADT ) is unclear . Our aim was to compare outcomes in such patients with locally advanced prostate cancer . Methods Patients with : locally advanced ( T3 or T4 ) prostate cancer ( n=1057 ) ; or organ-confined disease ( T2 ) with either a prostate-specific antigen ( PSA ) concentration more than 40 ng/mL ( n=119 ) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher ( n=25 ) , were r and omly assigned ( done central ly with stratification and dynamic minimisation , not masked ) to receive lifelong ADT and RT ( 65–69 Gy to the prostate and seminal vesicles , 45 Gy to the pelvic nodes ) . The primary endpoint was overall survival . The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded . All efficacy analyses were done by intention to treat and were based on data from all patients . This trial is registered at controlledtrials.com as IS RCT N24991896 and Clinical trials.gov as NCT00002633 . Results Between 1995 and 2005 , 1205 patients were r and omly assigned ( 602 in the ADT only group and 603 in the ADT and RT group ) ; median follow-up was 6·0 years ( IQR 4·4–8·0 ) . At the time of analysis , a total of 320 patients had died , 175 in the ADT only group and 145 in the ADT and RT group . The addition of RT to ADT improved overall survival at 7 years ( 74 % , 95 % CI 70–78 vs 66 % , 60–70 ; hazard ratio [ HR ] 0·77 , 95 % CI 0·61–0·98 , p=0·033 ) . Both toxicity and health-related quality -of-life results showed a small effect of RT on late gastrointestinal toxicity ( rectal bleeding grade > 3 , three patients ( 0·5 % ) in the ADT only group , two ( 0·3 % ) in the ADT and RT group ; diarrhoea grade > 3 , four patients ( 0·7 % ) vs eight ( 1·3 % ) ; urinary toxicity grade > 3 , 14 patients ( 2·3 % ) in both groups ) . Interpretation The benefits of combined modality treatment — ADT and RT — should be discussed with all patients with locally advanced prostate cancer . Funding Canadian Cancer Society Research Institute , US National Cancer Institute , and UK Medical Research Council",
"BACKGROUND In 2008 , we reported that radical prostatectomy , as compared with watchful waiting , reduces the rate of death from prostate cancer . After an additional 3 years of follow-up , we now report estimated 15-year results . METHODS From October 1989 through February 1999 , we r and omly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy . Follow-up was complete through December 2009 , with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death . Relative risks , with 95 % confidence intervals , were estimated with the use of a Cox proportional-hazards model . RESULTS During a median of 12.8 years , 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died ( P=0.007 ) . In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting , death was due to prostate cancer . This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6 % and 20.7 % , respectively ( a difference of 6.1 percentage points ; 95 % confidence interval [ CI ] , 0.2 to 12.0 ) , and a relative risk with surgery of 0.62 ( 95 % CI , 0.44 to 0.87 ; P=0.01 ) . The survival benefit was similar before and after 9 years of follow-up , was observed also among men with low-risk prostate cancer , and was confined to men younger than 65 years of age . The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age . Among men who underwent radical prostatectomy , those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth ( relative risk , 6.9 ; 95 % CI , 2.6 to 18.4 ) . CONCLUSIONS Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer . Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment . ( Funded by the Swedish Cancer Society and the National Institutes of Health . )",
" A recent r and omized trial to compare external beam radiation therapy ( EBRT ) to cryoablation for localized disease showed cryoablation to be noninferior to external beam EBRT in disease progression and overall and disease‐specific survival . We report on the quality of life ( QOL ) outcomes for this trial",
"PURPOSE To examine consequences of deferred treatment ( DT ) as initial management of prostate cancer ( PCa ) in a contemporary , prospect i ve cohort of American men diagnosed with PCa . PARTICIPANTS AND METHODS We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study , a prospect i ve study of 51,529 men . Cox proportional hazards models were used to calculate hazard ratios ( HRs ) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis . HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis . RESULTS From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007 , 342 ( 10.3 % ) initially deferred treatment . Of these , 174 ( 51 % ) remained untreated throughout follow-up ( mean 7.7 years ) ; the remainder were treated an average of 3.9 years after diagnosis . Factors associated with progression to treatment among DT patients included younger age , higher clinical stage , higher Gleason score , and higher prostate-specific antigen at diagnosis . We observed similar rates for development of metastases ( n = 20 and n = 199 ; 7.2 v 8.1 per 1,000 person-years ; P = .68 ) and death as a result of PCa ( n = 8 and n = 80 ; 2.4 v 2.6 per 1,000 person-years ; P = .99 ) for DT and immediate treatment , respectively . CONCLUSION In this nationwide cohort , more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis . Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated . PCa mortality did not differ between DT and active treatment patients",
"OBJECTIVE To evaluate the risk of reclassification on serial biopsy for Caucasian and African American ( AA ) men with very low-risk ( VLR ) prostate cancer enrolled in a large prospect i ve active surveillance ( AS ) registry . METHODS The Johns Hopkins AS registry is a prospect i ve observational study that has enrolled 982 men since 1994 . Including only men who met all National Comprehensive Cancer Network VLR criteria ( clinical stage ≤T1 , Gleason score ≤6 , prostate-specific antigen [ PSA ] level , we analyzed a cohort of 654 men ( 615 Caucasians and 39 AAs ) . The association of race with reclassification on serial biopsy was assessed with competing-risks regressions . RESULTS AA men on AS were more likely than Caucasians to experience upgrading on serial biopsy ( 36 % vs 16 % ; adjusted P for PSA level , prostate size , volume of cancer on biopsy , treatment year , and body mass index , AA race was an independent predictor of biopsy reclassification ( subdistribution hazard ratio , 1.8 ; P = .003 ) . Examining specific modes of reclassification , AA race was independently associated with reclassification by grade ( subdistribution hazard ratio , 3.0 ; P = .002 ) but not by volume . CONCLUSION AA men with VLR prostate cancer followed on AS are at significantly higher risk of grade reclassification compared with Caucasians . Therefore , if the goal of AS is to selectively monitor men with low- grade disease , AA men may require alternate selection criteria",
"OBJECTIVES To determine in a prospect i ve pilot study the safety and efficacy of cryosurgical ablation for localized prostate carcinoma . METHODS A total of 87 cryosurgical procedures were performed on 76 consecutive patients between December 1994 and February 1998 . All patients had histologically proved adenocarcinoma of the prostate , with prostate-specific antigen ( PSA ) readings of less than 30 ng/mL. Clinical evaluations , PSA determinations , and patient self-reported quality -of-life question naires ( functional assessment of cancer treatment-prostate ; FACT-P ) were used to determine biochemical and clinical disease-free status and complications . Patients had a mean follow-up of 50 months ( minimum 36 ) . RESULTS Follow-up biopsies were performed in 73 patients , and 72 were negative for malignancy after one or more treatments . Ten patients required two treatments and 1 patient required three treatments . The 5-year overall and cancer-specific survival rate was 89 % ( 95 % confidence interval , 83 % to 97 % ) and 98.6 % ( 95 % confidence interval , 96 % to 100 % ) , respectively . The undetectable PSA rate ( less than 0.3 ng/mL ) for low-risk patients ( n = 13 ) was 60 % at 5 years ; for moderate-risk patients ( n = 23 ) , it was 77 % , and for high-risk patients ( n = 40 ) , 48 % . The corresponding percentage of patients with a PSA level less than 1.0 ng/mL at 5 years was 75 % , 89 % , and 76 % . Sloughing occurred in 3 patients ( 3.9 % ) , incontinence in 1 ( 1.3 % ) , and testicular abscess in 1 ( 1.3 % ) . At 3 years , 18 ( 47 % ) of 38 patients capable of unassisted intercourse at the time of cryosurgery had resumed sexual intercourse , 5 spontaneously and 13 with sildenafil or prostagl and in . CONCLUSIONS The results of this prospect i ve evaluation show cryosurgery to be both a safe and an effective option in the treatment of localized prostate cancer",
"PURPOSE Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer . Long-term follow-up has been lacking . In this study , we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer . PATIENTS AND METHODS In a prospect i ve single-arm cohort study carried out at a single academic health sciences center , 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach . Intervention was offered for a prostate-specific antigen ( PSA ) doubling time of less than 3 years , Gleason score progression , or unequivocal clinical progression . Main outcome measures were overall and disease-specific survival , rate of treatment , and PSA failure rate in the treated patients . RESULTS Among the 819 survivors , the median follow-up time from the first biopsy is 6.4 years ( range , 0.2 to 19.8 years ) . One hundred forty-nine ( 15 % ) of 993 patients died , and 844 patients are alive ( censored rate , 85.0 % ) . There were 15 deaths ( 1.5 % ) from prostate cancer . The 10- and 15-year actuarial cause-specific survival rates were 98.1 % and 94.3 % , respectively . An additional 13 patients ( 1.3 % ) developed metastatic disease and are alive with confirmed metastases ( n = 9 ) or have died of other causes ( n = 4 ) . At 5 , 10 , and 15 years , 75.7 % , 63.5 % , and 55.0 % of patients remained untreated and on surveillance . The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1 . CONCLUSION Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame . In our cohort , 2.8 % of patients have developed metastatic disease , and 1.5 % have died of prostate cancer . This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention",
"BACKGROUND We did a r and omised phase III trial comparing external irradiation alone and external irradiation combined with an analogue of luteinising-hormone releasing hormone ( LHRH ) to investigate the added value of long-term and rogen suppression in locally advanced prostate cancer . METHODS Between 1987 and 1995 , 415 patients were r and omly assigned radiotherapy alone or radiotherapy plus immediate and rogen suppression . Eligible patients had T1 - 2 tumours of WHO grade 3 or T3 - 4 N0 - 1 M0 tumours ; the median age of participants was 71 years ( range 51 - 80 ) . In both treatment groups , 50 Gy radiation was delivered to the pelvis over 5 weeks , and 20 Gy over 2 weeks as a prostatic boost . Goserelin ( 3.6 mg subcutaneously every 4 weeks ) was started on the first day of irradiation and continued for 3 years ; cyproterone acetate ( 150 mg orally ) was given for 1 month starting 1 week before the first goserelin injection . The primary endpoint was clinical disease-free survival . Analyses were by intention to treat . FINDINGS 412 patients had evaluable data , with median follow-up of 66 months ( range 1 - 126 ) . 5-year clinical disease-free survival was 40 % ( 95 % CI 32 - 48 ) in the radiotherapy-alone group and 74 % ( 67 - 81 ) in the combined-treatment group ( p=0.0001 ) . 5-year overall survival was 62 % ( 52 - 72 ) and 78 % ( 72 - 84 ) , respectively ( p=0.0002 ) and 5-year specific survival 79 % ( 72 - 86 ) and 94 % ( 90 - 98 ) . INTERPRETATION Immediate and rogen suppression with an LHRH analogue given during and for 3 years after external irradiation improves disease-free and overall survival of patients with locally advanced prostate cancer",
"Because no adequate r and omized trials have compared active treatment modalities for localized prostate cancer , the authors analyzed risk‐adjusted , cancer‐specific mortality outcomes among men who underwent radical prostatectomy , men who received external‐beam radiation therapy , and men who received primary and rogen‐deprivation therapy",
"BACKGROUND The combination of radiotherapy plus long-term medical suppression of and rogens ( > or = 2 years ) improves overall survival in patients with locally advanced prostate cancer . We compared the use of radiotherapy plus short-term and rogen suppression with the use of radiotherapy plus long-term and rogen suppression in the treatment of locally advanced prostate cancer . METHODS We r and omly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of and rogen suppression to two groups , one to receive no further treatment ( short-term suppression ) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist ( long-term suppression ) . An outcome of noninferiority of short-term and rogen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival , with a one-sided alpha level of 0.05 . An interim analysis showed futility , and the results are presented with an adjusted one-sided alpha level of 0.0429 . RESULTS A total of 1113 men were registered , of whom 970 were r and omly assigned , 483 to short-term suppression and 487 to long-term suppression . After a median follow-up of 6.4 years , 132 patients in the short-term group and 98 in the long-term group had died ; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group . The 5-year overall mortality for short-term and long-term suppression was 19.0 % and 15.2 % , respectively ; the observed hazard ratio was 1.42 ( upper 95.71 % confidence limit , 1.79 ; P=0.65 for noninferiority ) . Adverse events in both groups included fatigue , diminished sexual function , and hot flushes . CONCLUSIONS The combination of radiotherapy plus 6 months of and rogen suppression provides inferior survival as compared with radiotherapy plus 3 years of and rogen suppression in the treatment of locally advanced prostate cancer . ( Clinical Trials.gov number , NCT00003026 ."
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4117c67a-06ff-11f0-808a-c43d1ab1c353
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The clinical sequelae of oestrogen deficiency during menopause are undoubted . However , the pathophysiological role of testosterone during the menopause is less clear . Several r and omized , placebo-controlled clinical trials suggest that testosterone therapy improves sexual function in postmenopausal women . Some studies suggest that testosterone therapy has additional effects , which include increased bone mineral density and decreased serum high-density lipoprotein ( HDL ) cholesterol . Furthermore , the long-term safety profile of testosterone therapy in postmenopausal women is not clear . This article will provide a concise and critical summary of the literature , to guide clinicians treating postmenopausal women
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"BACKGROUND The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown . METHODS We conducted a double-blind , placebo-controlled , 52-week trial in which 814 women with hypoactive sexual desire disorder were r and omly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo . Efficacy was measured to week 24 ; safety was evaluated over a period of 52 weeks , with a subgroup of participants followed for an additional year . The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes . RESULTS At 24 weeks , the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group ( an increase of 2.1 episodes vs. 0.7 , P placebo , both doses of testosterone were associated with significant increases in desire ( 300 microg per day , P in distress ( 300 microg per day , P rate of and rogenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group ( 30.0 % vs. 23.1 % ) . Breast cancer was diagnosed in four women who received testosterone ( as compared with none who received placebo ) ; one of the four received the diagnosis in the first 4 months of the study period , and one , in retrospect , had symptoms before undergoing r and omization . CONCLUSIONS In postmenopausal women not receiving estrogen therapy , treatment with a patch delivering 300 microg of testosterone per day result ed in a modest but meaningful improvement in sexual function . The long-term effects of testosterone , including effects on the breast , remain uncertain . ( Clinical Trials.gov number , NCT00131495 .",
"Objective To evaluate the efficacy and safety of a transdermal testosterone patch ( TTP , 300 μg/day ) in naturally menopausal women with hypoactive sexual desire disorder ( HSDD ) . Methods A total of 272 naturally menopausal women , predominantly not using hormone therapy , were r and omized in this 6-month , placebo-controlled , double-blind , multicenter study to receive twice weekly either TTP or an identical placebo . Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes ( SSE ) using the Sexual Activity Log , the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale . Safety was assessed by adverse events , laboratory parameters and hormone levels . Results The TTP group demonstrated significant improvements in SSE ( p = 0.0089 ) as well as in sexual desire ( p = 0.0007 ) and reduced personal distress ( p = 0.0024 ) versus placebo at 6 months ( intent-to-treat analysis , n = 247 ) . The results were significant for all three endpoints in the subgroup ( n = 199 ) not using hormone therapy . Similar numbers of women treated with placebo and TTP discontinued ( n = 39 , 27.5 % vs. n = 26 , 20 % ) , reported adverse events ( including application site reactions ) ( n = 101 , 71.1 % vs. n = 81 , 62.3 % ) and withdrew due to adverse events ( n = 20 , 14.1 % vs. n = 9 , 6.9 % ) . No clinical ly relevant changes were noted in laboratory parameters . Serum free and total testosterone levels increased from baseline in the TTP group ( geometric means 5.65 pg/ml and 67.8 ng/dl , respectively , at week 24 ) within the physiological range ; no changes were seen in estradiol and sex hormone binding globulin levels . Conclusions TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy",
"Objectives : To investigate the cognitive effects of high-dose oral estrogen alone or in combination with oral methyltestosterone in postmenopausal women . Methods : Participants were tested with a r and omized , double-blind design on the Identical Pictures , Cube Comparisons , Building Memory and Shape Memory tasks before and after 4 months of hormone treatment . Results : Women receiving estrogen and methyltestosterone maintained a steady level of performance on the Building Memory task , whereas those receiving estrogen alone showed a decrease in performance . Conclusions : These results indicate that the addition of testosterone to high-dose estrogen replacement exerts a protective effect on memory performance in postmenopausal women",
"CONTEXT Hypoactive sexual desire disorder ( HSDD ) is one of the most common sexual problems reported by women , but few studies have been conducted to evaluate treatments for this condition . OBJECTIVE The objective of this study was to evaluate the efficacy and safety of a testosterone patch in surgically menopausal women with HSDD . DESIGN The design was a r and omized , double-blind , parallel-group , placebo-controlled , 24-wk study ( the Intimate SM 1 study ) . SETTING The study was performed at private or institutional practice s. PATIENTS The subjects studied were women , aged 26 - 70 yr , with HSDD after bilateral salpingo-oophorectomy who were receiving concomitant estrogen therapy . Placebo ( n = 279 ) or testosterone 300 microg/d ( n = 283 ) was administered . There were 19 patients who withdrew due to adverse events in the placebo group and 24 in the 300 mug/d testosterone group . INTERVENTION Testosterone ( 300 microg/d ) or placebo patches were applied twice weekly . MAIN OUTCOME MEASURE(S ) The primary end point was the change in the frequency of total satisfying sexual activity at 24 wk . Secondary end points included other sexual functioning end points and safety assessment s. RESULTS At 24 wk , there was an increase from baseline in the frequency of total satisfying sexual activity of 2.10 episodes/4 wk in the testosterone group , which was significantly greater than the change of 0.98 episodes/4 wk in the placebo group ( P = 0.0003 ) . The testosterone group also experienced statistically significant improvements in sexual desire and a decrease in distress . The overall safety profile was similar in both treatment groups . CONCLUSION In the Intimate SM 1 study , the testosterone patch improved sexual function and decreased distress in surgically menopausal women with HSDD and was well tolerated in this trial",
"Objective To compare an oral estrogen- and rogen combination with estrogens alone on bone , menopausal symptoms , and lipoprotein profiles in postmenopausal women . Methods Surgically menopausal women received oral esterified estrogens ( 1.25 mg ) , or esterified estrogens ( 1.25 mg ) and methyltestosterone ( 2.5 mg ) daily , for 2 years . Bone mineral density of the lumbar spine and hip , menopausal symptoms , lipoprotein profiles , and biochemical and hematologic indices were evaluated . Results Sixty-six patients were enrolled in the study . Both treatment regimens prevented bone loss at the spine and hip ; combined estrogen- and rogen therapy was associated with a significant increase in spinal bone mineral density compared with baseline ( n = 24 ; mean score ± st and ard error 3.4 ± 1.2 % , P group , high-density lipoprotein ( HDL ) cholesterol increased significantly and low-density lipoprotein cholesterol decreased significantly . Cholesterol , HDL cholesterol , and triglycerides decreased significantly in the estrogen- and rogen group . Menopausal symptoms of somatic origin ( hot flashes , vaginal dryness , and insomnia ) were improved significantly by both treatments . Neither adverse hepatic effects nor significant safety or tolerance problems were reported in either group . Conclusion Oral estrogen- and rogen increased vertebral bone mineral density compared with pre-treatment values and relieved somatic symptoms . Safety indices , including lipoprotein levels , indicated that the combination was well tolerated over the 2 years of treatment",
"CONTEXT Changes in and rogen levels across the adult female life span and the effects of natural menopause and oophorectomy have not been clearly established . OBJECTIVE The objective of this study was to document the effects of age on and rogen levels in healthy women and to explore the effects of natural and surgical menopause . DESIGN , SETTING , AND PARTICIPANTS A cross-sectional study was conducted of 1423 non-healthcare-seeking women , aged 18 - 75 yr , r and omly recruited from the community over 15 months . MAIN OUTCOME MEASURES Serum levels by age of total testosterone ( T ) , calculated free T , dehydroepi and rosterone sulfate , and and rostenedione in a reference group of women free of confounding factors . Women in the reference group had no usage of exogenous steroid therapy ; no history of tubal ligation , hysterectomy , or bilateral oophorectomy ; and no hyperprolactinemia or polycystic ovarian syndrome . The effects of natural and surgical menopause on sex steroid levels were also examined . RESULTS In the reference population ( n = 595 ) , total T , calculated free T , dehydroepi and rosterone sulfate , and and rostenedione declined steeply with age ( P serum and rogen levels by year in women aged 45 - 54 yr showed no independent effect of menopausal status on and rogen levels . In women aged 55 yr or older , those who reported bilateral oophorectomy and were not on exogenous steroids had significantly lower total T and free T levels than women 55 yr or older in the reference group . CONCLUSIONS We report that serum and rogen levels decline steeply in the early reproductive years and do not vary because a consequence of natural menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production . These significant variations in and rogens with age must be taken into account when normal ranges are reported and in studies of the role of and rogens in women",
"OBJECTIVE In some women , a decline in sexual interest accompanies a relative and rogen insufficiency after menopause . We sought to characterize the hormonal effects of the combination of oral esterified estrogens and methyltestosterone and to investigate whether this regimen improves hypoactive sexual desire . DESIGN Double-blind r and omized trial . SETTING Healthy volunteers in a multicenter research environment . PATIENT(S ) Postmenopausal women taking estrogen therapy who were experiencing hypoactive sexual desire . INTERVENTION(S ) 4 months of treatment with 0.625 mg of esterified estrogens ( n = 111 ) or the combination of 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone ( n = 107 ) . MAIN OUTCOME MEASURES Baseline and end-of- study measurements of total and bioavailable testosterone and sex hormone-binding globulin ( SHBG ) , and mean change in level of sexual interest or desire as rated on the Sexual Interest Question naire . RESULT ( S ) Treatment with the combination of esterified estrogens and methyltestosterone significantly increased the concentration of bioavailable testosterone and suppressed SHBG . Scores measuring sexual interest or desire and frequency of desire increased from baseline with combination treatment and were significantly greater than those achieved with esterified estrogens alone . Treatment with the combination was well tolerated . CONCLUSION ( S ) Increased circulating levels of unbound testosterone and suppression of SHBG provide a plausible hormonal explanation for the significantly improved sexual functioning in women receiving the combination of esterified estrogen and methyltestosterone",
"Objective : The extent to which aromatization of testosterone ( T ) to estradiol is required for the observed effects of testosterone therapy on sexual function and well-being are not known . Therefore , the authors investigated the effects of aromatase enzyme inhibition on sexual function , well-being , and mood in estrogen- and T-replete postmenopausal women in a double-blind , r and omized , placebo-controlled study . Design : Postmenopausal women using transdermal estrogen therapy for at least 8 weeks and reporting low sexual satisfaction ( score Sexual Self-rating Scale [ SSS ] ) with a total T value of less than 1.2 nmol/L were treated with 400 μL of a 0.5 % T gel ( total dose 2 mg ) and were r and omly assigned to receive treatment with either 2.5 mg/day of letrozole or an identical placebo tablet . Women were assessed at baseline ( week −2 ) and at 0 , 4 , 8 , and 16 weeks . Sexual function was assessed with the SSS , well-being was assessed with the Psychological General Well-being Index , and mood was assessed with the Beck Depression Inventory at 0 and 16 weeks . Eighty-one women were screened , 76 were r and omly assigned to a treatment group , and 30 in each group completed the study . Because this was a mechanistic study , only the 60 women who completed the study per protocol were included in the final analysis . Results : Total T and calculated free T increased from baseline in both groups , with no difference between groups . At 16 weeks , estradiol , sex hormone-binding globulin , fasting lipids , lipoprotein(a ) , and C-reactive protein did not differ from baseline or between groups . Significant increases in total Sabbatsberg Sexual Self-rating Scale scores , total Psychological General Well-being Index scores , and a reduction in Beck Depression Inventory scores from baseline to 16 weeks was seen for both treatment groups , with no effect of treatment allocation . No adverse treatment effects were reported . Conclusions : Increases in total and free T in the physiologic range in postmenopausal women were associated with improved sexual satisfaction , well-being , and mood . In this study , aromatase inhibition did not influence any of these outcomes . Short-term transdermal T therapy did not modify fasting lipids , lipoprotein(a ) , or C-reactive protein ",
"Aim . To evaluate with vali date d instruments changes in quality of life and sexuality in women receiving hormonal replacement therapy ( AHT ) . Design . R and omised , double-blind , double-dummy study with two parallel treatment arms . Patients and methods . Forty-seven healthy post-menopausal women , aged 45–64 years , were evaluated using the Female Sexual Function Index ( FSFI ) and the menopause-specific quality of life question naire ( MENQOL ) . Of them , 40 diagnosed with sexual dysfunction were r and omised ( 1:1 ) to receive daily 0.625 mg of conjugated estrogens plus 1.25 mg of methyl-testosterone and 100 mg of micronised progesterone or placebo . After 3 months follow-up , FSFI and MENQOL question naires were administered for a second time . Results . Quality of life was unchanged in the placebo group whereas AHT significantly improved scores of vasomotor , psychological , physical and sexual symptoms . As expected , FSFI was not modified in the placebo group while in AHT group the FSFI score improved significantly . In addition , at the end of the study , 68.7 % of subjects of the AHT group did not fit did not fit the criteria for sexual dysfunction as per the FSFI ( p methyl-testosterone to hormone therapy improves quality of life and sexuality in post-menopausal women with sexual dysfunction",
"OBJECTIVE To investigate the efficacy of esterified estrogens alone and combined with oral and rogen on sexual function and menopausal symptoms in postmenopausal women . STUDY DESIGN Twenty postmenopausal women dissatisfied with their estrogen or estrogen-progestin therapy volunteered to enter a double-blind , r and omized trial in which they received either oral esterified estrogens or esterified estrogens + and rogen for eight weeks after a single-blind , placebo , lead-in period . Sexual function was assessed with a question naire used in the Yale midlife survey , and plasma levels of estradiol , estrone , sex hormone binding globulin ( SHBG ) and beta-endorphin were measured at two- to four-week intervals . RESULTS Estrogen- and rogen therapy significantly improved sexual sensation and desire after four and eight weeks of double-blind treatment in comparison to previous estrogen therapy and postplacebo baseline assessment s. Plasma levels of estradiol and estrone increased significantly in all patients as compared to the postplacebo baseline and decreased in comparison to circulating estrogen concentrations on previous therapy . Relative proportions of free and bound steroid hormone exhibited contrasting shifts during estrogen and estrogen- and rogen therapy . SHBG increased in the estrogen group and decreased in the estrogen- and rogen group , leading to lower amounts of free and rogens during estrogen therapy and increased free and rogen levels during estrogen- and rogen therapy . Since proportions of free ( bioavailable ) ovarian steroids would correlate inversely with plasma protein binding capacity , the beneficial effects of oral estrogen- and rogen therapy on sexual sensation and desire may be due either to the administered and rogen or to the increased availability of endogenous and exogenous and rogens , particularly in the central nervous system . CONCLUSION Sexual desire , satisfaction and frequency in postmenopausal women taking hormonal therapy were improved significantly by combined estrogen- and rogen therapy but not by estrogen or estrogen-progestin therapy . Sexual function improved with estrogen- and rogen therapy even though circulating estrogen levels were lower than those measured during previous estrogen therapy . This leads to the conclusion that and rogens play a pivotal role in sexual function but that estrogens are not a significant factor determining levels of sexual drive and enjoyment",
"Objective : Vaginal atrophy is a common chronic condition among postmenopausal women that can affect their quality of life . Recent studies have evaluated new treatment alternatives for vaginal atrophy ; however , few therapeutic options have been thoroughly evaluated . This study aim ed to compare the effectiveness and adverse effects of estrogen , testosterone , polyacrylic acid , and placebo lubricant for the treatment of postmenopausal women with vaginal atrophy . Methods : We conducted a r and omized clinical trial with 80 postmenopausal women aged between 40 and 70 years who were being followed up at the Menopause Clinic of CAISM UNICAMP between November 2011 and January 2013 . Women were r and omly assigned to topical vaginal treatment with estrogen , testosterone , polyacrylic acid , and placebo lubricant , three times a week for 12 weeks . We used the vaginal maturation index , pH , vaginal health score , vaginal flora , laboratory tests , and ultrasound to evaluate changes of vaginal atrophy at baseline and after 6 and 12 weeks of treatment . Results : After a 12-week treatment with topical estrogen and testosterone compared with the lubricant , an increased percentage of participants had vaginal pH less than 5 , increased vaginal score , and an increase in the number of lactobacilli . Treatment with topical estrogen improved the vaginal maturation index and showed increased levels of estradiol in three women . No changes were observed in the endometrial evaluation of all treatment groups . Conclusions : After a 12-week treatment with testosterone and estrogen compared with placebo lubrication , there was a significant improvement in vaginal trophism in postmenopausal women with vaginal atrophy",
"Objective : The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepi and rosterone ( DHEA , Prasterone ) on moderate to severe dyspareunia or pain at sexual activity , the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause ( GSM ) . Methods : In a prospect i ve , r and omized , double-blind , and placebo-controlled phase III clinical trial , the effect of daily intravaginal 0.50 % DHEA ( 6.5 mg ) ( Prasterone , EndoCeutics ) was examined on four co primary objectives , namely percentage of parabasal cells , percentage or superficial cells , vaginal pH , and moderate to severe pain at sexual activity ( dyspareunia ) identified by the women as their most bothersome vulvovaginal atrophy symptom . The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups , respectively . Results : After daily intravaginal administration of 0.50 % DHEA for 12 weeks , when compared to baseline by the analysis of covariance test , the percentage of parabasal cells decreased by 27.7 % over placebo ( P percentage of superficial cells increased by 8.44 % over placebo ( P vaginal pH decreased by 0.66 pH unit over placebo ( P pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo ( P = 0.0002 ) . On the other h and , moderate to severe vaginal dryness present in 84.0 % of women improved at 12 weeks by 1.44 severity score unit compared to baseline , or 0.27 unit over placebo ( P = 0.004 ) . At gynecological evaluation , vaginal secretions , epithelial integrity , epithelial surface thickness , and color all improved by 86 % to 121 % over the placebo effect ( P Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology . The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6 % of the participants . Conclusions : The daily intravaginal administration of 0.50 % ( 6.5 mg ) DHEA ( Prasterone ) has shown clinical ly and highly statistically significant effects on the four co primary parameters suggested by the US Food and Drug Administration . The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events , thus showing the high benefit-to-risk ratio of this treatment based upon the novel underst and ing of the physiology of sex steroids in women",
"OBJECTIVE : To examine the possible beneficial effect of and rogens in postmenopausal women with active rheumatoid arthritis . METHODS : 107 women participated in a double blind placebo controlled trial to evaluate the effect of 50 mg testosterone propionate intramuscularly every two weeks for one year . RESULTS : An improvement in ESR , Dutch health assessment question naire , and pain was noted . In addition , 21 % of patients treated with testosterone fulfilled the ACR improvement criteria after one year , versus only 4 % of the placebo group . The treatment was well tolerated . CONCLUSIONS : Testosterone may improve the general wellbeing of postmenopausal women with active rheumatoid arthritis",
"Objective The cardioprotective effects of postmenopausal estrogen replacement therapy are mediated by several mechanisms , including favorable effects on lipids and lipoproteins . The extent to which the latter reflects modification of body fat distribution by sex steroids is not known . Hence , we investigated the relationships between changes in lipids and measures of body composition in postmenopausal women who were administered estrogen therapy with and without testosterone . Design We r and omized 33 postmenopausal women to treatment with either estradiol 50 mg ( E ) alone or estradiol 50 mg plus testosterone 50 mg implants ( E&T ) administered every 3 months for 2 years in conjunction with cyclic oral progestins for women with an intact uterus . Results Both therapies were associated with sustained reductions in total cholesterol and low-density lipoprotein ( LDL ) cholesterol . In women who received E but not E&T , hip ( p abdominal circumferences ( p fat mass : fat-free mass ( FM : FFM ) ratio over the abdomen ( p E&T but not E result ed in increased FFM ( p reduced FM : FFM ratio ( p LDL cholesterol was significantly related to changes in total and compartmental body fat and to change in the FM : FFM ratio ( p Estrogen replacement has effects on body fat distribution in postmenopausal women that are associated with improved lipid parameters . Addition of parenteral testosterone does not negate the favorable effects of estrogen on LDL cholesterol levels but may attenuate the reduction in central ized body fat achieved with E implants",
"Purpose To determine the dose-dependent effects of testosterone administration on cognition in women with low testosterone levels . Methods 71 hysterectomized women with or without oophorectomy with total testosterone received a st and ardized transdermal estradiol regimen during the 12-week run-in period and were then r and omized to receive weekly intramuscular injections of placebo , 3 , 6.25 , 12.5 , or 25 mg testosterone enanthate for 24 weeks . Total testosterone was measured in serum by LC – MS/MS , and free testosterone levels were measured by equilibrium dialysis . Cognitive function was evaluated using a comprehensive battery of st and ardized neuropsychological tests at baseline and 24 weeks . Results 46 women who had baseline and end-of-treatment cognitive function data constituted the analytic sample . The five groups were similar at baseline . Mean on-treatment nadir total testosterone concentrations were 15 , 89 , 98 , 134 , and 234 ng/dl in the placebo , 3 , 6.25 , 12.5 , and 25 mg groups , respectively . No significant changes in spatial ability , verbal fluency , verbal memory , or executive function were observed in any treatment arm compared to placebo even after adjustment for baseline cognitive function , age , and education . Multiple regression analysis did not show any significant relation between changes in testosterone concentrations and change in cognitive function scores . ConclusionS hort-term testosterone administration over a wide range of doses for 24 weeks in women with low testosterone levels was neither associated with improvements nor worsening of cognitive function",
"Objective . To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen therapy on bone markers , bone mineral density and body composition in oophorectomized women . Methods . Fifty women , 45–60 years old , who had undergone a hysterectomy and bilateral salpingo-oophorectomy for benign disorders , were r and omly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily . Twenty-four weeks later , cross-over was performed to the other treatment regimen . Forty-four women completed the study . Their serum concentrations of insulin-like growth factor (IGF)-I , IGF binding protein (IGFBP)-3 , osteocalcin , carboxyterminal telopeptide aminoterminal ( ICTP ) , of type I collagen propeptide of type I procollagen ( PICP ) and interleukin (IL)-1 receptor antagonist were measured at baseline and after 24 weeks of both treatments , as were also their body mass index ( BMI ) and blood pressure . Bone mineral density of the total body , spine and hip and total body fat , total lean body mass , trunk fat and trunk lean mass were determined by dual-energy X-ray absorptiometry measurements at baseline and after 24 weeks of both regimens . Results . During treatment , the addition of testosterone counteracted the decrease in IGF-I and PICP seen with estrogen therapy alone . Osteocalcin and ICTP were significantly reduced to the same extent by both therapies . No change ocurred in the IL-1 receptor antagonist . A significant increase was seen in total lean body mass with the estrogen/testosterone regimen , but the total fat mass , trunk lean or fat mass remained unchanged after 24 weeks of both treatments . No effect was detected on total , hip or spinal bone mineral density after treatment with estrogen alone or estrogen/testosterone . Likewise , BMI and blood pressure were unaffected . Conclusions . The addition of testosterone to oral estrogen might have positive effects on bone as suggested by the fact that it counteracted the decline in IGF-I and PICP levels . An anabolic effect on muscle was reflected by an increase in the total lean body mass . No adverse effects were noted on BMI , fat distribution or blood pressure during the 6-month treatment with oral testosterone undecanoate",
"BACKGROUND The ovaries provide approximately half the circulating testosterone in premenopausal women . After bilateral oophorectomy , many women report impaired sexual functioning despite estrogen replacement . We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause . METHODS Seventy-five women , 31 to 56 years old , who had undergone oophorectomy and hysterectomy received conjugated equine estrogens ( at least 0.625 mg per day orally ) and , in r and om order , placebo , 150 microg of testosterone , and 300 microg of testosterone per day transdermally for 12 weeks each . Outcome measures included scores on the Brief Index of Sexual Functioning for Women , the Psychological General Well-Being Index , and a sexual-function diary completed over the telephone . RESULTS The mean ( + /-SD ) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter ( 4.2+/-2.8 pmol per liter ) during placebo treatment to 3.9+/-2.4 pg per milliliter ( 13.5+/-8.3 pmol per liter ) and 5.9+/-4.8 pg per milliliter ( 20.5+/-16.6 pmol per liter ) during treatment with 150 and 300 microg of testosterone per day , respectively ( normal range , 1.3 to 6.8 pg per milliliter [ 4.5 to 23.6 pmol per liter ] ) . Despite an appreciable placebo response , the higher testosterone dose result ed in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women ( P=0.03 for both comparisons with placebo ) . At the higher dose the percentages of women who had sexual fantasies , masturbated , or engaged in sexual intercourse at least once a week increased two to three times from base line . The positive-well-being , depressed-mood , and composite scores of the Psychological General Well-Being Index also improved at the higher dose ( P=0.04 , P=0.03 , and P=0.04 , respectively , for the comparison with placebo ) , but the scores on the telephone-based diary did not increase significantly . CONCLUSIONS In women who have undergone oophorectomy and hysterectomy , transdermal testosterone improves sexual function and psychological well-being",
"Objective : To evaluate the efficacy and safety of a testosterone patch for the treatment of women with hypoactive sexual desire disorder after natural menopause . Design : A multicenter , r and omized , double-blind , placebo-controlled , parallel-group trial was conducted in naturally menopausal women with hypoactive sexual desire disorder receiving a stable dose of oral estrogen with or without progestin ( N = 549 ) . Women were r and omized to receive testosterone 300 & mgr;g/day or placebo patches twice weekly for 24 weeks . The primary efficacy measure was change from baseline in frequency of total satisfying sexual activity over a 4-week period ( weeks 21 - 24 ) . Results : A total of 483 women ( 88 % ) were included in the primary analysis population ( those with baseline sex hormone binding globulin levels ≤160 nmol/L ) . The change from baseline in number of total satisfying sexual episodes was significantly greater for testosterone compared with placebo ( participants with baseline sex hormone binding globulin levels ≤160 nmol/L , mean change of 2.1 ± 0.28 versus 0.5 ± 0.23 episodes/4 weeks ; P P 0.0001 ) . Testosterone also produced statistically significant improvements compared with placebo in all secondary efficacy measures , including sexual desire and personal distress . The testosterone patch was well tolerated . Conclusions : Testosterone patch treatment increased the frequency of satisfying sexual activity and sexual desire , decreased personal distress , and was well tolerated in naturally menopausal women with hypoactive sexual desire disorder",
"And rogens are known to lower plasma triglycerides , an independent risk factor for coronary heart disease ( CHD ) . Triglycerides are carried in plasma on very low density ( VLDL ) and low density ( LDL ) lipoprotein particles . Apolipoprotein CIII ( apoCIII ) , a strong predictor of CHD , impairs the metabolism of VLDL and LDL , contributing to increased triglycerides . The objective of this study was to assess the effect of oral methyltestosterone ( 2.5 mg/d ) , added to esterified estrogens ( 1.25 mg/d ) , on concentrations of apolipoproteins and lipoproteins , specifically those containing apoCIII , compared with esterified estrogens alone in surgically postmenopausal women . The women in the methyltestosterone plus esterified estrogen group had significant decreases in total triglycerides , apoCI , apoCII , apoCIII , apoE , and high density lipoprotein ( HDL ) cholesterol compared with those in the esterified estrogen group . The decreases in apoCIII concentrations occurred in VLDL ( 62 % ; P = 0.02 ) , LDL ( 35 % ; P = 0.001 ) , and HDL ( 17 % ; P cholesterol and triglycerides concentrations of apoCIII containing LDL , and apoCI concentration of apoCIII containing VLDL . There was no effect on VLDL and LDL particles that did not contain apoCIII or on apoB concentrations . In conclusion , methyltestosterone , when administered to surgically postmenopausal women taking esterified estrogen , has a selective effect to reduce the apoCIII concentration in VLDL and LDL , a predictor of CHD . Methyltestosterone may lower plasma triglycerides through a reduction in apoCIII",
"Background Adding testosterone to hormonal therapy could improve sexual function and general well-being among women during climacteric . We evaluated the effectiveness of testosterone undecanoate on sexual function in postmenopausal women utilizing the st and ardized question naire FSFI score . Methods Postmenopausal women with sexual complaints and Female Sexual Function Index ( FSFI ) ≤ 26.5 were enrolled in to this r and omized , double-blinded , placebo-controlled trial . Participants were r and omly assigned to 8-week treatment with either oral testosterone undecanoate 40 mg or placebo twice weekly with daily oral estrogen . The FSFI scores before and after treatment were compared to assess any improvement of sexual function . Results Seventy women were recruited of which each group had 35 participants . The baseline characteristics and baseline FSFI scores were comparable between both groups . After 8 weeks of treatment , the FSFI scores significantly improved in both groups when compared to the baseline but the FSFI scores from the testosterone group were significantly higher than in the placebo group post-treatment ( 28.6 ± 3.6 , 25.3 ± 6.7 , respectively , p = 0.04 ) . There was no difference in adverse effect between the two groups Conclusions The twice weekly addition of testosterone undecanoate to daily oral estrogen was associated with a significant improvement in sexual function among postmenopausal women than the use of the estrogen alone . Trial registration Clinical Trials.gov Identifier NCT01724658 ( February 17 , 2012 )",
"OBJECTIVE To determine the effect of the and rogen supplementation of hormone replacement therapy ( HRT ) on the vascular reactivity of cerebral arteries . DESIGN Open r and omized study . SETTING Healthy volunteers in an academic research environment . PATIENT(S ) Forty postmenopausal women who were treated with sequential HRT ( transdermal E2 50 microg/d + medroxyprogesterone acetate 10 mg/d for 12 days every other month ) for > or = 1 year and INTERVENTION(S ) Testosterone undecanoate ( 40 mg/d , p.o . ) was r and omly administered to 20 patients during ongoing HRT ; the other 20 served as controls . Doppler evaluations of the internal carotid and middle cerebral arteries were performed together with lipid levels assessment s. A visual analogue scale ( VAS ) was used to evaluate various parameters relating to sexual life and well-being . MAIN OUTCOME MEASURE(S ) Pulsatility index ( PI ) of the arteries , VAS assessment of psychophysical well-being . RESULT ( S ) The administration of testosterone undecanoate during HRT induced an increase in the PI of the middle cerebral artery and a reduction of high-density lipoprotein cholesterol . Sexual desire and satisfaction were greatly improved . CONCLUSION ( S ) In postmenopausal women , and rogen supplementation during HRT can partially counteract the beneficial effects of estrogens on cerebral vascular reactivity and lipid profiles , but sexual desire and satisfaction are greatly improved",
"INTRODUCTION Recent research on the impact of testosterone ( T ) on female sexual function has yielded inconsistent results , and few studies have used physiological measures of genital arousal . AIM This study examined the effects of an acute dose of methyltestosterone ( MT ) on physiological ( genital ) and subjective sexual response in postmenopausal women . MAIN OUTCOME MEASURES Vaginal pulse amplitude ( VPA ) and self-reported sexual response . METHODS R and omized , double-blind , crossover , placebo-controlled trial of 5 mg MT , consisting of two separate 8-hour visits . Participants were 10 postmenopausal women without sexual dysfunction . Participants viewed both neutral and erotic video segments during five post-dose trials while their genital and subjective responses were monitored . RESULTS The Wilcoxon signed rank test indicated a significant difference in VPA between the T ( M = 0.018 , SD = 0.018 ) and placebo ( M = 0.016 , SD = 0.017 ) conditions at 4.5 hours post-dose ( P = 0.03 ) . Higher difference scores were noted for 80 % of subjects during the T condition at 4.5 hours , in contrast with only 50 % of subjects responding to T at the other four time points . No differences were found on VPA relative change scores or subjective sexual arousal scores . When summed across all five time points , genital and subjective measures were correlated regardless of medication condition ( 0.62 and 0.60 for self-reported physical and mental sexual arousal scores , respectively ) . CONCLUSIONS These findings in postmenopausal women combined with those of two previous investigations in premenopausal women demonstrate a probable acute-dose time delay for genital sexual effects of exogenous T with no change in self-reported sexual arousal . Further investigation is needed to determine whether acute dosing of T has a consistent and predictable impact on genital arousal that has promise for the treatment of any subgroup of women with sexual disorders",
"INTRODUCTION Transdermal testosterone patch ( TTP ) treatment produced statistically significant improvements in a satisfying sexual activity ( SSA ) , sexual desire , and personal distress in postmenopausal women suffering from hypoactive sexual desire disorder ( HSDD ) , but clinical significance of these changes was not determined . AIM To quantify the magnitude of change in three principal outcomes measures determined by HSDD patients as associated with the perception of meaningful benefit with TTP therapy . METHODS The criteria for defining responders were determined using anchoring methodology and receiver operating characteristics analysis to establish minimum important differences ( MIDs ) in a representative sub sample of 132 patients in two r and omized , controlled trials in surgically menopausal women with HSDD ( N = 1,094 ) . Perceived benefit was established based upon the question \" Overall , would you say that you experienced a meaningful benefit from the study patches ? \" . These data defined responders and established MIDs for changes in sexual desire , SSA , and personal distress . The MIDs were applied to the two trials to establish responder rates in each treatment group . MAIN OUTCOME MEASURES Changes in score that correspond to the MID for sexual desire , SSA , and personal distress , and responder rates in each treatment group based upon these values . RESULTS Increases in frequency of SSA of greater than 1 activity/4 weeks , increases in sexual desire score of > or = 8.9 , and decreases in the personal distress score of > or = 20.0 were identified as threshold improvements best able to differentiate responders and nonresponders . The responder rate was significantly higher ( P personal distress , 51 % vs. 39 % ) . CONCLUSIONS Changes in sexual desire , SSA , and personal distress observed with TTP treatment in surgically menopausal women with HSDD were clinical ly significant and were associated with a meaningful treatment benefit",
"CONTEXT Aging in men is associated with reduced testosterone ( T ) levels and physiological changes leading to frailty , but the benefits of T supplementation are inconclusive . OBJECTIVE We studied the effects of T supplementation with and without progressive resistance training ( PRT ) on functional performance , strength , and body composition . DESIGN , SETTING , AND PARTICIPANTS We recruited 167 generally healthy community-dwelling older men ( 66 ± 5 years ) with low-normal baseline total T levels ( 200 - 350 ng/dL ) . INTERVENTION Subjects were r and omized to placebo or transdermal T gel [ 2 doses targeting either a lower ( 400 - 550 ng/dL ) or higher ( 600 - 1000 ng/dL ) T range ] and to either PRT or no exercise for 12 months . MAIN OUTCOME MEASURE The primary outcome was functional performance , whereas secondary outcomes were strength and body composition . RESULTS A total of 143 men completed the study . At 12 months , total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group . In the PRT group , function and strength were not different between T- and placebo-treated subjects , despite greater improvements in fat mass ( P = .04 ) and fat-free mass ( P = .01 ) with T. In the non-PRT group , T did not improve function but improved fat mass ( P = .005 ) , fat-free mass ( P = .03 ) , and upper body strength ( P = .03 ) compared with placebo . There were fewer cardiovascular events in the T-treated groups compared with placebo . CONCLUSIONS T supplementation was well tolerated and improved body composition but had no effect on functional performance . T supplementation improved upper body strength only in nonexercisers compared with placebo",
"& NA ; Various parameters of sexual functioning were assessed in a prospect i ve , crossover investigation of 53 surgically menopausal women . Patients r and omly received either an estrogen‐ and rogen combined preparation , an estrogen‐alone drug , an and rogen‐alone drug , or a placebo . Also included were a group of women who had undergone hysterectomy and whose ovaries had been left intact . Two treatment phases , each of 3 months ' duration , were separated by an intervening placebo month . Additionally , plasma levels of total estrogens and testosterone were assayed four times during the study concurrent with monitoring of sexual behaviors . It was clear that exogenous and rogen enhanced the intensity of sexual desire and arousal and the frequency of sexual fantasies in hysterectomized and oophorectomized women . However , there was no evidence that testosterone affected physiologic response or interpersonal aspects of sexual behavior . These findings suggest that the major impact of and rogen in women is on sexual motivation and not on sexual activity per se",
"Objective Women with primary ovarian insufficiency ( POI ) display low and rogen levels , which could contribute to mood and behavioral symptoms observed in this condition . We examined the effects of physiologic testosterone therapy added to st and ard estrogen/progestin therapy on quality of life , self-esteem , and mood in women with POI . Methods One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month r and omized , placebo-controlled , parallel- design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy . Quality of life , self-esteem , and mood symptoms were evaluated with st and ardized rating scales and a structured clinical interview . Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests . Results No differences in baseline characteristics , including serum hormone levels ( P > 0.05 ) , were found . Baseline mean ( SD ) Center for Epidemiologic Studies Depression Scale scores were 10.7 ( 8.6 ) and 9.2 ( 7.8 ) for testosterone and placebo , respectively ( P = 0.35 ) . After 12 months of treatment , measures of quality of life , self-esteem , and mood symptoms did not differ between treatment groups . Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo ( P Baseline testosterone levels were not associated with either adverse or beneficial clinical effects . Conclusions A 150-&mgr;g testosterone patch achieves physiologic hormone levels in women with POI . Our findings suggest that augmentation of st and ard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood . Other mechanisms might play a role in the altered mood accompanying this disorder",
"IMPORTANCE Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown . A recent r and omized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety . OBJECTIVES To assess the association between testosterone therapy and all-cause mortality , myocardial infa rct ion ( MI ) , or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease . DESIGN , SETTING , AND PATIENTS A retrospective national cohort study of men with low testosterone levels ( coronary angiography in the Veterans Affairs ( VA ) system between 2005 and 2011 . MAIN OUTCOMES AND MEASURES Primary outcome was a composite of all-cause mortality , MI , and ischemic stroke . RESULTS Of the 8709 men with a total testosterone level lower than 300 ng/dL , 1223 patients started testosterone therapy after a median of 531 days following coronary angiography . Of the 1710 outcome events , 748 men died , 443 had MIs , and 519 had strokes . Of 7486 patients not receiving testosterone therapy , 681 died , 420 had MIs , and 486 had strokes . Among 1223 patients receiving testosterone therapy , 67 died , 23 had MIs , and 33 had strokes . At 3 years after coronary angiography , the Kaplan-Meier estimated cumulative percentages with events were 19.9%in the no testosterone therapy group vs 25.7%in the testosterone therapy group , with an absolute risk difference of 5.8%(95%CI , -1.4%to 13.1 % ) [corrected].The Kaplan-Meier estimated cumulative percentages with events among the no testosterone therapy group vs testosterone therapy group at 1 year after coronary angiography were 10.1 % vs 11.3 % ; at 2 years , 15.4 % vs 18.5 % ; and at 3 years , 19.9 % vs 25.7 [corrected].There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease ( test for interaction , P = .41 ) . CONCLUSIONS AND RELEVANCE Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level , the use of testosterone therapy was associated with increased risk of adverse outcomes . These findings may inform the discussion about the potential risks of testosterone therapy",
"CONTEXT Greater mammographic density is associated with increased breast cancer risk and reduced diagnostic mammographic sensitivity and may be seen with estrogen/progestin therapy ( EPT ) . The effects of testosterone therapy on mammographic density in postmenopausal women not on EPT are not known . OBJECTIVE Our objective was to compare effects of two doses of the testosterone transdermal patch ( TTP ) with placebo in postmenopausal women without concomitant EPT on mammographic density over 52 wk . DESIGN We conducted a r and omized , double-blind , placebo-controlled , parallel-group , multinational trial . PATIENTS Patients included 279 postmenopausal women participating in a testosterone and sexual function study with paired mammograms for baseline and 52 wk/exit . INTERVENTIONS Patients were r and omized to placebo , TTP 150 microg/d , or TTP 300 microg/d , stratified by menopause type ( natural or surgical ) . MAIN OUTCOME MEASURES Change from baseline to wk 52 in the percentage of dense tissue ( PD ) on digital mammograms . RESULTS A total of 250 women with paired mammograms for study baseline and wk 52 were included in the primary analysis . Mean age was 54.6 yr , baseline body mass index was 27.5 kg/m(2 ) , and 78 % were naturally menopausal . There were no baseline differences between groups . Mean changes from baseline ( + /-SEM ) in PD for placebo , TTP 150 microg/d and TTP 300 microg/d were small ( 0.05 + /- 0.16 , 0.06 + /- 0.19 , and 0.21 + /- 0.17 % ) and not significantly different . There were no statistically significant differences from placebo for total dense or nondense area and no significant relationships between hormone levels and PD after adjustment for body mass index . CONCLUSION TTP therapy over 52 wk appears to have no significant effect on digitally quantified absolute or percent dense mammographic area in postmenopausal women not using EPT",
"OBJECTIVE To determine dose-dependent effects of T administration on cardiovascular risk markers in women with low T levels . METHODS Seventy-one hysterectomized women with or without oophorectomy with total T received a st and ardized transdermal estradiol regimen during the 12-week run-in period and were then r and omized to receive weekly i m injections of placebo or 3- , 6.25- , 12.5- , or 25-mg T enanthate for 24 weeks . Total and free T levels were measured by liquid chromatography-t and em mass spectrometry and equilibrium dialysis , respectively . Insulin resistance and inflammatory markers were measured at baseline and 24 weeks . In a subset of women , magnetic resonance imaging of the abdomen was performed to quantify abdominal fat volume . RESULTS Fifty-nine women who completed the 24-week intervention were included in the final analysis . The five groups were similar at baseline . Mean on-treatment nadir total T concentrations were 14 , 79 , 105 , 130 , and 232 ng/dL in the placebo group and the 3- , 6.25- , 12.5- , and 25-mg groups , respectively . No significant changes in fasting glucose , fasting insulin , homeostatic model assessment of insulin resistance , high sensitivity C-reactive protein , adiponectin , blood pressure , and heart rate were observed at any T dose when compared to placebo . Similarly , no dose- or concentration-dependent changes were observed in abdominal fat on magnetic resonance imaging . CONCLUSION Short-term T administration over a wide range of doses for 24 weeks in women with low T levels was not associated with worsening of cardiovascular risk markers",
"During a double-blind comparison of menopausal replacement therapy with estrogen alone compared with estrogen plus methyltestosterone ( meT ) , subjects who had been on conjugated equine estrogen ( CEE ) said they felt better when placed on esterified estrogen ( EE ) . We , therefore , tested whether these estrogen treatments differed in their neuropsychological effects . Subjects were 34 healthy menopausal respondents to advertisements younger than age 66 who were on CEE at baseline . Each was r and omized into the EE condition , either immediately after baseline or after they first took EE plus added meT for 8 weeks . We compared neuropsychological measures between these two conditions . Data included cognitive performance test results and symptom self-ratings . Multivariate techniques were used to adjust for the effects of treatment order . Compared with prior CEE treatment , EE treatment was associated with significantly improved scores on the Zung Self-Rated Depression Scale and on Switching Attention Test performance . Further investigation is warranted to determine if different forms of estrogen replacement induce different neuropsychological effects",
"OBJECTIVE To test the causal relationship between sex hormones and cognitive skills in postmenopausal women . We hypothesized that testosterone would decrease verbal memory and verbal fluency and increase spatial ability compared with a placebo . For estrogen , we conversely hypothesized that the treatment would increase verbal fluency and verbal memory and decrease spatial ability . DESIGN R and omized , double-blind , placebo-controlled , parallel-group trial . SETTING Women 's health clinical research unit at a university hospital . PATIENT(S ) Two-hundred healthy , naturally postmenopausal women aged 50 - 65 years . INTERVENTION(S ) R and omization to 4 weeks ' treatment with testosterone ( testosterone undecanoate , 40 mg/day ) , estrogen ( oral E2 2 mg/day ) or placebo . MAIN OUTCOME MEASURE(S ) Comparisons in verbal fluency , verbal memory , and spatial ability between the three treatment groups . RESULT ( S ) We found no significant effects of testosterone or estrogen on verbal fluency , verbal memory , or spatial ability . CONCLUSION ( S ) Our results give no support for short-term testosterone or estrogen treatment having any substantial effect on verbal fluency , verbal memory , or spatial ability in healthy postmenopausal women",
"Objective . To analyze the effects of testosterone addition to estrogen therapy in comparison with estrogen alone on cardiovascular risk factors in postmenopausal women . Methods . Fifty surgically postmenopausal women were included in this double-blind , placebo-controlled and r and omized study to receive daily oral treatment with estradiol valerate 2 mg + placebo ( E/P ) or estradiol valerate 2 mg + testosterone undecanoate 40 mg ( E/T ) for 24 weeks and then switched to the other regimen for another 24 weeks . Sex hormones , High sensitivity CRP ( hsCRP ) , Interleukin-6 ( IL-6 ) , Tissue necrosis factor (TNF)-α , Insulin-like growth factor binding globulin ( IGFBP-1 ) , vascular cell adhesion molecule (VCAM)- 1 , and homocysteine were analyzed at baseline and after 6 and 12 months . Results . Estradiol and and rogens increased as expected during the treatments . After 6 months of E/P , increases of hsCRP and IGFBP-1 and a decline of VCAM were recorded , whereas IL-6 , TNF-α , and homocysteine were unchanged . When testosterone was added to estrogen , the increase of IGFBP-1 and decline in VCAM was similar as with estrogen treatment alone . However , testosterone addition counteracted the estrogen-induced rise in hsCRP but had no effects on IL-6 , TNF-α , and homocysteine . Conclusion . Data suggest that testosterone addition to estrogen treatment in postmenopausal women has a modest influence on inflammatory markers and there were no apparent adverse effects . On the contrary , the estrogen-induced increase in hsCRP was suppressed",
"background Coronary heart disease ( CHD ) is the leading cause of mortality in women , with an incidence that increases after menopause , hence suggesting a cardioprotective role of oestrogen . Menopause also results in a decline in and rogen levels with result ing symptoms of decreased libido and sexual dysfunction . Recently , there has been a growing interest in the treatment of postmenopausal women with and rogens . However , no data are available on plasma viscosity and fibrinogen levels in postmenopausal women on combined oestrogen/ and rogen therapy",
"Percutaneous estradiol ( E2 ) implants effectively preserve bone density in postmenopausal women . However , these implants are often given with testosterone , which may itself have an anabolic effect on bone . To determine whether testosterone confers any additional bone-sparing effect , we studied 50 postmenopausal women r and omly allocated to receive E2 ( 75 mg ) alone or with testosterone ( 100 mg ) every 6 months for 1 year . Women with an intact uterus received cyclic norethindrone ( 5 mg ) for 10 days of each calendar month . Twenty-five untreated women were recruited to act as a reference group . Bone density was measured at the lumbar spine and proximal femur by dual x-ray densitometry . By 1 year , bone density at the lumbar spine had fallen by 1.8 % in the reference group . In the women treated with E2 alone , it increased significantly by 7.8 % ( P E2 with testosterone , it increased by 6.3 % ( P bone density decreased by 3 % in the controls and increased by approximately 4 % in both treated groups ( P bone density at these sites was unrelated to the woman 's chronological age , menopausal age , or initial bone density . However , it correlated significantly with the serum E2 levels attained after 1 year of therapy . In no treated patients did bone density decrease significantly . These data show that testosterone confers no additional bone-sparing effect in postmenopausal women",
"Both estrogen and testosterone insufficiency has been associated with reduced psychological well-being including fatigue . However , hormonal replacement studies on fatigue are rare . Therefore , we wanted to study the effect of testosterone and estrogen replacement therapy on cognitive fatigue and the relation between sex hormone levels and cognitive fatigue in oophorectomized women . Fifty women with surgically induced menopause ( mean age : 54.0 ± 2.9 years ) were r and omly assigned to treatment with estradiol valerate in combination with testosterone undecanoate or placebo for 24 weeks in a double-blind cross-over study . Neuropsychological tests and question naires were used to assess cognitive fatigue and psychological well-being . Cognitive fatigue was significantly associated to poor self-rated health and higher body mass index but not to general psychological well-being or sex hormone levels . Treatment with testosterone + estrogen had no significant effect on cognitive fatigue but the results indicated a curvilinear relation for hormonal levels . The estrogen/testosterone ratio was more related to functions rather than high or low hormone levels per se . We found that cognitive fatigue is frequent in oophorectomized women and negatively associated to self-perceived health and positively associated to BMI . A well-balanced ratio between estrogen and testosterone levels may be important for cognitive fatigue ",
"Objective This study aims to determine the dose-dependent effects of testosterone on sexual function , body composition , muscle performance , and physical function in hysterectomized women with or without oophorectomy . Methods Seventy-one postmenopausal women who previously underwent hysterectomy with or without oophorectomy and had total testosterone levels less than 31 ng/dL or free testosterone levels less than 3.5 pg/mL received a st and ardized transdermal estradiol regimen during the 12-week run-in period and were r and omized to receive weekly intramuscular injections of placebo or 3 , 6.25 , 12.5 , or 25 mg of testosterone enanthate for 24 weeks . Total and free testosterone levels were measured by liquid chromatography – t and em mass spectrometry and equilibrium dialysis , respectively . The primary outcome was change in sexual function measured by the Brief Index of Sexual Functioning for Women . Secondary outcomes included changes in sexual activity , sexual distress , Derogatis Interview for Sexual Functioning , lean body mass , fat mass , muscle strength and power , and physical function . Results Seventy-one women were r and omized ; five groups were similar at baseline . Sixty-two women with analyzable data for the primary outcome were included in the final analysis . The mean on-treatment total testosterone concentrations were 19 , 78 , 102 , 128 , and 210 ng/dL in the placebo , 3-mg , 6.25-mg , 12.5-mg , and 25-mg groups , respectively . Changes in composite Brief Index of Sexual Functioning for Women scores , thoughts/desire , arousal , frequency of sexual activity , lean body mass , chest-press power , and loaded stair-climb power were significantly related to increases in free testosterone concentrations ; compared with placebo , changes were significantly greater in women assigned to the 25-mg group , but not in women in the lower-dose groups . Sexual activity increased by 2.7 encounters per week in the 25-mg group . The frequency of and rogenic adverse events was low . Conclusions Testosterone administration in hysterectomized women with or without oophorectomy for 24 weeks was associated with dose and concentration-dependent gains in several domains of sexual function , lean body mass , chest-press power , and loaded stair-climb power . Long-term trials are needed to weigh improvements in these outcomes against potential long-term adverse effects",
"OBJECTIVES To eluci date if percutanous treatment with 10 mg testosterone per day could enhance sexuality and psychological well-being in postmenopausal women presenting problems with low libido . Secondary to study the influence on blood lipids , hemoglobin and erythropoietin levels . METHODS Fifty-three postmenopausal women participated . As a complement to their already on-going HRT , 10 mg of a testosterone gel ( Testogel , Besins-Iscovesco ) or placebo was administered . Treatment continued for three plus three months in a double blind , r and omized , crossover design . RESULTS The scores concerning \" frequency of sexual activity , orgasm and intercourse \" , \" sexual arousal , fantasies and enjoyment \" , \" satisfaction with orgasms \" , and \" interest in sex \" were all significally improved for testosterone addition as compared to placebo both before and after crossover . Testosterone levels increased more than 10-fold during treatment while DHT-levels were more than doubled . Estrogen levels were not affected during the addition of testosterone . Liver enzymes , total cholesterol , triglycerides , HDL and LDL revealed no significant differences between any of the periods or groups . Endometrial thickness did not change significantly during treatment . Hemoglobin and erythropoietin remained unchanged . No significant differences in the number of experienced side effects were found . CONCLUSION Testosterone gel of 10 mg had positive effects on several aspects of sexual life such as frequency of sexual activity , orgasm , arousal , fantasies and sexual interest in postmenopausal women on HRT . Several psychological variables were positively influenced . The given dose result ed in too high serum levels . Even if no negative effects were observed , monitoring of serum levels and a decreased dose should be considered in future studies",
"Objective To study the effect on mammographic breast density of testosterone addition during combined estrogen/progestogen therapy in postmenopausal women . Methods A prospect i ve , r and omized , double-blind , placebo-controlled trial . A total of 99 women were given 2 mg 17β-estradiol and 1 mg norethisterone acetate in combination with either a testosterone patch ( 300 μg/24 h ) or a placebo patch . Mammographic breast density at baseline and after 6 months was assessed by visual classification scales and by digitized quantification . A st and ardized question naire was used to quantify subjective breast symptoms . Results Visual classifications showed an increase in mammographic density in 18–30 % of the women , with no significant differences between the treatment groups . The mean increase of the area of dense breast during treatment according to digitized assessment was 7.4 % in the placebo group and 5.4 % in the testosterone group . Breast symptoms showed a positive association with the increase in density ( rs = 0.34 ; p treatment . Density , both at baseline ( rs = −0.35 ; p addition of testosterone does not appear to influence mammographic breast density in women concurrently treated with a common oral estrogen/progestogen regimen for a period of 6 months",
"INTRODUCTION Postmenopausal women with hypoactive sexual desire disorder ( HSDD ) experienced statistically significant improvements in the frequency of satisfying sexual activity , sexual desire , and distress with testosterone treatment in phase III trials , but it was not known whether the magnitude of these effects was clinical ly meaningful . The clinical relevance study was design ed to answer this question . AIM To evaluate the clinical relevance of the treatment benefits . METHODS This study involved a representative sample of 132 surgically postmenopausal women with HSDD who were enrolled in two r and omized , placebo-controlled trials ( N = 1094 ) assessing the efficacy and safety of transdermal testosterone treatment ( 300 mcg/day ) for 6 months . At the end of the studies , prior to unblinding , a sample of women ( 12 % ) was interviewed concerning their experiences with the treatment . MAIN OUTCOME MEASURES Women were asked \" Overall , would you say that you experienced a meaningful benefit from the study patches ? \" Changes in the efficacy end points in the double-blind studies were compared for the women who did and did not experience an overall meaningful benefit . RESULTS Overall , 33 of 64 women ( 52 % ) who received testosterone reported experiencing a meaningful treatment benefit , compared with 21 of 68 women ( 31 % ) who received placebo ( P = 0.025 ) . Among the women who identified themselves as experiencing a meaningful benefit , the mean ( SE ) change from baseline in 4-week frequency of satisfying sexual activity was 4.4 ( 0.76 ) , in desire score was 21.0 ( 2.78 ) , moving from \" seldom \" to \" sometimes \" feeling sexual desire , and in distress score was -36.5 ( 3.96 ) , moving from \" often \" to \" seldom \" being distressed . Among the women who identified themselves as not experiencing a meaningful benefit , the mean ( SE ) change from baseline in 4-week frequency of satisfying sexual activity was 0.5 ( 0.31 ) , in desire score was 2.9 ( 1.42 ) , and in distress score was -8.8 ( 2.23 ) . CONCLUSIONS Surgically menopausal women with HSDD in these studies received clinical ly meaningful benefits , including improvements in satisfying sexual activity , sexual desire , and personal distress",
"In a prospect i ve , double-blind , crossover study , it was found that surgically menopausal women who received an estrogen drug alone and those who were given a combined estrogen- and rogen preparation reported a significantly reduced frequency of hot flushes compared to a placebo group ( p less than 0.01 ) coincident with their higher total plasma estrogen levels ( p less than 0.01 ) . The administration of testosterone alone , however , was ineffective in alleviating hot flushes , even though these patients had plasma estrogen values that were not different from those of women with intact ovaries . It was proposed that , in women with very low levels of endogenous estrogens , changes in sex hormone-binding globulin ( SHBG ) concentrations induced by exogenous testosterone may reduce the amount of non-SHBG-bound estrogens , thereby obviating estrogenic effects on hot flushes",
"To investigate the role of and rogens in increasing bone density and improving low libido in postmenopausal women , we have studied the long-term effects of estradiol and testosterone implants on bone mineral density and sexuality in a prospect i ve , 2 year , single-blind r and omised trial . Thirty-four postmenopausal volunteers were r and omised to treatment with either estradiol implants 50 mg alone ( E ) or estradiol 50 mg plus testosterone 50 mg ( E&T ) , administered 3-monthly for 2 years . Cyclical oral progestins were taken by those women with an intact uterus . Thirty-two women completed the study . BMD ( DEXA ) of total body , lumbar vertebrae ( L1-L4 ) and hip area increased significantly in both treatment groups . BMD increased more rapidly in the testosterone treated group at all sites . A substantially greater increase in BMD occurred in the E&T group for total body ( P sexual parameters ( Sabbatsberg sexual self-rating scale ) improved significantly in both groups . Addition of testosterone result ed in a significantly greater improvement compared to E for sexual activity ( P satisfaction ( P pleasure ( P orgasm ( P relevancy ( P Total cholesterol and LDL-cholesterol fell in both groups as did total body fat . Total body fat-free mass ( DEXA , anthropometry , impedance ) increased in the E&T group only . We concluded that in postmenopausal women , treatment with combined estradiol and testosterone implants was more effective in increasing bone mineral density in the hip and lumbar spine than estradiol implants alone . Significantly greater improvement in sexuality was observed with combined therapy , verifying the therapeutic value of testosterone implants for diminished libido in postmenopausal women . The favourable estrogenic effects on lipids were preserved in women treated with T , in association with beneficial changes in body composition",
"OBJECTIVE To compare the effects of two doses of conjugated equine estrogen ( CEE ) and two of esterified estrogen plus methyltestosterone ( E + A ) in surgically menopausal women . STUDY DESIGN A two-year , parallel-group , double-blind study of 311 women who were r and omly assigned to one of four regimens : ( 1 ) CEE , 0.625 mg/d ; ( 2 ) CEE , 1.25 mg/d ; ( 3 ) esterified estrogens , 0.625 mg , + methyltestosterone , 1.25 mg/d ; or ( 4 ) esterified estrogens , 1.25 , + methyltestosterone , 2.5 mg/d . Study parameters were symptoms , lipids , bone mineral density , side effects and safety . RESULTS All treatments prevented loss of bone in the spine and hip . The higher E + A dose increased spine and hip BMD more than other treatments ( P menopausal symptoms , with non-significantly greater improvements in well-being and sexual interest in the E + A groups . Similar and significant decreases in low-density lipoprotein were observed in all groups , but high-density lipoprotein and triglycerides were increased only in the unopposed estrogen groups ( P Hirsutism was uncommon and similar in all groups at two years . Discontinuation rates and reasons for withdrawal from the study were similar in both groups . No clinical ly significant side effects or laboratory test abnormalities were seen . CONCLUSION As compared to estrogen alone , E + A significantly improved BMD and was well tolerated in surgically menopausal women",
"Previous studies indicated an enhanced capability of divergent creative thinking in young women during the ovulatory phase , which expressed itself also by an increased dimensional complexity of ongoing electroencephalographic ( EEG ) activity . Considering the enhanced plasma levels of estrogen and testosterone characterizing the ovulatory phase , we tested whether short-term administration of estrogen or testosterone in postmenopausal women with constantly low levels of gonadal steroids induces similar changes in divergent thinking . In two placebo-controlled cross-over studies , healthy postmenopausal women ( n=12 , in each study , mean age 58 years , range 47–65 years ) were treated transdermally over 3 days with estrogen and testosterone , respectively , at doses inducing plasma hormone concentrations comparable with those observed in young women around ovulation . Capabilities of divergent thought and convergent analytical thought , performance on motor perseveration , and verbal memory were examined . EEG activity was recorded while subjects performed on tasks of thinking and during mental relaxation . Estrogen impaired divergent thinking ( p enhanced convergent thinking , motor perseveration , and memory for the initial word list ( p , EEG dimensional complexity was reduced ( p performance on some of the divergent thinking tasks ( p increase EEG dimensional complexity during divergent thinking . Data indicate a differential sensitivity of modes of thinking to short-term treatment with estrogen and testosterone in postmenopausal women",
"BACKGROUND Oophorectomy reduces serum testosterone levels . We studied the efficacy and safety of transdermal testosterone in treating hypoactive sexual desire disorder in surgically menopausal women . METHODS A 24-week , r and omized , double-blind , placebo-controlled , parallel-group , multicenter trial was conducted in women ( aged 24 - 70 years ) who developed distressful low sexual desire after bilateral salpingo-oophorectomy and hysterectomy and who were receiving oral estrogen therapy . Women were r and omized to receive placebo ( n = 119 ) or testosterone patches in dosages of 150 microg/d ( n = 107 ) , 300 microg/d ( n = 110 ) , or 450 microg/d ( n = 111 ) twice weekly for 24 weeks . Sexual desire and frequency of satisfying sexual activity were primary efficacy outcome measures . RESULTS Of the 447 women r and omized , 318 ( 71 % ) completed the trial . Compared with placebo , women receiving the 300-microg/d testosterone patch had significantly greater increases from baseline in sexual desire ( 67 % vs 48 % ; P = .05 ) and in frequency of satisfying sexual activity ( 79 % vs 43 % ; P = .049 ) . The 150-microg/d group showed no evidence of a treatment effect . The 450-microg/d group also was not statistically different from the 300-microg/d or placebo groups . Marginally significant linear dose-response trends were observed for total satisfying sexual activity and sexual desire at 24 weeks ( P = .06 and .06 , respectively ) . Adverse events occurred with similar frequency in both groups ; no serious safety concerns were observed . CONCLUSIONS The 300-microg/d testosterone patch increased sexual desire and frequency of satisfying sexual activity and was well tolerated in women who developed hypoactive sexual desire disorder after surgical menopause",
"Objective : To compare the effect of esterified estrogens and methyltestosterone versus esterified estrogens alone on diminished sexual interest in surgically menopausal women . Design : This r and omized , double-blind study compared the effect of combined esterified estrogens ( 1.25 mg ) and methyltestosterone ( 2.5 mg ) ( EE/MT ) versus esterified estrogens ( 1.25 mg ) alone ( EE ) for 8 weeks . Several different sexual function question naires were used to measure response to therapy . Changes from baseline in sexual interest/function and hormone levels were evaluated after 4 and 8 weeks of treatment . Results : A total of 102 women were r and omized into the study ; 52 ( age range , 32 - 61 years ) to EE/MT and 50 ( age range , 33 - 62 years ) to EE . After 8 weeks , significant differences between treatments were not seen in the Changes in Sexual Functioning Question naire ( CSFQ-F-C ) sexual desire/interest subscale score , the primary efficacy variable . In contrast statistically significant between-treatment differences were found for several secondary efficacy variables including Menopausal Sexual Interest Question naire ( MSIQ ) sexual interest/desire score , CSFQ-F-C arousal/erection subscale score and Women 's Health Question naire sexual functioning subscale score . The mean serum concentration of bioavailable and free testosterone significantly increased , approximately doubling between baseline and the end of the study in patients receiving EE/MT , with a significant ( P mean serum concentration of sex hormone-binding globulin significantly decreased to less than one third of the pretreatment levels in patients receiving EE/MT ( P tolerated . Conclusions : The mixed results seen with the different sexual function question naires may be due to the CSFQ-F-C 's lack of specificity for this population . Increased levels of bioavailable and free testosterone paralleled the improved MSIQ item scores . Both the EE and EE/MT treatments were well tolerated",
"Objective : To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen replacement on sexual function , psychological well-being and self-esteem in surgically postmenopausal women . Methods : A letter of invitation to participate in the study was mailed to women who had undergone hysterectomy and bilateral oophorectomy for benign disorders during 1990 - 98 . Fifty women , 45 - 60 years old , were consecutively recruited and r and omly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily for 24 weeks . A double-blind design was chosen , with cross-over to the other regimen for another 24 weeks of treatment . Forty-four women completed the study . Outcome included scores on McCoy 's sex scale question naire , the Psychological General Well-Being index and a self-esteem question naire , at baseline and after 24 weeks of either treatment . Serum concentrations of total testosterone , sex hormone binding globulin , free testosterone , dihydrotestosterone , and rostenedione , estradiol , follicle stimulating hormone and luteinizing hormone were analyzed at baseline and after 24 weeks of both treatment regimens . Results : After 24 weeks , both treatment regimens had significantly improved some of the sexual variables . The addition of testosterone had a significantly better effect on the sex variables ' enjoyment of sex ' , ' satisfaction with frequency of sexual activity ' and ' interest in sex ' . The total McCoy score was significantly increased by both treatments , but there was a stronger effect when testosterone was also given . Although both regimens improved psychological well-being and self-esteem , we found no significant differences between testosterone-estrogen or estrogen alone at 24 weeks . Serum levels of all and rogens , with considerable individual variation , increased significantly from baseline after 24 weeks of testosterone-estrogen treatment . Supraphysiological levels were achieved in a significant proportion of the women . Increases in estradiol and sex hormone binding globulin were less marked when testosterone was also given . Both treatments reduced gonadotropin levels . Conclusions : The addition of testosterone undecanoate improved specific aspects of sexual function more than treatment with estrogen alone . Improvements in well-being and self-esteem were similar for both treatments . If testosterone undecanoate 40 mg daily should be used for clinical treatment , regular monitoring of and rogen serum levels is needed",
"OBJECTIVE To evaluate the effects of giving testosterone undecanoate ( TU ) in addition to estrogen replacement on serum lipids in oophorectomized women . METHOD Women with surgically induced menopause ( n = 50 ) were r and omly assigned to oral treatment with 2 mg of estradiol valerate in combination with 40 mg of TU or placebo for 24 weeks . The study was double-blind with cross-over to the other regimen for further 24 weeks of treatment . Forty-four women completed the study . Their serum concentrations of total , high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol , triglycerides , lipoprotein-(a ) ( Lp-(a ) ) , total testosterone , estradiol and sex hormone-binding globulin ( SHBG ) were analyzed at baseline and after 24 weeks of each treatment . RESULTS Serum levels of total testosterone increased markedly from a baseline mean of 0.8 - 4.9 nmol/l during testosterone addition . The levels of free testosterone significantly increased during the combined treatment and fell when given estrogen alone . Total and LDL-cholesterol levels were significantly reduced by both treatments as also were those of Lp-(a ) although the difference was not significant . We found a 13 % reduction in HDL-cholesterol levels when testosterone was added , but no change with estrogen alone . Triglyceride levels were increased by estrogen treatment , but not affected by the combination of estrogen plus testosterone . CONCLUSIONS These findings suggest that 40 mg of TU can be given in addition to estrogen replacement with only little side-effects on the pattern of circulating lipids . Although supraphysiological concentrations of testosterone were induced a significant reduction in total and LDL-cholesterol levels occurred",
"Objective : During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy , in particular about its effects on the breast . Several observations suggest that and rogens may counteract the proliferative effects of estrogen and progestogen in the mammary gl and . Thus , we aim ed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy . Design : We conducted a 6-month prospect i ve , r and omized , double-blind , placebo-controlled study . A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally r and omly assigned to receive additional treatment with either a testosterone patch releasing 300 & mgr;g/24 hours or a placebo patch . Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months , and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody . Results : A total of 88 women , 47 receiving active treatment and 41 in the placebo group , completed the study . In the placebo group there was a more than fivefold increase ( P total breast cell proliferation from baseline ( median 1.1 % ) to 6 months ( median 6.2 % ) . During testosterone addition , no significant increase was recorded ( 1.6 % vs 2.0 % ) . The different effects of the two treatments were apparent in both epithelial and stromal cells . Conclusions : Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women",
"OBJECTIVE To evaluate the benefits and risks of hormone replacement therapy ( HRT ) combined with methyltestosterone ( MT ) in postmenopausal women with sexual dysfunction . DESIGN This study was a r and omized , double-blind , placebo-controlled and crossover trial . Eighty-five women using HRT were divided into four treatment groups : GI-HRT plus placebo for 4 months ; GII-HRT plus MT 2.5mg/day for 4 months ; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months ; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months . Blood was collected at baseline , after 2 months ( T1 ) and 4 months ( T2 ) of treatment for hormone determinations of estradiol , FSH , total and free testosterone , GOT , GPT , glucose , total and fractions of cholesterol and triglycerides . All participants answered clinical questions and a vali date d question naire of modified McCoy 's sex scale . RESULTS The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors . The patients of GII , GIIII and GIV when using MT presented amelioration of sex symptoms , mainly satisfaction and desire ( p problem score results as compared to GIII at T2 ( 1.5+/-0.6 ) . CONCLUSION All data suggest that combined HRT- and rogen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy",
"BACKGROUND Decreased libido is one of several changes in sexual function that are often experienced by female cancer patients . Transdermal testosterone therapy has been associated with increased libido among estrogen-replete women who report low libido . METHODS In a phase III r and omized , placebo-controlled crossover clinical trial , we evaluated whether transdermal testosterone would increase sexual desire in female cancer survivors . Postmenopausal women with a history of cancer and no current evidence of disease were eligible if they reported a decrease in sexual desire and had a sexual partner . Eligible women were r and omly assigned to receive 2 % testosterone in Vanicream for a testosterone dose of 10 mg daily or placebo Vanicream for 4 weeks and were then crossed over to the opposite treatment for an additional 4 weeks . The primary endpoint was sexual desire or libido , as measured using the desire subscales of the Changes in Sexual Functioning Question naire , as assessed at baseline and at the end of 4 and 8 weeks of treatment . Serum levels of bioavailable testosterone were measured at the same times . All statistical tests were two-sided . RESULTS We enrolled 150 women . Women who were on active testosterone cream had higher serum levels of bioavailable testosterone than women on placebo ( mean change from baseline , testosterone versus placebo , week 4 , 11.57 % versus 0 % , difference = 11.57 % , 95 % confidence interval [ CI ] = 8.49 % to 14.65 % ; week 8 , 10.21 % versus 0.28 % , difference = 9.92 % , 95 % CI = 5.42 % to 14.42 % ; P average intrapatient libido change from baseline to weeks 4 and 8 was similar on both arms . CONCLUSION Increased testosterone level did not translate into improved libido , possibly because women on this study were estrogen depleted",
"Objective : Evaluation of the use of testosterone therapy for hypoactive sexual desire disorder ( HSDD ) after oophorectomy has mostly involved women treated with oral estrogen preparations . We investigated the efficacy and safety of a testosterone patch in surgically menopausal women receiving concurrent transdermal estrogen . Design : Women with HSDD after oophorectomy , for whom this was a concern , who were using transdermal estrogen , were recruited to a 24-week , r and omized , double-blind , placebo-controlled trial in Europe and Australia . Patients were r and omly allocated to placebo ( n = 40 ) or testosterone 300 & mgr;g/day ( n = 37 ) treatment . Primary endpoints were changes in sexual desire measured by the sexual desire domain of the Profile of Female Sexual Function and the frequency of satisfying sexual activity at 24 weeks . Results : Sixty-one women ( 79 % ) completed the trial . All subjects who received at least one application of study medication were included in analysis . The testosterone-treated group experienced a significantly greater change from baseline in the domain sexual desire score compared with placebo ( change from baseline , 16.43 versus 5.98 ; P = 0.02 ) . The domain scores for arousal , orgasm , decreased sexual concerns , responsiveness , and self-image as well as decreased distress were also significantly greater with testosterone therapy than placebo . The frequency of satisfactory sexual events increased but was not statistically different between treatment groups ( P = 0.06 ) Adverse events occurred with similar frequency in both groups , and no serious risks of therapy were observed Conclusions : In this study , transdermal testosterone therapy via a skin patch improved sexual desire and other sexual function domains . It was well tolerated in these oophorectomized women with HSDD receiving concomitant transdermal estrogen",
"Objective : To compare the efficacy and safety of esterified estrogens with and without methyltestosterone . Methods : Twenty-six women participated in a doubleblind r and omized trial for 6 months . Outcome measures included serum total and lipoprotein-bound cholesterol , vasomotor symptoms , vaginal cytology and endometrial histology , and chemistry values . Analysis of variance and t test statistics were used to assess differences . Results : After 6 months of therapy , the treatment groups were comparable with regard to symptom scores , vaginal cytology and endometrial histology scores , and clinical laboratory test values . Treatment with esterified estrogens plus methyltestosterone significantly decreased total cholesterol , high-density lipoprotein cholesterol ( HDL ) , HDL2 , HDL3 , and apolipoprotein Al compared to esterified estrogens alone . Conclusions : Esterified estrogens with or without methyltestosterone were effective at reducing menopausal symptoms and were well tolerated over 6 months of continuous treatment . A significant decrease in cholesterol and apolipoproteins in the estrogen plus methyltestosterone group suggests a potentially adverse impact on the beneficial effect normally imparted by estrogen therapy",
"Objectives To assess the safety and efficacy of 10 mg topical testosterone therapy daily ( 2 cm And ro-Feme ® cream ) as a treatment for low sexual desire in postmenopausal hysterectomized women who were already on transdermal estrogen . Methods A double-blind , r and omized , placebo-controlled , cross-over study ( each period being of 3 months ' duration ) was performed in the research center of a tertiary referral women 's hospital . Thirty-six menopausal healthy women were recruited who had undergone a hysterectomy , who were not depressed , were in a stable relationship and who fulfilled diagnostic criteria for low sexual desire , as measured by the Brief Index of Sexual Function for Women ( BISF-W ) . Main outcome measures The primary outcome measure was improvement in the sexuality score as measured by a vali date d tool ( BISF-W ) ; secondary measures were sub-scores of the BISF-W , effect on mood and energy , lipids and testosterone levels . Results Testosterone cream significantly improved sexual desire , frequency of sex , receptivity and initiation as measured by the BISF-W score . It did not change mood , energy , lipids , blood pressure or weight over the study period . Conclusions Testosterone cream significantly improved sexual scores in menopausal women with low sexual desire . It was effective , easy to use and had no side-effects over the 3-month period of active treatment . It offers a novel and acceptable method of administering testosterone to menopausal women",
" Summary . Forty postmenopausal women , referred for hormone replacement therapy and all of whom reported a significant concern about a decline in their sexual interest , were r and omly allocated to one of two hormone implant treatment groups : either oestradiol ( 50 mg ) alone , or oestradiol ( 50 mg ) and testosterone ( l00 mg ) . Comparison between the two groups as a whole revealed no significant differences on any measure , both treatments being associated with a significant reduction in the severity of psychological , somatic and vasomotor symptoms , and with a significant improvement in sexual interest and responsiveness . Similar effects were also observed in patients who denied , pretreatment , any concurrent dyspareunia . Although it is not possible to identify the reasons for change , the results indicate no advantages of supplementary testosterone administration over oestradiol alone for sexually unresponsive postmenopausal women",
"OBJECTIVE To assess the efficacy and safety of a 300 mug/d testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women on concomitant estrogen therapy . METHODS Five hundred thirty-three women with hypoactive sexual desire disorder who had undergone previous hysterectomy and bilateral oophorectomy were enrolled in a 24-week , multicenter , double-blind , placebo-controlled trial . Patients were r and omly assigned to receive placebo or the testosterone patch twice weekly . The primary efficacy endpoint was change from baseline at week 24 in the frequency of total satisfying sexual activity , measured by the Sexual Activity Log . Secondary measures included sexual desire using the Profile of Female Sexual Function and personal distress as measured by the Personal Distress Scale . Hormone levels , adverse events , and clinical laboratory measures were review ed . RESULTS Total satisfying sexual activity significantly improved in the testosterone patch group compared with placebo after 24 weeks ( mean change from baseline , 1.56 compared with 0.73 episodes per 4 weeks , P = .001 ) . Treatment with the testosterone patch also significantly improved sexual desire ( mean change , 10.57 compared with 4.29 , P personal distress ( P = .009 ) . Serum free , total , and bioavailable testosterone concentrations increased from baseline . Overall , adverse events were similar in both groups ( P > .05 ) . The incidence of and rogenic adverse events was higher in the testosterone group ; most and rogenic adverse events were mild . CONCLUSION In surgically menopausal women with hypoactive sexual desire disorder , a 300 mug/d testosterone patch significantly increased satisfying sexual activity and sexual desire , while decreasing personal distress , and was well tolerated through up to 24 weeks of use",
"OBJECTIVES The primary objective of this study was to assess the effect of a 6-month testosterone supplementation therapy on functional capacity and insulin resistance in female patients with chronic heart failure ( CHF ) . BACKGROUND Patients with CHF show decreased exercise capacity and insulin sensitivity . Testosterone supplementation improves these variables in men with CHF . No study has evaluated the effects of testosterone supplementation on female patients with CHF . METHODS Thirty-six elderly female patients with stable CHF , ( ejection fraction 32.9 ± 6 ) were r and omly assigned ( 2:1 ratio ) to receive testosterone transdermal patch ( T group , n = 24 ) or placebo ( P group , n = 12 ) , both on top of optimal medical therapy . At baseline and after 6 months , patients underwent 6-min walking test ( 6MWT ) , cardiopulmonary exercise test , echocardiogram , quadriceps maximal isometric voluntary contraction , dynamic quadriceps isokinetic strength ( peak torque ) , and insulin resistance assessment by homeostasis model . RESULTS Distance walked at 6MWT as well as peak oxygen consumption significantly improved in the T group , whereas they were unchanged in the P group ( p comparisons ) . The homeostasis model was significantly reduced in the T group in comparison with the P group ( -16.5 % vs. + 5 % , respectively ; p increased significantly in the T group but did not change in the P group . Increase in distance walked at 6MWT was related to the increase in free testosterone levels ( r = 0.593 , p = 0.01 ) . No significant changes in echocardiographic parameters were observed in either group . No side effects requiring discontinuation of T were detected . CONCLUSIONS Testosterone supplementation improves functional capacity , insulin resistance , and muscle strength in women with advanced CHF . Testosterone seems to be an effective and safe therapy for elderly women with CHF",
"Objective : Testosterone insufficiency has been associated with psychosexual problems , reduced psychological well-being , and negative metabolic consequences , whereas less is known about the effects on cognition . The aim of this study was to investigate the effect of adding testosterone to estrogen therapy on memory functions in oophorectomized women . Methods : In a r and omized , double-blind , placebo-controlled design , women with surgically induced menopause ( n = 50 ; mean [ SD ] age , 54.0 [ 2.9 ] y ) received estradiol valerate in combination with testosterone undecanoate or placebo . The women were assessed with a self-report question naire regarding memory and neuropsychological tests for verbal and spatial episodic memory and incidental learning at baseline , at the time of crossover , and after completion of treatment . Results : Testosterone undecanoate 40 mg added to estrogen therapy had a negative effect on immediate but not delayed verbal memory at 24 weeks . Subjective and objective memory showed some correspondence as the women in the estrogen + placebo treatment group rated decreased everyday memory problems at 24 weeks compared with baseline . This was not observed in the women in the estrogen + testosterone treatment . Verbal attention span deteriorated from baseline with estrogen + placebo treatment but not with the estrogen + testosterone treatment . However , there was no significant treatment effect between the two groups . Conclusions : Adding testosterone to estrogen treatment deteriorated immediate verbal memory compared with estrogen + placebo , while other memory functions were unaffected",
"Objective To evaluate the effect of the addition of methyltestosterone to estrogen and progestogen therapy on postmenopausal sexual energy and orgasm . Methods Sixty postmenopausal women in a stable relationship with a partner capable of intercourse , and presenting sexual complaints that appeared after menopause , were r and omly divided into two groups : EP ( n = 29 ) received one tablet of equine estrogens ( CEE ) 0.625 mg plus medroxyprogesterone acetate ( MPA ) 2.5 mg and one capsule of placebo ; EP + A ( n = 31 ) received one tablet of CEE 0.625 mg plus MPA 2.5 mg and one capsule of methyltestosterone 2.0 mg ; The treatment period was 12 months . The effects of treatment on sexual energy were assessed using the Sexual Energy Change Scale . The ability to reach orgasm in sexual relations with the partner was verified through monthly calendars and by calculating the ratio between monthly frequency of orgasms in sexual relations and monthly sexual frequency . Results There was a significant relationship between improvement in level of sexual energy and the addition of methyltestosterone to CEE/MPA treatment ( p = 0.021 ) . No significant effect on orgasmic capacity was noted after the treatment period . Conclusion Addition of methyltestosterone to CEE/MPA therapy may increase sexual energy , but might not affect the ability to obtain orgasm in sexual relations",
"INTRODUCTION A significant number of postmenopausal women suffer from distressing problems because of urogenital atrophy secondary to the decline in circulating estrogen levels . Treatment with topical hormones may provide relief in such women when used judiciously . AIM To study the effects of local estrogen with or without local testosterone on urogenital and sexual health in postmenopausal women . METHODS Seventy-five postmenopausal women symptomatic for urogenital atrophy and sexual dysfunction were r and omly divided into two study groups and one control group . The women in study group 1 received local estrogen cream ; study group 2 received local estrogen and testosterone cream ; the control group received nonhormonal lubricant KY gel for 12 weeks . The urogenital and sexuality score , along with the vaginal health index and the vaginal maturation index ( VMI ) , was calculated at the beginning of therapy and 12 weeks later . MAIN OUTCOME MEASURES Changes in the urogenital and sexuality score along with vaginal health index and VMI . RESULTS After 12 weeks of therapy , there was a significant improvement in all the four study parameters , which correlated well with the improvement in symptoms of urogenital atrophy and sexual dysfunction in both the study groups as compared with the control group . Improvement in sexuality score was greatest with combined estrogen- and rogen therapy . There were no adverse effects and the therapies were well accepted without any compliance issue . CONCLUSION Local estrogen either alone or with and rogen is highly effective in relieving symptoms of urogenital atrophy and in improving sexual function in symptomatic postmenopausal women",
"INTRODUCTION Female libido is multifactorial and complex . Declining estrogen levels in postmenopausal women affects vaginal function . AIM The aim of this study was to evaluate female sexual function after using topical estrogen , testosterone , or polyacrylic acid as vaginal lubricants with K-Y jelly as a placebo lubricant . METHODS This was a r and omized controlled clinical trial on 80 postmenopausal women between 40 and 70 years of age with follow-up at the Menopause Clinic of the CAISM Unicamp . The women were r and omized to treatment with topical vaginal estrogen , testosterone , polyacrylic acid , or oil lubricant alone , three times a week for a period of 12 weeks from November 2011 to January 2013 . MAIN OUTCOME MEASURE We used the Female Sexual Function Index ( FSFI ) to assess changes in sexual response at baseline , and after 6 and 12 weeks . RESULTS After 12 weeks of treatment , polyacrylic acid and topical testosterone produced improvements in the FSFI domains of sexual desire , lubrication , satisfaction , reduced pain during intercourse , and total score compared with lubricant alone . Treatment with topical estrogen in comparison with lubricant alone showed an improvement in the FSFI field of desire . The intragroup analysis over the time of the treatment showed improvements in the fields of desire , lubrication , and reduced pain for polyacrylic acid , testosterone , and estrogen . Furthermore , women who used testosterone showed improvements over time in the fields of arousal , orgasm , and satisfaction . CONCLUSIONS Treatment of postmenopausal women with symptoms of vaginal atrophy with polyacrylic acid , testosterone , and estrogen for 12 weeks produced improvements in self-reported female sexual function when compared with a placebo lubricant "
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BACKGROUND Approximately 188 million people use cannabis yearly worldwide , and it has recently been legalised in 11 US states , Canada , and Uruguay for recreational use . The potential for increased cannabis use highlights the need to better underst and its risks , including the acute induction of psychotic and other psychiatric symptoms . We aim ed to investigate the effect of the cannabis constituent Δ9-tetrahydrocannabinol ( THC ) alone and in combination with cannabidiol ( CBD ) compared with placebo on psychiatric symptoms in healthy people . METHODS In this systematic review and meta- analysis , we search ed MEDLINE , Embase , and PsycINFO for studies published in English between data base inception and May 21 , 2019 , with a within-person , crossover design . Inclusion criteria were studies reporting symptoms using psychiatric scales ( the Brief Psychiatric Rating Scale [ BPRS ] and the Positive and Negative Syndrome Scale [ PANSS ] ) following the acute administration of intravenous , oral , or nasal THC , CBD , and placebo in healthy participants , and presenting data that allowed calculation of st and ardised mean change ( SMC ) scores for positive ( including delusions and hallucinations ) , negative ( such as blunted affect and amotivation ) , and general ( including depression and anxiety ) symptoms . We did a r and om-effects meta- analysis to assess the main outcomes of the effect sizes for total , positive , and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo . Because the number of studies to do a meta- analysis on CBD 's moderating effects was insufficient , this outcome was only systematic ally review ed . This study is registered with PROSPERO , CRD42019136674 . FINDINGS 15 eligible studies involving the acute administration of THC and four studies on CBD plus THC administration were identified . Compared with placebo , THC significantly increased total symptom severity with a large effect size ( assessed in nine studies , with ten independent sample s , involving 196 participants : SMC 1·10 [ 95 % CI 0·92 - 1·28 ] , p ) ; positive symptom severity ( assessed in 14 studies , with 15 independent sample s , involving 324 participants : SMC 0·91 [ 95 % CI 0·68 - 1·14 ] , p with a large effect size ( assessed in 12 studies , with 13 independent sample s , involving 267 participants : SMC 0·78 [ 95 % CI 0·59 - 0·97 ] , p CBD 's effects on THC-induced symptoms , only one identified a significant reduction in symptoms . INTERPRETATION A single THC administration induces psychotic , negative , and other psychiatric symptoms with large effect sizes . There is no consistent evidence that CBD induces symptoms or moderates the effects of THC . These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purpose s. FUNDING UK Medical Research Council , Maudsley Charity , Brain and Behavior Research Foundation , Wellcome Trust , and the UK National Institute for Health Research
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"OBJECTIVE Research in both animals and humans indicates that cannabidiol ( CBD ) has antipsychotic properties . The authors assessed the safety and effectiveness of CBD in patients with schizophrenia . METHOD In an exploratory double-blind parallel-group trial , patients with schizophrenia were r and omized in a 1:1 ratio to receive CBD ( 1000 mg/day ; N=43 ) or placebo ( N=45 ) alongside their existing antipsychotic medication . Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale ( PANSS ) , the Brief Assessment of Cognition in Schizophrenia ( BACS ) , the Global Assessment of Functioning scale ( GAF ) , and the improvement and severity scales of the Clinical Global Impressions Scale ( CGI-I and CGI-S ) . RESULTS After 6 weeks of treatment , compared with the placebo group , the CBD group had lower levels of positive psychotic symptoms ( PANSS : treatment difference=-1.4 , 95 % CI=-2.5 , -0.2 ) and were more likely to have been rated as improved ( CGI-I : treatment difference=-0.5 , 95 % CI=-0.8 , -0.1 ) and as not severely unwell ( CGI-S : treatment difference=-0.3 , 95 % CI=-0.5 , 0.0 ) by the treating clinician . Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance ( BACS : treatment difference=1.31 , 95 % CI=-0.10 , 2.72 ) and in overall functioning ( GAF : treatment difference=3.0 , 95 % CI=-0.4 , 6.4 ) . CBD was well tolerated , and rates of adverse events were similar between the CBD and placebo groups . CONCLUSIONS These findings suggest that CBD has beneficial effects in patients with schizophrenia . As CBD 's effects do not appear to depend on dopamine receptor antagonism , this agent may represent a new class of treatment for the disorder",
"Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans . However , the neural correlates of these deficits have remained elusive . The current study examined the acute , dose-related effects of delta-9-tetrahydrocannabinol ( Δ9-THC ) on psychophysiological indices of information processing in humans . Healthy subjects ( n=26 ) completed three test days during which they received intravenous Δ9-THC ( placebo , 0.015 and 0.03 mg/kg ) in a within-subject , double-blind , r and omized , cross-over , and counterbalanced design . Psychophysiological data ( electroencephalography ) were collected before and after drug administration while subjects engaged in an event-related potential ( ERP ) task known to be a valid index of attention and cognition ( a three-stimulus auditory ‘ oddball ’ P300 task ) . Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a . Δ9-THC did not have any effect on the latency of either the P300a or P300b , or on early sensory-evoked ERP components preceding the P300 ( the N100 ) . Concomitantly , Δ9-THC induced psychotomimetic effects , perceptual alterations , and subjective ‘ high ’ in a dose-dependent manner . Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations . Lastly , exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC , there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users . Overall , these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis , Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs . Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention , while leaving processing speed and earlier sensory ERP components intact . Collectively , the findings suggest that CB1R systems modulate top-down and bottom-up processing",
"CONTEXT Cannabis use can both increase and reduce anxiety in humans . The neurophysiological substrates of these effects are unknown . OBJECTIVE To investigate the effects of 2 main psychoactive constituents of Cannabis sativa ( Delta9-tetrahydrocannabinol [ Delta9-THC ] and cannabidiol [ CBD ] ) on regional brain function during emotional processing . DESIGN Subjects were studied on 3 separate occasions using an event-related functional magnetic resonance imaging paradigm while viewing faces that implicitly elicited different levels of anxiety . Each scanning session was preceded by the ingestion of either 10 mg of Delta9-THC , 600 mg of CBD , or a placebo in a double-blind , r and omized , placebo-controlled design . PARTICIPANTS Fifteen healthy , English-native , right-h and ed men who had used cannabis 15 times or less in their life . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygenation level-dependent response ) , electrodermal activity ( skin conductance response [ SCR ] ) , and objective and subjective ratings of anxiety . RESULTS Delta9-Tetrahydrocannabinol increased anxiety , as well as levels of intoxication , sedation , and psychotic symptoms , whereas there was a trend for a reduction in anxiety following administration of CBD . The number of SCR fluctuations during the processing of intensely fearful faces increased following administration of Delta9-THC but decreased following administration of CBD . Cannabidiol attenuated the blood oxygenation level-dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing intensely fearful faces , and its suppression of the amygdalar and anterior cingulate responses was correlated with the concurrent reduction in SCR fluctuations . Delta9-Tetrahydrocannabinol mainly modulated activation in frontal and parietal areas . CONCLUSIONS Delta9-Tetrahydrocannabinol and CBD had clearly distinct effects on the neural , electrodermal , and symptomatic response to fearful faces . The effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety , whereas the anxiogenic effects of Delta9-THC may be related to effects in other brain regions",
"Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol ( THC ) but low in cannabidiol ( CBD ) are particularly hazardous for mental health . Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form , under controlled conditions . In a between-subjects design , we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment . Healthy participants were r and omised to receive oral CBD 600 mg ( n=22 ) or placebo ( n=26 ) , 210 min ahead of intravenous ( IV ) THC ( 1.5 mg ) . Post-THC , there were lower PANSS positive scores in the CBD group , but this did not reach statistical significance . However , clinical ly significant positive psychotic symptoms ( defined a priori as increases ≥3 points ) were less likely in the CBD group compared with the placebo group , odds ratio (OR)=0.22 ( χ2=4.74 , p , post-THC paranoia , as rated with the State Social Paranoia Scale ( SSPS ) , was less in the CBD group compared with the placebo group ( t=2.28 , p , indexed by scores on the Hopkins Verbal Learning Task-revised ( HVLT-R ) , was poorer , relative to baseline , in the placebo pre-treated group ( -10.6±18.9 % ) compared with the CBD group ( -0.4%±9.7 % ) ( t=2.39 , p high-THC/low-CBD cannabis products are associated with increased risks for mental health ",
"Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more",
"Recent advances in the underst and ing of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis . In a 3-day , double-blind , r and omized , and counterbalanced study , the behavioral , cognitive , and endocrine effects of 0 , 2.5 , and 5 mg intravenous delta-9-tetrahydrocannabinol ( Δ-9-THC ) were characterized in 22 healthy individuals , who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder . Prospect i ve safety data at 1 , 3 , and 6 months post study was also collected . Δ-9-THC ( 1 ) produced schizophrenia-like positive and negative symptoms ; ( 2 ) altered perception ; ( 3 ) increased anxiety ; ( 4 ) produced euphoria ; ( 5 ) disrupted immediate and delayed word recall , sparing recognition recall ; ( 6 ) impaired performance on tests of distractibility , verbal fluency , and working memory ( 7 ) did not impair orientation ; ( 8) increased plasma cortisol . These data indicate that Δ-9-THC produces a broad range of transient symptoms , behaviors , and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses . These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders",
"CONTEXT Cannabis sativa use can impair verbal learning , provoke acute psychosis , and increase the risk of schizophrenia . It is unclear where C. sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms . OBJECTIVES To investigate the effects of 2 main psychoactive constituents of C. sativa , Delta9-tetrahydrocannabinol ( Delta9-THC ) and cannabidiol , on regional brain function during verbal paired associate learning . DESIGN Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task . Each imaging session was preceded by the ingestion of Delta9-THC ( 10 mg ) , cannabidiol ( 600 mg ) , or placebo in a double-blind , r and omized , placebo-controlled , repeated- measures , within-subject design . SETTING University research center . PARTICIPANTS Fifteen healthy , native English-speaking , right-h and ed men of white race/ethnicity who had used C. sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygen level-dependent response ) , performance in a verbal learning task , and objective and subjective ratings of psychotic symptoms , anxiety , intoxication , and sedation . RESULTS Delta9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety , intoxication , and sedation , whereas no significant effect was noted on these parameters following administration of cannabidiol . Performance in the verbal learning task was not significantly modulated by either drug . Administration of Delta9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident . Delta9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs , which was directly correlated with concurrently induced psychotic symptoms . In contrast , administration of cannabidiol had no such effect . CONCLUSION The modulation of mediotemporal and ventrostriatal function by Delta9-THC may underlie the effects of C. sativa on verbal learning and psychotic symptoms , respectively",
"Although a wealth of pre clinical evidence indicates an interplay between the μ-opioid ( MOR ) and cannabinoid 1 receptor ( CB1R ) systems , the precise nature of the cross modulation in humans is unclear . The objective of this study was to evaluate the effects of pretreatment with the MOR antagonist , naltrexone , on the subjective , behavioural and cognitive effects of the CB1R agonist , Δ9-tetrahydrocannabinol ( THC ) , in healthy human subjects . Healthy human subjects , screened carefully for any medical or psychiatric illness , were administered either placebo or active naltrexone ( 25 mg ) orally on each test day , followed 45 min later by placebo and 165 min later by active i.v . THC ( 0.025 mg/kg ) in a r and omized , fixed-order , double-blind manner . Subjective , behavioural and cognitive effects were assessed before and at several points after each drug administration . THC produced expected effects , including euphoria , anxiety , transient perceptual alterations , transient psychotomimetic effects and cognitive impairments . However , naltrexone did not produce any effects alone , nor did it attenuate any of THC 's effects . Thus , in healthy human subjects who use cannabis intermittently , MOR antagonism does not modulate the common acute subjective , behavioural and cognitive effects of THC",
"Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis . Delta-9-Tetrahydrocannabinol ( Δ-9-THC ) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals . Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established . In a 3-day , double-blind , r and omized , placebo-controlled study , the dose-related effects of 0 , 2.5 , and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls . Δ-9-THC ( 1 ) produced transient psychotomimetic effects and perceptual alterations ; ( 2 ) impaired memory and attention ; ( 3 ) increased subjective effects of ‘ high ’ ; ( 4 ) produced tachycardia ; and ( 5 ) increased serum cortisol in both groups . However , relative to controls , frequent users showed blunted responses to the psychotomimetic , perceptual altering , cognitive impairing , anxiogenic , and cortisol increasing effects of Δ-9-THC but not to its euphoric effects . Frequent users also had lower prolactin levels . These data suggest that frequent users of cannabis are either inherently blunted in their response to , and /or develop tolerance to the psychotomimetic , perceptual altering , amnestic , endocrine , and other effects of cannabinoids",
"Δ9-Tetrahydrocannabinol ( THC ) produces transient psychomimetic effects in healthy volunteers , constituting a pharmacological model for psychosis . The dopaminergic antagonist haloperidol has previously been shown to reduce these effects . This placebo-controlled , cross-over study in 49 healthy , male , mild cannabis users aim ed to further explore this model by examining the effect of a single oral dose of olanzapine ( with dopaminergic , serotonergic , adrenergic , muscarinergic and histaminergic properties ) or two oral doses of diphenhydramine ( histamine antagonist ) on the effects of intrapulmonarily administered THC . Transient psychomimetic symptoms were seen after THC administration , as measured on the positive and negative syndrome scale ( 20.6 % increase on positive subscale , p visual analogue scale for psychedelic effects ( increase of 10.7 mm on feeling high ) . Following the combination of THC and olanzapine , the positive subscale increased by only 13.7 % and feeling high by only 8.7 mm . This reduction of THC effects on the positive subscale failed to reach statistical significance ( p=0.066 ) . However , one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone . Within responders , olanzapine reduced the effects of THC on the positive subscale ( p=0.005 ) . Other outcome measures included pharmacokinetics , eye movements , postural stability , pupil/iris ratio , and serum concentrations of cortisol and prolactin",
"Intravenous ( IV ) Δ9-tetrahydrocannabinol ( THC ) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients , but the psychotomimetic mechanism is unknown . One possibility is that THC stimulates dopamine ( DA ) release in the striatum . In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo . We also investigated whether DA release and positive psychotic symptoms were related . Eleven healthy male volunteers completed two 123I-iodobenzamide ( [123I]IBZM ) single photon emission tomography ( SPET ) sessions and received IV THC ( 2.5 mg ) or placebo in a r and omized counterbalanced order , under double-blind conditions . Analysable data were obtained from nine participants . The Positive and Negative Syndrome Scale ( PANSS ) was used to rate psychotomimetic effects . Striatal binding index values were calculated using the occipital cortex as a reference region . Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC . There were no significant differences in binding index in the cau date or putamen under THC compared to placebo conditions . Positive psychotic symptoms and DA release were unrelated . THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms . These findings do not support a central role for striatal DA in THC-elicited psychosis",
"The main active ingredient in cannabis , delta-9-tetrahydrocannabinol ( THC ) , can acutely induce psychotic symptoms and impair episodic and working memory . Another major constituent , cannabidiol ( CBD ) , may attenuate these effects . This study aim ed to determine the effects of THC and CBD , both alone and in combination on psychotic symptoms and memory function . A r and omised , double-blind crossover design compared the effects of ( i ) placebo , ( ii ) THC 8 mg , ( iii ) CBD 16 mg and ( iv ) THC 8 mg + CBD 16 mg administered by inhalation through a vaporiser . Using an experimental medicine approach to predict treatment sensitivity , we selected 48 cannabis users from the community on the basis of ( 1 ) schizotypal personality question naire scores ( low , high ) and ( 2 ) frequency of cannabis use ( light , heavy ) . The Brief Psychiatric Rating Scale ( BPRS ) , Psychotomimetic States Inventory ( PSI ) , immediate and delayed prose recall ( episodic memory ) , 1- and 2-back ( working memory ) were assessed on each day . Results indicated that THC increased overall scores on the PSI , negative symptoms on BPRS , and robustly impaired episodic and working memory . Co-administration of CBD did not attenuate these effects . CBD alone reduced PSI scores in light users only . At a ratio of 2:1 , CBD does not attenuate the acute psychotic and memory impairing effects of vaporised THC . Frequent cannabis users may show a blunted anti- psychotic response to CBD , which is of concern due to the high rates of cannabis use disorders in patients with schizophrenia"
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4117c6f2-06ff-11f0-808a-c43d1ab1c353
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Background Online question naires for measuring common mental health disorders such as depression and anxiety disorders are increasingly used . The psychometrics of several pen- and -paper question naires have been re-examined for online use and new online instruments have been developed and tested for validity as well . This study aims to review and synthesis e the literature on this subject and provide a framework for future research . Methods We search ed Medline and PsycINFO for psychometric studies on online instruments for common mental health disorders and extracted the psychometric data . Studies were coded and assessed for quality by independent raters . Results We included 56 studies on 62 online instruments . For common instruments such as the CES-D , MADRS-S and HADS there is mounting evidence for adequate psychometric properties . Further results are scattered over different instruments and different psychometric characteristics . Few studies included patient population s. Conclusions We found at least one online measure for each of the included mental health disorders and symptoms . A small number of online question naires have been studied thoroughly . This study provides an overview of online instruments to refer to when choosing an instrument for assessing common mental health disorders online , and can structure future psychometric research
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[
"Background The COSMIN checklist is a tool for evaluating the method ological quality of studies on measurement properties of health-related patient-reported outcomes . The aim of this study is to determine the inter-rater agreement and reliability of each item score of the COSMIN checklist ( n = 114 ) . Methods 75 articles evaluating measurement properties were r and omly selected from the bibliographic data base compiled by the Patient-Reported Outcome Measurement Group , Oxford , UK . Raters were asked to assess the method ological quality of three articles , using the COSMIN checklist . In a one-way design , percentage agreement and intraclass kappa coefficients or quadratic-weighted kappa coefficients were calculated for each item . Results 88 raters participated . Of the 75 selected articles , 26 articles were rated by four to six participants , and 49 by two or three participants . Overall , percentage agreement was appropriate ( 68 % was above 80 % agreement ) , and the kappa coefficients for the COSMIN items were low ( 61 % was below 0.40 , 6 % was above 0.75 ) . Reasons for low inter-rater agreement were need for subjective judgement , and accustom to different st and ards , terminology and definitions . Conclusions Results indicated that raters often choose the same response option , but that it is difficult on item level to distinguish between articles . When using the COSMIN checklist in a systematic review , we recommend getting some training and experience , completing it by two independent raters , and reaching consensus on one final rating . Instructions for using the checklist are improved",
"Introduction Despite welcomed changes in societal attitudes and practice s towards sexual minorities , instances of heteronormativity can still be found within healthcare and research . The Social Interaction Anxiety Scale ( SIAS ) is a valid and reliable self-rating scale of social anxiety , which includes one item ( number 14 ) with an explicit heteronormative assumption about the respondent´s sexual orientation . This heteronormative phrasing may confuse , insult or alienate sexual minority respondents . A clinical ly vali date d version of the SIAS featuring a non-heteronormative phrasing of item 14 is thus needed . Methods 129 participants with diagnosed social anxiety disorder , enrolled in an Internet-based intervention trial , were r and omly assigned to responding to the SIAS featuring either the original or a novel non-heteronormative phrasing of item 14 , and then answered the other item version . Within-subject , correlation between item versions was calculated and the two scores were statistically compared . The two items ’ correlations with the other SIAS items and other psychiatric rating scales were also statistically compared . Results Item versions were highly correlated and scores did not differ statistically . The two items ’ correlations with other measures did not differ statistically either . Conclusions The SIAS can be revised with a non-heteronormative formulation of item 14 with psychometric equivalence on item and scale level . Implication s for other psychiatric instruments with heteronormative phrasings are discussed",
"Background When evaluating hearing rehabilitation , it is reasonable to use self-report question naires as outcome measure . Question naires used in audiological research are developed and vali date d for the paper- and -pencil format . As computer and Internet use is increasing , st and ardized question naires used in the audiological context should be evaluated to determine the viability of the online administration format . The aim of this study was to compare administration of question naires online versus paper- and pencil of four st and ardised question naires used in hearing research and clinic . We included the Hearing H and icap Inventory for the Elderly ( HHIE ) , the International Outcome Inventory for Hearing Aids ( IOI-HA ) , Satisfaction with Amplification in Daily Life ( SADL ) , and the Hospital Anxiety and Depression Scale ( HADS ) . Methods A cross-over design was used by r and omly letting the participants complete the question naires either online or on paper . After 3 weeks the participants filled out the same question naires again but in the other format . A total of 65 hearing-aid users were recruited from a hearing clinic to participate on a voluntary basis and of these 53 completed both versions of the question naires . Results A significant main effect of format was found on the HHIE ( p interaction effect . For the other question naires were no significant main or interaction effects of format . Significant correlations between the two ways of presenting the measures was found for all question naires ( p showed Cronbachs α ’s above .70 for all four question naires and differences in Cronbachs α between administration formats were negligible . Conclusions For three of the four included question naires the participants ’ scores remained consistent across administrations and formats . For the fourth included question naire ( HHIE ) a significant difference of format with a small effect size was found . The relevance of the difference in scores between the formats depends on which context the question naire is used in . On balance , it is recommended that the administration format remain stable across assessment points",
"Background Semi-structured interview scales for psychosis are the gold st and ard approach to assessing psychotic and other symptoms . However , such assessment s have limitations such as recall bias , averaging , insensitivity to change and variable interrater reliability . Ambulant , real-time self-report assessment devices may hold advantages over interview measures , but it needs to be shown that the data thus collected are valid , and the collection method is acceptable , feasible and safe . We report on a monitoring system for the assessment of psychosis using smartphone technology . The primary aims were to : i ) assess validity through correlations of item responses with those on widely accepted interview assessment s of psychosis , and ii ) examine compliance to the procedure in individuals with psychosis of varying severity . Methods A total of 44 participants ( acute or remitted DSM-4 schizophrenia and related disorders , and prodromal ) completed 14 branching self-report items concerning key psychotic symptoms on a touch-screen mobile phone when prompted by an alarm at six pseudo-r and om times , each day , for one week . Face to face PANSS and CDS interviews were conducted before and after the assessment period blind to the ambulant data . Results Compliance as defined by completion of at least 33 % of all possible data -points over seven days was 82 % . In the 36 compliant participants , 5 items ( delusions , hallucinations , suspiciousness , anxiety , hopelessness ) showed moderate to strong ( rho 0.6 - 0.8 ) associations with corresponding items from interview rating scales . Four items showed no significant correlation with rating scales : each was an item based on observable behaviour . Ambulant ratings showed excellent test-retest reliability and sensitivity to change . Conclusions Ambulatory monitoring of symptoms several times daily using smartphone software applications represents a feasible and valid way of assessing psychotic phenomena for research and clinical management purpose s. Further evaluation required over longer assessment periods , in clinical trials and service setting",
"Objectives For the measurement of patient-reported outcomes , such as ( health-related ) quality of life , often many measurement instruments exist that intend to measure the same construct . To facilitate instrument selection , our aim was to develop a highly sensitive search filter for finding studies on measurement properties of measurement instruments in PubMed and a more precise search filter that needs less abstract s to be screened , but at a higher risk of missing relevant studies . Methods A r and om sample of 10,000 PubMed records ( 01 - 01 - 1990 to 31 - 12 - 2006 ) was used as a gold st and ard . Studies on measurement properties were identified using an exclusion filter and h and search ing . Search terms were selected from the relevant records in the gold st and ard as well as from 100 systematic review s of measurement properties and combined based on sensitivity and precision . The performance of the filters was tested in the gold st and ard as well as in two validation sets , by calculating sensitivity , precision , specificity , and number needed to read . Results We identified 116 studies on measurement properties in the gold st and ard . The sensitive search filter was able to retrieve 113 of these 116 studies ( sensitivity 97.4 % , precision 4.4 % ) . The precise search filter had a sensitivity of 93.1 % and a precision of 9.4 % . Both filters performed very well in the validation sets . Conclusion The use of these search filters will contribute to evidence -based selection of measurement instruments in all medical fields",
"This study examines whether the Internet-based question naire is psychometrically equivalent to the paper-based question naire . A r and om sample of 2,400 teachers in Taiwan was divided into experimental and control groups . The experimental group was invited to complete the electronic form of the Chinese version of Center for Epidemiologic Studies Depression Scale ( CES-D ) placed on the Internet , whereas the control group was invited to complete the paper-based CES-D , which they received by mail . The multi sample invariance approach , derived from structural equation modeling ( SEM ) , was applied to analyze the collected data . The analytical results show that the two groups have equivalent factor structures in the CES-D. That is , the items in CES-D function equivalently in the two groups . Then the e quality of latent mean test was performed . The latent means of \" depressed mood , \" \" positive affect , \" and \" interpersonal problems \" in CES-D are not significantly different between these two groups . However , the difference in the \" somatic symptoms \" latent means between these two groups is statistically significant at alpha = 0.01 . But the Cohen 's d statistics indicates that such differences in latent means do not apparently lead to a meaningful effect size in practice . Both CES-D question naires exhibit equal validity , reliability , and factor structures and exhibit a little difference in latent means . Therefore , the Internet-based question naire represents a promising alternative to the paper-based question naire",
"Background The majority of Internet-mediated studies use measures developed as paper- and -pencil measures or face-to-face-delivered material . Previous research suggests that the equivalence between online and offline measures must be demonstrated rather than assumed . Objective The objective of this study was to explore the equivalence 4 measures completed in an online or offline setting . Methods A sample of students ( n = 1969 ) was r and omly assigned to complete 4 popular scales ( the SF-12v2 , the Hospital Anxiety and Depression Scale ( HADS ) , the Fatigue Symptom Inventory , and a single-item fatigue measure ) either online or by mail survey ( pencil and paper ) . The response rate was 52.51 % ( n = 1034 ) and comparable between the online and offline groups . Results Significant differences were noted in fatigue levels between the online and offline group ( P = .01 ) as measured by the Fatigue Symptom Inventory , with the online sample demonstrating higher levels of fatigue . Equivalency was noted for the SF-12v2 , the Hospital Anxiety and Depression Scale , and the single-item fatigue measure . Internal consistency was high except for the SF-12v2 . The SF-12v2 may not be an ideal measure to use for remote administration . Conclusions Equivalency of the Hospital Anxiety and Depression Scale ( HADS ) and the Physical Component Score and Mental Component Score of the SF-12v2 for online and offline data were demonstrated . Equivalency was not demonstrated for the Fatigue Symptom Inventory . Explanations for the difference in fatigue score between the online and offline sample s are unclear . Research that seeks to match sample s and control for extraneous online and offline variables is called for , along with exploration of factors that may mediate the completion of question naires or alter the respondents ’ relationship with the same , to enhance progress in this area",
"Background Self-report measures can guide clinical decisions and are useful when evaluating treatment outcomes . However , many clinicians do not use self-report measures systematic ally in their clinical practice . Internet-based question naires could facilitate administration , but the psychometric properties of the online version of an instrument should be explored before implementation . The recommendation from the International Test Commission is to test the psychometric properties of each question naire separately . Objective Our objective was to compare the psychometric properties of paper- and -pencil versions and Internet versions of two question naires measuring depressive symptoms . Methods The 87 participating patients were recruited from primary care and psychiatric care within the public health care system in Sweden . Participants completed the Beck Depression Inventory ( BDI-II ) and the Montgomery-Åsberg Depression Rating Scale — Self-rated ( MADRS-S ) , both on paper and on the Internet . The order was r and omized to control for order effects . Symptom severity in the sample ranged from mild to severe depressive symptoms . Results Psychometric properties of the two administration formats were mostly equivalent . The internal consistency was similar for the Internet and paper versions , and significant correlations were found between the formats for both MADRS-S ( r = .84 ) and the BDI-II ( r = .89 ) . Differences between paper and Internet total scores were not statistically significant for either question naire nor for the MADRS-S question dealing with suicidality ( item 9 ) when analyzed separately . The score on the BDI-II question about suicidality ( item 9 ) was significantly lower when administered via the Internet compared with the paper score , but the difference was small ( effect size , Cohen ’s [ d ] = 0.14 ) . There were significant main effects for order of administration on both question naires and significant interaction effects between format and order . This should not , however , pose a problem in clinical use as long as the administration format is not changed when repeated measurements are made . Conclusions The MADRS-S can be transferred to online use without affecting the psychometric properties in a clinical ly meaningful way . The full BDI-II also seems to retain its properties when transferred ; however , the item measuring suicidality in the Internet version needs further investigation since it was associated with a lower score in this study . The use of online question naires offers clinicians a more practical way of measuring depressive symptoms and has the potential to save re sources"
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4117c72e-06ff-11f0-808a-c43d1ab1c353
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Abstract Probiotics are increasingly being used to treat and prevent urogenital infections . However , a critical assessment of their efficacy in major urogenital infections is lacking . We report the results of a systematic review to determine the efficacy of probiotics for prevention or treatment of three major urogenital infections : bacterial vaginosis , vulvovaginal c and idiasis , and urinary tract infection . Using multiple computeriz ed data bases , we extracted data from clinical trials using a lactobacillus-containing preparation to either prevent or treat a urogenital infection . Of 25 included studies , 18 studies used lactobacillus preparations for treatment or prevention of urogenital infections and seven studies focused solely on vaginal colonization . Four studies included patients with vaginal c and idiasis , five included patients with urinary tract infections , and eight included patients with bacterial vaginosis . One included several types of genitourinary infections . Overall , lactobacilli were beneficial for the treatment of patients with bacterial vaginosis . No clear benefit was seen for c and idiasis or urinary tract infection . Studies were heterogenous , with some limited by a small population size . In conclusion , the use of certain lactobacillus strains such as L. rhamnosus GR-1 and L. reuteri for prevention and treatment of recurrent urogenital infection is promising , especially for recurrent bacterial vaginosis . Scant data on the use of probiotics for urinary tract infection and vulvovaginal c and idiasis precludes definitive recommendations . Further research and larger studies on types of lactobacilli strains , dosage of lactobacilli , optimal route and vehicle of administration are needed
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[
"Intermittent treatment with an acid lactate gel ( Lactal , ACO , Sweden ) reduced symptoms of bacterial vaginosis ( BV ) and promoted the reestablishment of the normal vaginal flora of lactobacilli . Forty-two women seriously affected by recurrent BV were initially given acid gel ( lactate gel , pH 3.8 , 5 ml ) to be inserted into the vagina daily for 7 consecutive days . Thereafter they entered into a double blind clinical trial and were treated prophylactically 3 days monthly for 6 months with either lactate gel or a placebo gel . Women treated with the lactate gel were clinical ly improved , i.e. no signs of BV in 88 % compared to 10 % in the placebo group ( p less than 0.001 ) . The vaginal lactobacilli flora was reestablished in 83 % of the lactate group and in 16 % of the placebo group . Local intermittent application of lactate gel was found to be free of side effects and is a preferable alternative to repeated treatments with antibiotics in patients with recurrent BV",
"Forty-one adult women with acute lower urinary tract infections ( UTI ) were r and omly treated for three days with norfloxacin or trimethoprim/sulfamethoxazole ( TMP/SMX ) . Infection was eradicated in 100 % of norfloxacin-treated patients and in 95 % of TMP/SMX-treated patients . UTI recurred in 29 % of patients treated with norfloxacin and in 41 % of those treated with TMP/SMX . Post-therapy vaginal administration of lactobacillus suppositories result ed in a recurrence rate of UTI of only 21 % , while in patients given sterilized skim-milk suppositories the recurrence rate was 47 % . This study indicates that lactobacillus vaginal suppositories are safe and may be effective in reducing the recurrence of UTI following antimicrobial therapy",
"Objective : The objective of this study was to determine why different criteria for response to treatment of bacterial vaginosis ( BV ) led to markedly different conclusions about treatment efficacy in a r and omized trial comparing metronidazole gel versus metronidazole/nystatin ovules . Study : We compared the impact of two treatment regimens on individual components of Amsel and Nugent criteria at follow-up visits 14 , 42 , and 104 days after initiating treatment . Results : Compared with gel , ovules more effectively eliminated amines , clue cells , and Gardnerella , Prevotella , or Mobiluncus morphotypes from vaginal fluid , thus achieving cure based on “ usual ” criteria ( absence of BV by Amsel or Nugent criteria ) , but did not more effectively restore Lactobacillus morphotypes or lower vaginal pH , thus not meeting Federal Drug Administration ( FDA ) criteria for cure . Conclusion : Because early vaginal recolonization by lactobacilli was poor after both gel and ovules , FDA draft criteria for cure missed marked differences in treatment efficacies against Gardnerella , clue cells , and amines . Cure defined more “ usually ” may give more useful information",
"60 women with bacterial vaginosis were entered into a double blind , placebo-controlled treatment trial with lyophilized Lactobacillus acidophilus . The lactobacilli used were producing H2O2 . Immediately after completion of treatment , 16 out of 28 women who were treated with lactobacilli had normal vaginal wet smear results , in comparison to none of the 29 women treated with placebo . All women harboured Bacteroides at inclusion . Bacteroides was eliminated from the vagina of 12 out of 16 healthy women after treatment . Only three of the women who received the Lactobacillus suppository were free of bacterial vaginosis after the subsequent menstruation",
"This study enrolled 125 premenopausal women diagnosed with bacterial vaginosis ( BV ) by presence of vaginal irritation , discharge and ' fishy ' odor , and Nugent criteria and detection of sialidase enzyme . The subjects were treated with oral metronidazole ( 500 mg ) twice daily from days 1 to 7 , and r and omized to receive oral Lactobacillus rhamnosus GR-1 ( 1 x 10(9 ) ) and Lactobacillus reuteri RC-14 ( 1 x 10(9 ) ) or placebo twice daily from days 1 to 30 . Primary outcome was cure of BV as determined by normal Nugent score , negative sialidase test and no symptoms or signs of BV at day 30 . A total of 106 subjects returned for 30-day follow-up , of which 88 % were cured in the antibiotic/probiotic group compared to 40 % in the antibiotic/placebo group ( p had BV , while 30 % in the placebo and 12 % in the probiotic group fell into the intermediate category based upon Nugent score , sialidase result and clinical findings . High counts of Lactobacillus sp. ( > 10(5 ) CFU/ml ) were recovered from the vagina of 96 % probiotic-treated subjects compared to 53 % controls at day 30 . In summary , this study showed efficacious use of lactobacilli and antibiotic in the eradication of BV in black African women",
"OBJECTIVE To assess whether daily ingestion of yogurt containing Lactobacillus acidophilus prevents vulvovaginal c and idal infections . DESIGN Crossover trial for at least 1 year during which patients were examined for c and idal infections and colonizations while receiving either a yogurt-free or a yogurt-containing diet . Patients served as their own controls . SETTING Ambulatory infectious disease center in a teaching hospital providing tertiary care . PATIENTS Thirty-three women with recurrent c and idal vaginitis were eligible after recruitment from community practice s and clinics and through advertising . Twelve patients were eliminated for protocol violations . Of the remaining 21 patients , 8 who were assigned to the yogurt arm initially refused to enter the control phase 6 months later . Thus , 13 patients completed the protocol . INTERVENTIONS Women ate yogurt for 6 months of the study period . MEASUREMENTS Colonization of lactobacilli and c and ida in the vagina and rectum ; c and idal infections of the vagina . MAIN RESULTS Thirty-three eligible patients were studied . A threefold decrease in infections was seen when patients consumed yogurt containing Lactobacillus acidophilus . The mean ( + /- SD ) number of infections per 6 months was 2.54 + /- 1.66 in the control arm and 0.38 + /- 0.51 per 6 months in the yogurt arm ( P = 0.001 ) . C and idal colonization decreased from a mean of 3.23 + /- 2.17 per 6 months in the control arm to 0.84 + /- 0.90 per 6 months in the yogurt arm ( P = 0.001 ) . CONCLUSION Daily ingestion of 8 ounces of yogurt containing Lactobacillus acidophilus decreased both c and idal colonization and infection",
"Probiotics , beneficial living microorganisms , have been proven to be effective in preventing gastrointestinal infections , but their effect in preventing urinary tract infection ( UTI ) is inconclusive . A prospect i ve r and omized controlled study was done to compare the preventive effect of probiotics with conventional antibiotics in children with persistent primary vesicoureteral reflux ( VUR ) . One hundred twenty children who had had persistent primary VUR after antibiotic prophylaxis for 1 year were r and omly allocated into a probiotics ( Lactobacillus acidophilus 108 CFU/g 1 g b.i.d . , n = 60 ) or an antibiotics ( trimethoprim/sulfamethoxazole 2/10 mg/kg h.s . , n = 60 ) prophylaxis group during the second year of follow-up . The incidence of recurrent UTI was 18.3 % ( 11/60 ) in the probiotics group , which was not different from 21.6%(13/60 ) in the antibiotic group ( P = 0.926 ) . The causative organisms of recurrent UTI were not significantly different between the two groups ( P = 0.938 ) . Even after stratification by VUR grade , age , gender , phimosis , voiding dysfunction and renal scar , the incidence of recurrent UTI did not differ significantly between the two groups ( P > 0.05 ) . The development of new renal scar was not significantly different between the two groups ( P > 0.05 ) . In conclusion , probiotics prophylaxis was as effective as antibiotic prophylaxis in children with persistent primary VUR",
"We compared the efficacy and safety of estriol-containing vaginal pessary use with those of oral nitrofurantoin macrocrystal ( NM ) therapy for preventing urinary tract infection ( UTI ) in postmenopausal women with recurrent UTI . Over a period of 9 months , 86 women received an estriol-containing vaginal pessary ( 0.5 mg estriol ) twice weekly , and 85 women received NM ( 100 mg ) once daily . We recorded 124 episodes of UTI in women who received estriol-releasing pessaries and 48 episodes of UTI in women treated with NM ( P=.0003 ) . Twenty-eight women ( 32.6 % ) who received estriol had no episodes of UTI versus 41 women ( 48.2 % ) in the NM group . There was a significant increase in the number of superficial cells in women who received estriol , whereas in the NM group , no such changes occurred . However , there was no change in the extent of Lactobacillus colonization and in the vaginal pH in women who received estriol . Use of an estriol-containing pessary is less effective than oral NM therapy in the prevention of bacteriuria in postmenopausal women because of its failure to restore the population of lactobacilli and to reduce the vaginal pH in these women",
"Abstract Objective To test whether oral or vaginal lactobacillus can prevent vulvovaginitis after antibiotic treatment . Design R and omised , placebo controlled , double blind , factorial 2 × 2 trial . Setting Fifty general practice s and 16 pharmacies in Melbourne , Australia . Participants Non-pregnant women aged 18 - 50 years who required a short course of oral antibiotics for a non-gynaecological infection : 278 were enrolled in the study , and results were available for 235 . Interventions Lactobacillus preparations taken orally or vaginally , or both , from enrolment until four days after completion of their antibiotic course . Main outcome measures Participants ' reports of symptoms of post-antibiotic vulvovaginitis , with microbiological evidence of c and idiasis provided by a self obtained vaginal swab . Results Overall , 55/235 ( 23 % ( 95 % confidence interval 18 % to 29 % ) ) women developed post-antibiotic vulvovaginitis . Compared with placebo , the odds ratio for developing post-antibiotic vulvovaginitis with oral lactobacillus was 1.06 ( 95 % confidence interval 0.58 to 1.94 ) and with vaginal lactobacillus 1.38 ( 0.75 to 2.54 ) . Compliance with antibiotics and interventions was high . The trial was terminated after the second interim analysis because of lack of effect of the interventions . Given the data at this time , the chances of detecting a significant reduction in vulvovaginitis with oral or vaginal lactobacillus treatment were less than 0.032 and 0.0006 respectively if the trial proceeded to full enrolment . Conclusions The use of oral or vaginal forms of lactobacillus to prevent post-antibiotic vulvovaginitis is not supported by these results . Further research on this subject is unlikely to be fruitful , unless new underst and ings about the pathogenesis of post-antibiotic vulvovaginitis indicate a possible role for lactobacillus",
" Forty-two healthy women were r and omized to receive one of three encapsulated Lactobacillus rhamnosus GR-1 plus Lactobacillus fermentum RC-14 probiotic dosage regimens or L. rhamnosus GG by mouth each day for 28 days . However , the vaginal flora , assessed by Nugent scoring , was only normal in 40 % of the cases , and 14 patients had asymptomatic bacterial vaginosis . Treatment with L. rhamnosus GR-1/L. fermentum RC-14 once and twice daily correlated with a healthy vaginal flora in up to 90 % of patients , and 7/11 patients with bacterial vaginosis converted to normal or intermediate scores within 1 month . Ingestion of L. rhamnosus GG failed to have an effect . This study confirms the potential efficacy of orally administered lactobacilli as a non-chemotherapeutic means to restore and maintain a normal urogenital flora , and shows that over 10(8 ) viable organisms per day is the required dose",
"Vaginal c and idiasis ( VC ) is a common concern for women living with HIV infection . The authors evaluated the effectiveness of two self-care approaches to prophylaxis of VC among HIV-infected women , weekly intravaginal application of Lactobacillus acidophilus or weekly intravaginal application of clotrimazole tablets , in a r and omized , double-blind , placebo-controlled trial . VC was defined as a vaginal swab positive for C and ida species in the presence of signs/symptoms of vaginitis and the absence of a diagnosis of Trichomonas vaginalis or bacterial vaginosis . Thirty-four episodes of VC occurred among 164 women followed for a median of 21 months . The relative risk of experiencing an episode of VC was 0.4 ( 95 % CI = 0.2 , 0.9 ) in the clotrimazole arm and 0.5 ( 95 % CI = 0.2 , 1.1 ) in the Lactobacillus acidophilus arm . The estimated median time to first episode VC was longer for clotrimazole ( p = .03 , log rank test ) and Lactobacillus acidophilus ( p = .09 , log rank test ) compared with placebo . Vaginal yeast infections can be prevented with local therapy . Education about self-care for prophylaxis of VC should be offered to HIV-infected women",
"BACKGROUND Recurrent urinary tract infections are a problem for many postmenopausal women . Estrogen replacement restores atrophic mucosa , lowers vaginal pH , and may prevent urinary tract infections . METHODS We enrolled 93 postmenopausal women with a history of recurrent urinary tract infections in a r and omized , double-blind , placebo-controlled trial of a topically applied intravaginal estriol cream . Midstream urine cultures were obtained at enrollment , monthly for eight months , and whenever urinary symptoms occurred . Vaginal cultures and pH measurements were obtained at entry and after one and eight months . The women were assigned to receive either estriol ( n = 50 ) or placebo ( n = 43 ) , both administered intravaginally ; 36 and 24 , respectively , completed the eight months of follow-up . RESULTS The incidence of urinary tract infection in the group given estriol was significantly reduced as compared with that in the group given placebo ( 0.5 vs. 5.9 episodes per patient-year , P Survival analysis showed that more of the women in the estriol group than in the placebo group remained free of urinary tract infection ( P Lactobacilli were absent in all vaginal cultures before treatment and reappeared after one month in 22 of 36 estriol-treated women ( 61 percent ) but in none of the 24 placebo recipients ( P mean vaginal pH declined from 5.5 to 3.8 ( P placebo . The rate of vaginal colonization with Enterobacteriaceae fell from 67 percent to 31 percent in estriol recipients but was virtually unchanged ( from 67 to 63 percent ) in the placebo recipients ( P Side effects were minor , but caused 10 estriol recipients ( 28 percent ) and 4 placebo recipients ( 17 percent ) to discontinue treatment . CONCLUSIONS The intravaginal administration of estriol prevents recurrent urinary tract infection in postmenopausal women , probably by modifying the vaginal flora",
"BACKGROUND & AIMS Pouchitis is the major long-term complication after ileal pouch-anal anastomosis for ulcerative colitis . Most patients have relapsing disease , and no maintenance treatment study has been performed . We evaluated the efficacy of a probiotic preparation ( VSL#3 ) containing 5 x 10(11 ) per gram of viable lyophilized bacteria of 4 strains of lactobacilli , 3 strains of bifidobacteria , and 1 strain of Streptococcus salivarius subsp . thermophilus compared with placebo in maintenance of remission of chronic pouchitis . METHODS Forty patients in clinical and endoscopic remission were r and omized to receive either VSL#3 , 6 g/day , or an identical placebo for 9 months . Patients were assessed clinical ly every month and endoscopically and histologically every 2 months or in the case of a relapse . Fecal sample s were collected for stool culture before and after antibiotic treatment and each month during maintenance treatment . RESULTS Three patients ( 15 % ) in the VSL#3 group had relapses within the 9-month follow-up period , compared with 20 ( 100 % ) in the placebo group ( P Fecal concentration of lactobacilli , bifidobacteria , and S. thermophilus increased significantly from baseline levels only in the VSL#3-treated group ( P < 0.01 ) . CONCLUSIONS These results suggest that oral administration of this new probiotic preparation is effective in preventing flare-ups of chronic pouchitis",
"Background and Objectives : Incidence of C and ida vaginitis by age and racial or ethnic group is poorly described . Goal : Estimate incidence , cumulative probability of presumed C vaginitis by age , racial or ethnic group , and associated costs . Study Design : R and om digit‐dialing survey of 2000 US women . Results : A total of 6.5 percent ( 95 % CI , 5.4‐7.5 % ) of women older than 18 years reported a least one episode of presumed C vaginitis during the previous 2 months . Women reporting a 1‐year period with four or more episodes comprised 8.0 % of the sample but accounted for 37.2 % of women reporting episodes . Black women reported approximately three times more yeast infections in the previous 2 months ( 17.4 % ; 95 % CI , 11.2‐23.5 % ) than white women ( 5.8 % ; 95 % CI , 4.7‐6.9 % ) . Conclusion : The high incidence and the propensity for recurrence underscore the need for a better underst and ing of the epidemiology and pathogenesis , and stress the need for the development of more accurate , rapid diagnostics and effective treatments",
"Bacterial vaginosis ( BV ) is particularly common in black women , and in Nigeria it is often caused by Mycoplasma , as well as Atopobium , Prevotella and Gardnerella sp. Antimicrobial metronidazole oral therapy is poorly effective in eradicating the condition and restoring the Lactobacillus microbiota in the vagina . In this study , 40 women diagnosed with BV by discharge , fishy odor , sialidase positive test and Nugent Gram stain scoring , were r and omized to receive either two dried capsules containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 each night for 5 days , or 0.75 % metronidazole gel , applied vaginally twice a day ( in the morning and evening ) . Follow-up at day 6 , 15 and 30 showed cure of BV in significantly more probiotic treated subjects ( 16 , 17 and 18/20 , respectively ) compared to metronidazole treatment ( 9 , 9 and 11/20 : P=0.016 at day 6 , P=0.002 at day 15 and P=0.056 at day 30 ) . This is the first report of an effective ( 90 % ) cure of BV using probiotic lactobacilli . Given the correlation between BV and HIV , and the high risk of the latter in Nigeria , intravaginal use of lactobacilli could provide women with a self-use therapy , similar to over-the-counter anti-yeast medication , for treatment of urogenital infections",
"Background : It has been suggested that probiotics can reduce the overgrowth of pathogens in the bowels of preterm infants and contribute to the reduction of the incidence of nosocomial infections in neonatal intensive care units ( NICUs ) . The purpose of this study was to evaluate the effectiveness of Lactobacillus GG supplementation in reducing the incidence of urinary tract infections ( UTIs ) , bacterial sepsis and necrotizing enterocolitis ( NEC ) in preterm infants . Methods : A double-blind study was conducted in 12 Italian NICUs . Newborn infants with a gestational age were r and omized to receive st and ard milk feed supplemented with Lactobacillus GG ( Dicoflor ® , Dicofarm , Rome , Italy ) in a dose of 6 × 109 colony-forming units ( cfu ) once a day until discharge , starting with the first feed or placebo . Results : Five hundred eighty-five patients were studied . The probiotics group ( n = 295 ) and the placebo group ( n = 290 ) exhibited similar clinical characteristics . The duration of Lactobacillus GG and placebo supplementation was 47.3 ± 26.0 and 48.2 ± 24.3 days , respectively . Although UTIs ( 3.4 vs. 5.8 % ) and NEC ( 1.4 vs. 2.7 % ) were found less frequently in the probiotic group compared to the control group , these differences were not significant . Bacterial sepsis was more frequent in the probiotics group ( 4.4 % , n = 11 ) than in the placebo group ( 3.8 % , n = 9 ) , but the difference was not significant . Conclusion : Seven days of Lactobacillus GG supplementation starting with the first feed is not effective in reducing the incidence of UTIs , NEC and sepsis in preterm infants . Further studies are required to confirm our results in lower birthweight population",
"The efficacy of vaginal tablets ( Gynoflor ) containing 50 mg of a lyophilisate of viable , H2O2-producing Lactobacillus acidophilus ( at least 10(7 ) colony forming units/tablet ) and 0.03 mg estriol ( CAS 50 - 27 - 1 ) for the treatment of bacterial vaginosis ( BV ) was tested in a multicentric , r and omised , placebo-controlled clinical trial with parallel-group design . 32 non-menopausal women with positive diagnoses for BV , including intermediate cases , participated in the trial . Patients were diagnosed using the classical clinical parameters of BV according to Amsel and using microscopic analysis of the Gram-stained vaginal smear . A positive clinical diagnosis of BV required at least 2 of the following 4 clinical criteria to be positive ; greyish-white , homogeneous leukorrhea ; vaginal pH > 4.5 ; KOH test for volatile amines ; presence of clue cells . Microscopic diagnosis of BV , on the other h and , was obtained if examination of the Gram-stained vaginal smear showed less than 6 lactobacilli per field of view ( 1000 x magnification ) . This corresponds to another definition of BV as \" lactobacilli deficiency syndrome \" . The efficacy of the 6-day therapy with 1 - 2 vaginal tablets daily was evaluated using both clinical and microscopic analysis . Using Amsel 's classical clinical parameters of BV , the cure rate ( defined as cure rate was 88 % in the verum group and 22 % in the placebo group . At both control examinations , the cure rate for the test group was significantly higher than that for the placebo group ( p lactobacilli were capable of recolonising the vagina . A significant increase in the number of lactobacilli was observed in the Gram-stained vaginal smear for the patient group treated with the test preparation compared to the placebo patient group ( p < 0.05 , Fisher 's exact test , 2-sided , significance level 0.05 ) , two and four weeks after the start of the 6-day treatment",
"OBJECTIVES Bacterial vaginosis is characterized by alteration of the normal vaginal microflora , in which a mixed anaerobic bacterial flora becomes prevalent over the population of lacobacilli . Because administration of probiotics might be of some utility in restoring a normal flora , the present study aim ed to evaluate the effect of a Lactobacillus acidophilus-strain-based douche on the vaginal environment in bacterial vaginosis . PATIENTS AND METHODS In an open-label pilot evaluation , 40 women with bacterial vaginosis as defined by Amsel 's criteria were treated for 6 days with a douche containing L. acidophilus . Vaginal smears were collected from the patients and analyzed according to Nugent 's criteria at the time of diagnosis , after 6 days of treatment , and again at 20 days after the last treatment . At the same times , determination of vaginal pH and a Whiff test were performed . RESULTS The Nugent score decreased significantly from bacterial vaginosis or an intermediate flora toward a normal flora during treatment , and remained low during the follow-up period for almost all of the patients , indicating bacterial vaginosis in 52.5 % and in 7.5 % of the patients before treatment and at follow-up , respectively . After treatment , significant decreases in vaginal pH were observed , to less than pH 4.5 in 34/40 women , and the odor test became negative in all of the patients . CONCLUSIONS In this preliminary study , treatment of bacterial vaginosis with a vaginal douche containing a strain of L. acidophilus contributed to the restoration of a normal vaginal environment",
"The expected 4-week cure rate after conventional treatment of bacterial vaginosis are only 65 - 70 % . In an attempt to improve the cure rate by adding probiotic lactobacilli we performed a double-blind placebo-controlled study of adjuvant lactobacilli treatment after an open treatment with vaginal clindamycin ovules . Women with bacterial vaginosis as defined by Amsel 's criteria were treated with clindamycin ovules . Vaginal smears were collected and analysed according to Nugent 's criteria . During the following menstruation period the women used , as an adjuvant treatment , either lactobacilli-prepared tampons or placebo tampons . The lactobacilli tampons were loaded with a mixture of freeze-dried L. fermentum , L. casei var . rhamnosus and L. gasseri . The cure rate was recorded after the second menstruation period . There was no improvement in the cure rate after treatment with lactobacilli-containing tampons compared to placebo tampons ; the cure rates as defined by Amsel 's criteria were 56 % and 62 % , respectively , and 55 % and 63 % , as defined by Nugent 's criteria . This is the first study to report cure rates for women with ' intermediate ' wet smear ratings according to Nugent 's classification and this group had an overall cure rate of 44 % . The cure rate of treatment of bacterial vaginosis was not improved by using lactobacilli-prepared tampons for one menstruation",
"Urogenital infections afflict an estimated one billion people each year . The size of this problem and the increased prevalence of multi-drug resistant pathogens make it imperative that alternative remedies be found . A r and omized , placebo-controlled trial of 64 healthy women given daily oral capsules of Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14 for 60 days showed no adverse effects . Microscopy analysis showed restoration from asymptomatic bacterial vaginosis microflora to a normal lactobacilli colonized microflora in 37 % women during lactobacilli treatment compared to 13 % on placebo ( P=0.02 ) . Lactobacilli were detected in more women in the lactobacilli-treated group than in the placebo group at 28 day ( P=0.08 ) and 60 day ( P=0.05 ) test points . Culture findings confirmed a significant increase in vaginal lactobacilli at day 28 and 60 , a significant depletion in yeast at day 28 and a significant reduction in coliforms at day 28 , 60 and 90 for lactobacilli-treated subjects versus controls . The combination of probiotic L. rhamnosus GR-1 and L. fermentum RC-14 is not only safe for daily use in healthy women , but it can reduce colonization of the vagina by potential pathogenic bacteria and yeast",
"Changes in the indigenous vaginal microflora with uropathogenic bacteria can predispose women to frequently recurring bacterial cystitis . Lactobacilli used as probiotics have played an important role in preventing the colonization of pathogenic bacteria in the vagina . A prospect i ve clinical pilot study was performed to confirm the safety and effectiveness of Lactobacillus vaginal suppositories against the recurrence of bacterial urinary tract infection ( UTI ) . The patients enrolled in the study were instructed to administer vaginal suppositories containing the strain Lactobacillus crispatus GAI 98322 . A significant reduction in the number of recurrences was noted , without any adverse complication ( P=0.0007 ) . The administration of vaginal suppositories containing L. crispatus GAI 98332 seemed to be a safe and promising treatment for the prevention of recurrent UTI",
"Objective To evaluate the effectiveness of live lactobacilli in combination with low dose oestriol for restoration of the vaginal flora after anti‐infective treatment",
"In a prospect i ve cohort study , 10 symptomatic women with recurrent vulvovaginal c and idiasis were taught how to prepare vaginal smears of their own vaginal fluids on days 7 , 14 , 21 , and 28 . The 40 smears were stained with the PAS- method and examined by three different cytopathologists for presence of C and ida . Thereafter , the smears were restained with Giemsa-stain to determine presence of lactobacilli , Gardnerella vaginalis ( \" clue cells \" ) and neutrophils . All three cytopathologists unequivocally established C and ida blastospores and (pseudo)hyphae in 27 out of the 40 PAS-stained vaginal smears , whereas in the remaining 13 smears C and ida was not found . All 10 patients had C and ida in their smears during the second half of their menstrual cycle . Self sample d smears prove to be reliable for establishing the presence of C and ida in symptomatic patients with c and idiasis . C and ida is associated with a lactobacillus-predominated vaginal flora , but with the absence of Gardnerella vaginalis . Further studies may be directed towards the interaction between the various members of the vaginal flora . This study should open molecular methodology for determining the possible interactions of lactobacilli and C and ida"
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4117c774-06ff-11f0-808a-c43d1ab1c353
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Direct pulp capping is one of the most common dental practice s in endodontic therapy . This systematic review and meta- analysis aim to determine whether the effect of mineral trioxide aggregate ( MTA ) and calcium hydroxide for direct pulp capping is different , as measured by the clinical and radiographic analysis . The study list was obtained by search ing PubMed , Springer Link , Scopus and Cochrane Data base . Only those papers that met the inclusion criteria were analyzed . The results indicated that four studies met the inclusion criteria . Statistically significant difference was found between the success rates of MTA and calcium hydroxide treated teeth that needed direct pulp capping ( P=0.002 ) . Clinical assessment s of the MTA versus calcium hydroxide for direct pulp capping suggested that MTA was superior to calcium hydroxide in direct pulp capping result ing in a lower failure rate ( risk difference 0.1 [ 95 % CI 0.04 to 0.16 ] ) . In conclusion , MTA has a higher clinical success rate for direct pulp capping comparing to calcium hydroxide , and might be a suitable replacement for calcium hydroxide
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"PURPOSE To evaluate the clinical , radiographical and histological findings in human third molars in which mechanical pulp exposures were capped with white ProRoot mineral trioxide aggregate ( WMTA ) . METHODS Forty-eight human third molars , caries-free or with incipient caries , scheduled to be extracted , were used and r and omly divided into two groups : Group A : ( n= 24 ) received WMTA and control Group B : ( n= 24 ) received chemical set calcium hydroxide ( Dycal ) . The teeth were isolated with rubber dam and Class I cavities prepared . Pulp exposure was performed using a sterile diamond bur and confirmed by frank bleeding . A sterile cotton pellet dipped in saline solution was placed over the exposure for 60 seconds . The preparation was then lightly rinsed with water and gently air-dried . WMTA or CH was placed over the exposure site followed by a small amount of a light-cured compomer . After etching with 35 % phosphoric acid gel for 15 seconds , rinsing and blot drying , Prime and Bond NT adhesive was applied and light-cured . The cavity was then restored with a resin composite and light-cured . Evaluations were performed by phone after 7 days and clinical ly at 30 + /- 5 and 136 + /- 24 days , using st and ardized tests and radiographs . The teeth were extracted after 136 + /- 24 days ; the roots were cut + /- 4 - 5 mm from the apex to allow for rapid fixation in 10 % neutral buffered formalin . They were then processed for routine histological evaluation , embedded in paraffin , sectioned and stained with hematoxylin and eosin and Brown and Brenn for recognition of bacteria . Statistical analyses were performed using a Mann-Whitney U-test , a Chi-square test , a Fisher 's exact test and an ANOVA . RESULTS No significant differences in post-operative sensitivity were reported after 7 days between the two material s ( P > 0.05 ) . Clinical examination demonstrated no significant differences at 30 + /- 5 days ( P > 0.05 ) and at 136 + /- 24 days ( P > 0.05 ) . Histological findings : 45 of 48 teeth were suitable for microscopic evaluation ( 22 with WMTA and 23 with CH ) . Twenty from the WMTA and 18 from the CH group had developed a bridge . No statistically significant differences were found for superficial and deep inflammatory cell response ( P > 0.05 ) , presence of a dentin bridge ( P > 0.01 ) , and pulp vitality ( P > 0.01 ) , between WMTA and calcium hydroxide . A statistically significant difference was found for the diameter of exposure ( P clinical and histological findings could be established for either material",
"This practice -based , r and omized clinical trial evaluated and compared the success of direct pulp capping in permanent teeth with MTA ( mineral trioxide aggregate ) or CaOH ( calcium hydroxide ) . Thirty-five practice s in Northwest PRECEDENT were r and omized to perform direct pulp caps with either CaOH ( 16 practice s ) or MTA ( 19 practice s ) . Three hundred seventy-six individuals received a direct pulp cap with CaOH ( n = 181 ) or MTA ( n = 195 ) . They were followed for up to 2 yrs at regular recall appointments , or as dictated by tooth symptoms . The primary outcomes were the need for extraction or root canal therapy . Teeth were also evaluated for pulp vitality , and radiographs were taken at the dentist ’s discretion . The probability of failure at 24 mos was 31.5 % for CaOH vs. 19.7 % for MTA ( permutation log-rank test , p = .046 ) . This large r and omized clinical trial provided confirmatory evidence for a superior performance with MTA as a direct pulp-capping agent as compared with CaOH when evaluated in a practice -based research network for up to 2 yrs ( Clinical Trials.gov NCT00812887 )",
"This study was conducted to observe the formation and nature of tunnel defects in dentin bridges , assess the nature of the associated soft tissue elements , and note the relationship of pulp inflammation and necrosis associated with these defects . A total of 235 teeth with class 5 cavity preparation exposures were r and omly distributed throughout the dentitions of 14 adult rhesus monkeys . Each pulp was exposed and left open to the oral microflora at one of four time intervals , flushed with saline , debrided , capped with one of two hard-set calcium hydroxide medicaments [ Ca(OH)2 ( Dycal or Life ) ] and restored with a dispersed-phase amalgam alloy . Observation times were 14 days , 5 weeks , and 1 and 2 years . A total of 192 dentin bridges formed against the Ca(OH)2 medicaments Life or Dycal in 235 pulp-capped teeth . Considering all four capping periods , 89 % of all dentin bridges contained tunnel defects ( 172 of 192 ) . Forty-one percent ( 78 ) of the 192 dentin bridges were associated with recurring pulp inflammation or necrosis and were always associated with the presence of inflammatory cells and stained bacterial profiles . This study demonstrates that a statistically significant number of dentin bridges contain multiple tunnel defects , most of which appear to remain patent . These patent tunnels fail to provide a hermetic seal to the underlying pulp against recurring infection due to microleakage . Most Ca(OH)2 medicaments have been reported to disintegrate and wash out after 6 months , leaving a void underneath the restoration and thereby a pathway for bacterial infection . This study reemphasizes the need to employ biologically relevant measures that will provide a long-term clinical seal against microleakage following direct pulp capping with Ca(OH)2 medicaments alone",
"PURPOSE To evaluate histological findings in human immature permanent premolars scheduled for extraction for orthodontic reasons , in which mechanical pulp exposures were capped with white ProRoot Mineral Trioxide Aggregate ( WMTA ) or calcium hydroxide ( CH ) . METHODS Forty-eight human immature premolars in 23 patients ( age 10 - 18 years ) were r and omly treated with WMTA or CH . After rubber dam isolation Cl I cavities were prepared and the pulps exposed . After hemostasis the pulps were capped with either material . The preparations were restored using an acid etch , bonding agent , flowable composite and composite resin technique . The teeth were extracted after 47 to 609 days and processed for routine histological examination , stained with hematoxylin and eosin and Brown and Brenn for recognition of bacteria . Statistical analyses of inflammation , bridge formation and bacterial leakage were performed using a Chi-square test and ANOVA . RESULTS Forty-four of 48 teeth were suitable for microscopic evaluation , 30 with WMTA , 14 with CH . Of the WMTA group , 29 teeth were vital , 28 had formed a bridge , and one specimen had failed . Twelve of 14 teeth with CH were vital , while three teeth failed to form a bridge . No statistically significant differences between WMTA and CH were found , except for superficial and deep inflammatory cell response ( P < or = 0.05 ) . Pulp capping of intentionally exposed human immature premolars performed slightly better when using MTA"
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4117c7b0-06ff-11f0-808a-c43d1ab1c353
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Mobile-bearing ( MB ) total knee replacement ( TKR ) was introduced to reduce the risk of aseptic loosening and wear of polyethylene inserts . However , no consistent clinical advantages of mobile- over fixed-bearing ( FB ) TKR have been found . In this study we evaluated whether mobile bearings have an advantage over fixed bearings with regard to revision rates and clinical outcome scores . Furthermore , we determined which modifying variables affected the outcome . A systematic search of the literature was conducted to collect clinical trials comparing MB and FB in primary TKR . The primary outcomes were revision rates for any reason , aseptic loosening and wear . Secondary outcomes included range of movement , Knee Society score ( KSS ) , Oxford knee score ( OKS ) , Short-Form 12 ( SF-12 ) score and radiological parameters . Meta-regression techniques were used to explore factors modifying the observed effect . Our search yielded 1827 publications , of which 41 studies met our inclusion criteria , comprising over 6000 TKRs . Meta-analyses showed no clinical ly relevant differences in terms of revision rates , clinical outcome scores or patient-reported outcome measures between MB and FB TKRs . It appears that theoretical assumptions of superiority of MB over FB TKR are not borne out in clinical practice
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"Abstract Anterior knee pain is one of the major short-term complaints after TKA . Since the introduction of the mobile-bearing TKA , numerous studies have attempted to confirm the theoretical advantages of a mobile-bearing TKA over a fixed-bearing TKA but most show little or no actual benefits . The concept of self-alignment for the mobile bearing suggests the posterior-stabilized mobile-bearing TKA would provide a lower incidence of anterior knee pain compared with a fixed-bearing TKA . We therefore asked whether the posterior-stabilized mobile-bearing knee would in fact reduce anterior knee pain . We r and omized 103 patients scheduled for cemented three-component TKA for osteoarthrosis in a prospect i ve , double-blind clinical trial . With a 1-year followup , more patients experienced persistent anterior knee pain in the posterior-stabilized fixed-bearing group ( 10 of 53 , 18.9 % ) than in the posterior-stabilized mobile-bearing group ( two of 47 , 4.3 % ) . No differences were observed for range of motion , visual analog scale for pain , Oxford 12-item question naire , SF-36 , or the American Knee Society score . The posterior-stabilized mobile-bearing knee therefore seems to provide a short-term advantage compared with the posterior-stabilized fixed-bearing knee . Level of Evidence : Level I , therapeutic study . See the Guidelines for Authors for a complete description of levels of evidence",
"A prospect i ve study was performed to compare the clinical and radiological results of mobile- and fixed-bearing total knee arthroplasty with specific attention to rotational alignment and range of motion . Sixty-one knees were assigned to total knee arthroplasty with either the NexGen LPS Flex fixed-bearing or with the NexGen LPS Flex mobile-bearing prosthesis . Postoperatively , knees were compared with regard to range of motion , clinical score , and radiographic findings . Rotational alignment of the femoral and tibial components was evaluated by computed tomography . The median follow-up period was 5.9 years ( range 2.1–8.8 years ) . Median postoperative Knee Society scores were 99 points ( 68–100 ) for the fixed-bearing group and 100 points ( 66–100 ) for the mobile-bearing group ( n.s . ) . The median postoperative flexion angles of 120 ° ( 90 ° –150 ° ) for the fixed-bearing group and 125 ° ( 90 ° –145 ° ) for the mobile-bearing group were not significantly different from each other ( n.s . ) . No knee required revision surgery due to wear of polyethylene or loosening of the component in either group . Computed tomography showed that 11 knees had rotational mismatches of more than 10 ° between the femoral and tibial components , but no significant difference was found in the postoperative extension and flexion angles or in the clinical score between the two treatment groups . Using the identical design for both fixed- and mobile-bearing prostheses , this prospect i ve , r and omized study did not show any clinical advantages of the mobile-bearing knee . Analysis of rotational alignment by CT scan did not reveal a particular advantage of the self-aligning mechanism of mobile-bearing implants",
"A prospect i ve , r and omized , controlled , double-blind trial was performed to compare outcomes between 61 mobile- and 58 fixed-bearing primary TKAs in patients aged 70 years or older . At last follow-up , no difference was found for Knee Society score . The mobile-bearing group had greater knee flexion at 3 and 6 months , but this was similar at 2 years . The patient satisfaction was better in the mobile-bearing group than in fixed-bearing group , with respect to Knee Society functional score , Western Ontario MacMasters University score , Short-Form 12 score , and visual analog scale score . A multivariate analysis confirmed that the only independent factors predictive of postoperative quality of life were early postoperative flexion . We believe that better perception and satisfaction with mobile-bearing in older patients was due to the earlier regain of their knee flexion . Our results justify the use of mobile-bearing design in the older population",
"Background : The mobile bearing design s have not yet been shown to improve clinical outcome of total knee arthroplasty ( TKA ) . In this prospect i ve r and omized study , we compared the short-term clinical results of a mobile bearing implant with those of the fixed bearing version of the same implant . Methods : We r and omized 100 knees into two double-blind groups who received either the fixed ( FB , 52 knees ) or the mobile bearing ( MB , 48 knees ) version of the same implant . We used navigation to st and ardize the surgical technique . For up to one year , we recorded the Knee Society ( KSS ) and Oxford ( OXF ) scores . We performed an exploratory analysis of variance ( ANOVA ) to determine the influence of baseline scores as covariate and the extent of improvement in clinical outcome over time . Results : After one year , we did not detect any statistically significant difference between the two groups . The KSS scores differed by 2 points , the OXF scores by 1.1 points . Conclusion : Even with identical geometry of implant surfaces and a navigated surgical technique , first-year results do not support a preference for either a fixed or a mobile design",
"The aim of this study was to determine whether there is a difference in functional outcome between the PFC Sigma fixed-bearing and rotating-platform total knee replacement systems . One hundred twenty patients were r and omised to receive either a fixed-bearing or rotating-platform PFC Sigma total knee replacement . Range of movement ( ROM ) , Oxford knee score ( OKS ) and Knee Society score ( KSS ) were assessed independently before and one year after surgery . Weight-bearing X-rays were taken immediately and one year post surgery to determine the incidence of osteolysis and loosening . At a mean follow-up of 13.4 months there was no statistically significant difference in mean ROM , OKS and KSS between the two groups . There was no evidence of osteolysis or loosening in either of the groups and no revision for infection or implant failure . This study shows that there is no statistically significant difference in functional outcome between the two types of implants at short-term follow-up",
"Background On theoretical grounds mobile bearing total knees should reduce the micromotion of the tibial component relative to the bone . Patients and methods We used radiostereometric analysis to measure the three-dimensional micromotion in 42 tibial components during 2 years of follow-up . The patients had been r and omized as to whether they would receive a mobile bearing ( MB ) or posterior stabilized ( PS ) design . We expected that the MB knee would facilitate dissipation of forces from the prosthesis-bone interface by the motion of the bearing and by load sharing with the soft tissues , leading to less micromotion . In the PS design s , limited free rotation caused by the campost articulation might cause additional stress at the bone-prosthesis interface . Results We found no significant differences between the MB and PS group at the 2-year follow-up evaluation with respect to Knee Society scores and radiographic results . The PS group had a higher variability in subsidence and anterior-posterior tilting of the component than the MB group . Interpretation The low variability of the data in the MB knee prosthesis group suggests that this design is more predictable and forgiving with respect to micromotion of the tibial component",
"Purpose The primary goal of this study was to assess the difference in active flexion between patients with a mobile versus a fixed bearing , cruciate retaining , and total knee arthroplasty . The study was design ed as a r and omised controlled multi-centre trial . Methods Participants were assigned to interventions by using block-stratified , r and om allocation . Outcome parameters were active flexion , passive flexion , and Knee Society Score ( KSS ) . Outcome parameters were assessed preoperatively and at 3 , 6 , and 12 months postoperatively by an independent nurse . Results Ninety-two patients from one centre were included , 46 in each group . Active flexion was comparable for the two groups , 99.9 ° for the mobile bearing group and 101 ° for the fixed bearing group with a baseline controlled difference of 1.0 ( 95 % CI −3.9 to 5.8 , n.s . ) . The Clinical KSS was comparable between the two bearing groups ( Mobile 90.0 vs. fixed 92.4 , n.s . ) . The functional KSS showed a difference that was attributable to the stair climbing subscore , which showed a difference in favour of the fixed bearing design between preoperative and 3 months ( 7.3 point difference ; 95 % CI 2.3–12.5 ; P = 0.005 ) as well as 12 months ( 4.8 point difference ; 95 % CI 0.1–9.6 ; P = 0.045 ) . Conclusions There were no short-term differences in active flexion between fixed bearing and mobile bearing total knee arthroplasty . Level of evidence",
"Concern about polyethylene wear and related osteolysis after knee arthroplasty has developed in the last years . Mobile-bearing knee prostheses were design ed in order to reduce the influence of this critical factor on long-term success of total knee replacement . We present a prospect i ve study comparing clinical and radiological results with a mobile-bearing ( Ceragyr ) and a fixed-bearing knee prosthesis ( posterior stabilized Hermes ) . Clinical results did not show any significant differences in Knee Society scores . We found better results in the mobile-bearing group for pain scores and subjective preference , but the difference did not reach statistical significance . Within the time limits of this study , radiological analysis showed no osteolysis in either group , but longer follow-up will be needed to confirm this",
"We have developed a 12-item question naire for patients having a total knee replacement ( TKR ) . We made a prospect i ve study of 117 patients before operation and at follow-up six months later , asking them to complete the new question naire and the form SF36 . Some also filled in the Stanford Health Assessment Question naire ( HAQ ) . An orthopaedic surgeon completed the American Knee Society ( AKS ) clinical score . The single score derived from the new question naire had high internal consistency , and its reproducibility , examined by test-retest reliability , was found to be satisfactory . Its validity was established by obtaining significant correlations in the expected direction with the AKS scores and the relevant parts of the SF36 and HAQ . Sensitivity to change was assessed by analysing the differences between the preoperative scores and those at follow-up . We also compared change in scores with the patients ' retrospective judgement of change in their condition . The effect size for the new question naire compared favourably with those for the relevant parts of the SF36 . The change scores for the new knee question naire were significantly greater ( p new question naire provides a measure of outcome for TKR that is short , practical , reliable , valid and sensitive to clinical ly important changes over time",
"We compared patient-reported outcomes of the Kinemax fixed- and mobile-bearing total knee replacement in a multi-centre r and omised controlled trial . Patients were r and omised to the fixed- or the mobile-bearing prosthesis via a sealed envelope method after the bone cuts had been made in the operating theatre . R and omisation was stratified by centre and diagnosis . Patients were assessed pre-operatively and at eight to 12 weeks , one year and two years post-operatively . Vali date d question naires were used which included the Western Ontario MacMasters University , Short-Form 12 , Mental Health Index-5 , Knee Injury and Osteoarthritis Outcome Score for Knee-Related Quality of Life and Function in Sport and Recreation scales and a vali date d scale of satisfaction post-operatively . In total , 242 patients ( 250 knees ) with a mean age of 68 years ( 40 to 80 ) were recruited from four NHS orthopaedic centres . Of these , 132 patients ( 54.5 % ) were women . No statistically significant differences could be identified in any of the patient-reported outcome scores between patients who received the fixed-bearing or the mobile-bearing knee up to two-years post-operatively",
"Introduction In a prospect i ve r and omized study , we compared the results after implantation of the mobile bearing high flex TKA with a fixed bearing posterior stabilized TKA in 60 patients ( 30 patients each group ) . Method We evaluated the hospital for special surgery-score ( HSS ) and different radiological parameters preoperatively , as well as 3 months , 3 and 5 years postoperatively . Result Three months postoperatively , the high flex group showed better results in scores for pain , ROM ( 122.5 ° vs. 107.33 ° ) , as well as in the overall HSS ( 87.21 vs. 82.68 points ) . Three and 5 years postoperatively , there were no differences between both the groups in all scores , but the HSS is still increasing . Conclusion The theoretical advantages of the mobile bearing knee prostheses were reflected in the clinical results , only partly and temporarily",
"BACKGROUND Proponents of mobile-bearing total knee arthroplasty believe that it has potential advantages over a fixed-bearing design in terms of diminished wear and improved motion and /or function , but these advantages have not been demonstrated in a r and omized clinical comparison to our knowledge . We conducted a patient-blinded , prospect i ve , r and omized clinical trial to compare mobile-bearing and fixed-bearing cruciate-substituting total knee arthroplasties of the same design . METHODS Patients between the ages of sixty and eighty-five years were prospect ively r and omized to receive a cruciate-substituting rotating-platform design or a fixed-bearing design with an all-polyethylene tibial component . There were no significant differences in the demographic characteristics ( mean age , 72.2 years ; mean American Society of Anesthesiologists score , 2.7 ; mean body mass index , 31.8 kg/m(2 ) ) or preoperative clinical or radiographic measures between the groups . Routine clinical and radiographic follow-up measures included the Knee Society score ( KSS ) , Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) , and Short Form-36 ( SF-36 ) outcome measures . RESULTS The results of 312 arthroplasties ( 136 with an all-polyethylene tibial component and 176 rotating-platform design s ) in 273 patients were analyzed at a minimum of two years ( mean , forty-two months ) postoperatively . Although there was significant improvement in both groups , there was no significant difference between the groups with regard to the mean postoperative range of motion ( 110.9 degrees and 109.1 degrees , respectively ; p = 0.21 ) , the mean KSS clinical score ( 90.4 and 88.2 points ; p = 0.168 ) , or the mean KSS pain score ( 44.9 and 43.1 points ; p = 0.108 ) at this follow-up point . There were ten revisions : seven because of infection , one because of patellar fracture , one because of instability , and one because of aseptic loosening . CONCLUSIONS The two design s functioned equivalently at the time of early follow-up in this low-to-moderate-dem and patient group . The rotating-platform design had no significant clinical advantage over the design with the all-polyethylene tibial component",
"Within the context of a double blind r and omized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs , we vali date d WOMAC , a new multidimensional , self-administered health status instrument for patients with osteoarthritis of the hip or knee . The pain , stiffness and physical function subscales fulfil conventional criteria for face , content and construct validity , reliability , responsiveness and relative efficiency . WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials",
"Few published reports have been published regarding a comparison of the long-term outcomes between mobile- ( MB ) and fixed-bearing component design s for knee arthroplasty . The minimum 10-year clinical and radiologic follow-up of an unselected consecutive series of 89 patients ( 107 knees ) who were r and omized to have one of these different design s for primary arthroplasty was done . Twenty-six patients ( 30 knees ) who had a fixed-bearing design and 24 patients ( 33 knees ) who had an MB prosthesis were available for follow-up . Two MB knees were revised for aseptic loosening of a tibial component in one and femoral component fracture in the other . In patients who did not have revision surgery , there were no differences between the groups with respect to mean Knee Society scores , knee flexion , or pain scores",
"The purpose of this prospect i ve r and omized study was to compare the postoperative recovery and early results of 2 groups of patients undergoing total knee arthroplasty : 107 patients received an established fixed-bearing posterior-stabilized prosthesis ( Legacy Posterior Stabilized [ LPS ] ) , and 103 patients the meniscal-bearing prosthesis ( Meniscal Bearing Knee [ MBK ] ) . Surgical procedures were the same for both groups except for posterior cruciate ligament management , which was sacrificed in the LPS group and spared but completely released from the tibia in the MBK group . At an average follow-up of 36 months , knee , function , and patellar scores were comparable in both groups . The LPS group showed a significantly higher maximum flexion than the MBK group ( 112 degrees vs 108 degrees ) . Using a fixed-bearing or a mobile-bearing design did not seem to influence the short-term recovery and early results after knee arthroplasty . Key words : total knee arthroplasty , mobile bearing , knee prosthesis , meniscal-bearing knee , posterior stabilized , prospect i ve r and omized",
"BACKGROUND The aim of continued development of total knee replacement systems has been the further improvement of the quality of life and increasing the duration of prosthetic survival . Our goal was to evaluate the effects of several design features , including metal backing of the tibial component , patellar resurfacing , and a mobile bearing between the tibial and femoral components , on the function and survival of the implant . METHODS A pragmatic , multicenter , r and omized , controlled trial involving 116 surgeons in thirty-four centers in the United Kingdom was performed ; 2352 participants were r and omly allocated to be treated with or without a metal backing of the tibial component ( 409 ) , with or without patellar resurfacing ( 1715 ) , and /or with or without a mobile bearing ( 539 ) . R and omization to more than one comparison was allowed . The primary outcome measures were the Oxford Knee Score ( OKS ) , Short Form-12 , EuroQol-5D , and the need for additional surgery . The results up to two years postoperatively are reported . RESULTS Functional status and quality -of-life scores were low at baseline but improved markedly across all trial groups following knee replacement ( mean overall OKS , 17.98 points at baseline and 34.82 points at two years ) . Most of the change was observed at three months after the surgery . Six percent of the patients had additional knee surgery within two years . There was no evidence of differences in clinical , functional , or quality -of-life measures between the r and omized groups at two years . CONCLUSIONS Patients have substantial improvement following total knee replacement . This is the first adequately powered r and omized controlled trial , of which we are aware , in which the effects of metal backing , patellar resurfacing , and a mobile bearing were investigated . We found no evidence of an effect of these variants on the rate of early complications or on functional recovery up to two years after total knee replacement",
"BACKGROUND Durable long-term independent results with the Low Contact Stress rotating-platform ( mobile-bearing ) and the Insall Burstein-II ( fixed-bearing ) total knee prostheses have been reported , but no studies describing either the mid-term or long-term results and comparing the two prostheses are available , to our knowledge . METHODS Thirty-two patients who had bilateral arthritis of the knee with similar deformity and preoperative range of motion on both sides and who agreed to have one knee replaced with a mobile-bearing total knee design and the other with a fixed-bearing design were prospect ively evaluated . Comparative analysis of both design s was done at a mean follow-up period of six years , minimizing patient , surgeon , and observer-related bias . Clinical and radiographic outcome , survival , and complication rates were compared . RESULTS Patients with osteoarthritis had better function scores and range of motion compared with patients with rheumatoid arthritis . However , with the numbers available , no benefit of mobile-bearing over fixed-bearing design s could be demonstrated with respect to Knee Society scores , range of flexion , subject preference , or patellofemoral complication rates . Radiographs showed no difference in prosthetic alignment . Two knees with a mobile-bearing prosthesis required a reoperation : one had an early revision because of bearing dislocation and another required conversion to an arthrodesis to treat a deep infection . CONCLUSIONS We found no advantage of the mobile-bearing arthroplasty over the fixed-bearing arthroplasty with regard to the clinical results at mid-term follow-up . The risk of bearing subluxation and dislocation in knees with the mobile-bearing prosthesis is a cause for concern and may necessitate early revision . LEVEL OF EVIDENCE Therapeutic Level II",
" 52 knees scheduled for a total knee arthroplasty were r and omised to either a fixed or a mobile polyethylene bearing . The design was identical in all parts . The knee systems used were the Rotaglide Total Knee System ( RTK ) and the Nuffield Total Knee System ( NTK ) , both from the same manufacturer ( Corin Medical Ltd. , UK ) . All knees implanted were uncemented . The patients were followed for 2 years clinical ly and with radiostereometric analyses to assess migration over time and inducible displacement of the tibial component . Separate analysis of the mobility of the tibial insert in the knees with a mobile bearing was also made . The migration measured with RSA between the 1st and 2nd year expressed as maximum total point motion ( MTPM ) might predict the risk of loosening of the implant . There were no differences between the groups regarding clinical outcome ( HSS Knee score ) , migration or inducible displacement during the 2 years follow-up . The movement between the tibial tray and the mobile meniscal insert expressed as maximum total point motion ( MTPM ) was 6.8+/-3.3 mm at the 1st year follow-up",
"Background Mobile bearing ( MB ) total knee design has been advocated as a means to enhance the functional characteristics and decrease the wear rates of condylar total knee arthroplasty ( TKA ) . However , it is unclear if these design s achieve these goals . Questions / purpose sWe asked whether function of patients or survivorship would be greater or complications would be lesser in groups of patients with MB compared with fixed bearing ( FB ) TKA . We also sought to describe retrieval findings . Methods We r and omized 507 primary TKAs in 416 eligible patients to receive MB ( n = 252 ) or FB ( n = 255 ) devices from November 2001 to August 2007 ( Investigational Device Exemption G000180 , Clinical Trials.gov registration number NCT00946075 ) . Patients were blinded to treatment allocation . WOMAC Index , SF-12 Health Survey , knee range of motion , and Knee Society scores were collected and compared preoperatively and at 6 , 12 , and 24 months postoperatively . We recorded device failures and complications until October 2009 . Kaplan-Meier survivorship was compared using the log rank test . Twelve retrieved MB devices underwent pathologic analysis . The minimum postoperative time was 2.2 years ( mean , 5.9 years ; range , 2.2–7.9 years ) . Results We found no differences in mean clinical assessment scores or mean score changes from baseline at any postoperative interval through 2 postoperative years . Nineteen of the 252 MB and 13 of the 255 FB knees had undergone revision of any component . Estimated survival at 6 postoperative years was similar for the two devices : 90.1 % ( 95 % confidence interval [ CI ] , 84.1–93.9 ) for MB and 94.2 % ( 95 % CI , 90.1–96.6 ) for FB . Two MB and no FB tibial components were revised for loosening . There was one case of MB insert dislocation . Retrieved MB devices demonstrated no unexpected wear or mechanical device failures . Conclusion We found no evidence of functional advantage of the MB design . Survivorship was similar , although the study is limited by short duration of followup . Level of Evidence Level I , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence",
"The purpose of this r and omized , single-blind clinical trial was to compare a rotating platform ( RP ) total knee arthroplasty to a fixed-bearing ( FB ) total knee arthroplasty . Ninety-five knees in 69 patients were implanted by 2 surgeons . There were no significant differences in the preoperative demographics . At a minimum of 2-year follow-up , clinical outcomes and complication rates were similar , with the exception that the RP group had significantly better stair-climbing scores ( P = .04 ) . Postoperative range of motion was equally good in both groups ( FB knees , 1 ° -125 ° ; RP knees , 1 - 126 ° ) . There were no bearing dislocations in the RP group . In conclusion , this RP design performs at least as well as the FB version , and the RP patients reported better stair-climbing ability . Enthusiasm for this finding should be tempered by the relatively small sample size",
"Mobile-bearing total knee arthroplasty ( TKA ) has several theoretical advantages over fixed-bearing TKA . We conducted a prospect i ve r and omized trial to compare the results of mobile-bearing and fixed-bearing posterior-stabilized TKA in the same patients using the same femoral component design of a mobile-bearing prosthesis in one knee and a fixed-bearing prosthesis in the other knee in 25 patients with osteoarthritis . The mean follow-up was 40 months . No significant differences were found in the mobile-bearing and fixed-bearing knees in terms of clinical and radiographic results . No osteolysis , loosening , or revision occurred . One knee with a mobile-bearing prosthesis had a dislocation of the rotating bearing ; however , spontaneous reduction occurred and the dislocation did not recur . Satisfactory early results can be achieved in both mobile-bearing and fixed-bearing knees . We could not demonstrate an advantage of a mobile-bearing TKA",
"The objective of this study was to investigate the range of motion ( ROM ) of the knee before and four years after total knee arthroplasty ( TKA ) with a mobile or fixed type of platform and to prospect ively evaluate whether there was a difference in ligament balance between the platform types . The subjects were 68 patients involving 76 joints . The mobile type was used in 31 joints and fixed type in 45 joints by employing a prospect i ve r and omised method . The passive maximum ROM was measured using a goniometer before and four years after surgery . Also , the intraoperative knee ligament balance was measured . The postoperative extension ROM was significantly improved after TKA using a mobile bearing type compared with that employing a fixed bearing type . In TKA using the former , the intraoperative gap difference was not related to the postoperative flexion angle of the knee . However , they were related in TKA using a fixed bearing type , with a positive correlation regarding the flexion gap",
"Purpose . To compare the mid-term clinical outcomes in Indian patients after total knee arthroplasty ( TKA ) using a fixed- or mobile-bearing prosthesis . Methods . 120 consecutive patients ( 50 men and 70 women ) aged 55 to 76 ( mean , 63 ) years who had arthritis of the knee with similar deformity and range of motion were r and omised to undergo TKA using a fixed- or mobile-bearing prosthesis . Patients with mediolateral instability and infective arthritis were excluded . Knee Society knee and functional scores , range of motion , and the presence of flexion contracture were assessed . Results . The mean follow-up duration was 3.5 ( range , 1–4.6 ) years . The mid-term outcome of the 2 groups was comparable . One patient with a mobile-bearing prosthesis had recurrent dislocation at postoperative week 2 , owing to iatrogenic medial collateral ligament injury . Conclusion . Long-term studies of both functional and radiological outcomes are needed to determine the indications for fixed- versus mobile-bearing prostheses",
"The purpose of the current study was to directly compare the results of fixed-bearing and mobile-bearing total knee arthroplasties in the same patient who had bilateral simultaneous total knee replacements . A fixed-bearing total knee prosthesis ( AMK ) was implanted in one knee and a mobile-bearing total knee prosthesis ( LCS ) was implanted in the other knee in 116 patients . The average age of the patients was 65 years ( range , 33–70 years ) . The average followup was 7.4 years ( range , 6–8 years ) . Clinical and radiographic followup was done using Knee Society and Hospital for Special Surgery knee rating systems at 6 weeks , 3 months , 6 months , 1 year after surgery , and yearly thereafter . Total knee score , pain score , mean functional score , and range of motion were comparable in both groups . Two knee replacements ( 2 % ) in one patient with AMK prostheses were revised because of complete wear of tibial bearing polyethylene . One knee replacement ( 1 % ) in one patient with an LCS prosthesis was revised because of dislocation of the medial tibial bearing polyethylene and one knee replacement ( 1 % ) in one patient with an LCS prosthesis was revised because of complete wear of the medial tibial bearing polyethylene . No knee had aseptic loosening or osteolysis in either group . After a minimum followup of 6 years , the results of fixed- and mobile-bearing total knee prostheses in the current series are favorable . However , there is no evidence to prove the superiority of the mobile-bearing total knee design",
"As part of the step-wise validation of a new prosthesis ( TMK ) , we previously published the 1 year results of a r and omised controlled trial in patients undergoing bilateral knee replacement [ Price A. , Rees J. , Beard D. , Juszczak E. et al. A mobile-bearing total knee prosthesis compared with a fixed-bearing prosthesis . JBJS B 2003;85-B-1:62 - 7 . ] . Forty patients had the new mobile-bearing prosthesis implanted in one knee and an established fixed-bearing device in the other ( AGC ) . We now report the 3 year status of these patients and , in addition , review a separate multi-centre cohort of 172 patients who had undergone unilateral arthroplasty with the TMK . No significant differences were found in outcome ( American Knee Society Score and Oxford Knee Score ) between the two prostheses . The greater incidence of \" clicking \" in the mobile-bearing knee , reported in the previous review , persisted ( TMK=48 % , AGC=30 % ) . The presence of this mechanical noise was found to have no relationship with outcome in either of the prostheses . The unilateral cohort study showed an acceptable complication rate for the new prosthesis , although some patients reported subjective instability . The method of controlled introduction of the TMK , of which this constitutes a further step , has allowed us to assess the significance of a reported problem ( clicking ) and to provide scientific data from which other surgeons can decide about use of the implant",
"Renewed interest in mobile-bearing total knee replacement design s has been generated by the concept of self alignment and the suggestion that those design s can accommo date small mismatches in the rotational position of the tibial and femoral components . Self alignment might improve patellar tracking , decrease the prevalence of lateral retinacular release and postoperative patellar tilt or subluxation , improve knee flexion , and improve patellofemoral function during daily activities such as stair climbing . This prospect i ve r and omized study of 240 patients used a single posterior-stabilized femoral component and included three groups of 80 patients : an all-polyethylene group , a modular metal-backed group , and a rotating platform tibia group . The prevalence of lateral retinacular release was 3.8 % in each group . The prevalence of patellar tilt was 5 % ( all-polyethylene group ) , 7 % ( modular metal-backed group ) , and 11 % ( rotating platform group ) . Preoperative motion was not significantly different and both the 3-month flexion ( 112 ° , 110 ° , and 108 ° ) and 1-year flexion ( 116 ° , 117 ° , and 115 ° ) were not significantly different among the all-polyethylene , modular metal-backed , and rotating platform groups , respectively . Preoperative stair climbing scores were not significantly different and both the 3-month ( 38 , 41 , and 35 points ) and 1-year ( 44 , 46 , and 42 points ) scores were not significantly different . In this prospect i ve r and omized study , the rotating platform knee design did not decrease the prevalence of lateral retinacular release or patellar tilt or subluxation and did not increase knee flexion or improve stair climbing ability at 3 months or at 1 year postoperatively when compared with a posterior-stabilized , fixed-bearing knee",
" Between May 2001 and June 2004 , 388 total knee arthroplasty cases were enrolled in a prospect i ve , r and omized , multicenter investigational device exemption trial . Patients received either the investigational high-flexion mobile-bearing knee or a fixed-bearing control . At 2 to 4 years of follow-up , results in 293 patients with degenerative joint disease were compared using Knee Society Assessment and Function scores , radiographic results , complications analysis , and survival estimates . The mobile-bearing and fixed-bearing groups demonstrated similar , significant improvement over preoperative assessment s in Knee Scores , maximum flexion , and range of motion . One mobile-bearing arthroplasty required revision . Radiographic results were unremarkable , and implant-related complications were rare in both groups . At this early follow-up , the investigational high-flexion mobile-bearing knee and its fixed-bearing counterpart demonstrated comparable , effective performance",
"Mobile bearings were introduced to improve wear and knee kinematics . By uncoupling the forces generated at the articulation from the implant-bone interface this would , theoretically , also improve the fixation of the implant to bone . We did this study to evaluate whether mobile bearings improve the fixation of the tibial component to bone . Fifty-two consecutive knees in 47 patients ( average age , 72 years ; range , 62 - 84 years ) with primary osteoarthrosis were r and omized into two groups to receive a cemented total knee arthroplasty with either a fixed-bearing or mobile-bearing tibial component . The quality of fixation was analyzed with radiostereometric analysis for up to 2 years . Mobile bearings did not improve fixation . Both magnitudes and directions of component rotations were similar , and the number of implants with continuous migration was almost identical . Both implant types had a combination of subsidence and lift-off , but where the mobile bearing implants displayed more of subsidence , the fixed bearing knees showed more lift-off . It might be that the somewhat stiffer cobalt-chromium baseplate or the different joint conformity used in the mobile-bearing knees counteracts any potential effects of the mobile bearing . Level of Evidence : Therapeutic Level I. See the Guidelines for Authors for a complete description of levels of evidence",
"Little is known about tibial bone remodeling with TKA and its clinical relevance . We performed a r and omized clinical trial to compare tibial bone density changes in cemented components with different bearing design s. Bone density changes were assessed using quantitative computed tomography (qCT)-assisted osteodensitometry . Twenty-eight rotating-platform and 26 fixed-platform cemented TKAs were included . The nonoperated contralateral side was used as a control . CT scans were performed postoperatively and 1 year and 2 years after the index operation . Cancellous bone density loss ( up to 12.6 % at 2 years ) was observed in all proximal tibial regions in both cohorts . In contrast , we found lower cortical bone density loss ( up to 3.6 % at 2 years ) . We found no differences in bone loss between fixed- and rotating-platform implants . The decrease of cancellous bone density after TKA suggests stress transfer to the cortical bone",
"We did an in vivo fluoroscopic study comparing the sagittal plane kinematics of mobile-bearing and fixed-bearing total knee arthroplasties in a unique group of patients . These patients were part of a larger bilateral r and omized controlled outcome trial with each patient having received both types of total knee arthroplasties . Invited patients did three exercises with each of their different knee replacements ; extension against gravity , flexion against gravity , and a step-up . These exercises were recorded using video fluoroscopy , and a series of still digital images over the flexion range were retrieved . The relationship of patella tendon angle to knee flexion angle for each patient was derived . The patella tendon angle to knee flexion angle of the mobile-bearing knee behaved in a linear manner more closely replicating the normal knee , whereas the fixed-bearing knee behaved in a nonlinear , more variable manner . This pattern of results was similar for all three exercises with each patient having one knee replacement that behaved differently in the sagittal plane when compared with their other knee replacement . These kinematic differences may explain the clinical differences observed in the r and omized controlled trials that compared these two total knee arthroplasties",
"Mobile-bearing ( MB ) total knee arthroplasty ( TKA ) was developed as an alternative to the established fixed-bearing ( FB ) design because of theoretical advantages . Short-term studies comparing these design s have not shown any differences in clinical and radiographic results . We compared the results at 7 years of a r and omised study of patients undergoing TKA using either a FB or a MB variant of the same prosthesis . Fifty-two patients ( 52 knees ) with an average age of 70 years received a FB posterior-stabilized prosthesis , and 50 patients ( 52 knees ) with an average age of 72 years , a MB prosthesis . All implants were cemented and the patella was routinely resurfaced . Preoperatively , there were no differences between the two groups , and surgical procedure and postoperative protocol were the same for both . At an average follow-up of 7.1 years , no significant differences of FB over MB design could be demonstrated with respect to the American Knee Society score ( AKSS ) , pain score , a question naire of general health ( SF-12 score ) , range of motion ( ROM ) , or complication rates . Radiographs showed no significant difference in prosthetic alignment or evidence of loosening . Two knees with a MB design required reoperation , one for persistent joint stiffness and another to treat septic loosening . One patient with a MB prosthesis with signs of tibial component loosening was asymptomatic . We conclude that at mid-term follow-up there is no evidence to prove the superiority of MB over FB TKA with regard to the clinical and radiographic results",
"The purpose of this prospect i ve , r and omized study was to compare the early clinical and functional results of primary total knee arthroplasty using a fixed-bearing ( FB ) and a rotating-platform ( RP ) prosthesis . Outcomes including range of motion ( ROM ) , Knee Society Score , Western Ontario MacMaster ( WOMAC ) , and Short Form-36 ( SF-36 ) were measured preoperatively and at 6 weeks , 3 months , 6 months , 1 year , and 2 years . Radiographic analysis was performed . There were 72 FB and 68 RP knees . The RP group had a greater ROM at 6 weeks and 1 year . This difference was not statistically significant at 2 years . There were no differences in the ROM at any other period . There were no significant differences in Knee Society Score , Short Form-36 , or Western Ontario MacMaster scores at any period . No clinical ly significant differences were noted in the radiographic analysis . The use of a FB or RP design did not affect the early functional outcomes after total knee arthroplasty",
"Purpose The anatomical l and mark for the anteroposterior ( AP ) axis of the proximal tibia and its variability was investigated in order to determine whether a certain l and mark could be employed as a reference axis for the proximal tibia after the rotating platform mobile bearing and fixed bearing total knee arthroplasties ( TKAs ) . Methods Eighty primary osteoarthritic knees were r and omized to undergo either rotating platform mobile bearing ( Group A , n = 40 ) or fixed bearing ( Group B , n = 40 ) TKAs , and were followed up for 31 and 30 months , respectively . The AP axes were defined for the distal femur , proximal tibia , ankle , and each TKA component on the reconstructed CT scan and the angles between the distal femoral AP axis and those of each bone or component were estimated . Clinical and radiographic outcomes were evaluated during the follow up . Results A significant difference was seen between the preoperative and postoperative rotational position of the proximal tibia relative to the distal femur following rotating platform mobile bearing TKA ( P = 0.014 ) whereas no such difference was seen after fixed bearing TKA . The mean postoperative alignment of the tibia differed between the two groups ( Group A : Group B = −2.9:0.2 , P = 0.010 ) and its variability was significantly greater in group A ( P including range of motion , knee society score , function score , HSS , and WOMAC score as well as the mean postoperative coronal tibiofemoral alignment between the two groups . Conclusion The unpredictable change in the rotational axis of the tibia and its broad variability after rotating platform mobile bearing TKA may provide a warning against the use of a fixed l and mark for establishing tibial rotational alignment . Level of evidence Prospect i ve comparative study , Level II",
"This prospect ively blinded r and omized controlled study evaluated the difference in the functional and radiological outcomes in patients who received a press-fit condylar Sigma cemented cruciate-substituting total knee arthroplasty with either a rotating platform ( RP ) or a fixed bearing ( FB ) . There were 51 joints in 49 patients : 24 joints in the RP group ( mean follow-up , 43 months ) and 27 joints in the FB group ( mean follow-up , 40 months ) . At baseline , there was no significant difference in age , body mass index , preoperative diagnosis , Charnley class , range of motion , clinical and functional scores , between the RP and FB groups . At mid-term follow up both the RP and FB give equivalent results , but patients with the RP tended to have a higher activity level score"
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BACKGROUND AND PURPOSE Several studies have suggested that exposure to " triggers , " could precipitate the onset of ischemic stroke ( IS ) . We performed a systematic review of the potential triggers of IS . METHODS Two independent review ers identified studies published between January 1980 and June 2010 from MEDLINE and Embase . Where appropriate , odds ratios ( ORs ) were combined . RESULTS A total of 26 studies identified 12 potential triggers . Twenty-two studies used a case-control design , and hazard period duration s ranged from 2 hours to 3 months . The majority of studies were dedicated to alcohol abuse ( n = 10 ) and clinical infection ( n = 12 ) . There was a significant association between IS and alcohol abuse of > 40 to 60 g within the preceding 24 hours ( OR = 2.66 ; 95 % CI , 1.54 to 4.61 ) or > 150 g within the previous week ( OR = 2.47 ; 95 % CI , 1.52 to 4.02 ) and infection within the previous week ( OR = 2.91 ; 95 % CI , 1.41 to 6.00 ) or within the previous month ( OR = 2.41 ; 95 % CI , 1.78 to 3.27 ) . Other triggers have been far less investigated . There was a significant association between IS and anger , heavy eating , negative or positive emotions , sudden posture change in response to a startling event , birthday , and psychological distress and no significant association with drug abuse or heavy physical exertion . Regarding method ological issues , patients were rarely blinded to study objectives , and interviewers were rarely blinded to patient status . CONCLUSIONS Research on triggers of IS has been mainly focused on acute alcohol abuse and clinical infection . More research is needed on factors such as physical exertion or acute stress . Future studies should use more appropriate design s and examine different hazard periods
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"Background and Purpose — Vascular death rates and hospitalizations for stroke are increased during influenza epidemics . Influenza vaccination may prevent stroke . We investigated whether influenza vaccination is associated independently with reduced odds of stroke and whether effects are confined to stroke subgroups and winter seasons and shared by other vaccinations . Methods — During 18 months , we performed st and ardized interviews assessing vaccination status , risk factors , health-related behavior , and socioeconomic factors in 370 consecutive patients with ischemic or hemorrhagic stroke or transient ischemic attack ( TIA ) and 370 age- and sex-matched control subjects selected r and omly from the population . Results — Influenza vaccination during the last vaccination campaign was less common in patients ( 19.2 % ) than control subjects ( 31.4 % ; P influenza vaccination ( odds ratio [ OR ] , 0.46 ; 95 % CI , 0.28 to 0.77 ) but not other combined recent vaccinations ( OR , 0.80 ; 95 % CI , 0.42 to 1.43 ) were associated with reduced odds of stroke/TIA . Significant effects were found in men , older subjects ( > 65 years ) , subjects with previous vascular diseases , and regarding ischemic stroke ; nonsignificant trends existed in women , younger subjects , and regarding hemorrhagic stroke . In etiologic subgroups of cerebral ischemia , similar effects were found . No protective effects were found during summer months ; however , results also varied considerably between both winter seasons examined . Conclusions — These results support the hypothesis that influenza vaccination may be associated with reduced stroke risk . However , residual confounding can not be excluded , and interventional studies are required to evaluate the role of influenza vaccination in stroke prevention",
"The association of cocaine and amphetamine use with hemorrhagic and ischemic stroke is based almost solely on data from case series . The limited number of epidemiologic studies of stroke and use of cocaine and /or amphetamine have been done in setting s that serve mostly the poor and /or minorities . This case-control study was conducted in the defined population comprising members of Kaiser Permanente of Northern and Southern California . We attempted to identify all incident strokes in women ages 15–44 years during a 3-year period using hospital admission and discharge records , emergency department logs , and payment requests for out-of-plan hospitalizations . We selected controls , matched on age and facility of usual care , at r and om from healthy members of the health plan . We obtained information in face-to-face interviews . There were 347 confirmed stroke cases and 1,021 controls . The univariate matched odds ratio for stroke in women who admitted to using cocaine and /or amphetamine was 8.5 ( 95 % confidence interval = 3.6–20.0 ) . After further adjustment for potential confounders , the odds ratio in women who reported using cocaine and /or amphetamine was 7.0 ( 95 % confidence interval = 2.8–17.9 ) . The use of cocaine and /or amphetamine is a strong risk factor for stroke in this socioeconomically heterogeneous , insured urban population . ( Epidemiology 1998 ; 9:596–600",
"Background and Purpose — The relationship between alcohol consumption and cerebral infa rct ion remains uncertain , and few studies have investigated whether the relationship varies by alcohol type or is present in young adults . We examined the relationship between alcohol consumption , beverage type , and ischemic stroke in the Stroke Prevention in Young Women Study . Methods — All 59 hospitals in the greater Baltimore-Washington area participated in a population -based case-control study of stroke in young women . Case patients ( n=224 ) were aged 15 to 44 years with a first cerebral infa rct ion , and control subjects ( n=392 ) , identified by r and om-digit dialing , were frequency matched by age and region of residence . The interview assessed lifetime alcohol consumption and consumption and beverage type in the previous year , week , and day . ORs were obtained from logistic regression models controlling for age , race , education , and smoking status , with never drinkers as the referent . Results — Alcohol consumption , up to 24 g/d , in the past year was associated with fewer ischemic strokes ( 24 g/d : OR 0.95 , 95 % CI 0.43 to 2.10 ) in comparison to never drinking . Analyses of beverage type ( beer , wine , liquor ) indicated a protective effect for wine consumption in the previous year ( risk of ischemic stroke in young women",
"A case-control design involving only cases may be used when brief exposure causes a transient change in risk of a rare acute-onset disease . The design resembles a retrospective nonr and omized crossover study but differs in having only a sample of the base population -time . The average incidence rate ratio for a hypothesized effect period following the exposure is estimable using the Mantel-Haenszel estimator . The duration of the effect period is assumed to be that which maximizes the rate ratio estimate . Self-matching of cases eliminates the threat of control- selection bias and increases efficiency . Pilot data from a study of myocardial infa rct ion onset illustrate the control of within-individual confounding due to temporal association of exposures",
"BACKGROUND AND PURPOSE Heavy binge drinking may trigger the onset of embolic stroke and acute myocardial infa rct ion , but the underlying mechanisms are unclear . The effects of binge drinking on the hemostatic system and its circadian variation have not been investigated . We investigated the effects of an acute intake of a large dose of alcohol ( 1.5 g/kg ) . METHODS Twelve healthy , nonsmoking men participated in sessions where they were served ethanol in fruit juice or served fruit juice alone and , lying in a supine position , were followed up for 12 to 24 hours . The treatments were r and omized and separated from each other by a 1-week washout period . Blood and urine were collected for hemostatic measurements . RESULTS The urinary excretion of the platelet thromboxane A(2 ) metabolite 2 , 3-dinor-thromboxane B(2 ) was significantly ( P endothelial prostacyclin metabolite 2,3-dinor-6-ketoprostagl and in F(1alpha ) excretion were negligible . A 7-fold increase in plasminogen activator inhibitor 1 activity was observed after both morning ( P thromboxane-mediated platelet activation . The observations also demonstrate alcohol-induced changes in the normal circadian periodicity of the hemostatic system in subjects not accustomed to consumption of alcohol ",
"This study , conducted in Auckl and , New Zeal and , over 2 years from March 1986 , used a case-control design to investigate the hypothesis that alcohol acutely increases the risk of both nonfatal myocardial infa rct ion and coronary death in the 24 hours after drinking , among regular drinkers . The nonfatal myocardial infa rct ion analyses included 278 male and 60 female cases identified from a population -based coronary heart disease surveillance program and 458 male and 266 female controls r and omly selected from the same population matched by age and sex . In the coronary death analyses , 172 male and 16 female coronary death cases from the same surveillance program and a population -based sample of 294 males and 165 females who were age and sex matched were examined . Information on alcohol consumption in the 24 hours before the coronary event in cases and a comparable 24-hour period in controls was collected . Study subjects all drank alcohol regularly at least once per month and were aged 25 - 64 years . Controls were more likely than cases to report a drinking episode in the 24-hour period examined in both sexes and for fatal and nonfatal disease . After controlling for possible confounding , the authors found that drinkers had a consistently lower estimated risk of both fatal and nonfatal coronary heart disease than participants reporting no alcohol in the previous 24 hours . The odds ratios ranged from 0.75 ( 95 % confidence interval 0.62 - 0.90 ) for nonfatal myocardial infa rct ion in men to 0.46 ( 95 % confidence interval 0.19 - 1.10 ) for coronary death in women . There were no clear differences in estimated acute risk among those who drank one or two drinks , three or four drinks , or more than four drinks in the 24-hour period . These findings suggest that , contrary to previous speculation , alcohol consumption may acutely reduce coronary heart disease risk",
"The role of preceding infection as a risk factor for ischaemic stroke was investigated in a case-control study of 54 consecutive patients under 50 years of age with brain infa rct ion and 54 r and omly selected controls from the community matched for sex and age . Information about previous illnesses , smoking , consumption of alcohol , and use of drugs was taken . A blood sample was analysed for st and ard biochemical variables and serum cholesterol , high density lipoprotein cholesterol , triglyceride , and fasting blood glucose concentrations determined . Titres of antimicrobial antibodies against various bacteria , including Staphylococcus , Streptococcus , Yersinia , and Salmonella and several viruses were determined . Febrile infection was found in patients during the month before the brain infa rct ion significantly more often than in controls one month before their examination ( 19 patients v three controls ; estimated relative risk 9·0 ( 95 % confidence interval 2·2 to 80·0 ) ) . The most common preceding febrile infection was respiratory infection ( 80 % ) . Infections preceding brain infa rct ion were mostly of bacterial origin based on cultural , serological , and clinical data . In conditional logistic regression analysis for matched pairs the effect of preceding febrile infection remained significant ( estimated relative risk 14·5 ( 95 % confidence interval 1·9 to 112·3 ) ) when tested with triglyceride concentration , hypertension , smoking , and preceding intoxication with alcohol . Although causality can not be inferred from these data and plausible underlying mechanisms remain undetermined , preceding febrile infection may play an important part in the development of brain infa rct ion in young and middle aged patients",
"BACKGROUND AND PURPOSE An increasing number of reports have linked infections to atherosclerosis and thrombosis . Thus , use of antibiotics may lower the risk of developing cerebrovascular disease . We investigated whether antibiotic use is associated with the risk of stroke in elderly individuals treated for hypertension . METHODS A cohort of 29 937 elderly subjects initiating antihypertensive therapy between 1982 and 1995 was formed from the Quebec healthcare insurance data base . A nested case-control design was used in which each subject hospitalized with a primary discharge diagnosis of stroke between 1987 and 1995 was matched on calendar time to 5 r and omly selected controls from the cohort . Conditional logistic regression was used to estimate odds ratios of stroke after adjustment for predisposing factors . RESULTS We identified 1888 cases and 9440 controls . The overall adjusted odds ratio for current antibiotic use was 0.80 ( 95 % confidence interval , 0.63 to 1.01 ) , and that for recent use was 0.81 ( 95 % confidence interval , 0.70 to 0.94 ) . Penicillin was the only individual antibiotic class that showed a protective association across different time windows . No significant association was found between stroke risk and the use of fluoroquinolones , macrolides , tetracyclines , or cephalosporins . CONCLUSIONS Although no clear , consistent associations between overall antibiotic use and cerebrovascular disease could be found , an intriguing association between penicillin use and stroke should be explored further",
"BACKGROUND AND PURPOSE Previous infection is discussed as a risk factor for ischemic stroke in children and younger adults . We tested the hypothesis that the role of recent infection in cerebrovascular ischemia is not restricted to younger patients and investigated which infections are mainly relevant in this respect . METHODS We performed a case-control study with 197 patients aged 18 to 80 years with acute cerebrovascular ischemia and 197 r and omly selected control subjects matched for sex , age , and area of residence . RESULTS Infection within 1 week before ictus or examination was significantly more common among patients ( 38 of 197 ) than control subjects ( 10 of 197 ; odds ratio [ OR ] , 4.5 ; 95 % confidence interval [ CI ] , 2.1 to 9.7 ) . Patients more often had febrile and subfebrile infections ( > or = 37.5 degrees C ) than control subjects ( 29 of 197 versus 5 of 197 ; OR , 7.0 ; 95 % CI , 2.5 to 20 ) . Respiratory tract infections were most common in both groups . Bacterial infections dominated among patients but not among control subjects . Infection increased the risk for cerebrovascular ischemia in all age groups ; this reached significance for patients aged 51 to 60 and 61 to 70 years . The profile of vascular risk factors was similar in patients with and patients without previous infection . Infection remained a significant risk factor when previous stroke , hypertension , diabetes mellitus , coronary heart disease , and current smoking were included as covariates in a logistic model ( OR , 4.6 ; 95 % CI , 1.9 to 11.3 ) . CONCLUSIONS Recent infection , primarily of bacterial origin , may be a risk factor for cerebrovascular ischemia in older as well as younger patients",
"Background : Recent studies have suggested that previous infection may be a risk factor for ischemic stroke mainly in young and middle-aged patients . The present study sought to further investigate the association between recent inflammatory events ( IE ) and ischemic stroke without age restriction and to determine the role of recent IE in different ischemic stroke subtypes . Methods : We performed a case-control study with 93 consecutive hospitalized stroke patients and 200 ( 107 hospital and 93 community ) controls . Acute IE , both infective and non-infective , occurring in the previous 30 days were assessed using a st and ard question naire . The TOAST criteria were used for ischemic stroke subtypes classification . Results : Acute IE in the previous 30 and 7 days were significantly and independently associated with ischemic stroke ( 37/93 vs. 47/200 ; OR 2.23 , 95 % CI 1.26–3.96 and 17/93 vs.16/200 ; OR 2.45 , 95 % IC 1.11–5.39 , respectively ) . Stratifying for stroke subtypes , acute IE significantly and independently increased the risk of atherothrombotic ( OR 5.72 , 95 % CI 2.14–15.25 ) and cardioembolic stroke ( OR 3.02 , 95%CI 1.20–7.63 ) . Conclusions : Acute IE increase the risk of acute ischemic stroke of atherothrombotic and cardioembolic type independently of other predisposing factors . Implication s for daily clinical practice , in relation to prevention and treatment of IE in patients at risk , have to be explored",
"Background More attention has been paid to psychosocial conditions as possible risk factors for cardiovascular disease ( CVD ) and the impact of accumulated major life events ( MLE ) on the development of CVD has received little attention . Design The aim of this study was to explore the influences of MLE on CVD risk in a large cohort study . Methods The study population consisted of 9542 r and omly selected adults free of CVD examined in the Copenhagen City Heart Study in 1991 - 1994 and followed up for CVD defined as myocardial infa rct ion or ischaemic stroke until 2001 . MLE were analysed using an 11-item question naire and hazard ratios ( HR ) were calculated using the Cox proportional hazards model . Results During follow-up there were 443 myocardial infa rct ions ( MI ) and 350 ischaemic strokes . Financial problems in both childhood and adulthood were associated with risk of stroke with an HR of 1.71 ( 95 % CI : 1.29 - 2.26 ) and 1.60 ( 1.12 - 2.30 ) , respectively . Accumulation of M LE was also associated with risk of stroke with HR reaching a maximum of 1.41 ( 95 % CI : 1.06 - 1.90 ) for more than one event in childhood and 1.49 ( 95 % CI : 1.09 - 2.04 ) for more than one event in adulthood . MLE accumulated over a life course showed a dose-response relationship with stroke . Associations were somewhat attenuated by adjustment for vital exhaustion suggesting a mediating role , but not by adjustment for behavioural risk factors . There were no associations between MLE and MI . Conclusion In this population -based cohort study , we found that MLE conveyed a moderately increased risk of stroke partly mediated through vital exhaustion . We found no association between MLE and the risk of MI",
"Background and Purpose — Increasing evidence links infections to atherosclerosis . Case – control and cohort studies have found that infections , especially respiratory and dental , are associated with coronary heart disease . However , data on the association of infections with cerebrovascular disease are limited , especially beyond Europe and the United States . We assessed the relationship between recent infections and atherothrombotic disease in a South American cohort . Methods — We conducted a case – control study of 105 cases and 354 control subjects in a Buenos Aires healthcare system matched by age ( mean age , 73.2±12.3 and 72.9±12.8 years ) , sex , and major cardiovascular risk factors . Cases were patients hospitalized with atherothrombotic ischemic stroke from December 2006 to October 2007 . Control subjects were r and omly assigned from an electronic outpatient data base . Data from the preceding year on inpatient and ambulatory respiratory , urinary and abdominal infections as well as peripheral white blood cell count were collected . Results — Infections were more frequent in cases than control subjects ( 29 % versus 13 % ; OR , 2.6 ; 95 % CI , 1.4 to 4.5 ; P=0.0004 ) ; however , this was driven by community-acquired respiratory tract infections ( 19 % versus 6 % ; OR , 3.9 ; 95 % CI , 1.9 to 8 ; P types of infection . Respiratory tract infections were the most prevalent type of infection during the 3 months before an atherothrombotic ischemic event , occurring more in cases compared with control subjects ( 17 % versus 4 % ; OR , 5 ; 95 % CI , 2.2 to 11.3 ; P ) . White blood cell count was slightly higher in cases versus control subjects ( 7602±2058 versus 7121.6±1947 , P=0.01 ) . Conclusion — In this South American cohort , recent respiratory tract infections were significantly associated with atherothrombotic stroke , suggesting that prompt identification and treatment of individuals with or at risk for these infections may mitigate the burden from this type of stroke",
"Objective : To investigate the role of vigorous physical exertion and anger as triggers of acute coronary syndromes ( ACS ) and to identify the clinical and sociodemographic correlates of triggering . Design : Prospect i ve observational clinical cohort study . Setting : Four coronary care units in the London area . Patients : 295 men and women with electrocardiographically and biochemically verified ACS . Main outcome measures : Physical exertion in the 1 h and anger in the 2 h before symptom onset were assessed with structured interviews . Control periods were the equivalent hours one day earlier and usual rates over the past six months . Data were analysed by case-crossover methods . Results : Physical exertion was reported by 10 % and anger by 17.4 % of patients in the hazard period . The risk of ACS onset after physical exertion compared with light or no activity was 3.50 ( 95 % confidence interval ( CI ) 1.37 to 10.6 ) . The risk of onset with anger was 2.06 ( 95 % CI 1.12 to 3.92 ) . Physical exertion during the hazard period was related to an absence of premonitory symptoms , presentation with an ST elevation myocardial infa rct ion ( STEMI ) , low socioeconomic deprivation and higher future cardiovascular risk . Anger during the hazard period was more common in younger , socioeconomically deprived patients who presented with a STEMI . Conclusions : Triggers are relevant across the spectrum of ACS . The distinct clinical and sociodemographic factors associated with physical exertion and anger suggest that different pathophysiological processes may be involved",
"BACKGROUND Alcohol has been implicated as a risk factor for idiopathic dilated cardiomyopathy ( DCM ) , but a causal relation has not been established . The objective of this study was to determine the association between alcohol consumption and DCM . METHODS Question naires detailing average weekly intake of alcohol , total lifetime consumption , and alcohol abuse were administered in a cohort of well-defined patients with DCM and a r and omly selected , population -based control group . RESULTS Significantly more of the 100 patients with DCM than the 211 members of the control group drank greater than the recommended weekly intake of alcohol ( 40 % vs 24 % ; p alcohol abusers according to the CAGE question naire ( 27 % vs 16 % ; p average total lifetime consumption measured in units of alcohol was also significantly greater in cases than in the control group ( 31,200 vs 7,904 ; p Patients with familial DCM were not significantly more likely to consume alcohol above recommended limits or to be alcohol abusers compared with nonfamilial cases . CONCLUSIONS This study confirms previous suspicion of a causal association between alcohol and DCM , with significantly more patients than members of the control group either abusing alcohol or drinking it in excess of recommended limits"
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Many chronic diseases and illnesses are caused by the lifestyle , including the physical activity habits , of an individual . As such , consistent high levels of exercise should be encouraged across the lifespan , to limit the risk of developing one of these conditions and allowing for healthy aging to occur . Exercise prescriptions that encourage high completion and adherence rates in an independent manner and improve health related outcomes should be provided to individuals . To date , no review has identified optimal prescriptions of exercise to achieve this in sedentary middle-aged adults and this is important , given the higher risk of developing illnesses in this population as they age . This review examines the effects prescriptions of self-directed ( SD ) exercise has on adherence and health related outcomes in sedentary middle-aged individuals in good general health currently and aims to identify the most suitable forms of planned SD exercise that can be carried out independently . A systematic search of the electronic data base PubMed was conducted . R and omised controlled trials published in English between February 2007 and February 2017 examining healthy , sedentary middle-aged participants only were included . Studies were critically appraised using the PEDro scale and data were presented on st and ardised tables . Twenty-one articles examining different aerobic activities , combined training and non-traditional exercise prescriptions were included . This review summarised in detail the effects SD exercise interventions had on sedentary middle-aged individuals alongside the adherence to the prescriptions . SD exercise was seen to be beneficial for improving metabolic outcomes physical characteristics , cardiorespiratory fitness and functional measures
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"Background Raisins are a significant source of dietary fiber and polyphenols , which may reduce cardiovascular disease ( CVD ) risk by affecting lipoprotein metabolism and inflammation . Walking represents a low intensity exercise intervention that may also reduce CVD risk . The purpose of this study was to determine the effects of consuming raisins , increasing steps walked , or a combination of these interventions on blood pressure , plasma lipids , glucose , insulin and inflammatory cytokines . Results Thirty-four men and postmenopausal women were matched for weight and gender and r and omly assigned to consume 1 cup raisins/d ( RAISIN ) , increase the amount of steps walked/d ( WALK ) or a combination of both interventions ( RAISINS + WALK ) . The subjects completed a 2 wk run-in period , followed by a 6 wk intervention . Systolic blood pressure was reduced for all subjects ( P = 0.008 ) . Plasma total cholesterol was decreased by 9.4 % for all subjects ( P in plasma LDL cholesterol ( LDL-C ) ( P were decreased by 19.5 % for WALK ( P effect ) . Plasma TNF-α was decreased from 3.5 ng/L to 2.1 ng/L for RAISIN ( P reduction in plasma sICAM-1 ( P adding raisins to the diet or increasing steps walked have distinct beneficial effects on CVD risk",
"Background National guidelines call for exercise of at least moderate intensity ; however , recommending self-paced exercise may lead to better adherence , particularly among overweight and obese adults . Purpose The purpose of this study was to test proof-of-concept for recommending self-paced exercise among overweight adults . Methods Fifty-nine healthy , low-active ( exercise a 6-month print-based exercise promotion program with the goal of walking 30–60 min/day . Participants were surreptitiously r and omly assigned to receive a recommendation for either self-paced ( n = 30 ) or moderate ( 64–76 % maximum heart rate ; n = 29 ) intensity exercise . All participants used electronic diaries and heart rate monitors to track exercise frequency , duration , and intensity . Results The self-paced condition reported more minutes/week of walking ( f2 = 0.17 , p = 0.045 ) and a trend toward greater exercise-related energy expenditure/week ( f2 = 0.12 , p = 0.243 ) , corresponding to approximately 26 additional minutes/week and 83 additional kilocalories/week over 6 months . Conclusions Explicit recommendation for self-paced exercise may improve adherence to exercise programs among overweight and obese adults",
"INTRODUCTION Exercise can increase bone strength , but to be effective in reducing fracture risk , exercise must be feasible enough to be adopted into daily life and influence potentially vulnerable skeletal sites such as the superolateral cortex of the femoral neck , where thinning is associated with increased fracture risk . Brief , high-impact exercise increases femoral neck bone density but the optimal frequency of such exercise and the location of bone accrual is unknown . This study thus examined ( 1 ) the effectiveness of different weekly frequencies of exercise on femoral neck BMD and ( 2 ) whether BMD change differed between hip sites using a high-impact , unilateral intervention . METHODS Healthy premenopausal women were r and omly assigned to exercise 0 , 2 , 4 , or 7 days/week for 6 months . The exercise intervention incorporated 50 multidirectional hops on one r and omly selected leg . BMD was measured by DXA at baseline and after 6 months of exercise . Changes in the exercise leg were compared between groups using ANCOVA , with change in the control leg and baseline BMD as covariates . RM-MANOVA was conducted to determine whether bone changes from exercise differed between hip sites . RESULTS 61 women ( age 33.6+/-11.1 years ) completed the intervention . Compliance amongst exercisers was 86.7+/-10.6 % . Peak ground reaction forces during exercise increased from 2.5 to 2.8 times body weight . The change in femoral neck BMD in the exercise limb ( adjusted for change in the control limb and baseline BMD ) differed between groups ( p=0.015 ) , being -0.3 % ( -1.2 to 0.6 ) , 0.0 % ( -1.0 to 1.0 ) , 0.9 % ( -0.1 to 2.0 ) and 1.8 % ( 0.8 to 2.8 ) in those exercising 0 , 2 , 4 and 7 days per week , respectively . When BMD changes at upper neck , lower neck and trochanter were compared using RM-MANOVA , a significant exercise effect was observed ( p=0.048 ) , but this did not differ significantly between sites ( p=0.439 ) despite greatest mean increases at the upper femoral neck . CONCLUSIONS Brief , daily hopping exercises increased femoral neck BMD in premenopausal women but less frequent exercise was not effective . Brief high-impact exercise may have a role in reducing hip fragility , but may need to be performed frequently for optimal response",
"Aims To investigate the effect of 16 weeks of aerobic training performed at two different intensities on nitric oxide ( tNOx ) availability and iNOS/nNOS expression , oxidative stress ( OS ) and inflammation in obese humans with or without type 2 diabetes mellitus ( T2DM ) . Methods Twenty-five sedentary , obese ( BMI > 30 kg/m2 ) males ( 52.8 ± 7.2 years ) ; 12 controls versus 13 T2DM were r and omly allocated to four groups that exercised for 30 min , three times per week either at low ( Fat-Max ; 30–40 % VO2max ) or moderate ( Tvent ; 55–65 % VO2max ) intensity . Before and after training , blood and muscle sample s ( v. lateralis ) were collected . Results Baseline erythrocyte glutathione was lower ( 21.8 ± 2.8 vs. 32.7 ± 4.4 nmol/ml ) and plasma protein oxidative damage and IL-6 were higher in T2DM ( 141.7 ± 52.1 vs. 75.5 ± 41.6 nmol/ml ) . Plasma catalase increased in T2DM after Tvent training ( from 0.98 ± 0.22 to 1.96 ± 0.3 nmol/min/ml ) . T2DM groups demonstrated evidence of oxidative damage in response to training ( elevated protein carbonyls ) . Baseline serum tNOx were higher in controls than T2DM ( 18.68 ± 2.78 vs. 12.34 ± 3.56 μmol/l ) . Training at Tvent increased muscle nNOS and tNOx in the control group only . Pre-training muscle nNOS was higher in controls than in T2DMs , while the opposite was found for iNOS . No differences were found after training for plasma inflammatory markers . Conclusion Exercise training did not change body composition or aerobic fitness , but improved OS markers , especially when performed at Tvent . Non-diabetics responded to Tvent training by increasing muscle nNOS expression and tNOx levels in skeletal muscle while these parameters did not change in T2DM , perhaps due to higher insulin resistance ( unchanged after intervention )",
"Aims . High-intensity interval training ( HIIT ) leads to improvements in various markers of cardiometabolic health but adherence to HIIT following a supervised laboratory intervention has yet to be tested . We compared self-report and objective measures of physical activity after one month of independent exercise in individuals with prediabetes who were r and omized to HIIT ( n = 15 ) or traditional moderate-intensity continuous training ( MICT , n = 17 ) . Method . After completing 10 sessions of supervised training participants were asked to perform HIIT or MICT three times per week for four weeks . Results . Individuals in HIIT ( 89 ± 11 % ) adhered to their prescribed protocol to a greater extent than individuals in MICT ( 71 ± 31 % ) as determined by training logs completed over one-month follow-up ( P = 0.05 , Cohen 's d = 0.75 ) . Minutes spent in vigorous physical activity per week measured by accelerometer were higher in HIIT ( 24 ± 18 ) as compared to MICT ( 11 ± 10 ) at one-month follow-up ( P = 0.049 , Cohen 's d = 0.92 ) . Cardiorespiratory fitness and systolic blood pressure assessed at one-month follow-up were equally improved ( P 's individuals with prediabetes can adhere to HIIT over the short-term and do so at a level that is greater than MICT ",
"QUESTIONS Does the PEDro scale measure only one construct ie , the method ological quality of clinical trials ? What is the hierarchy of items of the PEDro scale from least to most adhered to ? Is there any effect of year of publication of trials on item adherence ? Are PEDro scale ordinal scores equivalent to interval data ? DESIGN Rasch analysis of two independent sample s of 100 clinical trials from the PEDro data base scored using the PEDro scale . RESULTS Both sample s of PEDro data showed fit to the Rasch model with no item misfit . The PEDro scale item hierarchy was the same in both sample s , ranging from the most adhered to item r and om allocation , to the least adhered to item therapist blinding . There was no differential item functioning by year of publication . Original PEDro ordinal scores were highly correlated with transformed PEDro interval scores ( r = 0.99 ) . CONCLUSION The PEDro scale is a valid measure of the method ological quality of clinical trials . It is valid to sum PEDro scale item scores to obtain a total score that can be treated as interval level measurement and subjected to parametric statistical analysis",
"OBJECTIVE To evaluate short- ( 3 months ) and long-term ( 9 months ) effects of home-based exercise on adiponectin , exercise behavior and metabolic risk factors in middle-aged adults at diabetic risk . METHODS One hundred and thirty-five middle-aged adults ( 38 men , 97 women ) with at least one diabetic risk factor were r and omly assigned to either a home-based exercise group ( Ex-group ) or a usual care group ( C-group ) . Outcome measures included plasma adiponectin , exercise self-efficacy , physical activity , and metabolic risk factors , as follows : insulin levels , insulin resistance by homeostasis model assessment ( HOMA-IR ) , physical fitness , and components of metabolic syndrome . This study was conducted in metropolitan Taipei from 2004 to 2005 . RESULTS The Ex-group had improvements in exercise self-efficacy ( + 2.5 , p = 0.01 ) , body mass index ( BMI ) ( -0.6 kg/m2 , p flexibility ( + 2.4 cm , p BMI and flexibility at 9-month follow-up . The Ex-group exhibited significantly increased physical activity while the C-group exhibited decreased physical activity at 9-month follow-up ( p adiponectin ( p = 0.64 ) or other outcome measures over time . CONCLUSIONS Home-based exercise did not improve adiponectin levels , but significantly improved exercise behavior , and certain metabolic risk factors , with the effects maintained for 9-months in subjects with type 2 diabetic risk",
"The combination of low physical activity rates and increased cardiovascular deaths indicate the overwhelming need for behaviour change interventions that can effectively promote physical activity among sedentary women . This 11-week r and omised controlled trial examined the effects of an implementation intentions intervention on sedentary women 's walking behaviour . Seventy-five women ( M age = 48.17 ) were r and omly assigned to either a control group where they were required to self-monitor their daily pedometer-determined step count or to an experimental group where they were asked to form specific walking plans ( i.e. implementation intentions ) every 6 weeks and to self-monitor their daily pedometer-determined step count . Measures of exercise intentions , perceived behavioural control , scheduling and barrier self-efficacy were administered at baseline , week 6 and week 11 . Analyses indicated higher step counts over the first 6 weeks for women in the experimental condition ( p higher self-efficacy to schedule ( p overcome walking barriers ( p higher perceptions of behavioural control ( p women 's walking behaviour . Furthermore , the intervention did not have any effect on the strength of the goal intention – behaviour relationship . The findings suggest implementation intentions are an effective strategy for initiating leisure-time walking within sedentary women",
"This r and omized controlled trial examined whether the number of steps walked during an 11-week action planning intervention would mediate changes in sedentary women 's body image . Seventy-five healthy , sedentary women were r and omly assigned to either a control group , where they were required to self-monitor their daily pedometer-determined step count , or to an experimental group , where they were asked to self-monitor and form specific action plans for walking . Of the 75 participants r and omized , 41 were included in the efficacy analyses . Measured outcomes were satisfaction with physical functioning and physical appearance , and daily pedometer-determined step counts . Greater satisfaction with physical functioning and higher step counts were found for the experimental group . Moreover , the total number of steps walked over Weeks 2 - 11 was shown to partially mediate the effect of the intervention on satisfaction with physical functioning . These findings suggest that walking greater distances is associated with greater improvement in at least one aspect of women 's body images",
"Walking with poles ( Nordic walking , NW ) has become popular . We compared training responses of brisk walking ( W ) or NW on cardiorespiratory and neuromuscular fitness . We r and omized 121 non-obese sedentary women ( aged 50 - 60 ) to an NW or W group ( NWG , WG ) , to train 40 min four times weekly for 13 weeks . Intensity was based on subjective perception of exertion . Cardiorespiratory performance was assessed in four levels corresponding to 50 % , 65 % , 80 % and 100 % of peak VO(2 ) . Fifty-four NWG and 53 WG subjects completed the study . The mean intensity was about 50 % of heart rate ( HR ) reserve . The baseline peak VO(2 ) was 25.8 ( SD 3.9 ) mL/min/kg . Both groups improved peak VO(2 ) similarly ( NWG 2.5 mL/min/kg , 95 % confidence interval ( CI ) 1.9 - 3.3 ; WG 2.6 , CI 1.9 - 3.3 ) . In the submaximal stages while walking with or without poles , HR and lactate decreased after training in both groups , but the changes were not statistically significantly different between the groups . Of the neuromuscular tests after training , the only significant difference between the groups was in the leg strength in the one-leg squat , favoring WG . In conclusion , both training modes improved similarly health-enhancing physical fitness , and they were feasible and safe",
"BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However , the reliability of data obtained with most quality assessment scales has not been established . This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions . METHOD In the first study , 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base . In the second study , 2 raters rated 120 RCTs r and omly selected from the PEDro data base , and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings . The process was repeated by independent raters to create a second set of individual and consensus ratings . Reliability of ratings of PEDro scale items was calculated using multirater kappas , and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ) . RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters . The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals , and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ) . DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from \" fair \" to \" substantial , \" and the reliability of the total PEDro score was \" fair \" to \" good .",
"BACKGROUND The accumulation of physical activity ( PA ) throughout the day has been suggested as a means to increase PA behavior . It is not known , however , if accumulated PA results in equivalent increases in PA behavior compared with one continuous session . The purpose of this investigation was to compare changes in PA between participants assigned to walk daily in accumulated shorter bouts vs. one continuous session . METHODS In this 8-week r and omized controlled trial , 60 inactive women were r and omly assigned to one of the following : ( 1 ) control group , ( 2 ) 30 minutes a day of walking 5 days a week in one continuous long bout ( LB ) , or ( 3 ) three short 10-minute bouts ( SB ) of walking a day , all at a prescribed heart rate intensity . Walking was assessed by pedometer and self-reported walking log . Before and after measures were taken of average steps/day , resting systolic and diastolic blood pressure ( SBP , DBP ) , resting heart rate ( RHR ) , six-minute walk test ( 6MWT ) distance , height , weight , body mass index ( BMI ) , and hip and waist circumference . RESULTS Both walking groups significantly increased PA measured as steps/day compared to controls ( p hip circumference and significant increases in 6MWT distance compared to the control group . CONCLUSIONS Both walking groups significantly increased PA participation . LB group participants completed more walking at a higher intensity than the SB and control groups , which result ed in significant increases in health benefits",
"BACKGROUND Physical activity remains a valuable prevention for metabolic disease . The effects of Nordic walking on cardiovascular risk factors were determined in overweight individuals with normal or disturbed glucose regulation . METHODS We included 213 individuals , aged 60 ± 5.3 years and with body mass index ( BMI ) of 30.2 ± 3.8 kg/m(2 ) ; of these , 128 had normal glucose tolerance ( NGT ) , 35 had impaired glucose tolerance ( IGT ) and 50 had type 2 diabetes mellitus ( T2DM ) . Participants were r and omized to unaltered physical activity or to 5 h per week of Nordic walking with poles , for a 4-month period . Dietary habits were unaltered . BMI , waist circumference , blood pressure , glucose tolerance , clinical chemistry , maximal oxygen uptake ( peak VO(2 ) ) and self-reported physical activity ( question naire ) were assessed at the time of inclusion and after 4 months . The participants in the exercise-intervention group kept a walking diary . RESULTS In the NGT exercise group , self-reported physical activity increased markedly , and body weight ( -2.0 ± 3.8 kg ) , BMI ( -0.8 ± 1.4 kg/m(2 ) ) and waist circumference ( -4.9 ± 4.4 cm ) ( mean ± SD ) decreased . Exercise power output ( 12.9 ± 9.9 W ) and peak VO(2 ) ( 2.7 ± 2.8 mL/kg/min ) increased in the IGT exercise group . More cardiovascular risk factors were improved after exercise intervention in people with NGT compared with those with IGT or T2DM . Exercise capacity improved significantly in all three groups of participants who reported at least 80 % compliance with the scheduled exercise . CONCLUSIONS Nordic walking improved anthropometric measurements and exercise capacity . However , unsupervised Nordic walking may not provide a sufficient increase in exercise intensity to achieve ultimate health-promoting benefits on the cardiovascular parameters assessed in this study , particularly for those with disturbed glucose regulation",
"Abstract Aims /hypothesisBy use of a parallel and partly crossover r and omised , controlled trial design we sought to eluci date the underlying mechanisms behind the advantageous effects of interval walking training ( IWT ) compared with continuous walking training ( CWT ) on glycaemic control in individuals with type 2 diabetes . We hypothesised that IWT , more than CWT , would improve insulin sensitivity including skeletal muscle insulin signalling , insulin secretion and disposition index ( DI ) . Methods By simple r and omisation ( sequentially numbered , opaque sealed envelopes ) , eligible individuals ( diagnosed with type 2 diabetes , no exogenous insulin treatment ) were allocated to three groups : a control group ( CON , n = 8) , an IWT group ( n = 12 ) and an energy expenditure-matched CWT group ( n = 12 ) . Training groups were prescribed free-living training , five sessions per week ( 60 min/session ) . A three-stage hyperglycaemic clamp , including glucose isotope tracers and skeletal muscle biopsies , was performed before and after a 4 month intervention in a hospitalised setting . No blinding was performed . Results The improved glycaemic control , which was only seen in the IWT group , was consistent with IWT-induced increases in insulin sensitivity index ( 49.8 ± 14.6 % ; p ) , peripheral glucose disposal ( 14.5 ± 4.9 % ; p and DI ( 66.2 ± 21.8 % ; p only IWT improved insulin signalling in skeletal muscle via increased insulin-stimulated phosphorylation of AS160 ( 29.0 ± 10.8 % ; p in insulin secretion during hyperglycaemia alone , hyperglycaemia + glucagon-like peptide 1 infusion or arginine injection . Conclusions /interpretationIWT maintains insulin secretion and improves insulin sensitivity and DI , in contrast to energy expenditure-matched CWT . These results suggest that training with alternating intensity , and not just training volume and mean intensity , is a key determinant of changes in whole body glucose disposal in individuals with type 2 diabetes . Trial registration : Clinical Trials ( NCT01234155 )",
"OBJECTIVE To evaluate the effect of structured vs. non-structured internet-delivered exercise recommendations on aerobic exercise capacity and cardiovascular risk profile in overweight sedentary employees . METHODS 140 employees of an automobile company ( 11 % female , median age 48 years ( range 25 - 60 ) , BMI 29.0 kg/m(2 ) ( 25.0 - 34.8 ) ) were r and omized in a 3:2 ratio to an intervention group receiving structured exercise schedules or a control group choosing workouts individually via an interactive website . The 12-week intervention took place in Munich , Germany , during summer 2008 . Main outcome measure was performance at the lactate anaerobic threshold ( P(AT)/kg ) during ergometry . RESULTS 77 participants completed the study . The intervention group ( n=50 ) improved significantly in P(AT)/kg ( ( mean ( SD ) ) 1.68 ( 0.31 ) vs. 1.81 ( 0.33 ) W/kg ; p=0.002 ) , VO(2)peak ( 3.21 ( 0.63 ) vs. 3.35 ( 0.74 ) L/min ; p=0.04 ) , and waist circumference ( 100.5 ( 7.9 ) vs. 98.0 ( 7.8 ) cm ; p=0.001 ) . The control group ( n=27 ) improved significantly in P(AT)/kg ( 1.59 ( 0.38 ) vs. 1.80 ( 0.49 ) ; p waist circumference ( 101.9 ( 8.7 ) vs. 98.3 ( 8.5 ) cm ; p VO(2)peak . No significant between group differences in these outcome measures were noted . CONCLUSION Structured , internet-delivered exercise recommendations are not superior to internet-delivered non-structured exercise recommendations in a workplace setting . Both lifestyle intervention strategies are , however , limited by high dropout rates",
"The adipokines chemerin and adiponectin are reciprocally related in the pathogenesis of insulin resistance and inflammation in obesity . Weight loss increases adiponectin and reduces chemerin , insulin resistance , and inflammation , but the effects of caloric restriction and physical activity are difficult to separate in combined lifestyle modification . We compared effects of diet- or exercise-induced weight loss on chemerin , adiponectin , insulin resistance , and inflammation in obese men . Eighty abdominally obese Asian men ( body mass index [ BMI ] ≥ 30 kg/m(2 ) , waist circumference [ WC ] ≥ 90 cm , mean age 42.6 years ) were r and omized to reduce daily intake by ~500 kilocalories ( n = 40 ) or perform moderate-intensity aerobic and resistance exercise ( 200 - 300 min/week ) ( n = 40 ) to increase energy expenditure by a similar amount for 24 weeks . The diet and exercise groups had similar decreases in energy deficit ( -456 ± 338 vs. -455 ± 315 kcal/day ) , weight ( -3.6 ± 3.4 vs. -3.3 ± 4.6 kg ) , and WC ( -3.4 ± 4.4 vs. -3.6 ± 3.2 cm ) . The exercise group demonstrated greater reductions in fat mass ( -3.9 ± 3.5 vs. -2.7 ± 5.3 kg ) , serum chemerin ( -9.7 ± 11.1 vs. -4.3 ± 12.4 ng/ml ) , the inflammatory marker high-sensitivity C-reactive protein ( -2.11 ± 3.13 vs. -1.49 ± 3.08 mg/L ) , and insulin resistance as measured by homeostatic model assessment ( -2.45 ± 1.88 vs. -1.38 ± 3.77 ) . Serum adiponectin increased only in the exercise group . Exercise-induced fat mass loss was more effective than dieting for improving adipokine profile , insulin resistance , and systemic inflammation in obese men , underscoring metabolic benefits of increased physical activity",
"Abstract Bressel , E , Wing , JE , Miller , AI , and Dolny , DG . High-intensity interval training on an aquatic treadmill in adults with osteoarthritis : effect on pain , balance , function , and mobility . J Strength Cond Res 28(8 ) : 2088–2096 , 2014—Although aquatic exercise is considered a potentially effective treatment intervention for people with osteoarthritis ( OA ) , previous research has focused primarily on calisthenics in a shallow pool with the inherent limitations on regulating exercise intensity . The purpose of this study was to quantify the efficacy of a 6-week aquatic treadmill exercise program on measures of pain , balance , function , and mobility . Eighteen participants ( age = 64.5 ± 10.2 years ) with knee OA completed a non-exercise control period followed by a 6-week exercise period . Outcome measures included visual analog scales for pain , posturography for balance , sit-to-st and test for function , and a 10-m walk test for mobility . The exercise protocol included balance training and high-intensity interval training ( HIT ) in an aquatic treadmill using water jets to destabilize while st and ing and achieve high ratings of perceived exertion ( 14–19 ) while walking . In comparison with pretests , participants displayed reduced joint pain ( pre = 50.3 ± 24.8 mm vs. post = 15.8 ± 10.6 mm ) , improved balance ( equilibrium pre = 66.6 ± 11.0 vs. post = 73.5 ± 7.1 ) , function ( rising index pre = 0.49 ± 0.19 % vs. post = 0.33 ± 0.11 % ) , and mobility ( walk pre = 8.6 ± 1.4 s vs. post = 7.8 ± 1.1 s ) after participating in the exercise protocol ( p = 0.03–0.001 ) . The same benefits were not observed after the non-exercise control period . Adherence to the exercise protocol was exceptional and no participants reported adverse effects , suggesting that aquatic treadmill exercise that incorporates balance and HIT training was well tolerated by patients with OA and may be effective at managing symptoms of OA",
"Arterial stiffness is a major contributor to the development of atherosclerosis and consequently cardiovascular disease . This study aim ed to examine whether 6 months of accumulated ( 3 × 10 minutes , 5 days/week ) brisk walking was sufficient to reduce arterial stiffness in sedentary , overweight individuals . Seventy-seven individuals ( 19 men , 58 women ; age , 30 - 55 years ) were r and omly allocated to one of three groups ; two groups completed 30 minutes of accumulated walking with either monthly or weekly telephone support ; the third group ( control ) performed stretching exercises . The walking groups were combined and telephone support included as a covariate . Anthropometry , blood pressure ( BP ) , blood lipids , pulse wave velocity ( PWV ) , and NOx ( surrogate marker for nitric oxide ) were measured at baseline , post-intervention and 4 months post-intervention . No changes were observed for anthropometry , BP , or lipids . However , at the end of the intervention , there was a decrease in PWV ( P increase in NOx ( P between PWV and NOx was also observed ( P A lifestyle approach to meeting current physical activity guidelines results in favorable alterations in arterial function in overweight individuals"
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Aims /hypothesisA healthy lifestyle has been widely recommended for the prevention and management of type 2 diabetes . However , no systematic review has summarised the relationship between combined lifestyle factors ( including , but not limited to , smoking , alcohol drinking , physical activity , diet and being overweight or obese ) and incident type 2 diabetes and risk of health outcomes among diabetic individuals . Methods EMBASE and PubMed were search ed up to April 2019 without language restrictions . References included in articles in relevant publications were also screened . Cohort studies investigating the combined associations of at least three lifestyle factors with incident type 2 diabetes and health outcomes among diabetic individuals were included . Review ers were paired and independently screened studies , extracted data and evaluated study quality . R and om-effects models were used to calculate summary HRs . Heterogeneity and publication bias tests were also conducted . Results Compared with participants considered to have the least-healthy lifestyle , those with the healthiest lifestyle had a 75 % lower risk of incident diabetes ( HR 0.25 [ 95 % CI 0.18 , 0.35 ] ; 14 studies with approximately 1 million participants ) . The associations were largely consistent and significant among individuals from different socioeconomic background s and baseline characteristics . Among individuals with type 2 diabetes ( 10 studies with 34,385 participants ) , the HRs ( 95 % CIs ) were 0.44 ( 0.33 , 0.60 ) for all-cause death , 0.51 ( 0.30 , 0.86 ) for cardiovascular death , 0.69 ( 0.47 , 1.00 ) for cancer death and 0.48 ( 0.37 , 0.63 ) for incident cardiovascular disease when comparing the healthiest lifestyle with the least-healthy lifestyle . Conclusions /interpretationAdoption of a healthy lifestyle is associated with substantial risk reduction in type 2 diabetes and long-term adverse outcomes among diabetic individuals . Tackling multiple risk factors , instead of concentrating on one certain lifestyle factor , should be the cornerstone for reducing the global burden of type 2 diabetes
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"Objectives To prospect ively assess the joint association of birth weight and established lifestyle risk factors in adulthood with incident type 2 diabetes and to quantitatively decompose the attributing effects to birth weight only , to adulthood lifestyle only , and to their interaction . Design Prospect i ve cohort study . Setting Health Professionals Follow-up Study ( 1986 - 2010 ) , Nurses ’ Health Study ( 1980 - 2010 ) , and Nurses ’ Health Study II ( 1991 - 2011 ) . Participants 149 794 men and women without diabetes , cardiovascular disease , or cancer at baseline . Main outcome measure Incident cases of type 2 diabetes , identified through self report and vali date d by a supplementary question naire . Unhealthy lifestyle was defined on the basis of body mass index , smoking , physical activity , alcohol consumption , and the alternate healthy eating index . Results During 20 - 30 years of follow-up , 11 709 new cases of type 2 diabetes were documented . The multivariate adjusted relative risk of type 2 diabetes was 1.45 ( 95 % confidence interval 1.32 to 1.59 ) per kg lower birth weight and 2.10 ( 1.71 to 2.58 ) per unhealthy lifestyle factor . The relative risk of type 2 diabetes associated with a combination of per kg lower birth weight and per unhealthy lifestyle factor was 2.86 ( 2.26 to 3.63 ) , which was more than the addition of the risk associated with each individual factor , indicating a significant interaction on an additive scale ( P for interaction birth weight alone , 59 % ( 57.1 % to 61.5 % ) to unhealthy lifestyle alone , and 18 % ( 13.9 % to 21.3 % ) to their interaction . Conclusion Most cases of type 2 diabetes could be prevented by the adoption of a healthier lifestyle , but simultaneous improvement of both prenatal and postnatal factors could further prevent additional cases",
"OBJECTIVE To examine whether improvements in health behaviors are associated with reduced risk of cardiovascular disease ( CVD ) in individuals with newly diagnosed type 2 diabetes . RESEARCH DESIGN AND METHODS Population -based prospect i ve cohort study of 867 newly diagnosed diabetic patients aged between 40 and 69 years from the treatment phase of the ADDITION-Cambridge study . Because the results for all analyses were similar by trial arm , data were pooled , and results were presented for the whole cohort . Participants were identified via population -based stepwise screening between 2002 and 2006 , and underwent assessment of physical activity ( European Prospect i ve Investigation into Cancer-Norfolk Physical Activity Question naire ) , diet ( plasma vitamin C and self-report ) , and alcohol consumption ( self-report ) at baseline and 1 year . A composite primary CVD outcome was examined , comprised of cardiovascular mortality , nonfatal myocardial infa rct ion , nonfatal stroke , and revascularization . RESULTS After a median ( interquartile range ) follow-up period of 5.0 years ( 1.3 years ) , 6 % of the cohort experienced a CVD event ( 12.2 per 1,000 person-years ; 95 % CI 9.3–15.9 ) . CVD risk was inversely related to the number of positive health behaviors changed in the year after diabetes diagnosis . The relative risk for primary CVD event in individuals who did not change any health behavior compared with those who adopted three/four healthy behaviors was 4.17 ( 95 % CI 1.02–17.09 ) , adjusting for age , sex , study group , social class , occupation , and prescription of cardioprotective medication ( P for trend = 0.005 ) . CONCLUSIONS CVD risk was inversely associated with the number of healthy behavior changes adopted in the year after the diagnosis of diabetes . Interventions that promote early achievement of these goals in patients with newly diagnosed diabetes could help reduce the burden of diabetes-related morbidity and mortality",
"IMPORTANCE Short-term studies show that bariatric surgery causes remission of diabetes . The long-term outcomes for remission and diabetes-related complications are not known . OBJECTIVES To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery . DESIGN , SETTING , AND PARTICIPANTS The Swedish Obese Subjects ( SOS ) is a prospect i ve matched cohort study conducted at 25 surgical departments and 480 primary health care centers in Sweden . Of patients recruited between September 1 , 1987 , and January 31 , 2001 , 260 of 2037 control patients and 343 of 2010 surgery patients had type 2 diabetes at baseline . For the current analysis , diabetes status was determined at SOS health examinations until May 22 , 2013 . Information on diabetes complications was obtained from national health registers until December 31 , 2012 . Participation rates at the 2- , 10- , and 15-year examinations were 81 % , 58 % , and 41 % in the control group and 90 % , 76 % , and 47 % in the surgery group . For diabetes assessment , the median follow-up time was 10 years ( interquartile range [ IQR ] , 2 - 15 ) and 10 years ( IQR , 10 - 15 ) in the control and surgery groups , respectively . For diabetes complications , the median follow-up time was 17.6 years ( IQR , 14.2 - 19.8 ) and 18.1 years ( IQR , 15.2 - 21.1 ) in the control and surgery groups , respectively . INTERVENTIONS Adjustable or nonadjustable b and ing ( n = 61 ) , vertical b and ed gastroplasty ( n = 227 ) , or gastric bypass ( n = 55 ) procedures were performed in the surgery group , and usual obesity and diabetes care was provided to the control group . MAIN OUTCOMES AND MEASURES Diabetes remission , relapse , and diabetes complications . Remission was defined as blood glucose mg/dL and no diabetes medication . RESULTS The diabetes remission rate 2 years after surgery was 16.4 % ( 95 % CI , 11.7%-22.2 % ; 34/207 ) for control patients and 72.3 % ( 95 % CI , 66.9%-77.2 % ; 219/303 ) for bariatric surgery patients ( odds ratio [ OR ] , 13.3 ; 95 % CI , 8.5 - 20.7 ; P the diabetes remission rates decreased to 6.5 % ( 4/62 ) for control patients and to 30.4 % ( 35/115 ) for bariatric surgery patients ( OR , 6.3 ; 95 % CI , 2.1 - 18.9 ; P the cumulative incidence of microvascular complications was 41.8 per 1000 person-years ( 95 % CI , 35.3 - 49.5 ) for control patients and 20.6 per 1000 person-years ( 95 % CI , 17.0 - 24.9 ) in the surgery group ( hazard ratio [ HR ] , 0.44 ; 95 % CI , 0.34 - 0.56 ; P Macrovascular complications were observed in 44.2 per 1000 person-years ( 95 % CI , 37.5 - 52.1 ) in control patients and 31.7 per 1000 person-years ( 95 % CI , 27.0 - 37.2 ) for the surgical group ( HR , 0.68 ; 95 % CI , 0.54 - 0.85 ; P = .001 ) . CONCLUSIONS AND RELEVANCE In this very long-term follow-up observational study of obese patients with type 2 diabetes , bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care . These findings require confirmation in r and omized trials . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01479452",
"BACKGROUND Our objective was to describe the reduction in relative risk of developing major chronic diseases such as cardiovascular disease , diabetes , and cancer associated with 4 healthy lifestyle factors among German adults . METHODS We used data from 23,153 German participants aged 35 to 65 years from the European Prospect i ve Investigation Into Cancer and Nutrition-Potsdam study . End points included confirmed incident type 2 diabetes mellitus , myocardial infa rct ion , stroke , and cancer . The 4 factors were never smoking , having a body mass index lower than 30 ( calculated as weight in kilograms divided by height in meters squared ) , performing 3.5 h/wk or more of physical activity , and adhering to healthy dietary principles ( high intake of fruits , vegetables , and whole-grain bread and low meat consumption ) . The 4 factors ( healthy , 1 point ; unhealthy , 0 points ) were summed to form an index that ranged from 0 to 4 . RESULTS During a mean follow-up of 7.8 years , 2006 participants developed new-onset diabetes ( 3.7 % ) , myocardial infa rct ion ( 0.9 % ) , stroke ( 0.8 % ) , or cancer ( 3.8 % ) . Fewer than 4 % of participants had zero healthy factors , most had 1 to 3 healthy factors , and approximately 9 % had 4 factors . After adjusting for age , sex , educational status , and occupational status , the hazard ratio for developing a chronic disease decreased progressively as the number of healthy factors increased . Participants with all 4 factors at baseline had a 78 % ( 95 % confidence interval [ CI ] , 72 % to 83 % ) lower risk of developing a chronic disease ( diabetes , 93 % [ 95 % CI , 88 % to 95 % ] ; myocardial infa rct ion , 81 % [ 95 % CI , 47 % to 93 % ] ; stroke , 50 % [ 95 % CI , -18 % to 79 % ] ; and cancer , 36 % [ 95 % CI , 5 % to 57 % ] ) than participants without a healthy factor . CONCLUSION Adhering to 4 simple healthy lifestyle factors can have a strong impact on the prevention of chronic diseases",
"OBJECTIVE To date no clinical trials have evaluated the role of dietary patterns on the incidence of microvascular diabetes complications . We hypothesized that a nutritional intervention based on the Mediterranean diet ( MedDiet ) would have greater protective effect on diabetic retinopathy and nephropathy than a low-fat control diet . RESEARCH DESIGN AND METHODS This was a post hoc analysis of a cohort of patients with type 2 diabetes participating in the PREvención con DIeta MEDiterránea ( PREDIMED ) study , a multicenter r and omized nutritional intervention trial conducted in a population at high cardiovascular risk . Individuals with type 2 diabetes who were free of microvascular complications at enrollment ( n = 3,614 , aged 55–80 years ) were r and omly assigned to one of three dietary interventions : MedDiet supplemented with extravirgin olive oil ( MedDiet+EVOO ) , MedDiet supplemented with mixed nuts ( MedDiet+Nuts ) , or a low-fat control diet . Two independent outcomes were considered : new onset of diabetic retinopathy and nephropathy . Hazard ratios ( HRs ) were calculated using multivariable-adjusted Cox regression . RESULTS During a median follow-up of 6.0 years , we identified 74 new cases of retinopathy and 168 of nephropathy . Compared with the control diet , multivariable-adjusted HRs for diabetic retinopathy were 0.56 ( 95 % CI 0.32–0.97 ) for the MedDiet+EVOO and 0.63 ( 0.35–1.11 ) for the MedDiet+Nuts . No between-group differences were found for nephropathy . When the yearly up date d information on adherence to the MedDiet was considered , the HR for retinopathy in the highest versus the lowest quintile was 0.34 ( 0.13–0.89 ; P = 0.001 for trend ) . No significant associations were found for nephropathy . CONCLUSIONS A MedDiet enriched with EVOO may protect against diabetic retinopathy but not diabetic nephropathy",
"Background It is unclear whether ideal cardiovascular health ( CVH ) , and particularly cumulative exposure to ideal CVH ( cumCVH ) , is associated with incident diabetes . We aim ed to fill this research gap . Methods and Results The Kailuan Study is a prospect i ve cohort of 101 510 adults aged 18 to 98 years recruited in 2006–2007 and who were subsequently followed up at 2‐ ( Exam 2 ) , 4‐ ( Exam 3 ) , and 6 ( Exam 4)‐year intervals after baseline . The main analysis is restricted to those individuals with complete follow‐up at all 4 examinations and who had no history of diabetes until Exam 3 . Cumulative exposure to ideal CVH ( cumCVH ) was calculated as the summed CVH score for each examination multiplied by the time between the 2 examinations ( score × year ) . Logistic regression models were used to assess the association between cumCVH and incident diabetes . In fully adjusted models , compared with the lowest quintile of cumCVH , individuals in the highest quintile had ~68 % ( 95 % confidence interval [ CI ] 60‐75 ) lower risk for incident diabetes ( compared with 61 % [ 95 % CI 52‐69 ] lower risk when using baseline CVH ) . Every additional year lived with a 1‐unit increase in ideal CVH was associated with a 24 % ( 95 % CI 21‐28 ) reduction in incident diabetes . Conclusions Ideal CVH is associated with a reduced incidence of diabetes , but the association is likely to be underestimated if baseline measures of CVH exposure are used . Measures of cumulative exposure to ideal CVH are more likely to reflect lifetime risk of diabetes and possibly other health outcomes . Clinical Trial Registration URL : https://www.chictr.org . Unique identifier : ChiCTRTNC‐11001489",
"BACKGROUND Healthy lifestyle behaviors are among the cornerstones of diabetes self-management , but the extent to which healthy lifestyle factors could potentially prevent premature mortality among people with diabetes remains unknown . The aim of the present study was to estimate the reduction in mortality that could be achieved if people with diabetes did not smoke , had a body mass index kg/m(2 ) , performed physical activity for ≥3.5 h/week , reported better dietary habits , and consumed alcohol moderately . METHODS A prospect i ve cohort study of 1263 German men and women with diabetes aged 35 - 65 years who were followed for an average of 7.8 years was used and multivariate Cox regression models for all-cause and cause-specific mortality were calculated . RESULTS Approximately 7 % of study participants had no favorable factors , 24 % had one , 35 % had two , and 34 % had three or more . Compared with participants who had no favorable factors , the reduction in risk was 34 % [ 95 % confidence interval ( CI ) 19 % , 63 % ] for those with one favorable factor , 49 % ( 95 % CI 9 % , 71 % ) for those with two , and 63 % ( 95 % CI 31 % , 80 % ) for those with three or more . Furthermore , a competing risk analysis did not show any difference in the inverse associations with mortality due to cardiovascular disease , cancer , or other causes . CONCLUSIONS Favorable lifestyle factors can potentially achieve substantial reductions in premature mortality among people with diabetes . Our results emphasize the importance of helping people with diabetes optimize their lifestyle behaviors ",
"The objective was to examine the association between lifestyle and risk for diabetes . For an average of 9.9 years , this study prospect ively followed a cohort of 7,211 ( 2,524 men and 4,687 women ) community residents aged 30–69 years without diabetes at a health check-up conducted between April 1990 and March 1992 until diabetes was confirmed or until the end of 2006 . The subjects were divided into 6 groups according to their total scores of Breslow ’s lifestyle index ( 1–2 , 3 , 4 , 5 , 6 and 7 points ) . The association between lifestyle and diabetes incidence was investigated using Cox proportional hazards regression models . The results showed that the multivariate-adjusted hazard ratios were 0.45 in subjects who scored 5 points , 0.39 in subjects who scored 6 points , and 0.31 in subjects who scored 7 points , compared with subjects who scored 1–2 points . These data indicate that the healthy behaviors prevent the incidence of diabetes",
"BACKGROUND Epidemiologic data on the combined influence of several lifestyle factors on diabetes risk are rare , particularly among older adults . OBJECTIVE To examine how combinations of lifestyle risk factors relate to the 11-year risk for incident diabetes . DESIGN Population -based prospect i ve cohort study . SETTING National Institutes of Health (NIH)-AARP Diet and Health Study . PARTICIPANTS 114,996 men and 92,483 women , aged 50 to 71 years in 1995 to 1996 , without evidence of heart disease , cancer , or diabetes . MEASUREMENTS A comprehensive survey of demographic characteristics and lifestyle factors , including dietary intake , body weight and height , physical activity , smoking , and alcohol consumption at baseline ( 1995 to 1996 ) . Low-risk groups were formed by dichotomizing each lifestyle factor . Incident self-reported , physician-diagnosed diabetes was identified with a follow-up survey in 2004 to 2006 . RESULTS 11,031 men ( 9.6 % ) and 6969 women ( 7.5 % ) developed new-onset diabetes . For each additional lifestyle factor in the low-risk group , the odds for diabetes were 31 % lower ( odds ratio [ OR ] , 0.69 [ 95 % CI , 0.68 to 0.71 ] ) among men and 39 % lower ( OR , 0.61 [ CI , 0.60 to 0.63 ] ) among women . Men and women whose diet score , physical activity level , smoking status , and alcohol use were all in the low-risk group had ORs for diabetes of 0.61 ( CI , 0.56 to 0.66 ) and 0.43 ( CI , 0.34 to 0.55 ) , respectively . When absence of overweight or obesity was added , the respective ORs were 0.28 ( CI , 0.23 to 0.34 ) and 0.16 ( CI , 0.10 to 0.24 ) for men and women . Results did not differ by family history of diabetes or level of adiposity . LIMITATION The study was observational , with potential for residual confounding . CONCLUSION Lifestyle factors , when considered in combination , are associated with a substantial reduction in risk for diabetes . PRIMARY FUNDING SOURCE The NIH-AARP Diet and Health Study was supported by the Intramural Research Program of the NIH",
"BACKGROUND It has been suggested that the inverse association between alcohol and type 2 diabetes could be explained by moderate drinkers ' healthier lifestyles . OBJECTIVE We studied whether moderate alcohol consumption is associated with a lower risk of type 2 diabetes in adults with combined low-risk lifestyle behaviors . DESIGN We prospect ively examined 35,625 adults of the Dutch European Prospect i ve Investigation into Cancer and Nutrition ( EPIC-NL ) cohort aged 20 - 70 y , who were free of diabetes , cardiovascular disease , and cancer at baseline ( 1993 - 1997 ) . In addition to moderate alcohol consumption ( women : 5.0 - 14.9 g/d ; men : 5.0 - 29.9 g/d ) , we defined low-risk categories of 4 lifestyle behaviors : optimal weight [ body mass index ( in kg/m(2 ) ) , physically active ( > or = 30 min of physical activity/d ) , current nonsmoker , and a healthy diet [ upper 2 quintiles of the Dietary Approaches to Stop Hypertension ( DASH ) diet ] . RESULTS During a median of 10.3 y , we identified 796 incident cases of type 2 diabetes . Compared with teetotalers , hazard ratios of moderate alcohol consumers for risk of type 2 diabetes in low-risk lifestyle strata after multivariable adjustments were 0.35 ( 95 % CI : 0.17 , 0.72 ) when of a normal weight , 0.65 ( 95 % CI : 0.46 , 0.91 ) when physically active , 0.54 ( 95 % CI : 0.41 , 0.71 ) when nonsmoking , and 0.57 ( 95 % CI : 0.39 , 0.84 ) when consuming a healthy diet . When > or =3 low-risk lifestyle behaviors were combined , the hazard ratio for incidence of type 2 diabetes in moderate alcohol consumers after multivariable adjustments was 0.56 ( 95 % CI : 0.32 , 1.00 ) . CONCLUSION In subjects already at lower risk of type 2 diabetes on the basis of multiple low-risk lifestyle behaviors , moderate alcohol consumption was associated with an approximately 40 % lower risk compared with abstention ",
"BACKGROUND Lifestyle interventions can prevent the deterioration of impaired glucose tolerance to manifest type 2 diabetes , at least as long as the intervention continues . In the extended follow-up of the Finnish Diabetes Prevention Study , we assessed the extent to which the originally-achieved lifestyle changes and risk reduction remain after discontinuation of active counselling . METHODS Overweight , middle-aged men ( n=172 ) and women ( n=350 ) with impaired glucose tolerance were r and omly assigned to intensive lifestyle intervention or control group . After a median of 4 years of active intervention period , participants who were still free of diabetes were further followed up for a median of 3 years , with median total follow-up of 7 years . Diabetes incidence , bodyweight , physical activity , and dietary intakes of fat , saturated fat , and fibre were measured . FINDINGS During the total follow-up , the incidence of type 2 diabetes was 4.3 and 7.4 per 100 person-years in the intervention and control group , respectively ( log-rank test p=0.0001 ) , indicating 43 % reduction in relative risk . The risk reduction was related to the success in achieving the intervention goals of weight loss , reduced intake of total and saturated fat and increased intake of dietary fibre , and increased physical activity . Beneficial lifestyle changes achieved by participants in the intervention group were maintained after the discontinuation of the intervention , and the corresponding incidence rates during the post-intervention follow-up were 4.6 and 7.2 ( p=0.0401 ) , indicating 36 % reduction in relative risk . INTERPRETATION Lifestyle intervention in people at high risk for type 2 diabetes result ed in sustained lifestyle changes and a reduction in diabetes incidence , which remained after the individual lifestyle counselling was stopped",
"BACKGROUND Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance , but how long these benefits extend beyond the period of active intervention , and whether such interventions reduce the risk of cardiovascular disease ( CVD ) and mortality , is unclear . We aim ed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes , diabetes-related macrovascular and microvascular complications , and mortality . METHODS In 1986 , 577 adults with impaired glucose tolerance from 33 clinics in China were r and omly assigned to either the control group or to one of three lifestyle intervention groups ( diet , exercise , or diet plus exercise ) . Active intervention took place over 6 years until 1992 . In 2006 , study participants were followed-up to assess the long-term effect of the interventions . The primary outcomes were diabetes incidence , CVD incidence and mortality , and all-cause mortality . FINDINGS Compared with control participants , those in the combined lifestyle intervention groups had a 51 % lower incidence of diabetes ( hazard rate ratio [ HRR ] 0.49 ; 95 % CI 0.33 - 0.73 ) during the active intervention period and a 43 % lower incidence ( 0.57 ; 0.41 - 0.81 ) over the 20 year period , controlled for age and clustering by clinic . The average annual incidence of diabetes was 7 % for intervention participants versus 11 % in control participants , with 20-year cumulative incidence of 80 % in the intervention groups and 93 % in the control group . Participants in the intervention group spent an average of 3.6 fewer years with diabetes than those in the control group . There was no significant difference between the intervention and control groups in the rate of first CVD events ( HRR 0.98 ; 95 % CI 0.71 - 1.37 ) , CVD mortality ( 0.83 ; 0.48 - 1.40 ) , and all-cause mortality ( 0.96 ; 0.65 - 1.41 ) , but our study had limited statistical power to detect differences for these outcomes . INTERPRETATION Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention . However , whether lifestyle intervention also leads to reduced CVD and mortality remains unclear",
"BACKGROUND Type 2 diabetes affects approximately 8 percent of adults in the United States . Some risk factors -- elevated plasma glucose concentrations in the fasting state and after an oral glucose load , overweight , and a sedentary lifestyle -- are potentially reversible . We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes . METHODS We r and omly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo , metformin ( 850 mg twice daily ) , or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week . The mean age of the participants was 51 years , and the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 34.0 ; 68 percent were women , and 45 percent were members of minority groups . RESULTS The average follow-up was 2.8 years . The incidence of diabetes was 11.0 , 7.8 , and 4.8 cases per 100 person-years in the placebo , metformin , and lifestyle groups , respectively . The lifestyle intervention reduced the incidence by 58 percent ( 95 percent confidence interval , 48 to 66 percent ) and metformin by 31 percent ( 95 percent confidence interval , 17 to 43 percent ) , as compared with placebo ; the lifestyle intervention was significantly more effective than metformin . To prevent one case of diabetes during a period of three years , 6.9 persons would have to participate in the lifestyle-intervention program , and 13.9 would have to receive metformin . CONCLUSIONS Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk . The lifestyle intervention was more effective than metformin",
"BACKGROUND The joint effects of different lifestyle factors on stroke risk are still to some extent unclear , especially regarding hemorrhagic stroke . METHODS We prospect ively investigated the association of different indicators of lifestyle ( smoking , body mass index , physical activity , and vegetable and alcohol consumption ) with total and type-specific stroke incidence among 36 686 Finnish participants who were 25 to 74 years old and free of coronary heart disease and stroke at baseline . RESULTS During a mean follow-up period of 13.7 years , 1478 people developed an incident stroke event ( 1167 ischemic and 311 hemorrhagic ) . The multivariate-adjusted ( age , sex , education , family history of stroke , history of diabetes mellitus , systolic blood pressure , and serum total cholesterol level ) hazard ratios associated with adherence to 0 to 1 ( reference group ) , 2 , 3 , 4 , and 5 healthy lifestyle indicators were 1 , 0.66 , 0.57 , 0.51 , and 0.33 ( P and women . The partial population attributable risk percentages associated with adherence to 3 , 4 , and 5 healthy lifestyle indicators were 26.3 % , 43.8 % , and 54.6 % for total stroke ; 22.7 % , 45.3 % , and 59.7 % for ischemic stroke ; and 35.0 % , 35.0 % , and 36.1 % for hemorrhagic stroke , respectively . CONCLUSION Healthy lifestyle factors are associated with a lower risk of stroke , and there is a grade d inverse association between the number of healthy lifestyle indicators and the risks of total , ischemic , and hemorrhagic stroke",
"BACKGROUND The combined impact of lifestyle factors on incidence of diabetes mellitus later in life is not well established . The objective of this study was to determine how lifestyle factors , assessed in combination , relate to new-onset diabetes in a broad and relatively unselected population of older adults . METHODS We prospect ively examined associations of lifestyle factors , measured using repeated assessment s later in life , with incident diabetes mellitus during a 10-year period ( 1989 - 1998 ) among 4883 men and women 65 years or older ( mean [ SD ] age at baseline , 73 [ 6 ] years ) enrolled in the Cardiovascular Health Study . Low-risk lifestyle groups were defined by physical activity level ( leisure-time activity and walking pace ) above the median ; dietary score ( higher fiber intake and polyunsaturated to saturated fat ratio , lower trans-fat intake and lower mean glycemic index ) in the top 2 quintiles ; never smoked or former smoker more than 20 years ago or for fewer than 5 pack-years ; alcohol use ( predominantly light or moderate ) ; body mass index less than 25 ( calculated as weight in kilograms divided by height in meters squared ) ; and waist circumference of 88 cm for women or 92 cm for men . The main outcome measure was incident diabetes defined annually by new use of insulin or oral hypoglycemic medications . We also evaluated fasting and 2-hour postchallenge glucose levels . RESULTS During 34,539 person-years , 337 new cases of drug-treated diabetes mellitus occurred ( 9.8 per 1000 person-years ) . After adjustment for age , sex , race , educational level , and annual income , each lifestyle factor was independently associated with incident diabetes . Overall , the rate of incident diabetes was 35 % lower ( relative risk , 0.65 ; 95 % confidence interval , 0.59 - 0.71 ) for each 1 additional lifestyle factor in the low-risk group . Participants whose physical activity level and dietary , smoking , and alcohol habits were all in the low-risk group had an 82 % lower incidence of diabetes ( relative risk , 0.18 ; 95 % confidence interval , 0.06 - 0.56 ) compared with all other participants . When absence of adiposity ( either body mass index incidence of diabetes was 89 % lower ( relative risk , 0.11 ; 95 % confidence interval , 0.01 - 0.76 ) . Overall , 9 of 10 new cases of diabetes appeared to be attributable to these 5 lifestyle factors . Associations were slightly attenuated , but still highly significant , for incident diabetes defined by medication use or glucose level . CONCLUSION Even later in life , combined lifestyle factors are associated with a markedly lower incidence of new-onset diabetes mellitus",
"OBJECTIVE To examine the association between meeting behavioural goals and diabetes incidence over 10 years in a large , representative Swedish population . METHODS Population -based prospect i ve cohort study of 32,120 individuals aged 35 to 55 years participating in a health promotion intervention in Västerbotten County , Sweden ( 1990 to 2013 ) . Participants underwent an oral glucose tolerance test , clinical measures , and completed diet and activity question naires . Poisson regression quantified the association between achieving six behavioural goals at baseline - body mass index ( BMI ) diabetes incidence over 10 years . RESULTS Median interquartile range ( IQR ) follow-up time was 9.9 ( 0.3 ) years ; 2211 individuals ( 7 % ) developed diabetes . Only 4.4 % of participants met all 6 goals ( n=1245 ) and compared to these individuals , participants meeting 0/1 goals had a 3.74 times higher diabetes incidence ( 95 % confidence interval (CI)=2.50 to 5.59 ) , adjusting for sex , age , calendar period , education , family history of diabetes , history of myocardial infa rct ion and long-term illness . If everyone achieved at least four behavioural goals , 14.1 % ( 95 % CI : 11.7 to 16.5 % ) of incident diabetes cases might be avoided . CONCLUSION Interventions promoting the achievement of behavioural goals in the general population could significantly reduce diabetes incidence ",
"Abstract Objectives To prospect ively evaluate the joint association of duration of rotating night shift work and lifestyle factors with risk of type 2 diabetes risk , and to quantitatively decompose this joint association to rotating night shift work only , to lifestyle only , and to their interaction . Design Prospect i ve cohort study . Setting Nurses ’ Health Study ( 1988 - 2012 ) and Nurses ’ Health Study II ( 1991 - 2013 ) . Participants 143 410 women without type 2 diabetes , cardiovascular disease , or cancer at baseline . Exposures Rotating night shift work was defined as at least three night shifts per month in addition to day and evening shifts in that month . Unhealthy lifestyles included current smoking , physical activity levels below 30 minutes per day at moderate to vigorous intensity , diet in the bottom three fifths of the Alternate Healthy Eating Index score , and body mass index of 25 or above . Main outcome measures Incident cases of type 2 diabetes were identified through self report and vali date d by a supplementary question naire . Results During 22 - 24 years of follow-up , 10 915 cases of incident type 2 diabetes occurred . The multivariable adjusted hazard ratios for type 2 diabetes were 1.31 ( 95 % confidence interval 1.19 to 1.44 ) per five year increment of duration of rotating night shift work and 2.30 ( 1.88 to 2.83 ) per unhealthy lifestyle factor ( ever smoking , low diet quality , low physical activity , and overweight or obesity ) . For the joint association of per five year increment rotating night shift work and per unhealthy lifestyle factor with type 2 diabetes , the hazard ratio was 2.83 ( 2.15 to 3.73 ) with a significant additive interaction ( P for interaction unhealthy lifestyle alone , and 11.3 % ( 7.3 % to 17.3 % ) for their additive interaction . Conclusions Among female nurses , both rotating night shift work and unhealthy lifestyle were associated with a higher risk of type 2 diabetes . The excess risk of rotating night shift work combined with unhealthy lifestyle was higher than the addition of risk associated with each individual factor . These findings suggest that most cases of type 2 diabetes could be prevented by adhering to a healthy lifestyle , and the benefits could be greater in rotating night shift workers",
"BACKGROUND The importance of glycosylated hemoglobin A1c ( A1c ) control as part of comprehensive risk factor management in patients with stable ischemic heart disease ( SIHD ) and diabetes mellitus ( DM ) is controversial . OBJECTIVES The purpose of this study was to determine whether a greater number of controlled risk factors at 1 year , including A1c , affects survival in patients with DM and SIHD . METHODS Of 690 patients with DM followed in the COURAGE ( Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation ) trial , 592 ( 86 % ) had complete ascertainment of 7 pre-specified risk factors at baseline and after 1 year : systolic blood pressure , low-density lipoprotein cholesterol , nonsmoking , physical activity , diet adherence , body mass index , and A1c . The primary outcome measure was mortality beyond 1 year after r and omization . RESULTS During a mean follow-up of 7.0 ± 4.2 years beyond 1 year after r and omization , 186 subjects died ( 31.4 % overall , 4.5%/year ) . The greater the number of risk factors controlled at 1 year , the higher the probability of survival ( unadjusted log rank p = 0.002 ) . Compared with 0 to 1 controlled risk factors , attaining 3 to 7 goals predicted progressively lower mortality ( hazard ratio for control of 6 or 7 risk factors was 0.13 ; 95 % confidence interval : 0.05 to 0.40 ) . Importantly , only 10.3 % of subjects achieved control of 6 or 7 risk factors . In multivariate analysis , the strongest predictors of improved survival were no smoking , regular physical activity , dietary adherence , and A1c high-risk subset of SIHD patients with DM , the number of controlled risk factors , particularly lifestyle behaviors and A1c , were associated with improved survival . ( Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation ; NCT00007657 )",
"BACKGROUND Lifestyle interventions can delay the onset of type 2 diabetes in people with impaired glucose tolerance , but whether this leads subsequently to fewer complications or to increased longevity is uncertain . We aim ed to assess the long-term effects of lifestyle interventions in people with impaired glucose tolerance on the incidence of diabetes , its complications , and mortality . METHODS The original study was a cluster r and omised trial , started in 1986 , in which 33 clinics in Da Qing , China , were r and omly assigned to either be a control clinic or provide one of three interventions ( diet , exercise , or diet plus exercise ) for 6 years for 577 adults with impaired glucose tolerance who usually receive their medical care from the clinics . Subsequently , participants were followed for up to 30 years to assess the effects of intervention on the incidence of diabetes , cardiovascular disease events , composite microvascular complications , cardiovascular disease death , all-cause mortality , and life expectancy . FINDINGS Of the 577 participants , 438 were assigned to an intervention group and 138 to the control group ( one refused baseline examination ) . After 30 years of follow-up , 540 ( 94 % ) of 576 participants were assessed for outcomes ( 135 in the control group , 405 in the intervention group ) . During the 30-year follow-up , compared with control , the combined intervention group had a median delay in diabetes onset of 3·96 years ( 95 % CI 1·25 to 6·67 ; p=0·0042 ) , fewer cardiovascular disease events ( hazard ratio 0·74 , 95 % CI 0·59 - 0·92 ; p=0·0060 ) , a lower incidence of microvascular complications ( 0·65 , 0·45 - 0·95 ; p=0·025 ) , fewer cardiovascular disease deaths ( 0·67 , 0·48 - 0·94 ; p=0·022 ) , fewer all-cause deaths ( 0·74 , 0·61 - 0·89 ; p=0·0015 ) , and an average increase in life expectancy of 1·44 years ( 95 % CI 0·20 - 2·68 ; p=0·023 ) . INTERPRETATION Lifestyle intervention in people with impaired glucose tolerance delayed the onset of type 2 diabetes and reduced the incidence of cardiovascular events , microvascular complications , and cardiovascular and all-cause mortality , and increased life expectancy . These findings provide strong justification to continue to implement and exp and the use of such interventions to curb the global epidemic of type 2 diabetes and its consequences . FUNDING US Centers for Disease Control and Prevention , WHO , Chinese Center for Disease Control and Prevention , World Bank , Ministry of Public Health of the People 's Republic of China , Da Qing First Hospital , China-Japan Friendship Hospital , and National Center for Cardiovascular Diseases & Fuwai Hospital",
"BACKGROUND Findings from the Look AHEAD trial showed no significant reductions in the primary outcome of cardiovascular disease incidence in adults with type 2 diabetes r and omly assigned to an intensive lifestyle intervention for weight loss compared with those r and omly assigned to diabetes support and education ( control ) . We examined whether the incidence of cardiovascular disease in Look AHEAD varied by changes in weight or fitness . METHODS Look AHEAD was a r and omised clinical trial done at 16 clinical sites in the USA , recruiting patients from Aug 22 , 2001 , to April 30 , 2004 . In the trial , 5145 overweight or obese adults aged 45 - 76 years with type 2 diabetes were assigned ( 1:1 ) to an intensive lifestyle intervention or diabetes support and education . In this observational , post-hoc analysis , we examined the association of magnitude of weight loss and fitness change over the first year with incidence of cardiovascular disease . The primary outcome of the trial and of this analysis was a composite of death from cardiovascular causes , non-fatal acute myocardial infa rct ion , non-fatal stroke , or admission to hospital for angina . The secondary outcome included the same indices plus coronary artery bypass grafting , carotid endartectomy , percutaneous coronary intervention , hospitalisation for congestive heart failure , peripheral vascular disease , or total mortality . We adjusted analyses for baseline differences in weight or fitness , demographic characteristics , and risk factors for cardiovascular disease . The Look AHEAD trial is registered with Clinical Trials.gov , number NCT00017953 . FINDINGS For the analyses related to weight change , we excluded 311 ineligible participants , leaving a population of 4834 ; for the analyses related to fitness change , we excluded 739 participants , leaving a population of 4406 . In analyses of the full cohort ( ie , combining both study groups ) , over a median 10·2 years of follow-up ( IQR 9·5 - 10·7 ) , individuals who lost at least 10 % of their bodyweight in the first year of the study had a 21 % lower risk of the primary outcome ( adjusted hazard ratio [ HR ] 0·79 , 95 % CI 0·64 - 0·98 ; p=0·034 ) and a 24 % reduced risk of the secondary outcome ( adjusted HR 0·76 , 95 % CI 0·63 - 0·91 ; p=0·003 ) compared with individuals with stable weight or weight gain . Achieving an increase of at least 2 metabolic equivalents in fitness change was associated with a significant reduction in the secondary outcome ( adjusted HR 0·77 , 95 % CI 0·61 - 0·96 ; p=0·023 ) but not the primary outcome ( adjusted HR 0·78 , 0·60 - 1·03 ; p=0·079 ) . In analyses treating the control group as the reference group , participants in the intensive lifestyle intervention group who lost at least 10 % of their bodyweight had a 20 % lower risk of the primary outcome ( adjusted HR 0·80 , 95 % CI 0·65 - 0·99 ; p=0·039 ) , and a 21 % lower risk of the secondary outcome ( adjusted HR 0·79 , 95 % CI 0·66 - 0·95 ; p=0·011 ) ; however , change in fitness was not significantly associated with a change in the primary outcome . INTERPRETATION The results of this post-hoc analysis of Look AHEAD suggest an association between the magnitude of weight loss and incidence of cardiovascular disease in people with type 2 diabetes . These findings suggest a need to continue to refine approaches to identify individuals who are most likely to benefit from lifestyle interventions and to develop strategies to improve the magnitude of sustained weight loss with lifestyle interventions . FUNDING US National Institute of Diabetes and Digestive and Kidney Diseases",
"BACKGROUND Evidence is limited regarding the impact of healthy lifestyle practice s on the risk of subsequent cardiovascular events among patients with diabetes . OBJECTIVES The purpose of this study was to examine the associations of an overall healthy lifestyle , defined by eating a high- quality diet ( top two-fifths of Alternative Healthy Eating Index ) , nonsmoking , engaging in moderate- to vigorous-intensity physical activity ( ≥150 min/week ) , and drinking alcohol in moderation ( 5 to 15 g/day for women and 5 to 30 g/day for men ) , with the risk of developing cardiovascular disease ( CVD ) and CVD mortality among adults with type 2 diabetes ( T2D ) . METHODS This prospect i ve analysis included 11,527 participants with T2D diagnosed during follow-up ( 8,970 women from the Nurses ' Health Study and 2,557 men from the Health Professionals Follow-Up Study ) , who were free of CVD and cancer at the time of diabetes diagnosis . Diet and lifestyle factors before and after T2D diagnosis were repeatedly assessed every 2 to 4 years . RESULTS There were 2,311 incident CVD cases and 858 CVD deaths during an average of 13.3 years of follow-up . After multivariate adjustment of covariates , the low-risk lifestyle factors after diabetes diagnosis were each associated with a lower risk of CVD incidence and CVD mortality . The multivariate-adjusted hazard ratios for participants with 3 or more low-risk lifestyle factors compared with 0 were 0.48 ( 95 % confidence interval [ CI ] : 0.40 to 0.59 ) for total CVD incidence , 0.53 ( 95 % CI : 0.42 to 0.66 ) for incidence of coronary heart disease , 0.33 ( 95 % CI : 0.21 to 0.51 ) for stroke incidence , and 0.32 ( 95 % CI : 0.22 to 0.47 ) for CVD mortality ( all p trend ) . The population -attributable risk for poor adherence to the overall healthy lifestyle ( for CVD mortality . In addition , greater improvements in healthy lifestyle factors from pre-diabetes to post-diabetes diagnosis were also significantly associated with a lower risk of CVD incidence and CVD mortality . For each number increment in low-risk lifestyle factors there was a 14 % lower risk of incident total CVD , a 12 % lower risk of coronary heart disease , a 21 % lower risk of stroke , and a 27 % lower risk of CVD mortality ( all p risk of CVD incidence and CVD mortality among adults with T2D . These findings further support the tremendous benefits of adopting a healthy lifestyle in reducing the subsequent burden of cardiovascular complications in patients with T2D",
"BACKGROUND & AIMS The relationship between healthy lifestyle factors and mortality in people with type 2 diabetes is unclear . The purpose of this study was to examine whether healthy lifestyle factors are associated with mortality in people with type 2 diabetes . METHODS We prospect ively studied 1163 men with type 2 diabetes from the Physicians ' Health Study . Lifestyle factors consisted of currently not smoking , moderate drinking ( 1 - 2 drinks/day ) , vigorous exercise ( 1+/week ) , BMI , and being in the top 2 quintiles of the alternate healthy eating index-2010 ( AHEI-2010 ) . Multivariate Cox regression models were used to estimate hazard ratios ( 95 % confidence intervals ) of mortality . RESULTS At baseline , average age was 69 years and mean follow up was 9 years . About 22 % of study participants had ≤1 healthy lifestyle factor , 37 % had two , 29 % had three , and 12 % had four or more healthy lifestyle factors . An inverse relationship was found between the number of lifestyle factors and total mortality . Compared with participants who had ≤1 healthy lifestyle factor , the risk of death was 42 % ( 95 % CI ; 19%-58 % ) lower for those with two healthy lifestyle factors , 41 % ( 95 % CI ; 18%-58 % ) lower for those with three , and 44 % ( 95 % CI ; 12%-64 % ) lower for those with 4 or more healthy lifestyle factors . CONCLUSION Adherence to modifiable healthy lifestyle factors is associated with a lower risk of death among adult men with type 2 diabetes . Our study emphasizes the importance of educating individuals with diabetes to adhere to healthy lifestyle factors "
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BACKGROUND The Program in Evidence -Based Care ( pebc ) of Cancer Care Ontario recently created an evidence -based consensus guideline on the systemic treatment of early breast cancer . The evidence for the guideline was compiled using a systematic review to answer the question " What is the optimal systemic therapy for patients with early-stage , operable breast cancer , when patient and disease factors are considered ? " The question was addressed in three parts : cytotoxic chemotherapy , endocrine treatment , and human epidermal growth factor receptor 2 (her2)-directed therapy . METHODS For the systematic review , the medline and embase data bases were search ed for the period January 2008 to May 2014 . The St and ards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also search ed . The basic search terms were " breast cancer " and " systemic therapy " ( chemotherapy , endocrine therapy , targeted agents , ovarian suppression ) , and results were limited to r and omized controlled trials ( rcts ) , guidelines , systematic review s , and meta-analyses . RESULTS Several hundred documents that met the inclusion criteria were retrieved . The Early Breast Cancer Trialists ' Collaborative Group meta-analyses encompassed many of the rcts found . Several additional studies that met the inclusion criteria were retained , as were other guidelines and systematic review s. Chemotherapy was review ed mainly in three classes : anti-metabolite-based regimens ( for example , cyclophosphamide-methotrexate-5-fluorouracil ) , anthracyclines , and taxane-based regimens . In general , single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population . Anthracycline-taxane-based polychemotherapy regimens are , overall , considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes . Regimens with varying anthracycline and taxane doses and schedules are options ; in general , paclitaxel given every 3 weeks is inferior . Evidence does not support the use of bevacizumab in the adjuvant setting ; other systemic therapy agents such as metformin and vaccines remain investigatory . Adjuvant bisphosphonates for menopausal women will be discussed in later work . CONCLUSIONS The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 pebc guideline on systemic therapy for early breast cancer . Use of cytotoxic chemotherapy is presented here ; the results addressing endocrine therapy and her2-targeted treatment , and the final clinical practice recommendations , are published separately in this supplement
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"BACKGROUND A r and omized phase III trial in high-risk breast cancer patients was conducted , to further explore the impact of dose-density in the adjuvant treatment for breast cancer . The safety analysis is presented . PATIENTS AND METHODS From October 2000 until June 2005 , 1121 node-positive patients were r and omized to sequential dose-dense epirubicin 110 mg/m(2 ) and paclitaxel ( Taxol , Bristol Myers-Squibb , Princeton , New Jersey , USA ) 250 mg/m(2 ) ( group A ) , or concurrent epirubicin 83 mg/m(2 ) and paclitaxel 187 mg/m(2 ) ( group B ) , both followed by three cycles of ' intensified ' combination chemotherapy with cyclophosphamide , methotrexate and fluorouracil ( CMF ) . Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments . RESULTS Median dose intensity of epirubicin and paclitaxel was double in group A , as design ed , with significantly less cycles administered at full dose ( P Median cumulative dose of all drugs and total treatment duration , however , were identical between groups . Severe taxane-related toxic effects were more frequent in group A , while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects , including febrile neutropenia . The rates of secondary malignancies were low . CONCLUSION Both regimens as used in the present study are well tolerated and safe . The rates of severe taxane-related toxic effects and thrombocytopenia , although low overall , are significantly increased with the dose-dense sequential regimen",
"Introduction The Preoperative Chemotherapy in Primary Operable Breast Cancer ( POCOB ) study was design ed to compare preoperative with postoperative chemotherapy in patients with early breast cancer concerning breast conserving therapy ( BCT ) procedures , disease free survival ( DFS ) and overall survival ( OS ) . Methods Patients ( n = 698 ) with early breast cancer were enrolled between 1991 and 1999 and r and omized between preoperative versus postoperative chemotherapy ( four cycles of fluorouracil , epirubicin , and cyclophosphamide ) . Endpoints were BCT procedures , DFS , OS , and tumor response to preoperative chemotherapy . In addition , tumor tissue was collected for translational research and the following markers were examined : ER , PgR , HER2 , p21 , p53 , and bcl-2 expression . Results With a median follow-up of 10 years , there was no statistically significant difference between the two treatment arms for OS ( HR = 1.09 ; 95%CI 0.83–1.42 ; P = 0.54 ) , DFS ( HR = 1.12 ; 95%CI 0.90–1.39 ; P = 0.30 ) , or locoregional recurrences ( LRR , HR = 1.16 ; 95%CI 0.77–1.74 ) . Preoperative chemotherapy was associated with an increase in BCT rates . BCT in part feasible due to tumor downsizing after preoperative chemotherapy was not correlated with higher LRR or worse OS compared to BCT which was feasible without downsizing of the tumor . Using available tumor material , only tumor stage , nodal stage , and grade were independent prognostic factors for overall survival . Conclusions Preoperative chemotherapy does not result in a difference in OS or DFS compared to postoperative chemotherapy in patients with early breast cancer . Moreover , it increases BCT rates with no significant increase of LRR . This implies that preoperative chemotherapy is a safe procedure for patients with early breast cancer , even after a follow-up period of 10 years",
"Purpose : There are currently no vali date d factors predictive of response to taxanes in patients with breast cancer . We analyzed specimens from patients included in the Breast Cancer International Research Group ( BCIRG ) 001 trial , a r and omized study which showed the superiority of docetaxel/doxorubicin/cyclophosphamide over fluorouracil/doxorubicin/cyclophosphamide as adjuvant therapy for node-positive operable breast cancer in terms of disease-free survival ( DFS ) and overall survival ( OS ) . Experimental Design : Immunohistochemical assessment of biological markers included histologic grade , tumor size , estrogen and progesterone receptors , lymph node status , HER2 , MUC1 , Ki-67/MIB-1 , p53 , Bcl-2 , Bax , Bcl-XL , BAG-1 , β-tubulin isotypes II , III and IV , τ protein , and detyrosinated α tubulin . Associations between selected parameters and survival were tested through univariate analyses , then completed with multivariate analyses and a bootstrap resampling technique . Results : In univariate analysis histologic grade , tumor size , number of involved nodes , estrogen and progesterone receptor status , p53 , Ki-67 , tubulin III , and τ protein were associated both with DFS and with OS . In multivariate analysis estrogen and progesterone receptors , tumor size , number of involved nodes , and Ki-67 protein were associated both with DFS and with OS , whereas τ protein levels were correlated with DFS and tubulin III and P53 were correlated with OS . No interaction was observed between Ki-67 and treatment allocation . Conclusions : We conclude that the expression in primary tumors of Ki-67 and p53 protein , as well as of the microtubule-related parameters τ protein and tubulin III , are independent prognostic factors in patients receiving adjuvant chemotherapy for node-positive breast cancer but are not predictive of benefit from docetaxel-containing adjuvant chemotherapy . Clin Cancer Res ; 16(15 ) ; 3988–97 . © 2010 AACR",
"PURPOSE Capecitabine is an active agent in the treatment of breast cancer . It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane , an anthracycline , and cyclophosphamide improves outcome in early breast cancer . PATIENTS AND METHODS Women with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive either three cycles of docetaxel and capecitabine ( TX ) followed by three cycles of cyclophosphamide , epirubicin , and capecitabine ( CEX ; n = 753 ) or three cycles of docetaxel ( T ) followed by three cycles of cyclophosphamide , epirubicin , and fluorouracil ( CEF ; n = 747 ) . The primary end point was recurrence-free survival ( RFS ) . RESULTS During a median follow-up time of 59 months , 214 RFS events occurred ( local or distant recurrences or deaths ; TX/CEX , n = 96 ; T/CEF , n = 118 ) . RFS was not significantly different between the groups ( hazard ratio [ HR ] , 0.79 ; 95 % CI , 0.60 to 1.04 ; P = .087 ; 5-year RFS , 86.6 % for TX/CEX v 84.1 % for T/CEF ) . Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF ( HR , 0.73 ; 95 % CI , 0.52 to 1.04 ; P = .080 ) . In exploratory analyses , TX/CEX improved breast cancer-specific survival ( HR , 0.64 ; 95 % CI , 0.44 to 0.95 ; P = .027 ) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis . We detected little severe late toxicity . CONCLUSION Integration of capecitabine into a regimen that contains docetaxel , epirubicin , and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine",
"Background Adjuvant treatment decision-making based on conventional clinical /pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades . Response to therapy is currently not considered in the decision-making procedure . ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers , e.g. , Ki-67 , for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment . Methods / design The prospect i ve , multi-center , controlled , non-blinded , r and omized , investigator initiated phase II/III ADAPT trial has an innovative “ umbrella ” protocol design . The “ umbrella ” is common for all patients , consisting of dynamic testing of early therapy response . ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany ; 4,000 patients with hormone receptor positive ( HR+ ) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial , where treatment decision is based on risk assessment and therapy response to induction therapy , and 380 patients will be included in ADAPT HER2+/HR+ . A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative . These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting . Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy , as reported by local/ central pathology for HR and HER2 status . Discussion Recent trials , such as the GeparTrio , have shown that response-guided therapy using clinical response may improve outcome . For chemotherapy or HER2-targeted treatment , pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome . For endocrine therapy , response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome . ADAPT now aims to combine static prognostic and dynamic predictive markers , focusing not just on single therapeutic targets , but also on general markers of proliferation and cell death . Biomarker analysis will help to optimize selection of subtype-specific treatment . Trial registration Clinical Trials.gov : ADAPT Umbrella : NCT01781338 ; ADAPT HR+/HER2- : NCT01779206 ; ADAPT HER2+/HR+ : NCT01745965 ; ADAPT HER2+/HR- : NCT01817452 ; ADAPT TN : NCT01815242",
"PURPOSE This study was design ed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a st and ard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival . PATIENTS AND METHODS After surgical treatment , 3,121 women with operable breast cancer and involved lymph nodes were r and omly assigned to receive a combination of cyclophosphamide ( C ) , 600 mg/m(2 ) , with one of three doses of doxorubicin ( A ) , 60 , 75 , or 90 mg/m(2 ) , for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2 ) . Tamoxifen was given to 94 % of patients with hormone receptor-positive tumors . RESULTS There was no evidence of a doxorubicin dose effect . At 5 years , disease-free survival was 69 % , 66 % , and 67 % for patients r and omly assigned to 60 , 75 , and 90 mg/m(2 ) , respectively . The hazard reductions from adding paclitaxel to CA were 17 % for recurrence ( adjusted Wald chi(2 ) P = .0023 ; unadjusted Wilcoxon P = .0011 ) and 18 % for death ( adjusted P = .0064 ; unadjusted P = .0098 ) . At 5 years , the disease-free survival ( + /- SE ) was 65 % ( + /- 1 ) and 70 % ( + /- 1 ) , and overall survival was 77 % ( + /- 1 ) and 80 % ( + /- 1 ) after CA alone or CA plus paclitaxel , respectively . The effects of adding paclitaxel were not significantly different in subsets defined by the protocol , but in an unplanned subset analysis , the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 ( 95 % confidence interval , 0.59 to 0.86 ) for those with estrogen receptor-negative tumors and only 0.91 ( 95 % confidence interval , 0.78 to 1.07 ) for patients with estrogen receptor-positive tumors , almost all of whom received adjuvant tamoxifen . The additional toxicity from adding four cycles of paclitaxel was generally modest . CONCLUSION The addition of four cycles of paclitaxel after the completion of a st and ard course of CA improves the disease-free and overall survival of patients with early breast cancer",
"PURPOSE We assessed Tau protein expression in primary breast cancer specimens of patients included in the National Surgical Breast and Bowel Project ( NSABP ) -B 28 clinical trial . Expression levels were correlated with disease-free survival ( DFS ) and overall survival ( OS ) . Interaction between this marker and paclitaxel efficacy was also examined . METHODS Tissue microarrays were available for 1,942 patients ( 63 % of all trial participants ) who were r and omly assigned to receive either four courses of doxorubicin and cyclophosphamide ( AC ) or AC followed by four courses of adjuvant paclitaxel chemotherapy . All patients who were hormone receptor positive received adjuvant endocrine therapy . Immunohistochemistry was used to measure Tau expression at M. D. And erson Cancer Center blinded to clinical outcome . Correlation between Tau and OS and DFS was performed by the NSABP Biostatistical Center . RESULTS Forty-three percent of patients were Tau positive . Tau positivity correlated with estrogen receptor ( ER ) -positive status ( P Tau- and ER-positive status were both associated with better DFS and OS ( P worse DFS and OS ( P Tau expression and benefit from paclitaxel in the total population or among ER-positive or -negative patients . CONCLUSION High Tau protein expression is associated with better prognosis in patients treated with adjuvant anthracycline and paclitaxel chemotherapy and endocrine therapy , but there was no significant interaction between Tau expression and paclitaxel benefit",
"PURPOSE We previously reported that four cycles of docetaxel/cyclophosphamide ( TC ) produced superior disease-free survival ( DFS ) compared with four cycles of doxorubicin/cyclophosphamide ( AC ) in early breast cancer . Older women are under-represented in adjuvant chemotherapy trials . In our trial 16 % of patients were > or = 65 years . We now report 7-year results for DFS and overall survival ( OS ) as well as the impact of age , hormone receptor status , and HER2 status on outcome and toxicity . PATIENTS AND METHODS Patients were r and omly assigned to receive either four cycles of st and ard-dose AC ( 60/600 mg/m(2 ) ; n = 510 ) , or TC ( 75/600 mg/m(2 ) ; n = 506 ) , administered by intravenous infusion every 3 weeks . RESULTS The median age in women younger than 65 , was 50 years ( range , 27 to 64 ) and for women > or = 65 was 69 years ( range , 65 to 77 ) . Baseline characteristics in the two age subgroups were generally well matched , except that older women tended to have more lymph node involvement . At a median of 7 years follow-up , the difference in DFS between TC and AC was significant ( 81 % TC v 75 % AC ; P = .033 ; hazard ratio [ HR ] , 0.74 ; 95 % CI 0.56 to 0.98 ) as was OS ( 87 % TC v 82 % AC ; P = .032 ; HR , 0.69 ; 95 % CI , 0.50 to 0.97 ) . TC was superior in older patients as well as younger patients . There was no interaction of hormone-receptor status or HER-2 status and treatment . Older women experienced more febrile neutropenia with TC and more anemia with AC . CONCLUSION With longer follow-up , four cycles of TC was superior to st and ard AC ( DFS and OS ) and was a tolerable regimen in both older and younger patients",
"BACKGROUND The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide ( EC ) with four cycles of docetaxel ( Taxotere , D ) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer . PATIENTS AND METHODS Patients were r and omly assigned to EC ( E 120 mg/m(2 ) , C 600 mg/m(2 ) , arm A ) for four cycles or four cycles of D ( 100 mg/m(2 ) ) followed by four cycles of EC ( arm B ) , both regimens every 21 days . Hormone receptor-positive patients were given hormonal therapy for 5 years . Primary end point was 5-year disease-free survival ( DFS ) . Secondary objectives were overall survival ( OS ) and safety . RESULTS There were 750 patients enrolled . With a median follow-up of 64 months , 5-year DFS was 73.4 % in both arms , and 5-year OS was 89.5 % versus 90.7 % in arm A and B [ hazard ratio was 0.99 ( 95 % confidence interval for DFS 0.75 - 1.31 ; P = 0.95 ) ] , respectively . Grade 3 - 4 toxicity was more common in arm B. CONCLUSIONS This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer . The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms",
"The NEAT trial reported considerable benefit for ECMF ( epirubicin followed by cyclophosphamide , methotrexate and 5-fluorouracil ) of 28 % for relapse-free survival ( RFS ) and 30 % for overall survival ( OS ) , when compared with classical CMF in early breast cancer . To assess tolerability , toxicity , dose intensity and quality of life ( QoL ) analyses were undertaken . All 2021 eligible patients had common toxicity criteria ( CTC ) , delivered chemotherapy and supportive treatments details and long-term morbidities recorded . The QoL sub study used multiple vali date d measures . ECMF produced low CTC scores , although higher than CMF for nausea , vomiting , alopecia , constipation , stomatitis ( P infection ( P=0.001 ) and fatigue ( P=0.03 ) . Supportive treatments required , however , were similar across r and omised treatments . On-treatment deaths were more common with CMF ( 13 ) than ECMF(5 ) . Optimal course-delivered dose intensity ( CDDI ⩾85 % ) was received more often by ECMF patients ( 83 vs 76 % : P=0.0002 ) , and was associated with better RFS ( P=0.0006 ) . QoL over 2 years was equivalent across treatments , despite minimally worse side effects for ECMF during treatment . ECMF benefit spanned all levels of toxicity , CDDI and QoL. There are no reported acute myeloid leukaemias or cardiac dysfunctions . ECMF is tolerable , deliverable , and significantly more effective than CMF , with no serious long-term toxicity or QoL detriment",
"Summary Background Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment . The UK TACT study ( CRUK01/001 ) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with st and ard chemotherapy of similar duration . Methods In this multicentre , open-label , phase III , r and omised controlled trial , 4162 women ( aged > 18 years ) with node-positive or high-risk node-negative operable early breast cancer were r and omly assigned by computer-generated permuted block r and omisation to receive FEC ( fluorouracil 600 mg/m2 , epirubicin 60 mg/m2 , cyclophosphamide 600 mg/m2 at 3-weekly intervals ) for four cycles followed by docetaxel ( 100 mg/m2 at 3-weekly intervals ) for four cycles ( n=2073 ) or control ( n=2089 ) . For the control regimen , centres chose either FEC for eight cycles ( n=1265 ) or epirubicin ( 100 mg/m2 at 3-weekly intervals ) for four cycles followed by CMF ( cyclophosphamide 600 mg/m2 , methotrexate 40 mg/m2 , and fluorouracil 600 mg/m2 at 4-weekly intervals ) for four cycles ( n=824 ) . The primary endpoint was disease-free survival . Analysis was by intention to treat ( ITT ) . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N79718493 . Findings All r and omised patients were included in the ITT population . With a median follow-up of 62 months , disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls ( hazard ratio [ HR ] 0·95 , 95 % CI 0·85–1·08 ; p=0·44 ) . 75·6 % ( 95 % CI 73·7–77·5 ) of patients in the experimental group and 74·3 % ( 72·3–76·2 ) of controls were alive and disease-free at 5 years . The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group ( p were neutropenia ( 937 events vs 797 events ) , leucopenia ( 507 vs 362 ) , and lethargy ( 456 vs 272 ) . Interpretation This study did not show any overall gain from the addition of docetaxel to st and ard anthracycline chemotherapy . Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy . Funding Cancer Research UK ( CRUK 01/001 ) , Sanofi-Aventis , Pfizer , and Roche",
"Treatment with fluororacil , epirubicin , and cyclophosphamide followed by weekly paclitaxel ( FEC-P ) yielded superior disease-free survival than FEC in the adjuvant breast cancer trial GEICAM 9906 . We evaluate molecular subtypes predictive of prognosis and paclitaxel response in this trial . Two molecular subtype classifications based on conventional immunohistochemical and fluorescent in situ hybridization determinations were used : # 1 : Four groups segregated according to the combination of hormone receptor ( HR ) and HER2 status ; # 2 : Intrinsic subtype classification ( Triple Negative ( TN ) , HER2 , Luminal B and Luminal A ) . Results : Both subtype classifications yielded prognostic and predictive information . HR + /HER2− patients ( and Luminal A patients ) had a significantly better outcome than the other subgroups of patients . The superiority of FEC-P over FEC was clearly more marked in HR−/HER2− patients ( TN patients ) , particularly in the subset with basal phenotype ( TN and either EGFR+ or cytokeratins 5/6 + ) . The Luminal A subtype also achieved a significant benefit with FEC-P. The molecular-defined subgroup of TN was clearly predictive of better response to treatment with FEC-P. Luminal A patients had the best prognosis and also have a better outcome with weekly paclitaxel",
"PURPOSE Adding taxanes to anthracycline-based adjuvant therapy improves survival outcomes of patients with node-positive breast cancer ( BC ) . Currently , however , most patients with BC are node negative at diagnosis . The only pure node-negative study ( Spanish Breast Cancer Research Group 9805 ) reported so far showed a docetaxel benefit but significant toxicity . Here we tested the efficacy and safety of weekly paclitaxel ( wP ) in node-negative patients , which is yet to be established . PATIENTS AND METHODS Patients with BC having T1-T3/N0 tumors and at least one high-risk factor for recurrence ( according to St. Gallen 1998 criteria ) were eligible . After primary surgery , 1,925 patients were r and omly assigned to receive fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) × 6 or FAC × 4 followed by wP × 8 ( FAC-wP ) . The primary end point was disease-free survival ( DFS ) after a median follow-up of 5 years . Secondary end points included toxicity and overall survival . RESULTS After a median follow-up of 63.3 months , 93 % and 90.3 % of patients receiving FAC-wP or FAC regimens , respectively , remained disease free ( hazard ratio [ HR ] , 0.73 ; 95 % CI , 0.54 to 0.99 ; log-rank P = .04 ) . Thirty-one patients receiving FAC-wP versus 40 patients receiving FAC died ( one and seven from cardiovascular diseases , respectively ; HR , 0.79 ; 95 % CI , 0.49 to 1.26 ; log-rank P = .31 ) . The most relevant grade 3 and 4 adverse events in the FAC-wP versus the FAC arm were febrile neutropenia ( 2.7 % v 3.6 % ) , fatigue ( 7.9 % v 3.4 % ) , and sensory neuropathy ( 5.5 % v 0 % ) . CONCLUSION For patients with high-risk node-negative BC , the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS compared with FAC therapy , in addition to manageable toxicity , especially regarding long-term cardiac effects",
"Background : The National Epirubicin Adjuvant Trial ( NEAT ) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide , methotrexate and 5-fluorouracil ( E-CMF ) compared with st and ard CMF in adjuvant chemotherapy for women with early breast cancer . This report details longer follow-up with interesting additional time-dependent analyses . Methods : National Epirubicin Adjuvant Trial used epirubicin ( E ) 3-weekly for four cycles followed by classical ( c ) CMF for four cycles ( E-CMF ) compared with cCMF for six cycles . BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles , compared with CMF 3-weekly for eight cycles . Results : In all , 2391 eligible patients were r and omised and with a median 7.4-year follow-up , E-CMF confirmed a significant benefit over CMF in both relapse-free survival ( RFS ) ( 78 % vs 71 % 5 years RFS , respectively , hazard ratio (HR)=0.75 ( 95 % CI : 0.65–0.86 ) , P overall survival ( OS ) ( 84 % vs 78 % 5 years OS , respectively , HR=0.76 ( 95 % CI : 0.65–0.89 ) , P=0.0007 ) . Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration ( Ch17CEP ) as previously reported . Poor prognostic factors at diagnosis ( ER and PR negative and HER2 positive ) showed time-dependent annual hazard rates for RFS and OS . In univariate analysis , these factors demonstrated more favourable HRs for RFS after 5 years . Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours . Conclusion : Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients . Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction . St and ard poor prognostic factors at diagnosis were time-dependent , and after 5 years disease-free , poor prognosis patients demonstrated favourable HRs for survival",
"PURPOSE The initial report from the Programme Action Concertée Sein ( PACS ) PACS01 trial demonstrated a benefit at 5 years for disease-free survival ( DFS ) and overall survival ( OS ) rates with the sequential administration of docetaxel after FEC100 ( fluorouracil 500 mg/m(2 ) , epirubicin 100 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ) for patients with node-positive , operable breast cancer . We evaluate here the impact of this regimen at 8 years . PATIENTS AND METHODS Between June 1997 and March 2000 , a total of 1,999 patients ( age to receive either st and ard FEC100 for 6 cycles or 3 cycles of FEC100 followed by 3 cycles of 100 mg/m(2 ) docetaxel ( FEC-D ) , both given every 21 days . Radiotherapy was m and atory after conservative surgery and tamoxifen was given for 5 years to hormone receptor (HR)-positive patients . Five-year DFS was the trial 's main endpoint . Up date d 8-year survival data are presented . RESULTS With a median follow-up of 92.8 months , 639 patients experienced at least one event . A total number of 383 deaths were registered . Eight-year DFS rates were 65.8 % with FEC alone and 70.2 % with FEC-D. OS rates at 8 years were 78 % with FEC alone and 83.2 % with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15 % reduction in the relative risk of relapse and a 25 % reduction in the relative risk of death in favor of FEC-D. Significant relative risk reductions were observed in the HR-positive , HER2-positive , and Ki67 ≥20 % sub population s. CONCLUSION Benefits for DFS and OS rates with the sequential FEC-D regimen are fully confirmed at 8 years",
"Introduction Pre- clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity . However , dedicated clinical research has not defined a predictive role for TP53 gene mutations . The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02 - 98 r and omized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel . Methods The prognostic and predictive values of TP53 were analyzed in tumor sample s by gene sequencing within exons 5 to 8 . Patients were classified according to p53 protein status predicted from TP53 gene sequence , as wild-type ( no TP53 variation or TP53 variations which are predicted not to modify p53 protein sequence ) or mutant ( p53 nonsynonymous mutations ) . Mutations were subcategorized according to missense or truncating mutations . Survival analyses were performed using the Kaplan-Meier method and log-rank test . Cox-regression analysis was used to identify independent predictors of outcome . Results TP53 gene status was determined for 18 % ( 520 of 2887 ) of the women enrolled in BIG 02 - 98 . TP53 gene variations were found in 17 % ( 90 of 520 ) . Nonsynonymous p53 mutations , found in 16.3 % ( 85 of 520 ) , were associated with older age , ductal morphology , higher grade and hormone-receptor negativity . Of the nonsynonymous mutations , 12.3 % ( 64 of 520 ) were missense and 3.6 % were truncating ( 19 of 520 ) . Only truncating mutations showed significant independent prognostic value , with an increased recurrence risk compared to patients with non-modified p53 protein ( hazard ratio = 3.21 , 95 % confidence interval = 1.740 to 5.935 , P = 0.0002 ) . p53 status had no significant predictive value for response to docetaxel . Conclusions p53 truncating mutations were uncommon but associated with poor prognosis . No significant predictive role for p53 status was detected . Trial registration Clinical Trials.gov",
"BACKGROUND Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer . Strategies to improve efficacy include the use of anthracyclines , taxanes , and intensified dose with bone marrow support . PATIENTS AND METHODS Patients received neoadjuvant epirubicin 90 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) followed by paclitaxel 175 mg/m(2 ) ( EC→T ) , each 3-weekly for four cycles ( n = 370 ) , or epirubicin 150 mg/m(2 ) followed by paclitaxel 225 mg/m(2 ) with pegfilgrastim followed by CMF ( cyclophosphamide 500 mg/m(2 ) , methotrexate 40 mg/m(2 ) , fluorouracil 600 mg/m(2 ) ) on days 1 and 8 ( E(dd)→T(dd)→CMF ) , each 2-weekly and for three cycles ( n = 363 ) . Patients were r and omly allocated to either simultaneous darbepoetin alfa ( DA ) ( n = 356 ) or none ( n = 377 ) . RESULTS Pathological complete response ( pCR ) rate ( breast ) was higher with E(dd)→T(dd)→CMF , 18.7 % versus 13.2 % with EC→T ; P = 0.043 , ypT0/Tis ; ypN0 was reported in 20.9 % versus 14.3 % respectively ; P = 0.019 . Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate . Mean hemoglobin values maintained higher with DA ( 13.6 versus 12.6 g/dl ) . E(dd)→T(dd)→CMF regimen showed more grade 3 - 4 mucositis , sensory neuropathy , and neurological complaints . Thromboembolic events were more frequent on DA ( 3 % versus 6 % ; P = 0.055 ) . CONCLUSION Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR . Primary use of DA did not affect pCR",
"BACKGROUND Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival among women with operable lymph-node-positive breast cancer . The effectiveness of concurrent versus sequential regimens is not known . METHODS We r and omly assigned 5351 patients with operable , node-positive , early-stage breast cancer to receive four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel ( sequential ACT ) ; four cycles of doxorubicin and docetaxel ( doxorubicin-docetaxel ) ; or four cycles of doxorubicin , cyclophosphamide , and docetaxel ( concurrent ACT ) . The primary aims were to examine whether concurrent ACT was more effective than sequential ACT and whether the doxorubicin-docetaxel regimen would be as effective as the concurrent-ACT regimen . The secondary aims were to assess toxic effects and to correlate amenorrhea with outcomes in premenopausal women . RESULTS At a median follow-up of 73 months , overall survival was improved in the sequential-ACT group ( 8-year overall survival , 83 % ) as compared with the doxorubicin-docetaxel group ( overall survival , 79 % ; hazard ratio for death , 0.83 ; P=0.03 ) and the concurrent-ACT group ( overall survival , 79 % ; hazard ratio , 0.86 ; P=0.09 ) . Disease-free survival was improved in the sequential-ACT group ( 8-year disease-free survival , 74 % ) as compared with the doxorubicin-docetaxel group ( disease-free survival , 69 % ; hazard ratio for recurrence , a second malignant condition , or death , 0.80 ; P=0.001 ) and the concurrent-ACT group ( disease-free survival , 69 % ; hazard ratio , 0.83 ; P=0.01 ) . The doxorubicin-docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival ( hazard ratio , 0.96 ; 95 % confidence interval , 0.82 to 1.14 ) . Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups , independently of estrogen-receptor status . CONCLUSIONS Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT , and it improved overall survival as compared with doxorubicin-docetaxel . Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status . ( Clinical Trials.gov number , NCT00003782 .",
"PURPOSE We investigated whether capecitabine and docetaxel followed by fluorouracil , epirubicin , and cyclophosphamide ( FEC ) or weekly paclitaxel ( WP ) followed by FEC would improve relapse-free survival ( RFS ) in operable breast cancer . PATIENTS AND METHODS In this single-institution study , patients with clinical stages I to IIIC breast cancer were r and omly assigned on a 1:1 basis to WP 80 mg/m(2 ) for 12 weeks followed by fluorouracil 500 mg/m(2 ) , epirubicin 100 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ( FEC-100 ) every 3 weeks for four cycles or docetaxel 75 mg/m(2 ) on day 1 and capecitabine ( XT ) 1,500 mg/m(2 ) on days 1 through 14 every 3 weeks for four cycles followed by FEC for four cycles and stratified by timing of chemotherapy ( preoperative v adjuvant ) . Accrual was stopped short of 930 patients on the basis of a Bayesian predictive calculation that additional accrual would be unlikely to change the qualitative comparison of the two regimens . RESULTS After enrollment of 601 patients and a median follow-up of 50 months , we observed no improvement in RFS between XT ( 87.5 % ; 95 % CI , 82.7 % to 91.1 % ) and WP ( 90.7 % ; 95 % CI , 86.4 % to 93.7 % ; P = .51 ) . In the preoperative group , the pathologic complete response rate was 19.8 % and 16.4 % in the XT and WP arms , respectively ( P = .45 ) . Rates of breast-conserving surgery were similar between the two groups ( P = .48 ) . The XT arm had a significantly higher incidence of stomatitis ( P h and -foot syndrome ( P neutropenic infection ( P efficacy between WP and XT as used in this r and omized phase III trial . XT was associated with higher GI , skin , and neutropenic-related toxicities",
"PURPOSE Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional adjuvant therapy . We compared intense dose-dense ( IDD ) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer . PATIENTS AND METHODS In this r and omized , phase III trial , a total of 1,284 eligible patients with four or more involved axillary lymph nodes were r and omly assigned to receive IDD sequential epirubicin , paclitaxel , and cyclophosphamide ( IDD-ETC ) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks . The primary end point was event-free survival ( EFS ) . RESULTS At a median follow-up of 62 months , 5-year event-free survival rates were 62 % in the conventional arm and 70 % in the IDD-ETC arm , representing a 28 % reduction of the relative risk of relapse ( P 5-year overall survival rates were 77 % versus 82 % , representing a 24 % reduction of the relative risk of death ( P = .0285 ) . IDD therapy was associated with significantly more nonhematologic and hematologic toxicities , but no treatment-related death occurred . Four occurrences of acute myeloid leukemia or myelodysplastic syndrome ( MDS ) were observed in the IDD-ETC arm . No severe congestive heart failure was reported . CONCLUSION IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes",
"BACKGROUND Anthracyclines and taxanes have been the st and ard neoadjuvant chemotherapies for breast cancer in the past decade . We aim ed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide , and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel ( with or without gemcitabine ) . METHODS In our r and omised , open-label , 2 × 2 factorial phase 3 trial ( Neo-tAnGo ) , we enrolled women ( aged > 18 years ) with newly diagnosed breast cancer ( tumour size > 20 mm ) at 57 centres in the UK . Patients were r and omly assigned via a central r and omisation procedure to epirubicin and cyclophosphamide then paclitaxel ( with or without gemcitabine ) or paclitaxel ( with or without gemcitabine ) then epirubicin and cyclophosphamide . Four cycles of each component were given . The primary endpoint was pathological complete response ( pCR ) , defined as absence of invasive cancer in the breast and axillary lymph nodes . This study is registered with EudraCT ( 2004 - 002356 - 34 ) , IS RCT N ( 78234870 ) , and Clinical Trials.gov ( NCT00070278 ) . FINDINGS Between Jan 18 , 2005 , and Sept 28 , 2007 , we r and omly allocated 831 participants ; 207 received epirubicin and cyclophosphamide then paclitaxel ; 208 were given paclitaxel then epirubicin and cyclophosphamide ; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine ; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide . 828 patients were eligible for analysis . Median follow-up was 47 months ( IQR 37 - 51 ) . 207 ( 25 % ) patients had inflammatory or locally advanced disease , 169 ( 20 % ) patients had tumours larger than 50 mm , 413 ( 50 % ) patients had clinical involvement of axillary nodes , 276 ( 33 % ) patients had oestrogen receptor (ER)-negative disease , and 191 ( 27 % ) patients had HER2-positive disease . Addition of gemcitabine did not increase pCR : 70 ( 17 % , 95 % CI 14 - 21 ) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 ( 17 % , 14 - 21 ) of 408 patients who received additional gemcitabine ( p=0·98 ) . Receipt of a taxane before anthracycline was associated with improved pCR : 82 ( 20 % , 95 % CI 16 - 24 ) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 ( 15 % , 11 - 18 ) of 406 patients who received epirubicin and cyclophosphamide first ( p=0·03 ) . Grade 3 toxicities were reported at expected levels : 173 ( 21 % ) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia , 66 ( 8 % ) had infection , 41 ( 5 % ) had fatigue , 41 ( 5 % ) had muscle and joint pains , 37 ( 5 % ) had nausea , 36 ( 4 % ) had vomiting , 34 ( 4 % ) had neuropathy , 23 ( 3 % ) had transaminitis , 16 ( 2 % ) had acute hypersensitivity , and 20 ( 2 % ) had a rash . 86 ( 11 % ) patients had grade 4 neutropenia and 3 ( had grade 4 infection . INTERPRETATION Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR , sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in st and ard neoadjuvant chemotherapy for breast cancer . FUNDING Cancer Research UK , Eli Lilly , Bristol-Myers Squibb",
"tAnGo is a large r and omised trial assessing the addition of gemcitabine(G ) to paclitaxel(T ) , following epirubicin(E ) and cyclophosphamide(C ) in women with invasive higher risk early breast cancer . To assess the safety and tolerability of adding G , a detailed safety sub study was undertaken . A total of 135 patients had cardiac , pulmonary and hepatic function assessed at ( i ) r and omisation , ( ii ) mid-chemotherapy , ( iii ) immediately post-chemotherapy and ( iv ) 6 months post-chemotherapy . Skin toxicity was assessed during radiotherapy . No differences were detected in FEV1 or FVC levels between treatment arms or time points . Diffusion capacity ( TLCO ) reduced during treatment ( P EC and recovered by 6-months post treatment . There was no difference in cardiac function between treatment arms . Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment , with only five having LVEF Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy ( AST P=0.03 , ALT P=0.003 ) , although the majority was low grade . There was no correlation between transaminitis and other toxicities . Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels . Despite these being greater with EC-GT , both regimens appear well tolerated",
"To compare the long-term outcome of women with primary or locally advanced breast cancer r and omised to receive either doxorubicin and cyclophosphamide ( AC ) or doxorubicin and docetaxel ( AD ) as primary chemotherapy . Eligible patients with histologic-proven breast cancer with primary tumours ≥3 cm , inflammatory or locally advanced disease , and no evidence of distant metastases , were r and omised to receive a maximum of 6 cycles of either doxorubicin ( 60 mg/m2 ) plus cyclophosphamide ( 600 mg/m2 ) i/v or doxorubicin ( 50 mg/m2 ) plus docetaxel ( 75 mg/m2 ) i/v every 3 weeks , followed by surgery on completion of chemotherapy . Clinical and pathologic responses have previously been reported . Time to relapse , site of relapse , and all-cause mortality were recorded . This up date d analysis compares long-term disease-free ( DFS ) and overall survival ( OS ) using stratified log rank methods . A total of 363 patients were r and omised to AC ( n = 181 ) or AD ( n = 182 ) . A complete pathologic response was observed in 16 % for AC and 12 % for AD ( P = 0.43 ) . The number of patients with positive axillary nodes at surgery with AC was 61 % and AD 66 % ( P = 0.36 ) . At a median follow-up of 99 months there is no significant difference between the two groups for DFS ( P = 0.20 ) and OS ( P = 0.24 ) . Deaths were due to metastatic breast cancer in 96 % of patients . Our data do not support a clinical benefit for simultaneous administration of AD compared with AC . However , the data do not exclude a smaller benefit than the study was powered to detect and are consistent with an increase in both disease-free and overall survival of about 5 % for AD compared with AC . Outcome is consistent with the pathologic complete response following surgery",
"The r and omized multicenter study on rapidly proliferating breast cancer , assessed according to thymidine labelling index ( TLI ) , was activated at the end of the 1980s . The present work investigated whether and to what degree the short-term advantages observed from adjuvant CMF ( cyclophosphamide , methotrexate , 5-fluorouracil ) were maintained at a longer follow-up . Two hundred and eighty-one patients with node-negative and high TLI tumors were r and omized to receive six cycles of CMF or no further treatment . At a median follow-up of 12 years , CMF produced a 25 % and 20 % relative reduction in relapse and death cumulative incidence , respectively . A breakdown analysis identified a subgroup of patients with intermediate proliferating tumors for whom a 70 % and 73 % reduction in relapse and death was observed in the intention-to-treat population . An even higher reduction of 80 % and 84 % in relapse and death was seen for the patients who had received the full CMF dose . We identified a subgroup of patients with intermediate proliferating tumors in whom the high benefit obtained from adjuvant CMF was maintained at a long-term follow up",
"PURPOSE We investigated disease-free survival ( DFS ) and overall survival ( OS ) after response-guided neoadjuvant chemotherapy in patients with early breast cancer . PATIENTS AND METHODS We treated 2,072 patients with two cycles of docetaxel , doxorubicin , and cyclophosphamide ( TAC ) and r and omly assigned early responders to four ( n = 704 ) or six ( n = 686 ) additional TAC cycles , and early nonresponders to four cycles of TAC ( n = 321 ) or vinorelbine and capecitabine ( NX ; n = 301 ) before surgery . RESULTS DFS was longer in early responders receiving TAC × 8 than in those receiving TAC × 6 ( hazard ratio [ HR ] , 0.78 ; 95 % CI , 0.62 to 0.97 ; P = .026 ) , and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 ( HR , 0.59 ; 95 % CI , 0.49 to 0.82 ; P = .001 ) . Exploratory analysis showed that DFS after response-guided chemotherapy ( TAC × 8 or TAC-NX ) was significantly longer ( HR , 0.71 ; 95 % CI , 0.60 to 0.85 ; P was OS ( HR , 0.79 ; 95 % CI , 0.63 to 0.99 ; P = .048 ) , than on conventional chemotherapy ( TAC × 6 ) . DFS was longer after response-guided chemotherapy in all hormone receptor-positive tumors ( luminal A HR = 0.55 , luminal B [ human epidermal growth factor receptor 2 ( HER2 ) negative ] HR = 0.40 , and luminal B [ HER2 positive ] HR = 0.56 ) , but not in hormone receptor-negative tumors ( HER2 positive [ nonluminal ] HR = 1.01 and triple negative HR = 0.87 ) . Pathologic complete response did not predict these survival effects . pCR predicted an improved DFS in triple-negative ( HR = 6.67 ) , HER2-positive ( nonluminal ; HR 5.24 ) , or luminal B ( HER2-negative ) tumors ( HR = 3.74 ) . CONCLUSION This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor-positive tumors . If confirmed , the response-guided approach could provide a clinical ly meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer",
"BACKGROUND A regimen of docetaxel , doxorubicin , and cyclophosphamide ( TAC ) is superior to a regimen of fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) when used as adjuvant therapy in women with node-positive breast cancer . The value of taxanes in the treatment of node-negative disease has not been determined . METHODS We r and omly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence ( according to the 1998 St. Gallen criteria ) to treatment with TAC or FAC every 3 weeks for six cycles after surgery . The primary end point was disease-free survival after at least 5 years of follow-up . Secondary end points included overall survival and toxicity . RESULTS At a median follow-up of 77 months , the proportion of patients alive and disease-free was higher among the 539 women in the TAC group ( 87.8 % ) than among the 521 women in the FAC group ( 81.8 % ) , representing a 32 % reduction in the risk of recurrence with TAC ( hazard ratio , 0.68 ; 95 % confidence interval [ CI ] , 0.49 to 0.93 ; P=0.01 by the log-rank test ) . This benefit was consistent , regardless of hormone-receptor status , menopausal status , or number of high-risk factors . The difference in survival rates ( TAC , 95.2 % ; FAC , 93.5 % ) was not significant ( hazard ratio , 0.76 ; 95 % CI , 0.45 to 1.26 ) ; however , the number of events was small ( TAC , 26 ; FAC , 34 ) . Rates of grade 3 or 4 adverse events were 28.2 % with TAC and 17.0 % with FAC ( P Toxicity associated with TAC was diminished when primary prophylaxis with granulocyte colony-stimulating factor was provided . CONCLUSIONS As compared with adjuvant FAC , adjuvant TAC improved the rate of disease-free survival among women with high-risk , node-negative breast cancer . ( Funded by GEICAM and Sanofi-Aventis ; Clinical Trials.gov number , NCT00121992 . )",
"PURPOSE Using a 2 x 2 factorial design , we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin ( A ) , paclitaxel ( T ) , and cyclophosphamide ( C ) with concurrent doxorubicin and cyclophosphamide ( AC ) followed by paclitaxel ( T ) for disease-free ( DFS ) and overall survival ( OS ) ; to determine whether the dose density of the agents improves DFS and OS ; and to compare toxicities . PATIENTS AND METHODS A total of 2,005 female patients were r and omly assigned to receive one of the following regimens : ( I ) sequential A x 4 ( doses ) -- > T x 4 -- > C x 4 with doses every 3 weeks , ( II ) sequential A x 4 -- > T x 4 -- > C x 4 every 2 weeks with filgrastim , ( III ) concurrent AC x 4 -- > T x 4 every 3 weeks , or ( IV ) concurrent AC x 4 -- > T x 4 every 2 weeks with filgrastim . RESULTS A protocol -specified analysis was performed at a median follow-up of 36 months : 315 patients had experienced relapse or died , compared with 515 expected treatment failures . Dose-dense treatment improved the primary end point , DFS ( risk ratio [ RR ] = 0.74 ; P = .010 ) , and OS ( RR = 0.69 ; P = .013 ) . Four-year DFS was 82 % for the dose-dense regimens and 75 % for the others . There was no difference in either DFS or OS between the concurrent and sequential schedules . There was no interaction between density and sequence . Severe neutropenia was less frequent in patients who received the dose-dense regimens . CONCLUSION Dose density improves clinical outcomes significantly , despite the lower than expected number of events at this time . Sequential chemotherapy is as effective as concurrent chemotherapy",
"BACKGROUND E75 ( nelipepimut-S ) is a human leukocyte antigen (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein . We have conducted phase I/II clinical trials vaccinating breast cancer patients with nelipepimut-S and granulocyte-macrophage colony-stimulating factor ( GM-CSF ) in the adjuvant setting to prevent disease recurrence . All patients have completed 60 months follow-up , and here , we report the final analyses . PATIENTS AND METHODS The studies were conducted as dose escalation/schedule optimization trials enrolling node-positive and high-risk node-negative patients with tumors expressing any degree of HER2 ( immunohistochemistry 1 - 3 + ) . HLA-A2/3 + patients were vaccinated ; others were followed prospect ively as controls . Local and systemic toxicity was monitored . Clinical recurrences were documented , and disease-free survival ( DFS ) was analyzed by Kaplan-Meier curves ; groups were compared using log-rank tests . RESULTS Of 195 enrolled patients , 187 were assessable : 108 ( 57.8 % ) in the vaccinated group ( VG ) and 79 ( 42.2 % ) in the control group ( CG ) . The groups were well matched for clinicopathologic characteristics . Toxicities were minimal . Five-year DFS was 89.7 % in the VG versus 80.2 % in the CG ( P = 0.08 ) . Due to trial design , 65 % of patients received less than the optimal vaccine dose . Five-year DFS was 94.6 % in optimally dosed patients ( P = 0.05 versus the CG ) and 87.1 % in suboptimally dosed patients . A voluntary booster program was initiated , and among the 21 patients that were optimally boosted , there was only one recurrence ( DFS = 95.2 % ) . CONCLUSION The E75 vaccine is safe and appears to have clinical efficacy . A phase III trial evaluating the optimal dose and including booster inoculations has been initiated . CLINICAL TRIALS NCT00841399 , NCT00584789",
"Purpose : p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results . We studied p53 protein expression , by immunohistochemistry , in a r and omized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [ Cancer and Leukemia Group B ( CALGB ) 9344 , INT0148 ] . Patients and Methods : Epithelial p53 expression was evaluated using two immunohistochemical antibodies ( DO7 and 1801 ) in formalin-fixed , paraffin-embedded tissue from patients with node-positive breast cancer who were r and omized to four cycles of cyclophosphamide and one of three doses of doxorubicin ( 60 , 75 , or 90 mg/m2 ; AC ) and to receive four subsequent cycles of paclitaxel ( T ) or not . Prognostic and predictive value of p53 protein expression was assessed , independent of treatment assignment , for escalating doses of doxorubicin or addition of T with endpoints of relapse-free ( RFS ) and overall survival ( OS ) . Results : Of 3,121 patients , 1,887 patient specimens treated on C9344 were obtained , passed quality control , and evaluated for p53 expression . Expression was 23 % and 27 % for mAbs 1801 and D07 , respectively , with 92 % concordance . In univariate analysis , p53 positivity was associated with worse OS with either antibody , but only p53 staining with monoclonal antibody 1801 had significantly worse RFS . In multivariate analysis , p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody . Conclusion : Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node-positive patients treated with adjuvant doxorubicin-based chemotherapy but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel . Clin Cancer Res ; 17(15 ) ; 5170–8 . © 2011 AACR",
"Abstract This r and omized , multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide ( FEC ) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker . Patients were r and omized to 4 cycles of docetaxel/capecitabine ( docetaxel : 75 mg/m2 on day 1 ; capecitabine : 1,650 mg/m2 on days 1–14 every 3 weeks ) or docetaxel alone ( 75 mg/m2 on day 1 every 3 weeks ) after completion of 4 cycles of FEC ( 5-fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks ) . The primary endpoint was the pathological complete response ( pCR ) rate . Predictive factor analysis was conducted using clinicopathological markers , including hormone receptors and Ki67 labeling index ( Ki67LI ) . A total of 477 patients were r and omized ; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 % , respectively . There were no significant differences in the pCR rate ( docetaxel/capecitabine : 23 % ; docetaxel : 24 % ; p = 0.748 ) , disease-free survival , or overall survival . However , patients with mid-range Ki67LI ( 10–20 % ) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone . Furthermore , multivariate logistic regression analysis showed pre-treatment Ki67LI ( odds ratio 1.031 ; 95 % CI 1.014–1.048 ; p = 0.0004 ) to be a significant predictor of pCR in this neoadjuvant treatment setting . Docetaxel/capecitabine ( after 4 cycles of FEC ) did not generate significant improvement in pCR compared to docetaxel alone . However , exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer",
"BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer , and , as a consequence , they have also been studied in the adjuvant setting . METHODS After breast cancer surgery , women with lymph node-positive disease were r and omly assigned to treatment with fluorouracil , epirubicin , and cyclophosphamide ( FEC ) or with FEC followed by weekly paclitaxel ( FEC-P ) . The primary endpoint of study -5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis . Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular ( hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization ) markers . Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates : age , menopausal status , tumor size , lymph node status , type of chemotherapy , tumor size , positive lymph nodes , HER2 status , and hormone receptor status . All statistical tests were two-sided . RESULTS Among the 1246 eligible patients , estimated rates of DFS at 5 years were 78.5 % in the FEC-P arm and 72.1 % in the FEC arm ( difference = 6.4 % , 95 % confidence interval [ CI ] = 1.6 % to 11.2 % ; P = .006 ) . FEC-P treatment was associated with a 23 % reduction in the risk of relapse compared with FEC treatment ( 146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm , hazard ratio [ HR ] = 0.77 , 95 % CI = 0.62 to 0.95 ; P = .022 ) and a 22 % reduction in the risk of death ( 73 and 95 deaths , respectively , HR = 0.78 , 95 % CI = 0.57 to 1.06 ; P = .110 ) . Among the 928 patients for whom tumor sample s were central ly analyzed , type of chemotherapy ( FEC vs FEC-P ) ( P = .017 ) , number of involved axillary lymph nodes ( P tumor size ( P = .020 ) , hormone receptor status ( P = .004 ) , and HER2 status ( P = .006 ) were all associated with DFS . We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment . CONCLUSIONS Among patients with operable breast cancer , FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy",
"Purpose : Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens . We examined this hypothesis on NCIC.CTG MA.5 , a clinical trial r and omizing premenopausal women with node-positive breast cancer to adjuvant CMF ( cyclophosphamide-methotrexate-fluorouracil ) versus CEF ( cyclophosphamide-epirubicin-fluorouracil ) chemotherapy . Experimental Design : Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test . Luminal A , luminal B , HER2-enriched ( HER2-E ) , and basal-like subtypes were correlated with relapse-free survival ( RFS ) and overall survival ( OS ) , estimated using Kaplan – Meier plots and log-rank testing . Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes . Results : Intrinsic subtypes were associated with RFS ( P = 0.0005 ) and OS ( P CEF versus CMF , with absolute 5-year RFS and OS differences exceeding 20 % , whereas there was a less than 2 % difference for non – HER2-E tumors ( interaction test P = 0.03 for RFS and 0.03 for OS ) . Within clinical ly defined Her2 + tumors , 79 % ( 72 of 91 ) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF ( 62 % vs. 22 % , P = 0.0006 ) . There was no significant difference in benefit between CEF and CMF in basal-like tumors [ n = 94 ; HR , 1.1 ; 95 % confidence interval ( CI ) , 0.6–2.1 for RFS and HR , 1.3 ; 95 % CI , 0.7–2.5 for OS ] . Conclusion : HER2-E strongly predicted anthracycline sensitivity . The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF , suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required . Clin Cancer Res ; 18(8 ) ; 2402–12 . © 2012 AACR",
"BACKGROUND Predictive markers of response to chemotherapy are lacking in breast cancer patients . Forkhead Box Protein 3 ( FOXP3 ) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent . So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival ( OS ) benefit over anthracyclines alone , in patients with FOXP3-negative tumors . PATIENTS AND METHODS Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor sample s from 1097 patients who participated in the PACS01 r and omized trial that evaluated in adjuvant setting the adjunction of docetaxel ( Taxotere ) to anthracyclines in patients with localized breast cancer . Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells . RESULTS Four hundred and five tumors were found to express FOXP3 ( 37 % ) . FOXP3 expression in breast cancer cells was associated with better OS ( P = 0.003 ) . Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy , but not in patients treated with sequential anthracycline-taxane . Moreover , in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy . CONCLUSION FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer",
"BACKGROUND We compared docetaxel plus doxorubicin and cyclophosphamide ( TAC ) with fluorouracil plus doxorubicin and cyclophosphamide ( FAC ) as adjuvant chemotherapy for operable node-positive breast cancer . METHODS We r and omly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery . The primary end point was disease-free survival . RESULTS At a median follow-up of 55 months , the estimated rates of disease-free survival at five years were 75 percent among the 745 patients r and omly assigned to receive TAC and 68 percent among the 746 r and omly assigned to receive FAC , representing a 28 percent reduction in the risk of relapse ( P=0.001 ) in the TAC group . The estimated rates of overall survival at five years were 87 percent and 81 percent , respectively . Treatment with TAC result ed in a 30 percent reduction in the risk of death ( P=0.008 ) . The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group ( P of febrile neutropenia were 24.7 percent and 2.5 percent , respectively ( P Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC ( P=0.05 ) ; no deaths occurred as a result of infection . Two patients in each group died during treatment . Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group . Quality -of-life scores decreased during chemotherapy but returned to baseline levels after treatment . CONCLUSIONS Adjuvant chemotherapy with TAC , as compared with FAC , significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer",
"BACKGROUND Patients with an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery . The relationship between extended chemotherapy and pathological complete response at surgery was investigated in a clinical trial . METHODS Untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m(2 ) , doxorubicin at 50 mg/m(2 ) , and cyclophosphamide at 500 mg/m(2 ) ( TAC ) . Those whose tumor size decreased by 50 % or more by sonographic measurement ( ie , reduction in the product of the two largest perpendicular diameters by at least 50 % ) were classified as responders and r and omly assigned to receive four or six more cycles of TAC , for a total of six or eight TAC cycles . The primary aim was to increase the rate of a pathological complete response ( defined as no invasive or in situ residual tumor masses in the breast and lymph nodes ) from 20 % to 26 % . Sonographic response rates and rates of breast-conserving surgery and adverse effects were also assessed . All statistical tests were two-sided . RESULTS Of the 2090 patients in the GeparTrio trial , 1390 ( 66.5 % ) were r and omly assigned as responders after two initial TAC cycles to receive an additional four ( n = 704 ) or six ( n = 686 ) TAC cycles . Rates of pathological complete response were not statistically significantly different between the arms ( 21.0 % with six TAC cycles and 23.5 % with eight TAC cycles ; difference = 2.5 % , 95 % confidence interval [ CI ] = -1.8 % to 6.8 % ; P = .27 ) . More clinical ( 48.2 % vs 52.9 % , difference = 4.7 % ; 95 % CI = -0.55 % to 9.95 % ; P = .08 ) and sonographic ( 22.6 % vs 27.6 % , difference = 5 % ; 95 % CI = 0.45 % to 9.55 % ; P = .033 ) complete responses at surgery were observed with eight TAC cycles than with six TAC cycles . The rate of breast-conserving surgery was similar in both arms ( 67.5 % vs 68.5 % , respectively , P = .68 ) . Grade 3 or 4 leukopenia and edema and various grade 1 or 2 adverse events were more frequent in patients receiving eight TAC cycles than in those receiving six cycles . CONCLUSION Patients receiving eight TAC cycles had statistically significantly higher sonographic response rates but not pathological complete response rates than those receiving six TAC cycles . However , they also had more toxic effects . So far , eight cycles of TAC can not be recommended for the whole group of patients responding to two initial cycles of TAC",
"PURPOSE Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer . This trial ( NSABP B-38 ; Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer ) asked whether the incorporation of a fourth drug could improve outcomes relative to two st and ard regimens and provided a direct comparison of those two regimens . PATIENTS AND METHODS We r and omly assigned 4,894 women with node-positive early-stage breast cancer to six cycles of docetaxel , doxorubicin , and cyclophosphamide ( TAC ) , four cycles of dose-dense ( DD ) doxorubicin and cyclophosphamide followed by four cycles of DD paclitaxel ( P ; DD AC→P ) , or DD AC→P with four cycles of gemcitabine ( G ) added to the DD paclitaxel ( DD AC→PG ) . Primary granulocyte colony-stimulating factor support was required ; erythropoiesis-stimulating agents ( ESAs ) were used at the investigator 's discretion . RESULTS There were no significant differences in 5-year disease-free survival ( DFS ) between DD AC→PG and DD AC→P ( 80.6 % v 82.2 % ; HR , 1.07 ; P = .41 ) , between DD AC→PG and TAC ( 80.6 % v 80.1 % ; HR , 0.93 ; P = .39 ) , in 5-year overall survival ( OS ) between DD AC→PG and DD AC→P ( 90.8 % v 89.1 % ; HR , 0.85 ; P = .13 ) , between DD AC→PG and TAC ( 90.8 % v 89.6 % ; HR , 0.86 ; P = .17 ) , or between DD AC→P versus TAC for DFS ( HR , 0.87 ; P = .07 ) and OS ( HR , 1.01 ; P = .96 ) . Grade 3 to 4 toxicities for TAC , DD AC→P , and DD AC→PG , respectively , were febrile neutropenia ( 9 % , 3 % , 3 % ; P .001 ) , sensory neuropathy ( .001 ) , and diarrhea ( 7 % , 2 % , 2 % ; P with DFS events ( HR , 1.02 ; P = .95 ) . CONCLUSION Adding G to DD AC→P did not improve outcomes . No significant differences in efficacy were identified between DD AC→P and TAC , although toxicity profiles differed",
"Purpose : The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described . Experimental Design : Participants of the GeparTrio study with primary breast cancer r and omly received neoadjuvant response-guided [ 8 cycles TAC ( docetaxel/doxorubicin/cyclophosphamide ) in responding and TAC-NX ( vinorelbine/capecitabine ) in nonresponding patients ] or conventional ( 6 cycles TAC ) chemotherapy according to interim response assessment . Ki-67 levels were central ly measured immunohistochemically after neoadjuvant treatment if tumor tissue was available . Here , we analyze 1,151 patients having a pathologic complete response ( pCR ; n , 484 ) , or residual disease with low ( 0–15 % ) , intermediate ( 15.1–35 % ) , or high ( 35.1–100 % ) posttreatment Ki67 levels in 488 , 77 , and 102 patients , respectively . Results : Patients with high posttreatment Ki67 levels showed higher risk for disease relapse ( P and death ( P Ki67 levels showed a comparable outcome to patients with a pCR ( P = 0.211 for disease-free and P = 0.779 for overall survival ) . Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment . Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone – receptor-positive disease [ hazard ratios ( HR ) , 1.82–5.88 ] but not in hormone – receptor-negative disease ( HR : 0.61–1.73 ) . Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 ( P = 0.965 ) . Conclusions : Posttreatment Ki67 levels provide prognostic information for patients with hormone – receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy . Levels were not prognostic for outcome after response-guided chemotherapy . High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments . Clin Cancer Res ; 19(16 ) ; 4521–31 . © 2013 AACR",
"BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting . Micrometastases are dependent on angiogenesis , suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting . We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer . METHODS For this open-label , r and omised phase 3 trial we recruited patients with central ly confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries . We r and omly allocated patients aged 18 years or older ( 1:1 with block r and omisation ; stratified by nodal status , chemotherapy [ with an anthracycline , taxane , or both ] , hormone receptor status [ negative vs low ] , and type of surgery ) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab ( equivalent of 5 mg/kg every week for 1 year ) . The primary endpoint was invasive disease-free survival ( IDFS ) . Efficacy analyses were based on the intention-to-treat population , safety analyses were done on all patients who received at least one dose of study drug , and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample . This trial is registered with Clinical Trials.gov , number NCT00528567 . FINDINGS Between Dec 3 , 2007 , and March 8 , 2010 , we r and omly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy . Most patients received anthracycline-containing therapy ; 1638 ( 63 % ) of the 2591 patients had node-negative disease . At the time of analysis of IDFS , median follow-up was 31·5 months ( IQR 25·6 - 36·8 ) in the chemotherapy-alone group and 32·0 months ( 27·5 - 36·9 ) in the bevacizumab group . At the time of the primary analysis , IDFS events had been reported in 205 patients ( 16 % ) in the chemotherapy-alone group and in 188 patients ( 14 % ) in the bevacizumab group ( hazard ratio [ HR ] in stratified log-rank analysis 0·87 , 95 % CI 0·72 - 1·07 ; p=0·18 ) . 3-year IDFS was 82·7 % ( 95 % CI 80·5 - 85·0 ) with chemotherapy alone and 83·7 % ( 81·4 - 86·0 ) with bevacizumab and chemotherapy . After 200 deaths , no difference in overall survival was noted between the groups ( HR 0·84 , 95 % CI 0·64 - 1·12 ; p=0·23 ) . Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab ( Cox interaction test p=0·029 ) . Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension ( 154 patients [ 12 % ] vs eight patients [ 1 % ] ) , severe cardiac events occurring at any point during the 18-month safety reporting period ( 19 [ 1 % ] vs two [ ) , and treatment discontinuation ( bevacizumab , chemotherapy , or both ; 256 [ 20 % ] vs 30 [ 2 % ] ) ; we recorded no increase in fatal adverse events with bevacizumab ( four [ INTERPRETATION Bevacizumab can not be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer . Further follow-up is needed to assess the potential effect of bevacizumab on overall survival",
"LBA1000 Background : The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity . METHODS From Nov 3 , 2004 to May 3 , 2007 , 4894 women were r and omized ; 1630 to TAC ( docetaxel [ T ] 75 mg/m2 , doxorubicin [ A ] 50 mg/m2 , cyclophosphamide [ C ] 500 mg/m2 q3 wks x 6 ) , 1634 to DD AC→P ( A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4 ) , and 1630 to DD AC→PG ( A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4 ) . Primary G-CSF support was required and erythropoiesis-stimulating agents ( ESA ) were used at investigator discretion . 52 % were postmenopausal , 65 % had 1 - 3 positive nodes , and 80 % had HR+ breast cancer . Log-rank tests were used for pair-wise comparisons of the primary ( DFS ) and secondary ( OS ) endpoints among the three treatment arms . RESULTS With 64 months median follow-up , 5-year DFS in DD AC→PG group was 80.6 % compared with 82.2 % in DD AC→P group ( HR=1.1 ; p=0.27 ) and 80.1 % ( HR=0.97 ; p=0.71 ) in TAC group . 5-year OS was 90.8 % in DD AC→PG group as compared with 89.1 % ( HR=.89 ; p=0.25 ) in DD AC→P group and 89.6 % ( HR=0.90 ; p=0.32 ) in TAC group . HR for DFS and OS of DD AC→P vs. TAC were 0.89 ( p=0.14 ) and 1.01 ( p=0.92 ) respectively . Toxicities for TAC , DD AC→P , DD AC→PG , respectively : febrile neutropenia ( Gr 3/4 : 9 % , 4 % , 4 % [ p ) , sensory neuropathy ( Gr 3/4 : [ p ( Gr 3/4 : 8 % , 2 % , 2 % [ p Hgb was % . Deaths on treatment : N=13 , 5 , 7 ( p=0.2 ) . AML/MDS N=5 , 8 , 11 . All cycles completed in 91 % for TAC and 88 % for DD regimens . CONCLUSIONS Addition of G to DD AC→P did not improve outcomes . No significant differences in efficacy endpoints were identified between DD AC→P and TAC , though toxicity profiles differed . FUNDING NCI PHS U10-CA-37377 , -69974 , -12027 , -69651 and NCCTG U10-CA25224 , with additional funding from Eli Lilly & Company , and Amgen ,",
" PURPOSE A phase III trial ( Cancer and Leukemia Group B CALGB-49907 ) was conducted to test whether older patients with early-stage breast cancer would have equivalent relapse-free and overall survival with capecitabine compared with st and ard chemotherapy . The quality of life ( QoL ) sub study tested whether capecitabine treatment would be associated with a better QoL than st and ard chemotherapy . PATIENTS AND METHODS QoL was assessed in 350 patients r and omly assigned to either st and ard chemotherapy ( cyclophosphamide , methotrexate , and fluorouracil [ CMF ] or doxorubicin and cyclophosphamide [ AC ] ; n = 182 ) or capecitabine ( n = 168 ) . Patients were interviewed by telephone before treatment ( baseline ) , midtreatment , within 1 month post-treatment , and at 12 , 18 , and 24 months postbaseline by using question naires from the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ( EORTC QLQ-C30 ) , a breast systemic adverse effects scale ( EORTC BR23 ) , and the Hospital Anxiety and Depression Scale ( HADS ) . RESULTS Compared with patients who were treated with st and ard chemotherapy , patients who were treated with capecitabine had significantly better QoL , role function , and social function , fewer systemic adverse effects , less psychological distress , and less fatigue during and at the completion of treatment ( P ≤ .005 ) . Capecitabine treatment was associated with less nausea , vomiting , and constipation and with better appetite than st and ard treatment ( P ≤ .004 ) , but worse h and -foot syndrome and diarrhea ( P CONCLUSION St and ard chemotherapy was superior to capecitabine in improving relapse-free and overall survival for older women with early-stage breast cancer . Although capecitabine was associated with better QoL during treatment , QoL was similar for both groups at 1 year . The brief period of poorer QoL with st and ard treatment is a modest price to pay for a chance at improved survival",
"PURPOSE To evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic ( neoadjuvant ) therapy . PATIENTS AND METHODS A total of 1,355 women with operable breast cancer were r and omly assigned to one of three treatments : surgery followed by adjuvant doxorubicin ( 75 mg/m(2 ) ) followed by cyclophosphamide , methotrexate , and fluorouracil ( CMF ; arm A ) ; surgery followed by adjuvant paclitaxel ( 200 mg/m(2 ) ) plus doxorubicin ( 60 mg/m(2 ) ) , followed by CMF ( arm B ) ; or paclitaxel ( 200 mg/m(2 ) ) plus doxorubicin ( 60 mg/m(2 ) ) followed by CMF followed by surgery ( arm C ) . The two co primary objectives were to assess the effects on relapse-free survival ( RFS ) of the addition of paclitaxel to postoperative chemotherapy ( arm B v arm A ) and primary chemotherapy versus adjuvant chemotherapy ( arm B v arm C ) . RESULTS Doxorubicin plus paclitaxel followed by CMF was well-tolerated as adjuvant or as primary chemotherapy . The addition of paclitaxel to adjuvant doxorubicin followed by CMF significantly improved RFS compared with adjuvant doxorubicin alone followed by CMF ( hazard ratio [ HR ] , 0.73 ; P = .03 ) . Distant RFS was similarly improved ( HR , 0.70 ; P = .027 ) . There was no significant difference in RFS when the paclitaxel/doxorubicin/CMF chemotherapy was given before surgery compared with the same regimen given after surgery ( HR , 1.21 ; P = .18 ) . However , the rate of breast-conserving surgery was significantly higher with preoperative chemotherapy ( 63 % v 34 % ; P paclitaxel into anthracycline-based adjuvant therapy result ed in a significant improvement in RFS and distant RFS . When given as primary systemic therapy , the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients",
"BACKGROUND The NEAT/BR9601 trial showed benefit for addition of anthracyclines to cyclophosphamide , methotrexate , and fluorouracil ( CMF ) as adjuvant treatment for early breast cancer . We investigated prospect ively predictive biomarkers of anthracycline benefit including HER2 and TOP2A . METHODS 1941 tumours from 2391 women recruited to NEAT/BR9601 were analysed on tissue microarrays for HER2 and TOP2A amplification and deletion , HER1 - 3 and Ki67 expression , and duplication of chromosome 17 centromere enumeration probe ( Ch17CEP ) . Log-rank analyses identified factors affecting relapse-free and overall survival , and regression models tested independent prognostic effect of markers , with adjustment for known prognostic factors ( age , nodal status , oestrogen-receptor status , grade , and tumour size ) . The predictive value of markers was tested by treatment interactions for relapse-free and overall survival . FINDINGS 1762 patients were analysed . 21 % of tumours ( n=367 ) were HER2 amplified , 10 % were TOP2A amplified ( n=169 ) , 11 % showed TOP2A deleted ( n=191 ) , 23 % showed Ch17CEP duplication ( n=406 ) , and 61 % had high ( > 13.0 % ) Ki67 ( n=1136 ) . In univariate analyses , only HER2 amplification and TOP2A deletion were significant prognostic factors for relapse-free ( hazard ratio [ HR ] 1.59 , 95 % CI 1.32 - 1.92 , p overall survival ( 1.79 , 1.47 - 2.19 , p anthracycline benefit for Ki67 , HER2 , HER1 - 3 , or TOP2A . By contrast , in multivariate analyses , Ch17CEP duplication was associated with significant improvements in both relapse-free ( HR 0.92 , 95 % CI 0.72 - 1.18 for tumours with normal Ch17CEP vs 0.52 , 0.34 - 0.81 for tumours with abnormal Ch17CEP ; p for interaction=0.004 ) and overall survival ( 0.94 , 0.72 - 1.24 vs 0.57 , 0.36 - 0.92 ; p for interaction=0.02 ) with anthracycline use . INTERPRETATION In women with early breast cancer receiving adjuvant chemotherapy , the most powerful predictor of benefit from anthracyclines is Ch17CEP duplication . In view of the location of HER2/TOP2A on chromosome 17 , Ch17CEP duplication might explain the inconsistencies in previous studies of factors predicting benefit from anthracyclines . FUNDING Cancer Research UK and the Scottish Breast Cancer Clinical Trials Group",
"A r and omized multicenter phase III study was conducted to compare the sequential docetaxel followed by epirubicin/cyclophosphamide combination with that of FEC regimen as adjuvant chemotherapy in women with axillary node-positive early breast cancer . Seven hundred and fifty-six women with axillary lymph node-positive breast cancer were r and omized to receive either 4 cycles of docetaxel ( 100 mg/m2 ) followed by 4 cycles of epirubicin ( 75 mg/m2 ) plus cyclophosphamide ( 700 mg/m2 ) ( experimental arm ) or 6 cycles of FEC ( epirubicin 75 mg/m2 , cyclophosphamide 700 mg/m2 , and 5-fluorouracil 700 mg/m2 ; control arm ) . All regimes were administered every 3 weeks . The primary end point was five-year disease-free survival ( DFS ) . After a median follow-up period of 5 years , 233 ( 30.8 % ) relapses had occurred ( 108 and 125 in the experimental and control arms , respectively ; P = 0.181 ) . The five-year DFS was 72.6 % ( 95 % CI 63.8–81.3 % ) and 67.2 % ( 95 % CI 58.0–76.4 % ) for women r and omized in the experimental and control arms , respectively ( P = 0.041 ; log rank test ) . There was no difference in the overall survival between the two arms ( 83.8 and 81.4 % in the experimental and control arms , respectively ; P = 0.533 ) . The experimental arm was associated with increased neutropenia requiring administration of granulocyte colony-stimulating factor in 90.5 % of the patients as compared with 74.1 % in the control arm ( P = 0.0001 ) . The sequential docetaxel followed by epirubicin/cyclophosphamide adjuvant chemotherapy regimen result ed in improved five-year DFS in women with axillary node-positive early breast cancer at the expense of increased but manageable myelotoxicity ",
"PURPOSE The indications of adjuvant chemotherapy for patients with estrogen receptor ( ER ) -positive breast cancer are controversial . We analyzed the predictive value of Ki67 , HER2 , and progesterone receptor ( PR ) expression for the efficacy of docetaxel in patients with ER-positive , node-positive breast cancer . PATIENTS AND METHODS Expression of Ki67 , HER2 , and PR was measured by immunohistochemistry in tumor sample s from 798 patients with ER-positive breast cancer who participated in PACS01 , a r and omized trial that evaluated the efficacy of docetaxel . Risk reduction was evaluated using a Cox model adjusted for age , tumor size , nodal involvement , treatment arm , and biomarkers . The predictive value of biomarkers was assessed by an interaction test . Disease-free survival ( DFS ) was the primary end point . Results Ki67 , HER2 , and PR were expressed in 21 % , 9 % , and 62 % of sample s , respectively . Hazard ratios for relapse associated with docetaxel were 0.51 ( 95 % CI , 0.26 to 1.01 ) in ER-positive/Ki67-positive tumors and 1.03 ( 95 % CI , 0.69 to 1.55 ) in ER-positive/Ki67-negative tumors ( ratio for interaction : 0.53 ; 95 % CI , 0.24 to 1.16 ; P = .11 ) . Five-year DFS rates were 81 % ( 95 % CI , 76 % to 86 % ) and 84 % ( 95 % CI , 75 % to 93 % ) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81 % ( 95 % CI , 76 % to 86 % ) and 62 % ( 95 % CI , 52 % to 72 % ) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil , epirubicin , and cisplatin . No trend for interaction was observed between docetaxel and HER2 ( ratio for interaction : 0.83 ; 95 % CI , 0.35 to 1.94 ; P = .66 ) , nor between docetaxel and PR ( ratio for interaction : 0.89 ; 95 % CI , 0.47 to 1.66 ; P = .71 ) . CONCLUSION Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting",
"Background To compare the cyclophosphamide , methotrexate , and fluorouracil ( CMF ) chemotherapy and the anthracycline-containing regimen cyclophosphamide , epirubicin , and fluorouracil ( CEF ) to evaluate the efficacy and safety of the latter . Methods A total of 294 patients with axillary node-positive primary breast cancer of STAGE I – IIIa were r and omly assigned to either CEF [ cyclophosphamide ( CPA ) 500 mg/m2 i.v . days 1 and 8 ; epirubicin ( EPI ) 60 mg/m2 i.v . day 1 ; and 5-fluorouracil ( 5-FU ) 500 mg/m2 i.v . days 1 and 8 ] or CMF [ CPA 500 mg/m2 i.v . days 1 and 8 ; methotrexate ( MTX ) 40 mg/m2 i.v . days 1 and 8 ; and 5-FU 500 mg/m2 i.v . days 1 and 8 ] . Both treatment regimens were comprised of six cycles at 4-week intervals . Tamoxifen ( TAM ) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years . Results The overall 5-year survival was 77.1 % for CEF and 71.4 % for CMF [ p = 0.24 ; hazard ratio 0.79 ( 95 % CI 0.50–1.24 ) ] , and the 5-year disease-free survival was 55.7 % for CEF and 48.9 % for CMF [ p = 0.15 ; hazard ratio 0.80 ( 95 % CI 0.57–1.12 ) ] . Although the log-rank test did not show a significant difference , both overall and disease-free survivals were higher for CEF according to the point estimates . Adverse drug reactions ( ADRs ) occurred more frequently in CEF . Conclusion Whereas CEF had a good trend compare with CMF , it could not be proven statistically significant . The principal cause of the failure seems to be insufficient power , that is , the dose intensity ( EPI : 60 mg/m2 ) set 10 years ago , when the trial began , was low , and the number of trial subjects was small because of the background of the times , which made the accumulation of cases extremely difficult . However , the trial should be considered to be meaningful , as it was the first , formally conducted controlled trial on chemotherapy in Japan",
"Purpose To eluci date whether adjuvant taxane monotherapy is a feasible and tolerable for postoperative breast cancer patients , we evaluated the severity of chemotherapy-induced peripheral neuropathy ( CIPN ) and the relative tolerability of regimens by health-related quality of life ( HRQOL ) assessment in node-positive breast cancer patients treated with taxane-containing regimens . Methods We evaluated CIPN and HRQOL in the first 300 patients enrolled in a larger ( 1,060 total ) multicenter phase III trial r and omized to one of four adjuvant regimens : ( 1 ) anthracycline – cyclophosphamide followed by paclitaxel ( ACP ) , ( 2 ) AC followed by docetaxel ( ACD ) , ( 3 ) paclitaxel alone ( PTX ) , or ( 4 ) docetaxel alone ( DTX ) . CIPN was assessed by the Patient Neurotoxicity Question naire ( PNQ ) and the National Cancer Institute Common Toxicity Criteria , and HRQOL by Functional Assessment of Cancer Therapy-General ( FACT-G ) . CIPN and HRQOL scores were compared between ACP and ACD vs. PTX and DTX , and ACP and PTX vs. ACD and DTX . Results PNQ sensory scores were significantly higher in patients treated with taxane monotherapy compared to treatment with AC followed by taxane ( P = .003 ) . No significant differences in PNQ sensory scores were observed between the ACP and PTX vs. ACD and DTX regimens ( P = .669 ) . Regardless of taxane regimen , PNQ severity scores for CIPN appear to be largely reversible within 1 year of adjuvant treatment . No significant difference in FACT-G scores was observed between any regimens during the study treatments . Conclusions Patient-reported CIPN was significantly more severe with single-agent adjuvant taxane compared to AC followed by taxane treatment ; however , the HRQOL findings support that single-agent taxane treatment is tolerable",
"To explore the impact of dose intensity ( DI ) in the adjuvant setting of breast cancer , a r and omized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin , paclitaxel , and cyclophosphamide , methotrexate and fluorouracil (CMF)in high-risk breast cancer patients . From Oct 2000 to June 2005 , 1,121 node-positive patients were r and omized to dose-dense sequential epirubicin 110 mg/m2 and paclitaxel ( Taxol ® , Bristol Myers-Squibb , Princeton , NJ ) 250 mg/m2 ( group A ) , or concurrent epirubicin 83 mg/m2 and paclitaxel 187 mg/m2 ( group B ) , both followed by three cycles of “ intensified ” combination chemotherapy with CMF . By protocol design total cumulative dose and duration of treatment were identical in both groups . Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm . Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments . Disease-free survival ( DFS ) was the primary endpoint . At a median follow-up of 76 months , 253 patients ( 23 % ) had documented disease relapse ( 123 vs. 130 in groups A and B , respectively ) and 208 deaths ( 101 , group A and 107 , group B ) had been observed . The 5-year DFS rate of 74 and 74 % and OS rate of 86 and 85 % were observed for group A and group B , respectively . No differences were found in DFS or OS between the two treatment groups ( P = 0.78 and P = 0.45 for DFS and OS , respectively ) . Safety analysis results showing that both regimens were well tolerated and safe have been previously published ( Fountzilas et al. Ann Oncol 2008 ) . No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs . No additional safety issues were raised with long-term follow-up",
"10625 Background : Patients with hormone receptor positive breast cancer and 1 - 3 positive lymph nodes ( LN ) belong to the intermediate risk-group . Among these patients chemo-endocrine therapy may be considered according to the St. Gallen guidelines . We compared evidence -based cut-offs of Ki-67 for definition of molecular subtypes to central grade regarding their predictive value for benefit from taxane-based chemotherapy . METHODS The EC-Doc trial r and omized 1950 patients with 1 - 3 positive LN to 6x CEF/CMF vs. 4xEC-4xDoc . Significantly better DFS and OS favoring EC-Doc have been previously reported ( Nitz et al. , SABCS 2008 ) . Protein expression data ( ER , PR , HER2[+FISH ] , Ki-67 , Ck 5 , and EGFR ) and central histology/ grade were available for 772 patients . Molecular subgroups were classified using Ki-67 cut-off 's of 13.25 % and 20 % ( due to correlation with genomic grade index [ GGI ] ) . GGI analysis is planned . RESULTS The entire and the investigated study population s did not differ regarding baseline characteristics . After median follow up of 64 months , both DFS ( 5y 90 % vs. 80 % , p=0.006 ) and OS ( 5y 95 % vs. 92 % , p=0.022 ) rates significantly favored EC-Doc vs. CEF also in this cohort . 5-y DFS was longest in luminal A and shortest in basal-like tumors ( 97 % vs. 72 % , p Ki-67 cut-offs ( 13.25 % and 20 % ) used for defining luminal B subtype were predictive for taxane benefit . However , only Ki-67 cut-off of 20 % was significant regarding interaction with therapy ( HR=0.467 , p=0.02 ) in multivariate analysis including central grade , age , nodal status , tumor size , molecular subtypes , therapy , and predictive interactions between all factors and therapy . Only central grade ( HR=4.315 , p20 % or HER2 + is the only predictive factor for taxane benefit in intermediate risk BC and that both central grade and luminal A subtype are strong prognostic markers . These results are currently vali date d within the prospect i ve WSG PlanB trial",
"PURPOSE According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials , we investigated whether node-negative breast cancer patients , defined as high-risk cases on the basis of tumor cell proliferation , could benefit from cyclophosphamide , methotrexate , and fluorouracil ( CMF ) adjuvant therapy . PATIENTS AND METHODS Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors , defined according to thymidine labeling index ( TLI ) , were r and omized to receive six cycles of CMF or no further treatment after surgery + /- radiotherapy . RESULTS The 5-year disease-free survival ( DFS ) was 83 % for patients treated with CMF compared with 72 % in the control group ( P : = .028 ) . Adjuvant treatment reduced both locoregional and distant metastases . When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria , compared with patients in the control arm , 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second ( 78 % v 88 % , respectively ; P : = .037 ) and third tertiles ( 58 % v 78 % , respectively ; P : = .024 ) . CONCLUSION The results from this r and omized clinical study indicate that patients with node-negative , rapidly proliferating tumors significantly benefit from adjuvant CMF",
"PURPOSE The primary aim of this study was to compare the effectiveness of oral uracil-tegafur ( UFT ) with that of classical cyclophosphamide , methotrexate , and fluorouracil ( CMF ) given as postoperative adjuvant treatment to women with node-negative , high-risk breast cancer . PATIENTS AND METHODS Women with node-negative , high-risk breast cancer were r and omly assigned to receive either 2 years of UFT or six cycles of CMF after surgery . The primary end point was relapse-free survival ( RFS ) . Overall survival ( OS ) , toxicity , and quality of life ( QOL ) were secondary end points . The hypothesis was that UFT was not inferior to CMF in terms of RFS . RESULTS Between October 1996 and April 2001 , a total of 733 patients were r and omly assigned to receive either treatment . The median follow-up time was 6.2 years . The RFS rates at 5 years were 88.0 % in the CMF arm and 87.8 % in the UFT arm . OS rates were 96.0 % and 96.2 % , respectively . The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS ( 95 % CI , 0.66 to 1.45 ; P = .92 ) and 0.81 for OS ( 95 % CI , 0.44 to 1.48 ; P = .49 ) . The toxicity profiles differed between the two groups . The QOL scores were better for patients given UFT than those given CMF . CONCLUSION RFS and OS with oral UFT were similar to those with classical CMF . Given the higher QOL scores , oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative , high-risk breast cancer",
"OBJECTIVE To examine health-related quality of life , we investigated the effect of adjuvant chemotherapy regimens on utility scores assessed by the EuroQoL-5D ( EQ-5D ) instrument in a r and omized , controlled trial for breast cancer patients after surgery . We also investigated the relationship between Functional Assessment of Cancer Therapy ( FACT ) scale scores and EQ-5D utilities . METHODS Patients were r and omly assigned to the following four chemotherapy regimens : four cycles of anthracycline followed by paclitaxel ( ACP ) , four cycles of anthracycline-containing regimens followed by docetaxel ( ACD ) , eight cycles of paclitaxel ( PTX ) , and eight cycles of docetaxel ( DTX ) . Of 1060 registered , the first 300 consecutive patients were included in the current utility study . Utility scores were assessed using the EQ-5D instrument at baseline ; cycles 3 , 5 , and 7 ; 7 months ; and 1 year . We also evaluated the correlation between these scores and FACT-G , -B , and -Taxane scores at each time point . RESULTS Utility scores were significantly lower in the DTX group than in the ACP and ACD groups . Mean utility scores in the DTX group were lowest at 7 months and tended to remain low for a long time . The combined anthracycline followed by taxane group had significantly higher utility scores that the taxane-alone group , with no significant difference depending on the type of taxane . Only the FACT-G social/family well-being subscale had no relationship with EQ-5D responses and utility scores . CONCLUSIONS Although the regimens in this study were similar in that they included taxane , the mean utility scores and longitudinal patterns of utility scores were different among regimens",
"We aim ed to determine the efficacies of a non-anthracycline-containing regimen , docetaxel/capecitabine ( TX ) , in comparison with an anthracycline-containing regimen , doxorubicin/cyclophosphamide ( AC ) , as primary chemotherapy for node-positive early stage breast cancer . In this phase-III single center r and omized study , we r and omized 209 women with axillary node positive , stage II/III breast cancer to receive four cycles of either TX or AC followed by surgery and cross-over to the other treatment as an adjuvant therapy . The primary endpoint was tumor pathologic complete response ( pCR ) . Clinical response rates , toxicity profiles , disease free survival ( DFS ) , and overall survival were secondary objectives . In total , 204 patients had clinical and radiological evaluation of response , and underwent surgery . Compared with AC , TX increased pCR in primary tumors ( 21 % vs. 10 % , respectively , P = 0.024 ) and clinical response ( 84 % vs. 65 % , P = 0.003 ) . TX was associated with less nausea and vomiting , but more stomatitis , diarrhea , myalgia , and skin/nail changes than AC . With a median follow-up of 37 months , there was no significant difference in DFS by treatment groups ( P = 0.932 ) . Fewer patients developed recurrence who achieved pCR in lymph node ( LN ) ( P = 0.025 ; hazard ratio , 0.189 ; 95 % CI , 0.044–0.815 ) in the multivariate analysis . TX showed superior efficacies to AC with increased pathologic and clinical complete response rates . Although these findings did not translate into a gain in DFS , the patients who achieved pCR in LN developed significantly less recurrence",
"PURPOSE The primary aim of National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B-28 was to determine whether four cycles of adjuvant paclitaxel ( PTX ) after four cycles of adjuvant doxorubicin/cyclophosphamide ( AC ) will prolong disease-free survival ( DFS ) and overall survival ( OS ) compared with four cycles of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes . PATIENTS AND METHODS Between August 1995 and May 1998 , 3,060 patients were r and omly assigned ( AC , 1,529 ; AC followed by PTX [ AC -- > PTX ] , 1,531 ) . Patients > or = 50 years and those younger than 50 years with estrogen receptor ( ER ) or progesterone receptor ( PR ) -positive tumors also received tamoxifen for 5 years , starting with the first dose of AC . Postlumpectomy radiotherapy was m and ated . Postmastectomy or regional radiotherapy was prohibited . Median follow-up is 64.6 months . RESULTS The addition of PTX to AC significantly reduced the hazard for DFS event by 17 % ( relative risk [ RR ] , 0.83 ; 95 % CI , 0.72 to 0.95 ; P = .006 ) . Five-year DFS was 76 % + /- 2 % for patients r and omly assigned to AC -- > PTX compared with 72 % + /- 2 % for those r and omly assigned to AC . Improvement in OS was small and not statistically significant ( RR , 0.93 ; 95 % CI , 0.78 to 1.12 ; P = .46 ) . Five-year OS was 85 % + /- 2 % for both groups . Subset analysis of the effect of paclitaxel according to hormone receptors or tamoxifen administration did not reveal statistically significant interaction ( for DFS , P = .30 and P = .44 , respectively ) . Toxicity with the AC -- > PTX regimen was acceptable for the adjuvant setting . CONCLUSION The addition of PTX to AC result ed in significant improvement in DFS but no significant improvement in OS with acceptable toxicity . No significant interaction between treatment effect and receptor status or tamoxifen administration was observed",
"There are no vali date d predictors of benefit from anthracyclines . We compared cyclophosphamide , methotrexate , 5-fluorouracil ( CMF ) , and epirubicin in different sequences with CMF alone in a phase III trial on operable breast cancers . Outcomes were analyzed in relation to tumor biological profiles to identify potential predictors of the efficacy of different treatments/drug combinations . Patients with N− or 1–3N+ tumors , were r and omized to receive ( a ) epirubicin ( 4 cycles ) followed by CMF ( 4 cycles ) ; ( b ) CMF ( 4 cycles ) followed by epirubicin ( 4 cycles ) , or ( c ) CMF ( 6 cycles ) alone . Immunohistochemical assessment s of estrogen ( ER ) and progesterone ( PgR ) receptors , HER2 and Ki67 were available for 705 patients ( arm A/B/C : 276/269/160 ) . Prognostic and predictive relevance was analyzed by log-rank tests and Cox models . Ki67 > 20 % and absent/low expression of ER and PgR were associated with worsen disease-free ( DFS ) and overall survival ( OS ) . In patients with triple negative tumors ( ER− , PgR− , HER2− ) , epirubicin-containing regimens yielded better DFS ( HR 0.33 , 95 % CI 0.17–0.62 , P = 0.0007 ) and OS ( HR 0.24 , 95 % CI 0.10–0.57 , P = 0.001 ) compared with CMF alone , whereas no differences were found in patients with HER2-positive ( HER2 + , ER− , PgR− ) subtype . Treatment by subtype interaction ( HER2-positive vs. others ) was significant for DFS ( χ2 = 6.72 , P = 0.009 ) . In triple unfavorable ( ER− , PgR− , Ki67 > 20 % ) tumors , the use of epirubicin yielded better DFS ( HR 0.45,95 % CI 0.26–0.78 , P = 0.005 ) and OS ( HR 0.30 , 95 % CI 0.15–0.63 , P = 0.001 ) . Epirubicin-containing regimens seem to be superior to CMF alone in patients with highly proliferating , triple negative or triple unfavorable tumors",
"Adjuvant cyclophosphamide , methotrexate , and 5-fluorouracil ( CMF ) have proven highly effective in rapidly proliferating breast cancer ( RPBC ) . It has also been seen that sequential administration of doxorubicin and CMF is superior to their alternation , especially in indolent tumors . In a phase III study , we evaluated whether adjuvant epirubicin ( E ) followed by CMF is superior to the inverse sequence in RPBC . Patients with node-negative or 1–3 node-positive RPBC ( Thymidine Labeling Index > 3 % or histological grade 3 or S-phase > 10 % or Ki67 > 20 % ) were r and omized to receive E ( 100 mg/m2 i.v . d1 , q21 days for 4 cycles ) followed by CMF ( 600 , 40 , 600 mg/m2 i.v . d1 and 8 , q28 days for 4 cycles ) ( E → CMF ) or CMF followed by E ( CMF → E ) or CMF for 6 cycles . From November 1997 to December 2004 , 1066 patients were enrolled : E → CMF 440 , CMF → E 438 , and CMF 188 . At a median follow-up of 69 months , 5-year OS was 91 % ( 95 % CI 88–94 ) for E → CMF and 93 % ( 95 % CI 90–95 ) for CMF → E , with adjusted hazard ratio of 0.88 ( 95 % CI 0.58–1.35 ) , and DFS was 80 % in both arms , with adjusted hazard ratio of 0.99 ( 95 % CI 0.73–1.33 , Cox model ) . Adverse events were similar , apart from a higher rate of neutropenia in the CMF → E arm . No important differences in clinical outcome were observed between the two different sequences , making both a valid option in early breast cancer . Further molecular characterization of the tumors might help to identify subgroups achieving higher benefit from either sequence",
"PURPOSE The Docetaxel Epirubicin Adjuvant ( DEVA ) trial evaluated the efficacy and toxicity of incorporating docetaxel after epirubicin to create a sequential anthracycline-taxane regimen in early breast cancer . PATIENTS AND METHODS After complete tumor excision , postmenopausal women with node-positive early breast cancer were r and omly assigned to either epirubicin 50 mg/m(2 ) on days 1 and 8 every 4 weeks for six cycles ( EPI × 6 ) or three cycles of epirubicin 50 mg/m(2 ) on days 1 and 8 every 4 weeks followed by three cycles of docetaxel 100 mg/m(2 ) on day 1 every 3 weeks ( EPI-DOC ) . A subset of patients also participated in a quality of life ( QOL ) study . The primary end point was disease-free survival ( DFS ) . RESULTS From 1997 to 2005 , 803 patients entered DEVA ( EPI × 6 , n = 397 ; EPI-DOC , n = 406 ) . At a median follow-up of 64.7 months ( interquartile range , 45.2 to 84.4 months ) , 198 DFS events had been reported ( EPI × 6 , n = 114 ; EPI-DOC , n = 84 ) . The 5-year DFS rates were 72.7 % ( 95 % CI , 68.0 % to 77.3 % ) for epirubicin alone and 79.5 % ( 95 % CI , 75.2 % to 83.8 % ) for epirubicin followed by docetaxel ; evidence of improvement in DFS was observed with EPI-DOC ( hazard ratio [ HR ] , 0.68 ; 95 % CI , 0.52 to 0.91 ; P = .008 ) . One hundred twenty-seven patients have died ( EPI × 6 , n = 75 ; EPI-DOC , n = 52 ) ; a reduction in deaths was observed with EPI-DOC ( HR , 0.66 ; 95 % CI , 0.46 to 0.94 ; P = .02 ) . The 5-year overall survival rates were 81.8 % ( 95 % CI , 77.7 % to 85.9 % ) for epirubicin and 88.9 % ( 95 % CI , 85.5 % to 92.2 % ) for epirubicin followed by docetaxel . Assessment of toxicity and QOL showed that EPI-DOC was associated with greater toxicity but with no difference in QOL between arms during follow-up . CONCLUSION These results suggest , within a relatively small trial , that substitution of docetaxel for epirubicin for the last three cycles of chemotherapy results in improved outcome in postmenopausal women with node-positive , early breast cancer compared with six cycles of epirubicin monotherapy",
"BACKGROUND The National Epirubicin Adjuvant Trial ( NEAT ) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer . METHODS In NEAT , we compared four cycles of epirubicin followed by four cycles of cyclophosphamide , methotrexate , and fluorouracil ( CMF ) with six cycles of CMF alone . In the BR9601 trial , we compared four cycles of epirubicin followed by four cycles of CMF , with eight cycles of CMF alone every 3 weeks . The primary end points were relapse-free and overall survival . The secondary end points were adverse effects , dose intensity , and quality of life . RESULTS The two trials included 2391 women with early breast cancer ; the median follow-up was 48 months . Relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups ( 2-year relapse-free survival , 91 % vs. 85 % ; 5-year relapse-free survival , 76 % vs. 69 % ; 2-year overall survival , 95 % vs. 92 % ; 5-year overall survival , 82 % vs. 75 % ; P Hazard ratios for relapse ( or death without relapse ) ( 0.69 ; 95 % confidence interval [ CI ] , 0.58 to 0.82 ; P death from any cause ( 0.67 ; 95 % CI , 0.55 to 0.82 ; P nodal status , tumor grade , tumor size , and estrogen-receptor status ( P the presence or absence of vascular or lymphatic invasion ( P=0.01 ) . These factors did not significantly interact with the effect of epirubicin plus CMF . The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life . CONCLUSIONS Epirubicin plus CMF is superior to CMF alone as adjuvant treatment for early breast cancer . ( Clinical Trials.gov number , NCT00003577 [ Clinical Trials.gov ] . )",
"1070 Background : Taxane-based anthracycline containing chemotherapy has been established as treatment option in the adjuvant setting of early breast cancer . Indication was recently enlarged for high risk node negative breast cancer . Promising retrospective data indicate equi-efficacy of anthracycline-free chemotherapy in Her2/neu-negative patients ( Gennari et al. , Slamon et al. ) . Anthracycline-free regimens are probably associated with less long-term toxicities , especially cardiac toxicities . METHODS The SUCCESS-C trial is an open-label , multicenter , 2x2 factorial design , r and omized controlled , phase III study comparing the disease free survival in patients treated with 3 cycles fluorouracil 500mg/m2-epirubicine 100mg/m2-cyclophosphamide 500mg/m2 ( FEC ) chemotherapy , followed by 3 cycles docetaxel 100mg/m2 ( D ) chemotherapy , versus 6 cycles docetaxel 75mg/m2-cyclophosphamide 600mg/m2 ( DC ) chemotherapy . Monitored toxicity data after end of treatment are available from 1,452 patients . RESULTS Chemotherapy was prematurely stopped in 51 pts ( 7.2 % ) receiving FEC-D and in 57 pts ( 7.7 % ) with DC ( p=0.71 ) . Dose reductions occurred significantly more often in the FEC-D arm ( 2.7 % ) than in the DC arm ( 1.9 % , p=0.024 ) , reasons did not differ significantly between both arms ( p=0.093 ) . Incidence of treatment-postponement was significantly higher for FEC-D ( 9.4 % FEC-D vs. 7.6 % DC ; p=0.0008 ) . Haematological toxicity as a reason for treatment-postponement occurred significantly more frequent within the FEC-D-arm ( FEC-D : 18.1 % , DC : 6.6 % , p as a reason for treatment postponement was nearly equal within both arms ( 8.6 % FEC-D vs. 8.8 % DC , p=0.9 ) . G-CSF support was applied in 22.7 % of all chemotherapy cycles ( FEC-D : 22.2 % vs. DC : 23.2 % , p=0.21 ) . Severe toxicities ( NCI- grade > 2 ) were reported in 910 cases for FEC-D and in 848 cases for DC arm ( p= 0.02 ) . CONCLUSIONS Significantly more dose-reductions of chemotherapy and a significant higher incidence of treatment-postponement occurred in the FEC-D arm . The toxicity profiles of both treatment arms differ discretely and support the continuation of the trial until target recruitment ( n=3,547 )",
"PURPOSE This study compared disease-free survival ( DFS ) obtained with two different regimens of adjuvant therapy in high-risk breast cancer . METHODS Women ( who had performance status [ PS ] of 0 to 1 ) with operable , histologically confirmed , stage I to III adenocarcinoma of the breast were eligible . Patients had undergone primary surgery with no residual tumor . Treatments were as follows : arm 1 was doxorubicin 60 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) every 3 weeks for four cycles followed by paclitaxel 175 mg/m(2 ) every 3 weeks for four cycles ( ie , AC-P ) ; and arm 2 was doxorubicin 50 mg/m(2 ) plus paclitaxel 200 mg/m(2 ) every 3 weeks for four cycles followed by paclitaxel 80 mg/m(2 ) weekly for 12 weeks . RESULTS Overall , 1,830 patients were enrolled and 1,801 were treated : arm 1 ( n = 906 ; AC-->P ) and arm 2 ( n = 895 ; AP-WP ) . Overall , patients had a PS of 0 ( 88 % ) , had estrogen receptor and progesterone receptor-positive disease ( 52 % ) , had one to three positive nodes ( 46 % ) , and were postmenopausal ( 57 % ) ; the median age was 52 years . Currently , 1,640 patients ( 90 % ) are alive . The 6-year DFS was 79 % to 80 % in both groups . Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2 . Overall 6-year survival rates were 82 % and 87 % in arms 1 and 2 , respectively . Reasons for patients being taken off study treatment included toxicity ( 13 % in arm 1 v 20 % in arm 2 ) , progressive disease or recurrence ( 7 % v 5 % ) , and consent withdrawn ( 9 % v 8 % ) , respectively . The most frequent toxicities were hematologic , including neutropenia and leukopenia followed by neuropathy , myalgia , nausea , fatigue , headache , arthralgia , and vomiting . CONCLUSION The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer . The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen",
"BACKGROUND The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of st and ard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer . PATIENTS AND METHODS A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2 ) every 3 weeks ( EC→T ) , or three cycles of epirubicin 150 mg/m(2 ) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2 ) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide , methotrexate , and fluorouracil ( E(dd)→T(dd)→CMF ) . The patients were r and omly assigned to receive darbepoetin or none . The primary objective was to demonstrate a superior disease-free survival ( DFS ) of E(dd)→T(dd)→CMF compared with EC→T. RESULTS Estimated 3-year DFS was 75.8 % with EC→T versus 78.8 % with E(dd)→T(dd)→CMF [ hazard ratio ( HR ) 1.14 ; P = 0.37 ] and overall survival ( OS ) 88.4 % versus 91.5 % ( HR 1.26 ; P = 0.237 ) . Three-year DFS was 74.3 % with darbepoetin versus 80.0 % without ( HR 1.31 ; P = 0.061 ) and OS 88.0 % versus 91.8 % ( HR 1.33 ; P = 0.139 ) . Patients with a pathologically documented complete response [ pathological complete response ( pCR ) ] had a significantly better DFS compared with those without achieving a pCR ( estimated 3-year DFS : 89.2 % versus 74.9 % ; HR 2.27 ; P = 0.001 ) . CONCLUSION Neoadjuvant dose-intensified chemotherapy compared with st and ard chemotherapy did not improve DFS , whereas the addition of darbepoetin might have detrimental effects on DFS",
"A previous r and omized trial ( CALGB 9344/Intergroup 0148 ) compared four cycles of adjuvant doxorubicin/cyclophosphamide ( AC ) to four cycles of AC plus four cycles of paclitaxel ( AC + T ) and demonstrated that the addition of paclitaxel improved locoregional control ( LRC ) in patients with node-positive breast cancer . However , it could not be determined whether it was the paclitaxel or the increased duration of chemotherapy that led to this improvement . The present study aim ed to analyze whether the addition of paclitaxel to a doxorubicin-based regimen improves LRC in a cohort of patients who all received eight total cycles of chemotherapy . Five hundred eleven women with operable breast cancer were r and omized on a single-institution prospect i ve trial to receive 5-fluorouracil , doxorubicin , cyclophosphamide ( FAC ) × 8 cycles ( n = 252 ) or FAC × 4 cycles plus paclitaxel × 4 cycles ( TFAC ) ( n = 259 ) . Rates of LRC and overall survival ( OS ) were analyzed . Median follow-up was 124 months ( range 5–167 months ) . The 10-year LRC rate was 92.6 versus 93.1 % in the FAC versus TFAC arms , respectively ( P = 0.26 ) . The LRC between treatment arms did not differ when analyzed by locoregional treatment group : breast conservation therapy ( BCT ) , mastectomy alone ( M ) , and mastectomy + radiation ( M + RT ) . The 10-year LRC rates were 95.1 % ( FAC ) versus 91.2 % ( TFAC ) after BCT ( P = 0.98 ) , 89.5 % ( FAC ) versus 93.4 % ( TFAC ) after M ( P = 0.24 ) , and 94.7 % ( FAC ) versus 96.5 % ( TFAC ) after M + RT ( P = 0.59 ) . Additionally , there was no difference in OS between the treatment arms , with 10-year OS rates of 78.4 % ( FAC ) versus 81.7 % ( TFAC ) ( P = 0.93 ) . The addition of paclitaxel to a doxorubicin-based regimen had no impact on LRC , regardless of the type of local therapy received . Historically inferior LRC with AC chemotherapy alone versus AC + T may have been due to an inadequate duration of systemic therapy and not due to the absence of paclitaxel ",
"TPS103 Background : There has been a recent convergence of epidemiologic , clinical and pre clinical evidence suggesting metformin ( a biguanide used to treat type 2 diabetes ) may lower BC risk and improve BC outcomes . This evidence raises the intriguing possibility that metformin may act ( i ) indirectly by lowering circulating insulin levels ( secondary to reduced hepatic gluconeogenesis ) leading to reduced insulin/IGF-I receptor mediated PI3 K signaling in BC cells or ( ii ) directly on tumor cells , largely via an AMPK mediated mechanism , leading to mTOR inhibition . METHODS NCIC CTG led , CTEP sponsored , r and omized , phase III trial of metformin 850 mg po bid vs placebo bid for 5 years . Eligibility criteria : pTIcNO ( and > one : grade 3 , ER/PR- , HER2Neu+ , lymphovascular invasion , Oncotype DX recurrence score>25 , Ki67>14 % ) or pT2/T3 N0 or pT1 - 3 N1 - 3 . St and ard adjuvant therapy ( chemotherapy , hormone , biologics ) Adequate organ function and PS Age 18 - 75 Endpoints : Primary : invasive disease free survival ( IDFS ) . Secondary : overall survival , distant disease free survival , BC free survival , adverse events , new diabetes , cardiovascular hospitalizations , BMI , insulin resistance syndrome attributes ( ATP III criteria ) , Quality of Life , diet and physical activity . Correlative studies : Embedded correlative research examines prognostic factors and targets and predictors of metformin benefit . Variables include : Fasting Insulin , glucose , Homeostasis Model Assessment ( HOMA ) ( baseline , 6 months , end of treatment ) : genomic/gene expression analysis of blood and tumour , tumor insulin receptor ( IR ) , IGF-IR , tumor molecular markers of target pathways ( LKBI , PI3 K ( STMN1 ) , PKB/Akt ( P-PKB/Akt , ) mTOR ( P-4E-BP1 ) and IRS-1 ( P-IRS-1 ) ; Fatigue sub- study with biological correlates ( NSABP led ) . Statistical design : Planned accrual is 3,582 subjects over 3 years with 3 more years follow-up . Target hazard ratio is 0.76 ( 5 year IDFS of 88.4 % vs 85 % , power 0.80 , 2-tail type 1 error of 0.05 ) . Two interim analyses are planned . Conduct to Date : Study activation : June 2010 . Enrollment : 145 subjects . In Nov 2010 a DSMC review supported trial continuation",
"The Danish Breast Cancer Cooperative Group ( DBCG ) 77B trial examined the relative efficacy of levamisole , single‐agent oral cyclophosphamide , and the classic combination of cyclophosphamide , methotrexate , and 5‐fluorouracil ( CMF ) against no adjuvant systemic therapy in high‐risk breast cancer patients . The authors report the results from that trial after a potential follow‐up of 25 years",
"PURPOSE The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known . Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles . We also sought to determine whether paclitaxel ( T ) is as efficacious as doxorubicin/cyclophosphamide ( AC ) , but with reduced toxicity . PATIENTS AND METHODS Between 2002 and 2008 , the study enrolled women with operable breast cancer and zero to three positive nodes . Patients were r and omly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor ( ER/PgR ) , human epidermal growth factor receptor 2 ( HER2 ) , and menopausal status . After 2003 , all treatment was administered in dose-dense fashion . The primary efficacy end point was relapse-free survival ( RFS ) . RESULTS A total of 3,171 patients were enrolled ; 94 % were node-negative and 6 % had one to three positive nodes . At a median follow-up of 5.3 years , the 4-year RFS was 90.9 % and 91.8 % for six and four cycles , respectively . The adjusted hazard ratio ( HR ) of six to four cycles regarding RFS was 1.03 ( 95 % CI , 0.84 to 1.28 ; P=.77 ) . The 4-year OS was 95.3 % and 96.3 % for six and four cycles , respectively , with an HR of six to four cycles of 1.12 ( 95 % CI , 0.84 to 1.49 ; P=.44 ) . There was no interaction between treatment duration and chemotherapy regimen , ER/PgR , or HER2 status on RFS or OS . CONCLUSION For women with resected primary breast cancer and zero to three positive nodes , we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome",
"Background In women with node-positive breast cancer , the Breast International Group ( BIG ) 02 - 98 tested the incorporation of docetaxel ( Taxotere ) into doxorubicin (Adriamycin)-based chemotherapy , and compared sequential and concurrent docetaxel . At 5 years , there was a trend for improved disease-free survival ( DFS ) with docetaxel . We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes . Methods Patients were r and omly assigned to one of four treatments : ( i ) sequential control : doxorubicin ( A ) ( 75 mg/m(2 ) ) × 4 →classical cyclophosphamide , methotrexate , 5-fluorouracil ( CMF ) ; ( ii ) concurrent control : doxorubicin , cyclophosphamide (AC)(60/600 mg/m(2 ) ) × 4 →CMF ; ( iii ) sequential docetaxel : A ( 75 mg/m(2 ) ) × 3 → docetaxel ( T ) ( 100 mg/m(2 ) ) × 3 → CMF and ( iv ) concurrent docetaxel : AT(50/75 mg/m(2 ) ) × 4 →CMF . The primary comparison evaluated docetaxel efficacy regardless of the schedule . Exploratory analyses were undertaken within biologically defined subtypes . Results Two thous and eight hundred and eighty-seven patients were enrolled . After 93.4 months of median follow-up , there were 916 DFS events . For the primary comparison , there was no significant improvement in DFS from docetaxel [ hazard ratio ( HR ) = 0.91 , 95 % confidence interval ( CI ) = 0.80 - 1.05 , P = 0.187 ] . In secondary comparisons , sequential docetaxel significantly improved DFS compared with sequential control ( HR = 0.81 , 95 % CI = 0.67 - 0.99 , P = 0.036 ) , and significantly improved DFS ( HR = 0.84 , 95 % CI = 0.72 - 0.99 , P = 0.035 ) and overall survival ( OS ) ( HR = 0.79 , 95 % CI = 0.65 - 0.98 , P = 0.028 ) compared with concurrent doxorubicin-docetaxel . Luminal-A disease had the best prognosis . HRs favored addition of sequential docetaxel in all subtypes , except luminal-A ; but this observation was not statistically supported because of limited numbers . Conclusion With further follow-up , the sequential docetaxel schedule result ed in significantly better OS than concurrent doxorubicin-docetaxel , and continued to show better DFS than sequential doxorubicin-based control",
"PURPOSE Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea . The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history ( MH ) and quality -of-life ( QOL ) studies to compare treatments on these outcomes . PATIENTS AND METHODS Patients were r and omly assigned to sequential doxorubicin ( A ) and cyclophosphamide ( C ) followed by docetaxel ( T ; AC→T ) , concurrent TAC , or AT , which varied in duration ( 24 , 12 , 12 weeks , respectively ) , and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors . MH and QOL were assessed with st and ardized question naires at baseline ; cycle 4 , day 1 ; and every 6 months through 24 months . Prespecified analyses examined rates of amenorrhea by treatment arm , the relationship between amenorrhea and QOL , and QOL by treatment arm . RESULTS Amenorrhea 12 months after r and om assignment was significantly different between treatment groups : 69.8 % for AC→T , 57.7 % for TAC , and 37.9 % for AT ( P without tamoxifen had the lowest rate of amenorrhea . QOL was poorer for patients receiving AC→T at 6 months but similar to others by 12 months . Post-treatment symptoms were increased above baseline for all treatments . Multivariable repeated measures modeling demonstrated that treatment arm , time point , age , and tamoxifen use were significantly associated with symptom severity ( all P values CONCLUSION Amenorrhea rates differed significantly by treatment arm , with the AT arm having the lowest rate . Patients treated with longer duration therapy ( AC→T ) had greater symptom severity and poorer QOL at 6 months , but did not differ from shorter duration treatments at 12 months",
"500 Background : First results of study USON 01062 comparing adjuvant AC→T vs AC→XT in high-risk EBC [ O'Shaughnessy , SABCS 2010 ] showed the primary endpoint , improvement in DFS , was not met ( median FU 5 yrs : HR 0.84 , 95 % CI : 0.67 - 1.05 ; p%0.125 ; 304 events ) , but a statistically significant improvement in OS was seen with AC→XT ( HR 0.68 , 95 % CI : 0.51 - 0.92 ; p%0.011 ; 183 events ) . Given the current underst and ing of a lesser benefit of adjuvant chemotherapy in indolent BC , we performed unplanned exploratory subset analyses of Ki-67 expression , distant DFS and benefit from XT . METHODS Pts aged 18 - 70 yrs with surgically resectable EBC received 4 x 3-weekly AC ( A : 60mg/m2 , C : 600mg/m2 , d1 ) → 4 x 3-weekly T ( 100mg/m2 d1 ) or XT ( X : 825mg/m2 bid , d1 - 14 ; T : 75mg/m2 d1 ) . ER+ pts received endocrine therapy , and , after 2005 , HER2 + pts were offered 1-yr of trastuzumab . Primary endpoint : DFS ; secondary endpoints : OS ; safety . Ki-67 staining was done locally . RESULTS 2,611 pts were r and omized : AC→T ( n%1304 ) ; AC→XT ( n%1307 ) . Treatment arms were balanced . Exploratory distant DFS analysis favored the XT group ( HR 0.80 , 95 % CI : 0.63 - 1.02 ; p%0.067 ) . Analyses by Ki-67 expression showed a treatment effect with XT vs T in pts with Ki-67 ≥10 % ( HR for DFS : 0.70 ; OS : 0.52 ) ( table ) . Very few events ( DFS/OS ) were seen in pts with Ki-67 in DFS with XT vs T. In pts with ER+/HER2- tumors and Ki-67 ≥10 % , a trend towards DFS ( HR 0.66 ) and OS ( 0.30 ) benefit with XT was also seen . CONCLUSIONS Exploratory Ki-67 analyses suggested benefit of X in more highly proliferative tumors , reflecting the importance of pt selection in adjuvant trials . [ Table : see text ]",
"PURPOSE Cyclophosphamide , epirubicin , and fluorouracil ( CEF ) and doxorubicin and cyclophosphamide ( AC ) followed by paclitaxel ( T ) are commonly used adjuvant regimens in women with early breast cancer . In a previous trial in women with locally advanced breast cancer , 3 months of high-dose epirubicin and cyclophosphamide ( EC ) administered every 2 weeks ( dose-dense ) was equivalent to 6 months of CEF . We hypothesized that 3 months of paclitaxel after dose-dense EC ( EC/T ) would be superior to CEF or AC/T. METHODS After lumpectomy or mastectomy , women 60 years of age or younger with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive CEF , EC/T , or AC/T for 6 months . This article reports the interim analysis for recurrence-free survival ( RFS ) , which was planned after 227 recurrences . Results A total of 2,104 patients were enrolled . The median follow-up is 30.4 months . Hazard ratios for recurrence are as follows : AC/T versus CEF , 1.49 ( 95 % CI , 1.12 to 1.99 ) , P = .005 ; AC/T versus EC/T , 1.68 ( 95 % CI , 1.25 to 2.27 ) , P = .0006 ; and EC/T versus CEF , 0.89 ( 95 % CI , 0.64 to 1.22 ) , P = .46 . Three-year RFS rates for CEF , EC/T , and AC/T are 90.1 % , 89.5 % , and 85.0 % , respectively . There was more febrile neutropenia with CEF ( 22.3 % ) and EC/T ( 16.4 % ) compared with AC/T ( 4.8 % ) , but more neuropathy with the last two regimens . CONCLUSION Three-weekly AC/T is significantly inferior to CEF or EC/T in terms of RFS . It is too early to detect any difference between CEF and dose-dense",
"BACKGROUND Docetaxel is more effective than doxorubicin for patients with advanced breast cancer . The Breast International Group 02 - 98 r and omized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel . METHODS Patients with lymph node-positive breast cancer ( n = 2887 ) were r and omly assigned to one of four treatments : 1 ) sequential control ( four cycles of doxorubicin at 75 mg/m2 , followed by three cycles of cyclophosphamide , methotrexate , and 5-fluorouracil [ CMF ] ) ; 2 ) concurrent control ( four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2 , followed by three cycles of CMF ) ; 3 ) sequential docetaxel ( three cycles of doxorubicin at 75 mg/m2 , followed by three cycles of docetaxel at 100 mg/m2 , followed by three cycles of CMF ) ; 4 ) concurrent docetaxel ( four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2 , followed by three cycles of CMF ) . The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival ( DFS ) events ( ie , relapse , second primary cancer , or death from any cause ) . Docetaxel and control treatment groups were compared by log-rank tests , and hazard ratios ( HR ) of DFS events were calculated by Cox modeling . All statistical tests were two-sided . RESULTS Due to a lower-than-anticipated rate of relapse , this analysis was performed after 5 years with 732 events . Patients in control arms had a 5-year DFS of 73 % ( 95 % confidence interval [ CI ] = 70 % to 75 % ) . Docetaxel treatment result ed in an improvement in DFS of borderline statistical significance compared with control treatment ( HR = 0.86 , 95 % CI = 0.74 to 1.00 ; P = .05 ) . However , DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm ( HR = 0.83 , 95 % CI = 0.69 to 1.00 ) and in the sequential control arm ( HR = 0.79 , 95 % CI = 0.64 to 0.98 ) . CONCLUSIONS Incorporating docetaxel into anthracycline-based therapy result ed in an improvement in DFS that was of borderline statistical significance . However , important differences may be related to doxorubicin and docetaxel scheduling , with sequential but not concurrent administration , appearing to produce better DFS than anthracycline-based chemotherapy ",
"Purpose To evaluate the impact that pre- and postoperatively administered chemotherapy with cyclophosphamide , methotrexate and fluorouracil ( CMF ) and postoperative chemotherapy vs. postoperative chemotherapy alone have on long-term prognosis . Patients and Methods The ABCSG conducted a nationwide r and omized phase III trial in high-risk endocrine non-responsive breast cancer patients comparing pre- and postoperative chemotherapy containing CMF as preoperative treatment vs. postoperative chemotherapy alone between 1991 and 1999 . From 1996 the ABCSG-07 protocol was amended to also allow r and omization of high-risk endocrine-responsive patients . Of 423 eligible patients with high-risk primary breast cancer , 203 patients were r and omly assigned to preoperatively receive three cycles of CMF ( cyclophosphamide , methotrexate , fluorouracil ; 600/40/600 mg/m2 ) intravenously on day 1 and 8 , while 195 patients received postoperative chemotherapy alone . In both groups , three cycles of CMF were given initially , and another three cycles of CMF were administered in node-negative patients , whereas node-positive patients received three cycles of EC ( epirubicin , cyclophosphamide ; 70/600 mg/m2 ) . Results Overall response rate to preoperative chemotherapy with three cycles of CMF was 56.2 % ; complete pathological response was achieved in 12 patients ( 5.9 % ) . Recurrence-free survival was significantly better in patients receiving chemotherapy postoperatively ( HR 0.7 , 0.515–0.955 ; P = 0.024 ) . No survival difference was observed between the two therapy groups ( HR 0.800 , 0.563–1.136 ; P = 0.213 ) . Discussion Preoperative chemotherapy with CMF has to be considered as insufficient in high-risk breast cancer patients . Delayed surgery and anthracycline-based chemotherapy result in shorter recurrence-free survival but not overall survival ",
"This trial compared 6 cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) with a sequential regimen of 3 cycles of FEC followed by 3 cycles of docetaxel ( FEC-D ) as adjuvant treatment for women with node-positive or/ and T3 or T4 breast cancer . Between January 2006 and January 2010 , 657 patients with operable breast cancer were r and omly assigned to either FEC every 21 days for 6 cycles , or 3 cycles of FEC followed by 3 cycles of docetaxel , both given every 21 days . Radiotherapy was m and atory for all patients who had undergone breast conserving surgery . Radiation to the chest wall , supraclavicular area , was recommended following mastectomy . Hormone-receptor – positive patients received tamoxifen for 5 years after chemotherapy . The primary end point was 5-year disease-free survival ( DFS ) . Median follow-up was 61 months . Five-year DFS rates were 74 % with FEC and 78 % with FEC-D ( P = 0.013 ) . Multivariate analysis adjusted for prognostic factors showed a 17 % reduction in the relative risk of relapse with FEC-D. Five-year overall survival rates were 85 % with FEC and 89.4 % with FEC-D , demonstrating a 27 % reduction in the relative risk of death ( P = 0.014 ) . The incidence of grade 3–4 neutropenia , the need for hematopoietic growth factor , and incidence of nausea/vomiting were higher with FEC . Docetaxel was associated with more febrile neutropenia , stomatitis , edema , and nail disorders . Though rare overall , there were fewer cardiac events after FEC-D , attributable mainly to the lower anthracycline cumulative dose . Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive or/ and T3 or T4 breast cancer patients . Although the magnitude of the benefit observed with FEC-D , differences in the toxicity profiles of FEC and FEC-D may influence the choice of treatment for patients",
"PURPOSE Anthracyclines , taxanes , and alkylating agents are among the most active agents in treatment of adjuvant breast cancer ( BC ) , but the optimal schedule for their administration is unknown . We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide ( AC ) followed by docetaxel ( ie , AC > T ) with the combination regimen of TAC . PATIENTS AND METHODS Women with node-positive , human epidermal growth factor receptor 2-nonamplified , operable BC were stratified by number of axillary nodes and hormone receptor status and were r and omly assigned to adjuvant chemotherapy with six cycles of TAC ( 75/50/500 mg/m² every 3 weeks ) or four cycles of AC ( 60/600 mg/m² every 3 weeks ) followed by four doses of docetaxel at 100 mg/m² every 3 weeks ( AC > T ) . After completion of chemotherapy , radiation therapy was given as indicated , and patients with hormone receptor ( HR ) -positive disease received adjuvant hormonal therapy with tamoxifen and /or aromatase inhibitors . RESULTS In 30 months , 3,298 patients were enrolled ( n = 1,649 in each arm ) . The major baseline characteristics were well balanced between the groups . At a median follow-up of 65 months , estimated 5-year disease-free survival rates were 79 % in both groups ( log-rank P = .98 ; hazard ratio [ HR ] , 1.0 ; 95%CI , 0.86 to 1.16 ) , and 5-year overall survival rates for both arms were 88 % and 89 % , respectively ( log-rank P = .37 ; HR , 0.91 ; 95 % CI , 0.75 to 1.11 ) . TAC was associated with more febrile neutropenia and thrombocytopenia , and AC > T was associated with more sensory neuropathy , nail changes , and myalgia . The incidence of neutropenic infection was similar in both groups . CONCLUSION The sequential and combination regimens incorporating three drugs were equally effective but differed in toxicity profile ",
"CRA1008 Background : S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1 ) the weekly AC+G regimen is superior to ddAC x 6 and 2 ) 12 weeks of weekly paclitaxel ( wP ) is superior to q 2 week paclitaxel x 6 ( ddP ) . METHODS Between December 2003 and November 2010 , 2,716 patients were r and omized in a 2 x 2 factorial design to 1 ) AC+G vs ddAC and 2 ) P 80 mg/m2/week x 12 vs P 175 mg/m2 q 2 weeks x 6 . If there was no significant interaction between the factors , the trial was powered to find a disease-free survival hazard ratio ( HR ) ≤ 0.82 for weekly vs q 2 week for each factor . At the first interim analysis , the AC r and omization was halted for futility , and S0221 was closed to accrual 10 November 2010 . S0221 reopened 15 December 2010 , after which time all patients received 4 cycles of ddAC and r and omization to P weekly x 12 and ddP x 6 continued . Accrual halted at a total of 3,294 in January 2012 . RESULTS By September 7 , 2012 , 487 events and 340 deaths had occurred , prompting the third planned interim analysis . The Data Safety and Monitoring Committee recommended reporting the results since the futility boundary was crossed . A Cox model adjusting for the AC arms had a HR = 1.08 ( 95 % CI 0.90 - 1.28 ; p=0.42 ) , with the 99.5 % CI excluding the original alternative hypothesis that the HR=0.82 . There was no significant interaction of the two factors . Estimated 5-year progression-free survivals were 82 % for weekly P and 81 % for ddP. Toxicity data were available for 1,385 patients treated with ddP and 1,367 treated with weekly P. Grade 5 toxicity occurred in 4 patients on ddP and 2 on weekly P. Percent grade 3 - 4 toxicity per arm are shown in the Table . CONCLUSIONS Either ddPx6 or weekly P x 12 are acceptable schedules of P administration . The differences in leukopenia likely reflect ascertainment bias against weekly P. If this is accepted , weekly P x 12 produces less overall toxicity than 6 cycles of ddP. Support : NCI grants CA32102 , CA38926 , CA21115 , CA21076 , CA77597 , CA25224 , CA77202 , CCSRI15469 , and Amgen , Inc. CLINICAL TRIAL INFORMATION NCT00070564 . [ Table : see text ]",
"We compared the efficacy of CEF ( cyclophosphamide , epirubicin , and fluorouracil ) against CMF ( cyclophosphamide , methotrexate , and fluorouracil ) in moderate or high risk breast cancer patients . We r and omly assigned 1224 patients with completely resected unilateral breast cancer to receive nine cycles of three-weekly intravenous CMF or CEF . Patients were encouraged to take part in a parallel trial comparing oral pamidronate 150 mg twice daily for 4 years versus control ( data not shown ) . Substitution of methotrexate with epirubicin significantly reduced the unadjusted hazard for disease-free survival ( DFS ) by 16 % ( hazard ratio 0.84 ; 95 % CI ; 0.71 - 0.99 ) and for overall survival by 21 % ( hazard ratio 0.79 ; 95 % CI ; 0.66 - 0.94 ) . The risk of secondary leukaemia and congestive heart failure was similar in the two groups . Overall CEF was superior over CMF in terms of DFS and OS in patients with operable breast cancer without subsequent increase in late toxicities",
"PURPOSE The PACS 01 trial compared six cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel ( FEC-D ) as adjuvant treatment for women with node-positive early breast cancer . PATIENTS AND METHODS Between June 1997 and March 2000 , 1,999 patients with operable node-positive breast cancer were r and omly assigned to either FEC every 21 days for six cycles , or three cycles of FEC followed by three cycles of docetaxel , both given every 21 days . Hormone-receptor-positive patients received tamoxifen for 5 years after chemotherapy . The primary end point was 5-year disease-free survival ( DFS ) . RESULTS Median follow-up was 60 months . Five-year DFS rates were 73.2 % with FEC and 78.4 % with FEC-D ( unadjusted P = .011 ; adjusted P = .012 ) . Multivariate analysis adjusted for prognostic factors showed an 18 % reduction in the relative risk of relapse with FEC-D. Five-year overall survival rates were 86.7 % with FEC and 90.7 % with FEC-D , demonstrating a 27 % reduction in the relative risk of death ( unadjusted P = .014 ; adjusted P = .017 ) . The incidence of grade 3 to 4 neutropenia , the need for hematopoietic growth factor , and incidence of nausea/vomiting were higher with FEC . Docetaxel was associated with more febrile neutropenia in the fourth cycle , stomatitis , edema , and nail disorders . Though rare overall , there were fewer cardiac events after FEC-D ( P = .03 ) , attributable mainly to the lower anthracycline cumulative dose . CONCLUSION Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile",
"PURPOSE To compare the clinical and pathologic response rates of doxorubicin and cyclophosphamide ( AC ) with doxorubicin and docetaxel ( AD ) as primary chemotherapy in women with primary or locally advanced breast cancer . PATIENTS AND METHODS Eligible patients with histologically proven breast cancer with primary tumors > /= 3 cm , inflammatory or locally advanced disease , and no evidence of metastases were r and omly assigned to receive a maximum of six cycles of either doxorubicin ( 60 mg/m(2 ) ) plus cyclophosphamide ( 600 mg/m(2 ) ) administered intravenously ( IV ) every 3 weeks or doxorubicin ( 60 mg/m(2 ) ) plus docetaxel ( 75 mg/m(2 ) ) IV every 3 weeks , followed by surgery on completion of chemotherapy . Results A total of 363 patients were r and omly assigned to AC ( n = 180 ) or AD ( n = 183 ) . A complete clinical response was observed in 17 % and 20 % of patients treated with AC and AD , respectively ( P = .42 ) . Overall ( complete and partial ) clinical response rates for AC and AD were 61 % and 70 % , respectively ( P = .06 ) . There was no significant difference in either the pathologic complete response rates in the breast with AC ( 24 % ) and AD ( 21 % ; P = .61 ) or in the number of patients with positive axillary nodes at surgery with AC ( 61 % ) and AD ( 66 % ; P = .28 ) . At a median follow-up of 32 months , there is no significant difference between the two groups for the number of relapses . CONCLUSION In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer , our data do not suggest a benefit for simultaneous AD over AC",
"PURPOSE We compared radiotherapy ( RT ) delivery and locoregional control in patients with node-positive breast cancer r and omly assigned on Cancer and Leukemia Group B 9344 to receive adjuvant doxorubicin/cyclophosphamide ( AC ) with patients assigned to receive AC followed by paclitaxel ( AC+T ) . METHODS Eligible patients were r and omly assigned to receive adjuvant AC versus AC+T chemotherapy . RT was required if breast-conserving surgery was performed but was elective after mastectomy . Information about RT delivery was retrospectively collected . Cumulative incidence of locoregional recurrence ( LRR ) , use of elective RT , and RT delivery were compared between treatment arms . RESULTS For patients treated with breast-conserving surgery and RT , the 5-year cumulative incidence of isolated LRR was 9.7 % in the AC arm and 3.7 % in the AC+T arm ( P = .04 ) and of LRR as any component of failure was 12.9 % versus 6.1 % , respectively ( P = .04 ) . Although LRR rates in patients who did not receive postmastectomy RT were lower in the AC+T arm , the difference was not statistically significant . Despite the lack of protocol guidelines , RT use did not differ between arms , nor did RT dose , treatment interruption , or completion . CONCLUSION Despite the delay to RT during additional chemotherapy , adjuvant AC+T afforded better local control than AC alone in patients treated with breast-conserving therapy . Addition of paclitaxel did not adversely affect delivery or ability to tolerate RT , as indicated by similar rates of completion of timely , full-dose RT between arms",
"1004 Background : AC+G ( doxorubicin 24 mg/m2/week x 15 , cyclophosphamide 60 mg/m2/day po , and filgrastim daily except on the days of doxorubicin administration ) produced encouraging results in a SWOG Phase II trial of pre-operative chemotherapy in locally advanced breast cancer . S0221 is a SWOG-coordinated Phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer , which hypothesized that the AC+G regimen is superior to ddAC ( doxorubicin 60 mg/m2 , cyclophosphamide 600 mg/m2 IV and pegfilgrastim q 2 weeks x 6 ) and that weekly paclitaxel is superior to q 2 week paclitaxel . METHODS Between December 2003 and November 2010 , 2716 patients were r and omized in a 2x2 factorial design to 1 ) AC+G vs ddAC and 2 ) paclitaxel 80 mg/m2/week x 12 vs paclitaxel 175 mg/m2 q 2 weeks x 6 . If there was no significant interaction between the factors , the trial was powered to find a disease-free survival hazard ratio ( HR ) ≤ 0.82 for weekly vs q 2 week for each factor . RESULTS By September 8 , 2010 , 349 events ( 161 ddAC , 188 AC+G ) had occurred among 2,477 patients with follow-up , prompting the first planned interim analysis at 30 % of the expected events . The arms were balanced for st and ard prognostic factors , and a Cox model adjusting for the paclitaxel arms had a HR = 1.21 ( 95 % CI 0.98 - 1.50 ; p=0.071 ) favoring ddAC . The prescribed boundary for futility was the 99.5 % CI ( 0.90 - 1.64 ) excluding the original alternative hypothesis that HR=0.82 . No boundary was crossed for the paclitaxel comparison and there was no significant interaction of the two factors . Therefore , the Data Safety and Monitoring Committee recommended stopping r and omization to the AC+G arms due to futility . Analyses by nodal- , hormone-receptor- , and HER2 status found no subset in which AC+G appeared superior . S0221 has re-opened and r and omizes patients to the two paclitaxel arms after only 4 cycles of ddAC . CONCLUSIONS Accrual will continue to 3,250 patients and ancillary studies remain ongoing . We conclude that AC+G is not superior to ddAC x 6 , and do not recommend AC+G for routine use . Support : NCI grants CA32102 , CA38926 , CA21115 , CA21076 , CA77597 , CA25224 , CA77202 , CCSRI15469 , and Amgen ,",
"BACKGROUND Among breast cancer patients , nonresponse to initial neoadjuvant chemotherapy is associated with unfavorable outcome . We compared the response of nonresponding patients who continued the same treatment with that of patients who switched to a well-tolerated non-cross-resistant regimen . METHODS Previously untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m(2 ) , doxorubicin at 50 mg/m(2 ) , and cyclophosphamide at 500 mg/m(2 ) per day ( TAC ) . Patients whose tumors did not decrease in size by at least 50 % were r and omly assigned to four additional cycles of TAC or to four cycles of vinorelbine at 25 mg/m(2 ) and capecitabine at 2000 mg/m(2 ) ( NX ) . The outcome was sonographic response , defined as a reduction in the product of the two largest perpendicular diameters by at least 50 % . A difference of 10 % or less in the sonographic response qualified as noninferiority of the NX treatment . Pathological complete response was defined as no invasive or in situ residual tumor masses in the breast and lymph nodes . Toxic effects were assessed . All statistical tests were two-sided . RESULTS Of 2090 patients enrolled in the GeparTrio study , 622 ( 29.8 % ) who did not respond to two initial cycles of TAC were r and omly assigned to an additional four cycles of TAC ( n = 321 ) or to four cycles of NX ( n = 301 ) . Sonographic response rate was 50.5 % for the TAC arm and 51.2 % for the NX arm . The difference of 0.7 % ( 95 % confidence interval = -7.1 % to 8.5 % ) demonstrated noninferiority of NX ( P = .008 ) . Similar numbers of patients in both arms received breast-conserving surgery ( 184 [ 57.3 % ] in the TAC arm vs 180 [ 59.8 % ] in the NX arm ) and had a pathological complete response ( 5.3 % vs 6.0 % ) . Fewer patients in the NX arm than in the TAC arm had hematologic toxic effects , mucositis , infections , and nail changes , but more had h and -foot syndrome and sensory neuropathy . CONCLUSION Pathological complete responses to both regimens were marginal . Among patients who did not respond to the initial neoadjuvant TAC treatment , similar efficacy but better tolerability was observed by switching to NX than continuing with TAC",
"BACKGROUND We compared st and ard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer . Here we report the final , 10-year follow-up analysis of disease-free survival , overall survival , and long-term safety . METHODS BCIRG 001 was an open label , phase 3 , multicentre trial in which 1491 patients aged 18 - 70 years with node-positive , early breast cancer and a Karnofsky score of 80 % or more were r and omly assigned to adjuvant treatment with docetaxel , doxorubicin , and cyclophosphamide ( TAC ) or fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) every 3 weeks for six cycles . R and omisation was stratified according to institution and number of involved axillary lymph nodes per patient ( one to three vs four or more ) . Disease-free survival was the primary endpoint and was defined as the interval between r and omisation and breast cancer relapse , second primary cancer , or death , whichever occurred first . Efficacy analyses were based on the intention-to-treat principle . BCIRG 001 is registered with Clinical Trials.gov , number NCT00688740 . FINDINGS Enrolement took place between June 11 , 1997 and June 3 , 1999 ; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC . After a median follow-up of 124 months ( IQR 90 - 126 ) , disease-free survival was 62 % ( 95 % CI 58 - 65 ) for patients in the TAC group and 55 % ( 51 - 59 ) for patients in the FAC group ( hazard ratio [ HR ] 0·80 , 95 % CI 0·68 - 0·93 ; log-rank p=0·0043 ) . 10-year overall survival was 76 % ( 95 % CI 72 - 79 ) for patients in the TAC group and 69 % ( 65 - 72 ) for patients in the FAC group ( HR 0·74 , 0·61 - 0·90 ; log-rank p=0·0020 ) . TAC improved disease-free survival relative to FAC irrespective of nodal , hormone receptor , and HER2 status , although not all differences were significant in these subgroup analyses . Grade 3 - 4 heart failure occurred in 26 ( 3 % ) patients in the TAC group and 17 ( 2 % ) patients in the FAC group , and caused death in two patients in the TAC group and four patients in the FAC group . A substantial decrease in left ventricular ejection fraction ( defined as a relative decrease from baseline of 20 % or more ) was seen in 58 ( 17 % ) patients who received TAC and 41 ( 15 % ) patients who received FAC . Six patients who received TAC developed leukaemia or myelodysplasia , as did three patients who received FAC . INTERPRETATION Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years . However , a substantial percentage of patients had a decrease in left ventricular ejection fraction , probably caused by anthracycline therapy , which warrants further investigation . FUNDING Sanofi",
"BACKGROUND Older women with breast cancer are underrepresented in clinical trials , and data on the effects of adjuvant chemotherapy in such patients are scant . We tested for the noninferiority of capecitabine as compared with st and ard chemotherapy in women with breast cancer who were 65 years of age or older . METHODS We r and omly assigned patients with stage I , II , IIIA , or IIIB breast cancer to st and ard chemotherapy ( either cyclophosphamide , methotrexate , and fluorouracil or cyclophosphamide plus doxorubicin ) or capecitabine . Endocrine therapy was recommended after chemotherapy in patients with hormone-receptor-positive tumors . A Bayesian statistical design was used with a range in sample size from 600 to 1800 patients . The primary end point was relapse-free survival . RESULTS When the 600th patient was enrolled , the probability that , with longer follow-up , capecitabine therapy was highly likely to be inferior to st and ard chemotherapy met a prescribed level , and enrollment was discontinued . After an additional year of follow-up , the hazard ratio for disease recurrence or death in the capecitabine group was 2.09 ( 95 % confidence interval , 1.38 to 3.17 ; P capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who were r and omly assigned to st and ard chemotherapy ( P=0.02 ) . At 3 years , the rate of relapse-free survival was 68 % in the capecitabine group versus 85 % in the st and ard-chemotherapy group , and the overall survival rate was 86 % versus 91 % . Two patients in the capecitabine group died of treatment-related complications ; as compared with patients receiving capecitabine , twice as many patients receiving st and ard chemotherapy had moderate-to-severe toxic effects ( 64 % vs. 33 % ) . CONCLUSIONS St and ard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older . ( Clinical Trials.gov number , NCT00024102 .",
"BACKGROUND Neoadjuvant systemic therapy ( NST ) before surgery is a st and ard option for patients with early breast cancer ( EBC ) that allows in vivo chemosensitivity testing . Given the promising activity of pemetrexed plus doxorubicin in metastatic breast cancer , it was reasonable to evaluate the utility of this combination as part of an NST regimen in EBC . PATIENTS AND METHODS Patients with untreated operable T2-T4a-c N0 - 2 M0 breast cancer were r and omly assigned to receive either four cycles of pemetrexed 500 mg/m(2 ) plus doxorubicin 60 mg/m(2 ) every 3 weeks ( q3w ) followed by four cycles of docetaxel 100 mg/m(2 ) q3w ( AP-D ) or four cycles of doxorubicin 60 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) q3w followed by four cycles of docetaxel 100 mg/m(2 ) q3w ( AC-D ) . Surgery was carried out within 2 months after last chemotherapy . Primary end point was pathological complete response ( pCR ) rate in the breast . Secondary end points included clinical response rate , rate of histologically negative axillary lymph nodes , toxicity , and disease-free survival . RESULTS From September 2005 to August 2007 , 257 patients were r and omly allocated to 17 sites . Median age was 48 and 49 years for AP-D and AC-D , respectively . Overall pCR rates were 16.5 % for AP-D and 20.2 % for AC-D. With AP-D , pCR rate was 17.8 % for hormone receptor (HR)-negative patients and 15.9 % for HR-positive patients . With AC-D , pCR rates were 42.9 % and 7.8 % for HR-negative and HR-positive patients , respectively . Clinical response rates were 59.5 % in the AP-D group and 68.1 % in the AC-D group . The rate of histologically negative axillary lymph nodes was 53 % in both groups . Both treatments were well tolerated . Median disease-free survival is currently not mature . CONCLUSIONS AP-D and AC-D are well tolerated and active as NST in EBC . Of note , AC-D had a higher pCR rate in HR-negative tumors , whereas AP-D had more activity if HRs were expressed",
"PURPOSE The combination of doxorubicin and cyclophosphamide ( AC ) is a st and ard adjuvant regimen . Doxorubicin and docetaxel ( AT ) is one of the most active cytotoxic regimens for metastatic breast cancer . The purpose of this trial was to determine whether adjuvant AT improved disease-free survival compared with AC in operable breast cancer . PATIENTS AND METHODS Women with invasive breast cancer were eligible if there were one to three positive lymph nodes or if the node-negative tumor was greater than 1 cm . Patients were r and omly assigned after surgery to receive doxorubicin ( 60 mg/m(2 ) ) plus either cyclophosphamide ( 600 mg/m(2 ) ; AC ) or docetaxel ( 60 mg/m(2 ) ; AT ) given every 3 weeks for four cycles , followed by hormone therapy for patients with estrogen receptor ( ER ) and /or progesterone receptor (PR)-positive tumors . RESULTS There were 2,882 eligible patients enrolled . After a median follow-up of 79.5 months , there was no significant difference in disease-free survival ( DFS ; 85 % in both arms ) or overall survival ( 91 % v 92 % ) at 5 years . The hazard ratio for AC versus AT was 1.02 ( 95 % CI for DFS , 0.86 to 1.22 ; P = .78 ) . In an exploratory analysis of prespecified stratification factors by ER and PR expression there were trends toward improved DFS for AT in ER/PR-negative disease . Grade 3 neutropenia associated with fever or infection occurred more often with AT ( 26 % v 10 % ; P DFS or overall survival in this population , and was associated with more toxicity",
"PURPOSE The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide ( HEC ) is superior to a lower dose of epirubicin , 60 mg/m(2 ) ( EC ) , for event-free survival ( EFS ; 27 % reduction ) , but is not superior to classical oral cyclophosphamide , methotrexate , and fluorouracil ( CMF ) in the adjuvant treatment of node-positive breast cancer . Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial . PATIENTS AND METHODS Between March 1988 and December 1996 , 777 eligible patients were r and omly assigned to six cycles of CMF , eight cycles of EC , or eight cycles HEC . RESULTS The 15-year EFS was 45 % for patients who received CMF , 39 % for patients who received EC , and 50 % for patients who received HEC . The hazard ratios ( HR ) were 0.77 for HEC versus EC ( 95 % CI , 0.60 to 0.98 ; P = .03 ) , 0.90 for HEC versus CMF ( P = .39 ) , and 0.86 for EC versus CMF ( P = .21 ) . No difference in overall survival ( OS ) was seen . Cardiac toxicity was more frequent with HEC than with CMF ( 11 patients v 1 patient ; P = .006 ) , but no more than with EC ( P = .21 ) . CONCLUSION Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin . However , we do not recommend the use of HEC regimen in daily clinical practice , mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study",
"PURPOSE To compare preoperative intense dose-dense ( IDD ) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer ( BC ) . PATIENTS AND METHODS In this r and omized phase III trial a total of 668 eligible primary BC patients stratified for tumors > or = 3 cm ( n = 567 ) or inflammatory BC ( n = 101 ) were r and omly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks . All patients received three cycles of cyclophosphamide , methotrexate , and fluorouracil chemotherapy after surgery . RESULTS IDD treatment significantly improved pathologic complete response rate ( 18 % v 10 % ; odds ratio [ OR ] 1.89 ; P = .008 ) , disease-free survival ( DFS ; hazard ratio [ HR ] , 0.71 ; P = .011 ) , and overall survival ( OS ; HR , 0.83 ; P = .041 ) compared to epirubicin/paclitaxel . Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial ( DFS HR , 1.10 ; P = .739 ; OS HR , 1.25 ; P = .544 ) . In contrast , patients with noninflammatory BC significantly benefited from IDD treatment ( DFS HR , 0.65 , P = .005 ; OS HR , 0.77 , P = .013 ) . Treatment effects in multivariate analysis were significant for noninflammatory BC ( DFS HR , 0.65 , P = .015 ; OS HR , 0.79 , P = .034 ) , but not for all patients ( DFS HR , 0.76 ; P = .088 ; OS HR , 0.82 ; P = .059 ) . IDD therapy was associated with significantly more nonhematologic toxicities , anemia , and thrombocytopenia , but with similar neutropenia and infection rates . CONCLUSION Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy . IDD was less well tolerated compared to st and ard treatment , but improved clinical outcomes in patients with noninflammatory high-risk primary BC",
"PURPOSE Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer . Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 ( HER2 ) -positive cancer are unknown . PATIENTS AND METHODS One thous and ten women with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive three cycles of docetaxel or vinorelbine , followed in both groups by three cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) . Women with HER2-positive cancer ( n = 232 ) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine . The median follow-up time was 62 months after r and om assignment . RESULTS Women assigned to docetaxel had better distant disease-free survival ( DDFS ) than those assigned to vinorelbine ( hazard ratio [ HR ] = 0.66 ; 95 % CI , 0.49 to 0.91 ; P = .010 ) . In the subgroup of HER2-positive disease , patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only ( HR = 0.65 ; 95 % CI , 0.38 to 1.12 ; P = .12 ; with adjustment for presence of axillary nodal metastases , HR = 0.57 ; P = .047 ) . In exploratory analyses , docetaxel , trastuzumab , and FEC improved DDFS compared with docetaxel plus FEC ( HR = 0.32 ; P = .029 ) and vinorelbine , trastuzumab , and FEC ( HR = 0.31 ; P = .020 ) . The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up ; only one woman treated with trastuzumab was diagnosed with a heart failure . CONCLUSION Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine . A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation",
"BACKGROUND St and ard adjuvant chemotherapy regimens for patients with node positive ( N+ ) breast cancer consisted of anthracycline followed by taxane . The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol . Primary end-point was disease free survival . Secondary end-points were overall survival , local recurrence free interval , metastases free interval and safety . PATIENTS AND METHODS Between March 2000 and December 2002 , 837 patients were r and omised between 6FEC100 for 6 cycles ( 417 patients ) or FEC100 for 4 cycles then Taxol 175mg/m(2)/3 weeks for 4 cycles ( 4FEC100 - 4 T ) ( 420 patients ) . One thous and patients had been planned initially but the trial was closed earlier due to slow accrual . RESULTS Hazard ratios ( HRs ) were 0.99 for disease-free survival ( DFS ) ( 95%CI : 0.77 - 1.26 ; p=0.91 ) , and 0.85 for overall survival ( OS ) ( 95%CI : 0.62 - 1.15 ; p=0.29 ) . Nine-year DFS were 62.9 % versus 62.5 % for 6FEC100 and 4FEC100 - 4 T , respectively . Nine-year OS were 73.9 % versus 77 % for 6FEC100 and 4FEC100 - 4 T , respectively . Toxicity analyses based on 803 evaluable patients showed that overall grade 3 - 4 toxicities were similar in both arms ( 63 % versus 58 % for 6FEC100 arm and 4FEC100 - 4 T arm , respectively ; p=0.16 ) . CONCLUSION In this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage . The lack of a significant difference between the r and omised treatment arms may however be due to a lack of power of this trial to detect small , yet clinical ly worthwhile , treatment benefits",
"BACKGROUND The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide ( EC ) with four cycles of docetaxel ( Taxotere , D ) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer . PATIENTS AND METHODS Patients were r and omly assigned to EC ( E 120 mg/m2 , C 600 mg/m2 , arm A ) for four cycles or four cycles of D ( 100 mg/m2 ) followed by four cycles of EC ( arm B ) , both regimens every 21 days . Hormone receptor-positive patients were given hormonal therapy for 5 years . Primary end point was 5-year disease-free survival ( DFS ) . Secondary objectives were overall survival ( OS ) and safety . RESULTS There were 750 patients enrolled . With a median follow-up of 64 months , 5-year DFS was 73.4 % in both arms , and 5-year OS was 89.5 % versus 90.7 % in arm A and B [ hazard ratio was 0.99 ( 95 % confidence interval for DFS 0.75 - 1.31 ; P = 0.95 ) ] , respectively . Grade 3 - 4 toxicity was more common in arm B. CONCLUSIONS This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer . The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms"
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OBJECTIVE to determine the effects of power training with high movement velocity compared with conventional resistance training with low movement velocity for older community-dwelling people . DESIGN systematic review of r and omised controlled trials . DATA SOURCES the Cochrane Central Register of Controlled TRIALS , PubMed ( Medline ) , EMBASE , CINAHL , PEDro and Scholar-Google . TRIALS all r and omised or quasi-r and omised trials investigating power training with high movement velocity versus conventional resistance training with low movement velocity in elderly persons over the age of 60 years . The primary outcomes were measures of functional outcomes ; secondary outcomes were balance , gait , strength , power , muscle volume and adverse effects . RESULTS eleven trials were identified involving 377 subjects . The pooled effect size for the follow-up values of the functional outcomes was 0.32 in favour of the power training ( 95 % CI 0.06 to 0.57 ) and 0.38 ( 95 % CI -0.51 to 1.28 ) for the change value . The pooled effect from three studies for self-reported function was 0.16 in favour of power training ( 95 % CI -0.17 to 0.49 ) . CONCLUSION power training is feasible for elderly persons and has a small advantage over strength training for functional outcomes . No firm conclusion can be made for safety
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"Periodization is the most effective approach to resistance training ; however , optimal cycle lengths for older persons are not known . This study examined the duration s of performance increments , plateaus , and decrements in women , ages 61 - 75 yr , over 9 wk of isokinetic training . After a 2-wk adaptation cycle , older women trained for either power ( PWR ; 4.73 rad/s ; n = 9 ) or strength ( STR ; 1.05 rad/s ; n = 8) , 3 days/wk with a 1-day recovery between sessions . Repetitions were initially selected to equilibrate work volume between groups . Average power ( AP ) , peak torque ( PT ) , and total work ( TW ) curves were analyzed using forward and backward stepwise regression to ascertain inflections and plateaus . PWR training produced the highest AP , whereas STR produced the highest PT . TW was similar between groups . The AP curves of the PWR group initially showed a steep positive slope and then plateaued during week 3 . The right leg plateau lasted throughout training , whereas the left leg showed another positive inflection during weeks 7 and 8 . PWR group TW curves showed positive slopes throughout training . STR group PT curves for both legs showed initial positive slopes peaking between weeks 3 and 4 and declining thereafter . The TW curves for both legs showed slight negative slopes across the first 2 wk , steep positive slopes during weeks 3 - 6 , and a final plateau . Because improvements plateau early during PWR and STR training , isokinetic training prescriptions for optimizing strength and power improvements in older persons should use cycles of 3 - 4 wk to maximize gains",
"BACKGROUND Muscle power ( force x velocity ) recedes at a faster rate than strength with age and may also be a stronger predictor of fall risk and functional decline . The optimal training paradigm for improving muscle power in older adults is not known , although some literature suggests high velocity , low load training is optimal in young adults . METHODS One hundred twelve healthy older adults ( 69 + /- 6 years ) were r and omly assigned to either explosive resistance training at 20 % ( G20 ) , 50 % ( G50 ) , or 80 % ( G80 ) one repetition maximum ( 1RM ) for 8 - 12 weeks or to a nontraining control group ( CON ) . Participants trained twice per week ( five exercises ; three sets of eight rapidly concentric and slow eccentric repetitions ) using pneumatic resistance machines . Repeated- measures analysis of variance and covariance ( ANOVA and ANCOVA ) were used to determine the effects of training . RESULTS Average peak power increased significantly and similarly in G80 ( 14 + /- 8 % ) , G50 ( 15 + /- 9 % ) , and G20 ( 14 + /- 6 % ) compared to CON ( 3 + /- 6 % ) ( p average strength ( r = .40 , p = .0009 ) and endurance ( r = .43 , p = .0005 ) . Average strength increased in G80 ( 20 + /- 7 % ) , G50 ( 16 + /- 7 % ) , and G20 ( 13 + /- 7 % ) compared to CON ( 4 + /- 4 % ) ( p Average muscle endurance increased in G80 ( 185 + /- 126 % , p Peak muscle power may be improved similarly using light , moderate , or heavy resistances , whereas there is a dose-response relationship between training intensity and muscle strength and endurance changes . Therefore , using heavy loads during explosive resistance training may be the most effective strategy to achieve simultaneous improvements in muscle strength , power , and endurance in older adults",
"OBJECTIVE To determine the effect of training intensity on the contributions of force and velocity to improvements in peak power ( PP ) after explosive resistance training in older adults . METHODS 112 healthy older adults ( 69 + /- 6 yr ) were r and omized to explosive resistance training at 20 % ( G20 ) , 50 % ( G50 ) , or 80 % ( G80 ) maximal strength ( 1-repetition maximum ) for 8 - 12 wk ( twice weekly , 5 exercises , 3 sets of 8 explosive concentric/slow eccentric repetitions ) using pneumatic resistance machines or a nontraining control group ( CON ) . RESULTS Force at peak power ( FPP ) increased significantly and similarly among training groups compared with CON . Velocity at peak power ( VPP ) did not improve significantly and remained similar between all groups . Force contributed significantly more to PP production in G80 and G50 than in CON . The change in PP was independently predicted by changes in fat-free mass in G80 and by changes in both FPP and VPP in G50 and G20 . CONCLUSION Explosive resistance training in older adults results in the ability to produce higher PP outputs with heavier loads without loss of movement velocity . Moderate- to high-intensity training induced a greater relative contribution of force to PP production in this cohort",
"Background and aims : This study investigated whether high-velocity high-power training ( POW ) improved lower extremity muscle power and quality in functionally-limited elders greater than traditional slow-velocity progressive resistance training ( STR ) . Methods : Fifty-seven community-dwelling older adults aged 74.2±7 ( range 65–94 yrs ) , Short Physical Performance Battery score 7.7±1.4 , were r and omized to either POW ( n=23 ) ( 12 females ) , STR ( n=22 ) ( 13 females ) or a control group of lower extremity stretching ( CON ) ( n=12 ) ( 6 females ) . Training was performed three times per week for 12 weeks and subjects completed three sets of double leg press and knee extension exercises at 70 % of the one repetition maximum ( 1RM ) . Outcome measures included 1RM strength and peak power ( PP ) . Total leg lean mass was determined using dual-energy X-ray absorptiometry to estimate specific strength and specific PP . Results : During training , power output was consistently higher in POW compared to STR for knee extension ( ∼2.3-fold ) and leg press ( ∼2.8-fold ) exercises ( p this , PP and specific PP of the knee extensors increased similarly from baseline in POW and STR compared to CON ( p for PP of the leg extensors . However , gains in leg press specific PP were significantly greater in POW compared to both STR and CON ( p did not change within any group . Conclusions : A short-term intervention of high-velocity power training and traditional slow-velocity progressive resistance training yielded similar increases of lower extremity power in the mobility-impaired elderly . Neuromuscular adaptations to power training , rather than skeletal muscle hypertrophy , may have facilitated the improvements in muscle quality . Additional studies are warranted to test the efficacy of power training in older individuals with compromised physical functioning",
"OBJECTIVES To evaluate a dynamic form of weighted vest exercise suitable for home use and design ed to enhance muscle power , balance , and mobility . DESIGN A single-blind , r and omized , controlled trial . SETTING Outpatient exercise research facility situated within an academic long-term care center . PARTICIPANTS Twenty-one community-dwelling women aged 70 and older with a Short Physical Performance Battery ( SPPB ) score between 4 and 10 ( out of 12 ) . INTERVENTIONS Subjects were r and omized into a progressive resistance-training program using weighted vests for resistance with exercises design ed to be specific to mobility tasks and have a component performed at the fastest possible velocity ( Increased Velocity Exercise Specific to Task ( InVEST ) , n=11 ) or a control exercise group ( control , n=10 ) , which performed slow-velocity , low-resistance exercise . Both groups exercised three times a week for 12 weeks . MEASUREMENTS Changes in muscle power , balance , and physical performance were compared . RESULTS In comparison to control group , InVEST group manifested significant improvements ( P leg power across measurements obtained at 75 % to 90 % of the one-repetition maximum . Both groups demonstrated significant improvements in chair st and and SPPB score from baseline , and the InVEST group showed significant improvements in gait speed and chair st and from baseline ( P chair st and time than control ( P leg power and chair rise in this population and is worthy of further investigation as a means of enhancing balance and mobility",
"Cycling on a mechanically braked cycle ergometer was used as a novel approach to compare the effects of three different 16-wk resistance-training programs on isometric force , power output , and selected functional abilities in 31 healthy 65- to 74-yr-old women . Training was conducted three times per week . During each session , individuals of the speed group performed 8 sets of 16 pedal revolutions at 40 % of the maximal resistance to complete two revolutions ( 2 RM ) ; strength group performed 8 sets of 8 revolutions at 80 % of 2 RM ; and combination group performed 4 sets of 16 revolutions at 40 % and 4 sets of 8 revolutions at 80 % of 2 RM . During each set , all participants were required to pedal as fast as possible with a 2-min interval between sets . All training groups significantly increased force , power , and functional abilities ( maximal treadmill walking speed , vertical jumping , and box stepping ) at week 8 ( in the range from 6.5 to 20.8 % ) with no further improvement at week 16 ( except maximal treadmill walking speed ) , but no significant differences were observed between the three groups . The novel approach to performing both low- and high-resistance training , based on the use of a cycle ergometer , has been shown to be effective in improving strength , power , and functional abilities in a group of healthy women . Even fit older women can still improve in functional abilities . Interestingly , the \" high-speed \" and \" low-speed \" programs induced an increase in both power and strength of similar magnitude",
"Background Although progressive resistance strength training ( ST ) has been found to improve various measures of physical functioning in older adults , the benefit to quality of life is unclear . Additionally , recent evidence suggests that high velocity power training ( PT ) may be more beneficial for physical functioning than ST , but it is not known whether this type of training impacts quality of life . The purpose of this study was to compare changes in multiple measures of quality of life result ing from ST vs. PT in older adults . A no exercise group was also included as control comparison condition . Methods Forty-five older adults ( M age = 74.8 years ; SD = 5.7 ) were r and omly assigned to either a ) PT , b ) ST , or c ) control group ( no exercise ) . Measures of self-efficacy ( SE ) , satisfaction with physical function ( SPF ) , and the Satisfaction with Life Scale ( SWL ) were assessed at baseline and following training . The resistance training conditions met 3 times per week for 12 weeks at an intensity of 70 % 1 repetition maximum . Results A series of ANCOVA 's comparing between group differences in change and controlling for baseline values revealed significant group differences in all three measures : SE ( F(2,31 ) = 9.77 ; p SPF ( F(2,32 ) = 3.36 ; p = .047 ) ; SWL ( F(2,31 ) = 4.76 ; p = .016 ) . Follow up analyses indicated that the PT group reported significantly more change in SE , SPF , and SWL than the control group whereas the ST group reported greater change than the control group only in SE . Conclusion These pilot data indicate that high velocity power training may influence multiple levels of quality of life over and above the benefits gained through traditional strength training",
"BACKGROUND Loss of muscle power due to normal aging has greater functional impact than loss of strength alone . The present study compared two resistance training programs , one aim ed at enhancing muscle power and one at increasing muscle strength , on muscle function and functional performance in older adults . METHODS Sixty-seven healthy , independent older adults ( 65 - 84 years ) were r and omized to a high-velocity varied resistance ( HV ) , constant resistance ( ST ) , or nontraining control ( CO ) group . Participants trained twice weekly for 24 weeks using six exercises . Dynamic and isometric muscle strength , muscle power , movement velocity , muscle endurance , and a battery of functional performance tasks were assessed . Secondary outcomes included body composition , quality of life , and balance confidence . RESULTS Muscle strength increased significantly ( p Peak muscle power also increased with training ( p peak power was 50.5 + /- 4.1 % , 33.8 + /- 3.8 % , and -2.5 + /- 3.9 % in the HV , ST , and CO groups , respectively . Training also improved selected functional performance tasks in the HV and ST groups compared to controls ( p quality of life ( p = .018 ) . CONCLUSION Muscle power and muscle strength improved similarly using either resistance training protocol , and these changes were accompanied by improvements in several functional performance tasks . However , improvements in the HV group occurred with less total work performed per training session",
"BACKGROUND This study was design ed to evaluate the benefits of InVEST ( Increased Velocity Specific to Task ) training on limb power and mobility among mobility-limited older adults . METHODS We conducted a single blinded , r and omized controlled trial among 138 mobility-limited community-dwelling older adults , evaluating two 16-week supervised exercise programs . The intervention group participated in InVEST training , and the control group participated in the National Institute on Aging 's ( NIA ) strength training program . Primary outcomes were changes in limb power per kilogram and mobility performance as measured by the Short Physical Performance Battery ( SPPB ) . RESULTS After 16 weeks , InVEST produced significantly greater improvements in limb power than NIA ( p=.02 ) . There was no significant difference in strength improvements . Both groups had significant changes in SPPB of greater than 1 unit . Self-reported function was also significantly improved in both groups . Differences between groups were not statistically different . In a post hoc analysis when participants were categorized by the manifestation of baseline leg velocity impairments ( N=68 ) , InVEST training produced effect size differences in SPPB that were clinical ly meaningful ( SPPB Group x Time difference 0.73 units , p=.05 ) . CONCLUSIONS Among mobility-limited older adults , both NIA and InVEST produce robust changes in observed physical performance and self-reported function . These improvements were not meaningfully different by statistical or clinical criteria . Compared with NIA , InVEST training produced greater improvements in limb power and equivalent improvements in strength . Observed differences between NIA and InVEST based upon baseline leg impairment status are informative for futures studies",
"It is unclear whether strength training ( ST ) or power training ( PT ) is the more effective intervention at improving muscle strength and power and physical function in older adults . The authors compared the effects of lower extremity PT with those of ST on muscle strength and power in 45 older adults ( 74.8 + /- 5.7 yr ) with self-reported difficulty in common daily activities . Participants were r and omized to 1 of 3 treatment groups : PT , ST , or wait-list control . PT and ST trained 3 times/wk for 12 wk using knee-extension ( KE ) and leg-press ( LP ) machines at approximately 70 % of 1-repetition maximum ( 1RM ) . For PT , the concentric phase of the KE and LP was completed \" as fast as possible , \" whereas for ST the concentric phase was 2 - 3 s. Both PT and ST paused briefly at the midpoint of the movement and completed the eccentric phase of the movement in 2 - 3 s. PT and ST groups showed significant improvements in KE and LP 1RM compared with the control group . Maximum KE and LP power increased approximately twofold in PT compared with ST . At 12 wk , compared with control , maximum KE and LP power were significantly increased for the PT group but not for the ST group . In older adults with compromised function , PT leads to similar increases in strength and larger increases in power than ST",
"BACKGROUND Age-related decline in muscle power may be an early indicator of balance deficits and fall risk , even in nonfrail adults . This study examined the dose-dependent effect of power training on balance performance in healthy older adults . METHODS One hundred twelve community-dwelling healthy older adults ( 69 + /- 6 years ) were r and omized to 8 - 12 weeks of power training at 20 % ( LOW ) , 50 % ( MED ) , or 80 % ( HIGH ) of maximal strength , or a nontraining control ( CON ) group . Participants trained twice weekly ( five exercises ; three sets of eight rapid concentric/slow eccentric repetitions ) using pneumatic resistance machines . Balance , muscle performance ( strength , power , endurance , contraction velocity ) , and body composition were measured . RESULTS Power training significantly improved balance performance ( p = .006 ) in participants who underwent power training compared to controls . Low intensity power training produced the greatest improvement in balance performance ( p = .048 ) . Average contraction velocity at low load ( 40 % one repetition maximum [ 1RM ] ) at baseline independently predicted improvement in balance following training ( r = -.29 , p = .004 ) . CONCLUSIONS Power training improves balance , particularly using a low load , high velocity regimen , in older adults with initial lower muscle power and slower contraction . Further studies are warranted to define the mechanisms underlying this adaptation , as well as the optimum power training intensity for a range of physiological and clinical outcomes in older adults with varying levels of health status and functional independence",
"This study investigated the effect of a 10-week power training ( PT ) program versus traditional resistance training ( TRT ) on functional performance , and muscular power and strength in older men . Twenty inactive volunteers ( 60–76 years old ) were r and omly assigned to a PT group ( three 8–10 repetition sets performed as fast a possible at 60 % of 1-RM ) or a TRT group ( three 8–10 repetition sets with 2–3 s contractions at 60 % of 1-RM ) . Both groups exercised 2 days/week with the same work output . Outcomes were measured with the Rikli and Jones functional fitness test and a bench and leg press test of maximal power and strength ( 1-RM ) . Significant differences between and within groups were analyzed using a two-way analysis of variance ( ANOVA ) . At 10 weeks there was a significantly ( P measures of functional performance in the PT group . Arm curling improved by 50 versus 3 % and a 30 s chair-st and improved by 43 versus 6 % in the PT and TRT groups , respectively . There was also a significantly greater improvement in muscular power ( P The bench press improved by 37 versus 13 % , and the leg press by 31 and 8 % in the PT and TRT groups , respectively . There was no significant difference between groups in improved muscular strength . It appears that in older men there may be a significantly greater improvement in functional performance and muscular power with PT versus low velocity resistance training",
"BACKGROUND The performance of daily tasks , such as stair climbing or lifting an object , requires both muscle strength and power . Age-associated reductions in strength and power can affect an older adult 's ability to complete daily tasks such as stair climbing and lifting a child . METHODS The purpose s of this study were to determine whether power training was more efficacious than strength training for improving whole-body physical function in older adults and to examine the relationship between changes in anaerobic power and muscle strength and changes in physical function . Thirty-nine men and women ( mean age + /- SD = 72.5 + /- 6.3 years ) with below-average leg extensor power were r and omly assigned to control ( C , n = 15 ) , strength-training ( ST , n = 13 ) or power-training ( PT , n = 11 ) groups . The ST and PT groups met 3 days per week for 16 weeks ; the C group maintained usual activity and attended three lectures during the course of the study . Primary outcome measures included the Continuous Scale Physical Functional Performance test , maximal strength , and anaerobic power . RESULTS After baseline was controlled for , the Continuous Scale Physical Functional Performance test total score was significantly greater for the PT group than for the ST ( p = .033 ) and C ( p = .016 ) groups . Maximal strength was significantly greater for the ST group than for the C group ( p = .015 ) after the intervention . There was no significant difference between groups for peak anaerobic power . CONCLUSIONS Power training was more effective than strength training for improving physical function in community-dwelling older adults",
"Sayers SP , Bean J , Cuoco A , LeBrasseur NK , Jette A , Fielding RA : Changes in function and disability after resistance training : Does velocity matter ? A pilot study . Am J Phys Med Rehabil 2003;82:605–613 . Objective To compare the effects of high- and low-velocity resistance training on functional performance and disability outcomes in physically limited older women . Design A total of 16 wk of high-velocity resistance training or traditional low-velocity resistance training consisting of knee extension and leg press exercises was performed three times per week by 30 women with self-reported disability to compare their effect on functional performance and disability . Tests of dynamic balance , stair-climb time , chair-rise time , and gait velocity were used to assess changes in functional performance . Changes in disability were assessed using the Medical Outcomes Study Short Form . Results Dynamic balance and stair-climb time improved 8 % and 10 % , respectively , with training . Self-reported disability , physical functioning , role physical , and mental health improved 11 , 9 , and 5 % with training , respectively . There were no significant differences between high- and low-velocity training groups . Conclusions High- and low-velocity training achieved similar improvements in functional performance and disability . Improvements in functional performance and disability were modest compared with robust increases in strength and power . Specific modes of training or behavioral strategies may be necessary to optimize improvements in these outcomes",
"OBJECTIVES Peak power declines more precipitously than strength with advancing age and is a reliable measure of impairment and a strong predictor of functional performance . We tested the hypothesis that a high-velocity resistance-training program ( HI ) would increase muscle power more than a traditional low-velocity resistance-training program ( LO ) . DESIGN R and omized controlled trial . SETTING University-based human physiology laboratory . PARTICIPANTS Thirty women with self-reported dis-ability ( aged 73 + 1 , body mass index 30.1 + 1.1 kg/mn ) . INTERVENTION We conducted a r and omized trial comparing changes in skeletal muscle power and strength after 16 weeks of HI or LO . Training was performed three times per week , and subjects completed three sets ( 8 - 10 repetitions ) of leg press ( LP ) and knee extension ( KE ) exercises at 70 % of the one-repetition maximum ( IRM ) . MEASUREMENTS One-repetition maximum ( 1 RM ) and peak power for KE and LP . RESULTS LP and KE relative training force and total work were similar between groups ( P > .05 ) . However , HI generated significantly higher power during training sessions than LO for LP ( 3.7-fold greater , P LP and KE 1RM muscle strength increased similarly in both groups asa result of the training ( P LP peak power increased significantly more in HI than in LO ( 267 W vs 139 W , P improvement in LP power at 40 % , 50 % , 60%,70 % , 80 % , and 90 % of the 1 RM than did LO ( P 1RM strength similarly and was more effective in improving peak power than was traditional LO in older women . Improvements in lower extremity peak power may exert a greater influence on age-associated reductions in physical functioning than other exercise interventions",
"AIM Loss of muscle strength and balance are main characteristics of physical frailty in old age . Postural sway is associated with muscle contractile capacity and to the ability of rapidly correcting ankle joint changes . Thus , resistance training would be expected to improve not only strength but also postural balance . METHODS In this study , age-matched older individuals ( 69.9+/-1.3 years ) were r and omly assigned to flywheel ( n=12 ) , or weight-lifting ( n=12 ) groups , training the knee extensors thrice weekly for 12 weeks . The hypotheses were that owing to a larger eccentric loading of the knee extensors , flywheel training would result in ( a ) greater gains in quadriceps strength ; ( b ) greater improvements in balance performance compared with weight-lifting training . Isokinetic dynamometry , B-mode ultrasonography , electromyography , percutaneous muscle stimulation and magnetic resonance imaging were employed to acquire the parameters of interest . RESULTS Following training , knee extensors peak isokinetic power increased by 28 % ( P Adaptations of the gastrocnemius muscle also occurred in both groups . The gastrocnemius characteristic with the highest response to training was tendon stiffness , with increases of 54 % and 136 % in the weight-lifting and flywheel groups , respectively ( P tendon stiffness in the flywheel group was associated with an improvement in postural balance ( P Quadriceps flywheel loading not only produces a greater increase in power than weight training but its physiological benefits also transfer/overspill to the plantarflexor muscle-tendon unit result ing in a significantly improved balance . These findings support our initial hypotheses"
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Smoking cessation is a chronic issue surrounding individuals with schizophrenia . It is estimated that up to 90 % of patients diagnosed with schizophrenia smoke cigarettes . The purpose of this article is to provide a non systematic review of the efficacy of smoking cessation interventions as well as to explore the potential neuropsychiatric adverse effects of these agents in patients with schizophrenia . Eighteen studies were found and included in the review . Overall , nicotine replacement therapy , bupropion , and varenicline have all proven their effectiveness at either promoting smoking abstinence or a significant reduction in cigarette use
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"Abstract Alcohol and nicotine dependence are common in schizophrenia . Varenicline is effective in smoking cessation and has also been shown to decrease alcohol consumption in smokers . The present pilot study assessed the safety and effectiveness of varenicline for treatment of concurrent nicotine and alcohol dependence in schizophrenia . Out patients with schizophrenia or schizoaffective disorder and concurrent alcohol and nicotine dependence were enrolled in this 8-week , double-blind , r and omized , placebo-controlled trial . Alcohol use and smoking were assessed using self-report ( Timeline Follow-Back ) and biological measures . Adverse events were recorded . Changes in the number of st and ard drinks per week and cigarettes per week were compared in the 2 groups . Because of safety concerns or loss to follow-up , of 55 patients enrolled , only 10 started study medication , 5 each on varenicline and placebo . Gastrointestinal adverse effects , such as severe abdominal pain , limited study completion to only 4 subjects . Number of st and ard alcoholic drinks consumed per week decreased by [ mean ( SD ) ] 16.6 ( 20.1 ) in the varenicline group and by 2.4 ( 27.4 ) in the placebo group . Mean ( SD ) number of cigarettes smoked per week decreased by 66 ( 65 ) in the varenicline group and by 47 ( 77 ) in the placebo group . Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia may be problematic because of safety concerns limiting recruitment and poor tolerability ( gastrointestinal adverse effects ) limiting retention . There was no increased number of serious neuropsychiatric adverse events in the varenicline group . Based on this small sample , concurrent alcohol and nicotine dependence in schizophrenia may present special obstacles to successful treatment with varenicline",
"BACKGROUND Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion . Their efficacy relative to nicotine patch largely relies on indirect comparisons , and there is limited information on safety and efficacy in smokers with psychiatric disorders . We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders . METHODS We did a r and omised , double-blind , triple-dummy , placebo-controlled and active-controlled ( nicotine patch ; 21 mg per day with taper ) trial of varenicline ( 1 mg twice a day ) and bupropion ( 150 mg twice a day ) for 12 weeks with 12-week non-treatment follow-up done at 140 centres ( clinical trial centres , academic centres , and outpatient clinics ) in 16 countries between Nov 30 , 2011 , and Jan 13 , 2015 . Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit . R and omisation was computer generated ( 1:1:1:1 ratio ) . Participants , investigators , and research personnel were masked to treatment assignments . The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events . The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9 - 12 . All participants r and omly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis . The trial is registered at Clinical Trials.gov ( number NCT01456936 ) and is now closed . FINDINGS 8144 participants were r and omly assigned , 4116 to the psychiatric cohort ( 4074 included in the safety analysis ) and 4028 to the non-psychiatric cohort ( 3984 included in the safety analysis ) . In the non-psychiatric cohort , 13 ( 1·3 % ) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group , 22 ( 2·2 % ) of 989 in the bupropion group , 25 ( 2·5 % ) of 1006 in the nicotine patch group , and 24 ( 2·4 % ) of 999 in the placebo group . The varenicline-placebo and bupropion-placebo risk differences ( RDs ) for moderate and severe neuropsychiatric adverse events were -1·28 ( 95 % CI -2·40 to -0·15 ) and -0·08 ( -1·37 to 1·21 ) , respectively ; the RDs for comparisons with nicotine patch were -1·07 ( -2·21 to 0·08 ) and 0·13 ( -1·19 to 1·45 ) , respectively . In the psychiatric cohort , moderate and severe neuropsychiatric adverse events were reported in 67 ( 6·5 % ) of 1026 participants in the varenicline group , 68 ( 6·7 % ) of 1017 in the bupropion group , 53 ( 5·2 % ) of 1016 in the nicotine patch group , and 50 ( 4·9 % ) of 1015 in the placebo group . The varenicline-placebo and bupropion-placebo RDs were 1·59 ( 95 % CI -0·42 to 3·59 ) and 1·78 ( -0·24 to 3·81 ) , respectively ; the RDs versus nicotine patch were 1·22 ( -0·81 to 3·25 ) and 1·42 ( -0·63 to 3·46 ) , respectively . Varenicline-treated participants achieved higher abstinence rates than those on placebo ( odds ratio [ OR ] 3·61 , 95 % CI 3·07 to 4·24 ) , nicotine patch ( 1·68 , 1·46 to 1·93 ) , and bupropion ( 1·75 , 1·52 to 2·01 ) . Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo ( OR 2·07 [ 1·75 to 2·45 ] and 2·15 [ 1·82 to 2·54 ] , respectively ) . Across cohorts , the most frequent adverse events by treatment group were nausea ( varenicline , 25 % [ 511 of 2016 participants ] ) , insomnia ( bupropion , 12 % [ 245 of 2006 participants ] ) , abnormal dreams ( nicotine patch , 12 % [ 251 of 2022 participants ] ) , and headache ( placebo , 10 % [ 199 of 2014 participants ] ) . Efficacy treatment comparison did not differ by cohort . INTERPRETATION The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo . Varenicline was more effective than placebo , nicotine patch , and bupropion in helping smokers achieve abstinence , whereas bupropion and nicotine patch were more effective than placebo . FUNDING Pfizer and GlaxoSmithKline",
"OBJECTIVE The present study sought to better underst and the relationships among smoking history , motivation to change , and smoking cessation outcomes in people with schizophrenia who smoke . METHOD We examined smoking and quit history , negative consequences due to smoking , readiness to change , smoking temptation , and confidence to quit in a sample of people diagnosed with schizophrenia or schizoaffective disorder according to DSM-IV criteria who were participating in a larger r and omized trial of bupropion SR and a psychoeducational intervention for smoking cessation . Data were collected from June 2003 to May 2005 . RESULTS At baseline , participants reported high levels of nicotine dependence and daily smoking , as well as multiple recent and lifetime quit attempts that were generally brief in nature . Participants were most concerned about the health effects of smoking and endorsed reasons for smoking related to coping with negative affect and boredom . Most participants reported wanting to quit smoking , but the sample generally reported low levels of confidence in their ability to quit . During the course of participation in the intervention , self-efficacy to quit increased while temptation to smoke decreased ; however readiness to quit remained unchanged . CONCLUSION Smoking cessation programs for people with schizophrenia should focus on teaching coping skills for negative affect , boredom , and specific \" high risk situations \" for smoking in addition to education , medication , or nicotine replacement therapy . Further , cessation efforts may benefit from directly addressing low self-efficacy for quitting , rather than readiness for change alone , among people with schizophrenia",
"BACKGROUND Schizophrenic patients have high rates of cigarette smoking compared with the general population . We compared sustained-release ( SR ) bupropion with placebo for smoking cessation in patients with schizophrenic disorders . We also examined how antipsychotic class predicts smoking cessation outcomes with bupropion . METHODS Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were r and omized to bupropion SR ( BUP , 300 mg/day ) or placebo ( PLA ) . Outcomes included treatment retention , smoking abstinence rates , expired breath carbon monoxide ( CO ) levels , psychotic symptoms , and medication side effects . RESULTS Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [ BUP , 8/16 ( 50.0 % ) , PLA , 2/16 ( 12.5 % ) ; chi(2 ) = 5.24 , df = 1 , p reduced CO levels during the trial [ Medication x Time interaction ; Z = 3.09 , p Positive schizophrenia symptoms were not altered by BUP , but negative symptoms were significantly reduced . Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP . Major side effects were dry mouth , gastrointestinal symptoms , headache , and insomnia . CONCLUSIONS Our results suggest that 1 ) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers ; 2 ) BUP is well-tolerated and safe for use in these patients ; and 3 ) atypical antipsychotics may enhance smoking cessation outcomes with BUP",
"OBJECTIVE Schizophrenic patients have high rates of cigarette smoking . The authors compared the outcomes of two group psychotherapy programs for smoking cessation in patients with schizophrenia or schizoaffective disorder who were also treated with the nicotine transdermal patch and with either atypical or typical antipsychotic medications . METHOD Forty-five subjects were r and omly assigned to 1 ) the group therapy program of the American Lung Association ( N=17 ) or 2 ) a specialized group therapy program for smokers with schizophrenia ( N=28 ) that emphasized motivational enhancement , relapse prevention , social skills training , and psychoeducation . All subjects participated in 10 weeks of treatment with the nicotine transdermal patch ( 21 mg/day ) and 10 weekly group therapy sessions and continued to receive their pre study atypical ( N=18 ) or typical ( N=27 ) antipsychotic medications . Outcome variables included treatment retention , rate of smoking abstinence , and expired-breath carbon monoxide level . RESULTS Smoking abstinence rates did not differ in the two group therapy programs . However , atypical antipsychotic agents , in combination with the nicotine transdermal patch , significantly enhanced the rate of smoking cessation ( 55.6 % in the atypical agent group versus 22.2 % in the typical group ) , which was reflected by a significant effect of atypical versus typical agents on carbon monoxide levels . Risperidone and olanzapine were associated with the highest quit rates . CONCLUSIONS The results suggest that 1 ) smoking cessation rates with the nicotine transdermal patch are modest in schizophrenia , 2 ) specialized group therapy for schizophrenic patients is not significantly different from American Lung Association group therapy in its effect on smoking cessation , and 3 ) atypical agents may be superior to typical agents in combination with the nicotine transdermal patch for smoking cessation in schizophrenia",
"The purpose of this study was to investigate the effect of adding sustained-release ( SR ) bupropion to cognitive behavioral therapy ( CBT ) on smoking behavior and stability of psychiatric symptoms in patients with schizophrenia . We conducted a 3-month , double-blind , placebo-controlled trial of bupropion SR , 150 mg/day , added to a concurrent CBT program with 3-month follow-up in 19 stable out patients with schizophrenia who wanted to quit smoking . Eighteen subjects completed the trial . Bupropion treatment was associated with significantly greater reduction in smoking , as measured by self-report verified by expired-air carbon monoxide ( 6/9 subjects , 66 % ) , than placebo ( 1/9 subjects , 11 % ) during the 3-month active treatment period and the 3-month follow-up period . One subject in the bupropion group ( 11 % ) and no subjects in the placebo group achieved sustained tobacco abstinence for the 6-month trial . Bupropion treatment was associated with improvement in negative symptoms and greater stability of psychotic and depressive symptoms , compared with placebo , during the quit attempt . Subjects in the bupropion group experienced significant weight loss , compared with those on placebo during the smoking cessation attempt . These data suggest that bupropion SR , 150 mg/day , combined with CBT , may facilitate smoking reduction in patients with schizophrenia while stabilizing psychiatric symptoms during a quit attempt",
"Background : Cigarette smoking is a tough addiction to break . This dependence is the most common dual diagnosis for individuals with schizophrenia . Currently three effective drugs are approved for smoking cessation : nicotine replacement therapy ( NRT ) , varenicline and bupropion . However , some serious side effects of varenicline have been reported , including depression , suicidal thoughts , and suicide . The use of bupropion also has side effects . It should not be used by people who have epilepsy or any condition that lowers the seizure threshold , nor by people who take a specific class of drugs called monoamine oxidase inhibitors . Hence , there are pharmacodynamic reason to believe they could precipitate or exacerbate psychosis . For its capacity to deliver nicotine and provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures , electronic-cigarettes may reduce nicotine withdrawal symptoms without serious side effects . Our recent work with ECs in healthy smokers not intending to quit consistently show surprisingly high success rates . We hypothesised that these positive findings could be replicated in difficult patients with schizophrenia This tool may help smokers with schizophrenia remain abstinent during their quitting attempts or to reduce cigarette consumption . Efficacy and safety of these devices in long-term smoking cessation and /or smoking reduction studies have never been investigated for this special population . Methods : In this study we monitored possible modifications in smoking habits of 14 smokers ( not intending to quit ) with schizophrenia experimenting with the “ Categoria ” e-Cigarette with a focus on smoking reduction and smoking abstinence . Study participants were invited to attend six study visits : at baseline , week-4 , week-8 , week-12 week-24 and week 52 . Product use , number of cigarettes smoked , carbon monoxide in exhaled breath ( eCO ) and positive and negative symptoms of schizophrenia levels were measured at each visit . Smoking reduction and abstinence rates were calculated . Adverse events were also review ed . Results : Sustained 50 % reduction in the number of cig/day at week-52 was shown in 7/14 ( 50 % ) participants ; their median of 30 cig/day decreasing significantly to 15 cig/day ( p = 0.018 ) . Sustained smoking abstinence at week-52 was observed in 2/14 ( 14.3 % ) participants . Combined sustained 50 % reduction and smoking abstinence was shown in 9/14 ( 64.3 % ) participants . Nausea was observed in 2/14 ( 14.4 % ) of participants , throat irritation in 2/14 ( 14.4 % ) of participants , headache in 2/14 ( 14.4 % ) of participants , and dry cough in 4/14 ( 28.6 % ) of participants . However , these adverse events diminished substantially by week-24 . Overall , one to two cartridges/day were used throughout the study . Positive and negative symptoms of schizophrenia are not increased after smoking reduction/cessation in patients using e-cigarettes . Conclusions : We have shown for the first time that the use of e-cigarette substantially decreased cigarette consumption without causing significant side effects in chronic schizophrenic patients who smoke not intending to quit . This was achieved without negative impacts on the symptoms of schizophrenia as assessed by SAPS and SANS symptoms scales",
"Nearly 90 % of schizophrenics smoke cigarettes , considerably higher than the general population 's rate of 25 % . There is some indication that schizophrenics may smoke as a form of self-medication . Nicotine has a variety of pharmacologic effects that may both counteract some of the cognitive deficits of schizophrenia and counteract some of the adverse side effects of antipsychotic drugs . In the current study , we assessed the interactions of haloperidol and nicotine on cognitive performance of a group of schizophrenics . These patients were in a double-blind study , r and omly assigning them to low , moderate , and high dose levels of haloperidol . The subjects , all smokers , came to the laboratory on four different mornings after overnight deprivation from cigarettes . In a double-blind fashion , they were administered placebo , low ( 7 mg/day ) , medium ( 14 mg/day ) , or high ( 21 mg/day ) dose nicotine skin patches . Three hours after administration of the skin patch , the subjects were given a computerized cognitive test battery including : simple reaction time , complex reaction time ( spatial rotation ) , delayed matching to sample , the Sternberg memory test , and the Conners continuous performance test ( CPT ) . With the placebo nicotine patch , there was a haloperidol dose-related impairment in delayed matching to sample choice accuracy and an increase in response time on the complex reaction time task . Nicotine caused a dose-related reversal of the haloperidol-induced impairments in memory performance and complex reaction time . In the CPT , nicotine reduced the variability in response that is associated with attentional deficit . These results demonstrate the effects of nicotine in reversing some of the adverse side effects of haloperidol and improving cognitive performance in schizophrenia . © 1996 American College of",
"OBJECTIVE Effective smoking cessation treatments are needed for patients with schizophrenia , who , compared with the general population , have high rates of cigarette smoking and more difficulty quitting . We evaluated the safety and efficacy of varenicline for smoking cessation in out patients with stable schizophrenia or schizoaffective disorder . METHOD In this 12-week , r and omized , double-blind , multicenter trial ( May 8 , 2008 , to April 1 , 2010 ) , 127 smokers ( ≥ 15 cigarettes/d ) with DSM-IV-confirmed schizophrenia or schizoaffective disorder received varenicline or placebo ( 2:1 ratio ) . The primary outcome was safety and tolerability of varenicline assessed by adverse events frequency and changes in ratings on the Positive and Negative Syndrome Scale and other psychiatric scales from baseline to 24 weeks . Abstinence was defined as no smoking 7 days prior to weeks 12 and 24 , verified by carbon monoxide level . RESULTS Eighty-four participants received varenicline ; 43 , placebo . At 12 weeks ( end of treatment ) , 16/84 varenicline-treated patients ( 19.0 % ) met smoking cessation criteria versus 2/43 ( 4.7 % ) for placebo ( P = .046 ) . At 24 weeks , 10/84 ( 11.9 % ) varenicline-treated and 1/43 ( 2.3 % ) placebo-treated patients , respectively , met abstinence criteria ( P = .090 ) . Total adverse event rates were similar between groups , with no significant changes in symptoms of schizophrenia or in mood and anxiety ratings . Rates of suicidal ideation adverse events were 6.0 % ( varenicline ) and 7.0 % ( placebo ) ( P = 1.0 ) . There was 1 suicide attempt by a varenicline patient with a lifetime history of similar attempts and no completed suicides . CONCLUSIONS Varenicline was well tolerated , with no evidence of exacerbation of symptoms , and was associated with significantly higher smoking cessation rates versus placebo at 12 weeks . Our findings suggest varenicline is a suitable smoking cessation therapy for patients with schizophrenia or schizoaffective disorder . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00644969",
"Rationale Individuals with schizophrenia have high smoking-related morbidity and mortality rates and need powerful and innovative smoking cessation interventions . Objectives This proof-of-concept study investigated the feasibility and initial efficacy of combining a contingency management intervention with bupropion to reduce smoking in people with schizophrenia . Methods Using a double-blind , placebo-controlled , between-groups design , 57 non-treatment-seeking participants were r and omized to receive 300 mg/day bupropion or placebo . One week later , participants were r and omized to a contingency management ( CM ) intervention in which reductions in urinary cotinine levels were reinforced , or a non-contingent reinforcement ( NR ) condition in which session attendance was reinforced , regardless of cotinine level . Over the 22-day study period , participants visited the laboratory approximately three times per week to provide urine sample s for analysis of cotinine levels , to give breath sample s for analysis of carbon monoxide ( CO ) levels , and to report number of cigarettes smoked per day , nicotine withdrawal symptoms , cigarette craving , and psychiatric symptoms . Results Cotinine and CO levels significantly decreased during the study period in participants r and omized to the CM condition , but not the NR condition . Bupropion did not reduce cotinine levels or increase the efficacy of CM . Cigarette craving and psychiatric symptom levels significantly decreased during the study in all groups . Conclusions The results of this study indicate the efficacy and feasibility of this CM intervention for reducing smoking in individuals with schizophrenia",
"Abstract : The objective of this study was to examine the efficacy of bupropion for smoking cessation in patients with schizophrenia . Adults with schizophrenia who smoked more than 10 cigarettes per day and wished to try to quit smoking were recruited from community mental health centers , enrolled in a 12-week group cognitive behavioral therapy intervention , and r and omly assigned to receive either bupropion sustained-release 300 mg/d or identical placebo . Fifty-three adults , 25 on bupropion and 28 on placebo , were r and omized , completed at least 1 postbaseline assessment and were included in the analysis . The primary outcome measures were 7-day point prevalence abstinence in the week after the quit date ( week 4 ) and at the end of the intervention ( week 12 ) . Subjects in the bupropion group were significantly more likely to be abstinent for the week after the quit date ( 36 % [ 9/25 ] vs. 7 % [ 2/28 ] , P = 0.016 ) and at end of the intervention ( 16 % [ 4/25 ] vs. 0 % , P = 0.043 ) . Subjects in the bupropion group also had a higher rate of 4-week continuous abstinence ( weeks 8 - 12 ) ( 16 % [ 4/25 ] vs. 0 % , P = 0.043 ) and a longer duration of abstinence ( 4.2 [ 3.2 ] weeks vs. 1.8 [ 0.96 ] weeks , t = 2.30 , P = 0.037 ) . The effect of bupropion did not persist after discontinuation of treatment . Subjects in the bupropion group had no worsening of clinical symptoms and had a trend toward improvement in depressive and negative symptoms . We conclude that bupropion does not worsen clinical symptoms of schizophrenia and is modestly effective for smoking cessation in patients with schizophrenia . The relapse rate is high after treatment discontinuation",
"The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy ( NRT ) and weekly group cognitive behavioral therapy ( CBT ) for smoking reduction or cessation in schizophrenia . Fifty-one adult smokers with schizophrenia were r and omly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch , nicotine polacrilex gum , and CBT . The treatment goal was smoking cessation . The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50 % to 100 % smoking reduction at week 12 . Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide ( CO ) and psychiatric symptoms . Subjects on bupropion + NRT had a greater rate of 50 % to 100 % smoking reduction at weeks 12 ( 60 % vs. 31 % ; P = 0.036 ) and 24 , a lower expired air CO in the treatment and follow-up periods , ( F = 13.8 ; P continuous abstinence rate at week 8 , before NRT taper , ( 52 % vs. 19 % ; P = 0.014 ) . However , relapse rates in subjects on bupropion + dual NRT were 31 % during NRT taper ( weeks 8 - 12 ) and 77 % at the 12-month follow-up . Abstinence rates did not differ by treatment group at weeks 12 ( 36 % vs. 19 % ) , 24 ( 20 % vs. 8 % ) , or 52 ( 12 % vs. 8 % ) . Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment , study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention",
"The purpose of this study was to determine the effectiveness of nicotine-patch therapy for smoking cessation in patients with schizophrenia . This was a longitudinal study and sixty-eight schizophrenic patients were assigned to 8 weeks of a nicotine-patch therapy program or a control group . The generalized estimating equation analysis revealed that there were significant reductions in the subjects ' nicotine dependence ( Fagerstrom Tolerance Question naire ) , the number of cigarettes per day , and CO levels over an 8-week period of nicotine-patch therapy and 3-month follow-up . The point-prevalence rates of abstinence from smoking were an abstinence of 26.9 % at 8 weeks and 26.9 % at a 3-month follow-up . At the 3-month follow-up , the rate of continuous smoking abstinence in the nicotine-patch group was 23.1 %",
"There have been many studies of smoking cessation using nicotine replacement therapy ( NRT ) with schizophrenic patients , but none exploring the smoking-reduction effects of varying doses of NRT in long-stay patients with schizophrenia . This study aim ed to examine the effect of different doses of the nicotine transdermal patch on smoking-reduction and cessation outcomes in long-term hospitalized schizophrenic patients . A total of 184 subjects participated in a r and omized , controlled , double-blind 8-week clinical trial . Participants were r and omized into two groups using two different doses of NRT : a high-dose NRT group ( 31.2 mg for the first 4 weeks , then 20.8 mg for 4 weeks , n = 92 ) or a low-dose NRT group ( 20.8 mg for 8 weeks , n = 92 ) . The 7-day point prevalence of abstinence was 2.7 % ( 5/184 ) . Participants in the low-dose NRT group reduced smoking by 3.1 more cigarettes on average than those in the high-dose group ( p = 0.005 ) . However , a repeated measures analysis of variance revealed that the main effect of changes in the number of cigarettes smoked , comparing the two types of treatment across periods , was not significant ( p = 0.35 , partial eta square = 0.018 ) . In summary , among a cohort of chronic institutionalized schizophrenic patients , smoking cessation and reduction outcomes were not correlated with NRT dose , and the cessation rate was much lower than rates in similar studies . It indicates that long-term hospitalized schizophrenic patients have more difficulties with quitting smoking . More effective integrative smoking cessation programs should be addressed for these patients",
"BACKGROUND We were interested in exploring the efficacy and safety of varenicline as an adjunct to a healthy lifestyle intervention for smoking cessation among individuals with a severe mental illness . METHODS We used varenicline as an adjunct to a healthy lifestyle intervention in 14 smokers with a psychotic illness . RESULTS Overall , smoking cessation rates were 36 % at 3 months and 42 % at 6 months . The most commonly reported side effects were sleep disturbance and nausea . These tended to occur early in treatment , and patients responded to general measures of support and reassurance . Of the 14 participants , 1 dropped out because of psychiatric problems and 2 because of other side effects . CONCLUSIONS Varenicline appears to be an effective adjunct to a healthy lifestyle intervention for smokers with a psychotic illness . Although the results of this open study are encouraging , replication in an adequately powered , r and omized controlled trial is required before definitive conclusions can be drawn",
"Schizophrenics have deficits in neuropsychological performance , some of which are modified by cigarette smoking . These patients also have high rates of smoking and resistance to smoking cessation interventions . We examined whether the presence of neuropsychological deficits prior to smoking cessation treatment was associated with smoking cessation treatment failure in schizophrenic as compared to non-psychiatric control smokers . Neuropsychological assessment s were performed prior to treatment with pharmacological agents during the course of placebo-controlled trials in schizophrenic and non-psychiatric control smokers , and included the Wisconsin Card Sorting Test ( WCST ) , a Visuospatial Working Memory ( VSWM ) task , the Stroop Color Word Test ( SCWT ) and the Continuous Performance Test ( CPT ) . In schizophrenics ( n=32 ) , subjects who had greater deficits in VSWM and WCST performance were significantly less likely to quit smoking , but this association was not observed in controls ( n=40 ) . Differences between quitters and non-quitters were not likely related to atypical antipsychotic treatment or differences in depressive symptoms . No associations between baseline performance on CPT or SCWT and quit status were found in either group . These preliminary data suggest that in schizophrenics , neuropsychological deficits are associated with smoking cessation treatment failure",
"Nicotine replacement therapy ( NRT ) repeatedly has been shown to improve smoking treatment outcome . The major mechanism posited for this improvement in outcome is that NRT reduces nicotine craving and withdrawal . The authors tested this hypothesized mechanism of action using real-time data on craving and withdrawal , collected by ecological momentary assessment s administered on a palm-top computer . Smokers ( N = 324 ) were r and omized to receive either active high-dose ( 35 mg ) 24-hr patches or placebo . Increases in positive affect and decreases in craving , negative affect , and attention disturbance severity were related to lower risk of lapsing . Although NRT treatment did significantly decrease withdrawal and craving severity , these reductions only partially accounted for NRT 's impact on time to first lapse : The results from a mediation analysis showed that the hazard ratio for NRT , when controlling for withdrawal and craving severity , was only a third to a half lower than the uncontrolled hazard ratio for NRT alone . This suggests that other mechanisms for the effectiveness of NRT need to be examined",
"IMPORTANCE It is estimated that more than half of those with serious mental illness smoke tobacco regularly . St and ard courses of pharmacotherapeutic cessation aids improve short-term abstinence , but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy . OBJECTIVE To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with st and ard treatment . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled , parallel-group , relapse-prevention clinical trial conducted in 10 community mental-health centers . Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012 , 203 received 12-weeks ' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention . INTERVENTIONS Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were r and omly assigned to receive cognitive behavioral therapy and double-blind varenicline ( 1 mg , 2 per day ) or placebo from weeks 12 to 52 . Participants then discontinued study treatment and were followed up to week 76 . MAIN OUTCOMES AND MEASURES Seven-day rate of continuous abstinence at study week 52 , the end of the relapse-prevention phase , confirmed by exhaled carbon monoxide . Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76 , based on self-reported smoking behavior . RESULTS Sixty-one participants completed the relapse-prevention phase ; 26 discontinued participation ( 7 varenicline , 19 placebo ) and were considered to have relapsed for the analyses ; 18 of these had relapsed prior to dropout . At week 52 , point-prevalence abstinence rates were 60 % in the varenicline group ( 24 of 40 ) vs 19 % ( 9 of 47 ) in the placebo group ( odds ratio [ OR ] , 6.2 ; 95 % CI , 2.2 - 19.2 ; P continuously abstinent ( OR , 4.6 ; 95 % CI , 1.5 - 15.7 ; P = .004 ) , and from weeks 12 through 76 , 30 % ( 12 of 40 ) in the varenicline group vs 11 % ( 5 of 47 ) in the placebo group were continuously abstinent ( OR , 3.4 ; 95 % CI , 1.02 - 13.6 ; P = .03 ) . There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events . CONCLUSIONS AND RELEVANCE Among smokers with serious mental illness who attained initial abstinence with st and ard treatment , maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00621777"
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BACKGROUND Uncertainty exists regarding the efficacy and safety of using probiotics and prebiotics in preterm infants . AIM To review the evidence on the effects of administering probiotics and /or prebiotics to preterm infants . METHODS MEDLINE and the Cochrane Library were search ed in August 2008 . A supplemental search was conducted in July 2009 . Only systematic review s/meta-analyses and r and omized controlled trials ( RCTs ) that evaluated the effects of probiotics and /or prebiotics on relevant short- and long-term primarily clinical ly important health outcomes published in the English language were included . RESULTS One systematic review and 2 well-performed meta-analyses suggest that probiotics reduce the risk of necrotizing enterocolitis ( NEC ) ( stage > or = 2 ) . One subsequently published RCT reported similar results . The 2 meta-analyses also demonstrated that probiotics reduce the risk of death due to all causes , but do not have an effect on the risk of sepsis or death due to NEC . Regarding prebiotics , one meta- analysis of 4 RCTs demonstrated that prebiotic-supplemented formula increases stool colony counts of bifidobacteria and lactobacilli in preterm neonates without adversely affecting weight gain . Because of the limited data regarding synbiotics , the relationship between their use and clinical outcomes in preterm infants remains unclear . CONCLUSIONS The findings from the 2 meta-analyses of the effects of probiotic administration on the prevention of NEC show potential for such dietary supplementation . However , they must be interpreted with caution because the beneficial effects of probiotics seem to be strain specific , thus , pooling data from different strains may result in misleading conclusions . Before the routine use of probiotics and /or prebiotics in preterm infants , data regarding which products should be administered , at what dose , and for how long are needed
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"Preterm infants are prone to abnormal bacterial colonization of the intestine with ensuing adverse health effects . To examine whether the oral application of Bifidobacterium lactis Bb12 ( probiotic ) may improve selected indicators of health status in preterm infants , a double blind , placebo controlled r and omized clinical study was performed on 69 preterm infants ( Weight gain was defined as the primary outcome measure . In antibiotic-treated infants , probiotic supplementation result ed in a higher body weight compared with placebo ( p fecal pH was significantly lower than in the placebo group . The fecal concentrations of acetate and lactate were 42 and 38 % higher , respectively , in the probiotic group than in the placebo group . Fecal calprotectin was lower in the probiotic group ( p = 0.041 ) , while fecal IgA was higher in this group compared with the placebo group ( p = 0.021 )",
"BACKGROUND It is known that the bifidobacteria flora play important roles in mucosal host defense and can prevent infectious diseases . Because bacterial population s develop during the first day of life , the authors examined whether the early administration of bifidobacteria has a positive effect on the health of low birth weight infants . METHODS The effects of oral administration of Bifidobacterium breve ( B. breve ) supplements were studied in a controlled trial with low birth weight infants ( average birth weight 1489 g ) . The infants were divided into three groups : Group A and B received a dose of 1.6 x 10(8 ) cells of B. breve supplement twice a day , commencing either from several hours after birth ( group A ) or 24 h after birth ( group B ) . Group C , the control group , received no supplement . RESULTS There were no significant differences in birth weight , treatment with antibiotics , and the starting time of breast-feeding among the three groups . A Bifidobacterium-predominant flora was formed at an average of 2 weeks after birth in group A and at an average of 4 weeks after birth in group B , while no Bifidobacterium was isolated in eight out of 10 infants in group C during the observation period of 7 weeks . In comparison between group A and B , Bifidobacterium was detected significantly earlier in group A , and the number of Enterobacteriaceae present in the infants at 2 weeks after birth was significantly lower in group A. CONCLUSION The results of the present study suggest that very early administration of B. breve to low birth weight infants is useful in promoting the colonization of the Bifidobacterium and the formation of a normal intestinal flora",
"The objectives of this study were to determine whether or not the probiotic Lactobacillus GG can colonise the immature bowel of premature infants and if so , does colonisation result in a reduction of the size of the bowel reservoir of nosocomial pathogens such as enterobacteriaceae , enterococci , yeasts or staphylococci , and does colonisation with Lactobacillus GG have any effect on the clinical progress and outcome . Twenty preterm infants with a gestational age of 33 weeks or less who were resident on a neonatal unit were studied from the initiation of milk feeds until discharge . The infants were r and omised to receive either milk feeds or milk feeds supplemented with Lactobacillus GG 10(8 ) colony forming units twice a day for two weeks . The clinical features of the two groups of infants were similar . Orally administered Lactobacillus GG was well tolerated and did colonise the bowel of premature infants . However , colonisation with Lactobacillus GG did not reduce the faecal reservoir of potential pathogens and there was no evidence that colonisation had any positive clinical benefit for this particular group of infants",
"Background : The establishment of a balanced intestinal microflora which may protect against infection is desirable for the preterm infant . Objective : To investigate the effect of a preterm formula milk supplement consisting of oligosaccharides in similar proportions to human milk on the faecal flora and stool characteristics of preterm infants . Study design : To resemble the effect of human milk , an oligosaccharide mixture consisting of 90 % galacto-oligosaccharides and 10 % fructo-oligosaccharides was used to supplement a st and ard preterm formula at a concentration of 10 g/l . This supplemented formula was studied in 15 preterm infants , and the results were compared with those found in 15 infants fed a formula supplemented with maltodextrin as placebo . A group fed fortified mother 's milk was investigated as a reference group ( n = 12 ) . On four days during a 28 day feeding period ( 1 , 7 , 14 , and 28 ) , the faecal flora was investigated , and stool characteristics , growth , and possible side effects were recorded . Results : During the study period , the number of bifidobacteria in the group fed the oligosaccharide supplemented formula increased to the upper range of bifidobacteria counts in the reference group . The difference between the supplemented and non-supplemented groups was highly significant ( p = 0.0008 ) . The stool characteristics were also influenced by the supplement : the stool frequency after 28 days was significantly lower in the control group than in the oligosaccharide supplemented group ( p = 0.0079 ) and the reference group ( p stool consistency in the control group became harder , but remained fairly stable in the other two groups . There was no effect of the different diets on the incidence of side effects ( crying , regurgitation , vomiting ) or on weight gain or length gain . Conclusion : Supplementing preterm formula with a mixture of galacto- and fructo-oligosaccharides at a concentration of 10 g/l stimulates the growth of bifidobacteria in the intestine and results in stool characteristics similar to those found in preterm infants fed human milk . Therefore prebiotic mixtures such as the one studied may help to improve intestinal tolerance to enteral feeding in preterm infants",
"The study aim ed to find out whether gut colonisation of premature babies with a probiotic , Lactobacillus GG , modified enteric carbohydrate fermentation . Twenty preterm infants were r and omised to receive Lactobacillus GG 10(8 ) colony forming units twice a day for two weeks or to a control group . Faecal short chain fatty acids ( SCFAs ) , ethanol , and urinary 2,3-butanediol , were measured in parallel with microbiological studies . Lactobacillus GG colonised nine babies . From 1 - 28 days of age faecal SCFAs did not differ significantly from controls . Median and ranges were ( treated and controls , respectively ) : acetic acid : 173 ( trace-799 ) , 166 ( trace-700 ) ; propionic acid : 44 ( trace-169 ) , 37 ( 11 - 229 ) ; butyric acid : 31 ( 5 - 107 ) , 37 ( 2 - 118 ) mumol/g dry weight . Ethanol was detected in more faecal sample s from treated babies ( 65 % v 37 % ) , and at higher concentration ( 6.3 ( trace-40 ) v 3.3 ( 0.6 - 8.8 ; one 229 ) mumol/g ) . 2,3-Butanediol was found in 66 % of urine sample s from treated babies and 58 % from controls . On 83 % of these occasions Klebsiella sp , Enterobacter sp , or Serratia sp were cultured from faeces . Lactobacillus GG had no obvious adverse effects on nutritionally important SCFAs . The small increase in ethanol excretion is unlikely to have clinical significance",
"BACKGROUND Preterm infants have increased intestinal permeability which can render them susceptible to infections from enterobacteriae . OBJECTIVES The primary objective was to investigate whether probiotic administration to preterm infants decreases intestinal permeability . Secondary outcomes studied were : somatic growth , tolerance , rates of sepsis and necrotizing enterocolitis . METHODS In a prospect i ve r and omized case-control study 41 stable preterm infants of 27 to 36 weeks gestation and 34 matched comparison infants consecutively admitted to the neonatal unit were studied . The study group received a preterm formula supplemented with Bifidobacter lactis ( 2 x 10(7 ) cfu/g of dry milk ) while the control group received the same formula but without supplementation . Intestinal permeability was measured within two days of birth and then seven and thirty days later using the sugar absorption test . Additionally anthropometric parameters were recorded throughout the study as well as acceptance and tolerance of the formula . RESULTS All infants tolerated the study formula well . Median counts of stool bifidobacteria and lactulose/mannitol ratios at baseline were comparable . After 7 days of supplementation median bifidobacteria counts were significantly higher in the study group than in the control group ( p=0.0356 ) and they remained higher to the end of the study ( p at day 30=0.075 ) . The L/M ratio in the study group was significantly lower at day 30 of the study as compared to the control group ( p=0.003 ) . Head growth was significantly higher in the study group ( p=0.001 ) . CONCLUSIONS The administration of a bifidobacter supplemented infant formula decreases intestinal permeability of preterm infants and leads to increased head growth",
"AIM The intestinal flora of breast-fed infants is generally dominated by bifidobacteria which have beneficial properties . Their presence is due to various components of breast milk , including prebiotic substances . This prospect i ve double-blind study compared the numbers of bifidobacteria in the stool flora of bottle-fed preterm infants r and omized to receive for 14 days either a formula with prebiotic fructo-oligosaccharides at a concentration of 0.4 g/dL or the same formula with maltodextrin as a placebo . METHODS Within 0 - 14 days after birth , 56 healthy bottle-fed infants were enrolled to receive either the prebiotic or placebo . Faecal sample s were taken at inclusion day and at study day 7 . The number of bifidobacteria in the stools , stool characteristics and somatic growth were recorded during the study . RESULTS In the group fed fructo-oligosaccharides , both the numbers of bifidobacteria in the stools and the proportion of infants colonized with them were significantly higher as compared to the placebo group ( p=0.032 and p=0.030 respectively ) . There was also a higher number of bacteroids in the fructo-oligosaccharide group as compared to the placebo ( p=0.029 ) . At the same time , reduction was noted in the numbers of Escherichia coli and enterococci . ( p=0.029 , and p=0.025 , respectively ) . Supplementation had also significant influence on stool frequency per day ( p=0.0080 ) . CONCLUSION An infant formula containing a small quantity of prebiotic oligosaccharides is well accepted and leads to rapid growth of bifidobacteria in the gut of bottle-fed preterm infants while decreasing the numbers of pathogenic microorganisms",
"Studies were carried out on premature infants in the neonatal intensive care unit to determine the effect of feeding of lactobacilli on colonization of the gastrointestinal tract by antibiotic-resistant gram-negative enteric organisms . Thirty premature infants were matched by birth weight and gestational age , r and omized and fed double blind either lactobacilli-containing formula or non-lactobacilli-containing formula within 72 hours of delivery . The two study groups were screened weekly by culture for stool lactobacilli , for gram-negative bacteria and for antibiotic resistance of these bacteria . Lactobacilli were cultured from the stools of 13 of 15 patients receiving lactobacilli and from 3 of 15 patients not receiving lactobacilli ( P Gram-negative enteric organisms were isolated during 40 of the 86 weeks ( 47 % ) of hospitalization for patients receiving lactobacilli and during 28 of 57 weeks ( 49 % ) for patients not receiving lactobacilli . There was no significant difference between the study groups in the number of resistant organisms or in the proportion of resistant organisms per gram-negative enteric isolates ( 4 of 40 vs. 0 of 28 ) . These results suggest that facultative gram-negative enteric bacterial colonization , with either total or aminoglycoside-resistant strains , is not decreased by oral feedings of Lactobacillus acidophilus in premature infants",
"Background : It has been suggested that probiotics can reduce the overgrowth of pathogens in the bowels of preterm infants and contribute to the reduction of the incidence of nosocomial infections in neonatal intensive care units ( NICUs ) . The purpose of this study was to evaluate the effectiveness of Lactobacillus GG supplementation in reducing the incidence of urinary tract infections ( UTIs ) , bacterial sepsis and necrotizing enterocolitis ( NEC ) in preterm infants . Methods : A double-blind study was conducted in 12 Italian NICUs . Newborn infants with a gestational age were r and omized to receive st and ard milk feed supplemented with Lactobacillus GG ( Dicoflor ® , Dicofarm , Rome , Italy ) in a dose of 6 × 109 colony-forming units ( cfu ) once a day until discharge , starting with the first feed or placebo . Results : Five hundred eighty-five patients were studied . The probiotics group ( n = 295 ) and the placebo group ( n = 290 ) exhibited similar clinical characteristics . The duration of Lactobacillus GG and placebo supplementation was 47.3 ± 26.0 and 48.2 ± 24.3 days , respectively . Although UTIs ( 3.4 vs. 5.8 % ) and NEC ( 1.4 vs. 2.7 % ) were found less frequently in the probiotic group compared to the control group , these differences were not significant . Bacterial sepsis was more frequent in the probiotics group ( 4.4 % , n = 11 ) than in the placebo group ( 3.8 % , n = 9 ) , but the difference was not significant . Conclusion : Seven days of Lactobacillus GG supplementation starting with the first feed is not effective in reducing the incidence of UTIs , NEC and sepsis in preterm infants . Further studies are required to confirm our results in lower birthweight population",
"AIM To investigate whether a mixture of prebiotic non-digestible oligosaccharides ( GosFos ; referring to galacto- and fructo-oligosaccharides ) would improve feeding tolerance in preterm infants on full enteral formula feeding . We hypothesized that GosFos would : ( 1 ) reduce stool viscosity and ( 2 ) accelerate gastrointestinal transport . METHODS In a placebo-controlled double-blind trial 20 preterm infants on full enteral nutrition ( gestational age 27 ( 24 - 31 ) weeks , postnatal age 42 ( 11 - 84 ) days , and weight at study entry 1570 ( 1080 - 2300 ) g were r and omly allocated to have their feedings supplemented with either GosFos ( 1 g/100 mL ) or placebo for 14 days . Stool viscosity was measured by high-pressure capillary rheometry . Gastrointestinal transport time was assessed as the time from feeding carmine red to its appearance in the diaper . The hypotheses were tested as a priori ordered hypotheses . Data are shown as median ( range ) . RESULTS Birth weight , gestational age , postnatal age , and weight at study entry did not differ between groups . GosFos significantly reduced both stool viscosity , as measured by extrusion force ( 32 ( 2 - 67 ) versus 158 ( 24 - 314 ) N ) , and gastrointestinal transit time ( 12 ( 4 - 33 ) versus 26 ( 5 - 52 ) h ) . No adverse effects were observed . CONCLUSION Formula supplementation with GosFos reduced stool viscosity and accelerated gastrointestinal transport . Further trials are required to investigate whether GosFos facilitates enteral feeding advancement and early enteral nutrition thereby eventually reducing the incidence of catheter-related nosocomial infections and improving long-term outcome",
"BACKGROUND Colonization by C and ida species is the most important predictor of the development of invasive fungal disease in preterm neonates , and the enteric reservoir is a major site of colonization . We evaluated the effectiveness of an orally supplemented probiotic ( Lactobacillus casei subspecies rhamnosus ; Dicoflor [ Dicofarm spa ] ; 6 x 10(9 ) cfu/day ) in the prevention of gastrointestinal colonization by C and ida species in preterm , very low birth weight ( i.e. , METHODS Over a 12-month period , a prospect i ve , r and omized , blind , clinical trial that involved 80 preterm neonates with a very low birth weight was conducted in a large tertiary neonatal intensive care unit . During the first 3 days of life , the neonates were r and omly assigned to receive either an oral probiotic added to human ( maternal or pooled donors ' ) milk ( group A ) or human milk alone ( group B ) for 6 weeks or until discharge from the NICU , if the neonate was discharged before 6 weeks . On a weekly basis , specimens obtained from various sites ( i.e. , oropharyngeal , stool , gastric aspirate , and rectal specimens ) were collected from all patients for surveillance culture , to assess the occurrence and intensity of fungal colonization in the gastrointestinal tract . RESULTS The incidence of fungal enteric colonization ( with colonization defined as at least 1 positive culture result for specimens obtained from at least 1 site ) was significantly lower in group A than in group B ( 23.1 % vs. 48.8 % ; relative risk , 0.315 [ 95 % confidence interval , 0.120 - 0.826 ] ; P = .01 ) . The numbers of fungal isolates obtained from each neonate ( P = .005 ) and from each colonized patient ( P = .005 ) were also lower in group A than in group B. L. casei subspecies rhamnosus was more effective in the subgroup of neonates with a birth weight of 1001 - 1500 g. There were no changes in the relative proportions of the different C and ida strains . No adverse effects potentially associated with the probiotic were recorded . CONCLUSIONS Orally administered L. casei subspecies rhamnosus significantly reduces the incidence and the intensity of enteric colonization by C and ida species among very low birth weight neonates",
"BACKGROUND Although recent reports suggest that supplementation with probiotics may enhance intestinal function in premature infants , the mechanisms are unclear , and questions remain regarding the safety and efficacy of probiotics in extremely low-birth-weight infants . OBJECTIVE The objective was to evaluate the efficacy of probiotics on the digestive tolerance to enteral feeding in preterm infants born with a very low or extremely low birth weight . DESIGN In a bicentric , double-blind , r and omized controlled clinical trial that was stratified for center and birth weight , 45 infants received enteral probiotics ( Bifidobacterium longum BB536 and Lactobacillus rhamnosus GG ; BB536-LGG ) and 49 received placebo . The primary endpoint was the percentage of infants receiving > 50 % of their nutritional needs via enteral feeding on the 14th day of life . A triangular test was used to perform sequential analysis . RESULTS The trial was discontinued after the fourth sequential analysis concluded a lack of effect . The primary endpoint was not significantly different between the probiotic ( 57.8 % ) and placebo ( 57.1 % ) groups ( P = 0.95 ) . However , in infants who weighed > 1000 g , probiotic supplementation was associated with a shortening in the time to reach full enteral feeding ( P = 0.04 ) . Other than colonization by the probiotic strains , no alteration in the composition of intestinal microbiota or changes in the fecal excretion of calprotectin was observed . No colonization by probiotic strains was detected in infants who weighed gastrointestinal tolerance to enteral feeding in very-low-birth-weight infants but may improve gastrointestinal tolerance in infants weighing > 1000 g. This trial was registered at clinical trials.gov as NCT 00290576",
"AIM To investigate the colonisation withBifidobacterium breve of the bowels of very low birthweight ( VLBW ) infants . METHODS The adverse effects of B breve were examined in 66 VLBW infants ( preliminary study ) . A prospect i ve r and omised clinical study of 91 VLBW infants was also completed and these infants were followed up for three years . Precise viable bacterial counts of serial stool specimens were examined for the first eight weeks after birth in 10 infants . The colonisation rates of administered bacteria were examined using immunohistochemical staining of stool specimens with a B breve specific monoclonal antibody . RESULTS In the preliminary study there were no side effects attributable to the bacteria . Immunohistochemical staining of stool specimens showed that the colonisation rates of the administered bacteria were 73 % at 2 weeks of age , but only 12 % in the control group . Early administration of B brevesignificantly decreased aspirated air volume from the stomach and improved weight gain . CONCLUSIONS B breve can colonise the immature bowel very effectively and is associated with fewer abnormal abdominal signs and better weight gain in VLBW infants , probably as a result of stabilisation of their intestinal flora and accelerated feeding schedules",
"This article by the ESPGHAN Committee on Nutrition summarizes available information on the effects of adding prebiotic oligosaccharides to infant and follow-on formulae . Currently there are only limited studies evaluating prebiotic substances in dietetic products for infants . Although administration of prebiotic oligosaccharides has the potential to increase the total number of bifidobacteria in feces and may also soften stools , there is no published evidence of clinical benefits of adding prebiotic oligosaccharides to dietetic products for infants . Data on oligosaccharide mixtures in infant formulae do not demonstrate adverse effects , but further evaluation is recommended . Combinations and dosages in addition to those so far studied need to be fully evaluated with respect to both safety and efficacy before their use in commercial infant food products . Well- design ed and carefully conducted r and omized controlled trials with relevant inclusion /exclusion criteria , adequate sample sizes and vali date d clinical outcome measures are needed both in preterm and term infants . Future trials should define optimal quantity and types of oligosaccharides with prebiotic function , optimal dosages and duration of intake , short and long term benefits and safety . At the present time , therefore , the Committee takes the view that no general recommendation on the use of oligosaccharide supplementation in infancy as a prophylactic or therapeutic measure can be made",
"The aim of this double-blind , r and omized , placebo-controlled study was to evaluate the effect of a prebiotic mixture on gastric motility in preterm newborns . After a feeding period of 15 days , gastric electrical activity was measured by electrogastrography , and the gastric emptying time was studied by ultrasound technique . No difference was seen in the daily increase of body weight , and no adverse events have been reported . The percentage of time in which propagation was detected in the electrogastrography signal was twice in newborns receiving formula with prebiotics with respect to placebo , and the gastric half-emptying time was 30 % faster in the prebiotic group than the placebo group . Prebiotic oligosaccharides can modulate the electrical activity and the gastric emptying and may improve the intestinal tolerance of enteral feeding in preterm infants",
"OBJECTIVE To investigate the effect of dietary supplementation with a probiotic on feeding tolerance and gastrointestinal motility in healthy formula-fed preterm infants . STUDY DESIGN Thirty preterm newborns were enrolled ; 10 were exclusively breast-fed , and the remaining 20 were r and omly assigned in a double-blind manner to receive either Lactobacillus reuteri ATCC 55730 ( at dose of 1 x 10(8 ) colony forming units a day ) or placebo for 30 days . Clinical symptoms of gastrointestinal function ( regurgitation , vomiting , inconsolable crying , and evacuation ) and physiological variables ( gastric electrical activity and emptying ) were recorded before and after the dietary intervention . RESULTS Body weight gains per day were similar for the 3 groups , and no adverse events were recorded . Newborns receiving probiotics showed a significant decrease in regurgitation and mean daily crying time and a larger number of stools compared with those given placebo . Gastric emptying rate was significantly increased , and fasting antral area was significantly reduced in both the newborns receiving L. reuteri and breast-fed newborns compared with placebo . CONCLUSIONS Our results suggest a useful role for L. reuteri supplementation in improving feeding tolerance and gut function in formula-fed preterm newborns"
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BACKGROUND Angiotensin converting enzyme inhibitors ( ACE inhibitors ) and angiotensin receptor blockers ( ARBs ) are widely prescribed for primary hypertension ( systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg ) . However , while ACE inhibitors have been shown to reduce mortality and morbidity in placebo-controlled trials , ARBs have not . Therefore , a comparison of the efficacies of these two drug classes in primary hypertension for preventing total mortality and cardiovascular events is important . OBJECTIVES To compare the effects of ACE inhibitors and ARBs on total mortality and cardiovascular events , and their rates of withdrawals due to adverse effects ( WDAEs ) , in people with primary hypertension . SEARCH METHODS We search ed the Cochrane Hypertension Group Specialized Register , the Cochrane Central Register of Controlled Trials ( CENTRAL ) , MEDLINE , EMBASE , the World Health Organization ( WHO ) International Clinical Trials Registry Platform , and the ISI Web of Science up to July 2014 . We contacted study authors for missing and unpublished information , and also search ed the reference lists of relevant review s for eligible studies . SELECTION CRITERIA We included r and omized controlled trials enrolling people with uncontrolled or controlled primary hypertension with or without other risk factors . Included trials must have compared an ACE inhibitor and an ARB in a head-to-head manner , and lasted for a duration of at least one year . If background blood pressure lowering agents were continued or added during the study , the protocol to do so must have been the same in both study arms . DATA COLLECTION AND ANALYSIS We used st and ard method ological procedures expected by The Cochrane Collaboration . MAIN RESULTS Nine studies with 11,007 participants were included . Of the included studies , five reported data on total mortality , three reported data on total cardiovascular events , and four reported data on cardiovascular mortality . No study separately reported cardiovascular morbidity . In contrast , eight studies contributed data on WDAE . Included studies were of good to moderate quality . There was no evidence of a difference between ACE inhibitors and ARBs for total mortality ( risk ratio ( RR ) 0.98 ; 95 % confidence interval ( CI ) 0.88 to 1.10 ) , total cardiovascular events ( RR 1.07 ; 95 % CI 0.96 to 1.19 ) , or cardiovascular mortality ( RR 0.98 ; 95 % CI 0.85 to 1.13 ) . Conversely , a high level of evidence indicated a slightly lower incidence of WDAE for ARBs as compared with ACE inhibitors ( RR 0.83 ; 95 % CI 0.74 to 0.93 ; absolute risk reduction ( ARR ) 1.8 % , number needed to treat for an additional beneficial outcome ( NNTB ) 55 over 4.1 years ) , mainly attributable to a higher incidence of dry cough with ACE inhibitors . The quality of the evidence for mortality and cardiovascular outcomes was limited by possible publication bias , in that several studies were initially eligible for inclusion in this review , but had no extractable data available for the hypertension subgroup . To this end , the evidence for total mortality was judged to be moderate , while the evidence for total cardiovascular events was judged to be low by the GRADE approach . AUTHORS ' CONCLUSIONS Our analyses found no evidence of a difference in total mortality or cardiovascular outcomes for ARBs as compared with ACE inhibitors , while ARBs caused slightly fewer WDAEs than ACE inhibitors . Although ACE inhibitors have shown efficacy in these outcomes over placebo , our results can not be used to extrapolate the same conclusion for ARBs directly , which have not been studied in placebo-controlled trials for hypertension . Thus , the substitution of an ARB for an ACE inhibitor , while supported by evidence on grounds of tolerability , must be made in consideration of the weaker evidence for the efficacy of ARBs regarding mortality and morbidity outcomes compared with ACE inhibitors . Additionally , our data mostly derives from participants with existing clinical sequelae of hypertension , and it would be useful to have data from asymptomatic people to increase the generalizability of this review . Unpublished subgroup data of hypertensive participants in existing trials comparing ACE inhibitors and ARBs needs to be made available for this purpose
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"OBJECTIVES The CORD trials tested ramipril and losartan in patients with hypertension . PATIENTS AND METHODS CORD IA involving switching from an angiotensin-converting enzyme inhibitor ( ACEI ) to the angiotensin II receptor blocker ( ARB ) losartan . 4,016 patients with blood pressure ( BP ) 3 months were enrolled . The mean age was 62.6 + /- 11.6 years and 53.1 % were women . The patients discontinued ACEI and switched to losartan 50 mg once daily . BP , heart rate , biochemistry , blood counts and ECGs were measured at day 1 and months 1 , 3 , 6 and 12 . If the BP was > or = 140/90 mm Hg after 1 month or more , the dose of losartan was increased to 100 mg . After 1 month the BP decreased from 147.4 + /- 14.8/87.7 + /- 9.3 mm Hg to 139.7 + /- 11.8/83.0 + /- 9.3 mm Hg ( p rate of adverse events did not significantly increase and no changes in plasma sodium , potassium , urea or creatinine were observed . CORD IB compared ramipril and losartan . 3,813 patients with BP > or = 140/90 mm Hg who were not being treated with an ACEI or ARB were enrolled . The mean age was 60.5 + /- 12.2 years and 50.5 % were women . The patients were r and omised to ramipril 5 mg ( n = 1,926 ) or losartan 50 mg ( n = 1,887 ) . The dose was doubled if BP after 1 month was > or = 140/90 mm Hg . If the BP after 3 months still was > or = 140/90 mm Hg , another antihypertensive drug was added , typically athiazide diuretic . RESULTS After 1 yearthe BP decreased in the ramipril group from 155.9 + /- 13.1/93.0 + /- 8.9 mm Hg to 134.1 + /- 11.2/81.5 + /- 6.8 mm Hg ( p losartan group from 156.5 + /- 13.1/93.4 + /- 8.8 to 134.55 + /- 11.3/80.16 + /- 6.6 mm Hg ( p significant differences were found between the groups . A slight increase in plasma potassium ( 0.2 mmol in both groups ) and urea ( 0.3 mmol in both groups ) was observed , but no change in plasma creatinine . There was a small , insignificant decrease in plasma uric acid ( in the ramipril group from 325.5 to 320.7 micromol/l and in the losartan group from 321.6 to 318.3 micromol/l ) and a slight decrease in plasma glucose and triglycerides ( 0.2 mmol/l in both measures in both groups ) . No severe adverse events were observed , but dry cough was 8 times more frequently reported in the ramipril group . CONCLUSION CORD IA confirmed that switching from an ACEI to losartan is safe and effective . Titrating the dose upwards or adding diuretics leads to good BP control in the majority of patients ( 2/3 ) . CORD IB showed no differences between ramipril and losartan in lowering BP and both drugs showed a trend to improve metabolic parameters such as glycaemia , triglyceridaemia and uric acid equally . Dry cough was more frequent after ACEI",
"BACKGROUND This study compared the effect of antihypertensive treatment with valsartan or ramipril on atrial fibrillation ( AF ) recurrence , on P-wave dispersion , ( PWD ) and on serum procollagen type I carboxy terminal peptide ( PIP ) . METHODS A total of 369 mild hypertensive ( systolic blood pressure ( SBP ) > 140 and /or 90 valsartan ( n = 122 ) , ramipril ( n = 124 ) , or amlodipine ( n = 123 ) for 1 year . Clinic blood pressure ( BP ) and a 24-h electrocardiogram ( ECG ) were evaluated monthly . Patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible . PWD and serum PIP levels were evaluated before and after each treatment period . RESULTS SBP and DBP were significantly reduced by the three treatments ( P amlodipine had a recurrence of AF as did 26 ( 27.9 % ) patients treated with ramipril ( P amlodipine ) and 16 ( 16.1 % ) patients treated with valsartan ( P amlodipine and P ramipril ) . The Kaplan-Meyer analysis showed a significant reduction of AF episodes in the valsartan group ( P = 0.005 log-rank test ) as well as in the ramipril group ( P = 0.021 ) , even if at a lesser degree . PWD values were significantly reduced by ramipril ( -4.2 ms , P valsartan ( -11.2 ms , P Serum PIP levels were reduced by ramipril ( -49.7 microg , P valsartan ( -49.3 microg , P ramipril were more effective than amlodipine in preventing new episodes of AF , but the effect of valsartan was greater than that of ramipril . This could be related to the greater PWD reduction observed with valsartan",
"BACKGROUND Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme ( ACE ) inhibitors in persons with type 2 diabetes . METHODS In this prospect i ve , multicenter , double-blind , five-year study , we r and omly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan ( 80 mg daily , in 120 subjects ) or the ACE inhibitor enalapril ( 20 mg daily , in 130 subjects ) . The primary end point was the change in the glomerular filtration rate ( determined by measuring the plasma clearance of iohexol ) between the baseline value and the last available value during the five-year treatment period . Secondary end points included the annual changes in the glomerular filtration rate , serum creatinine level , urinary albumin excretion , and blood pressure ; the rates of end-stage renal disease and cardiovascular events ; and the rate of death from all causes . RESULTS After five years , the change in the glomerular filtration rate was -17.5 ml per minute per 1.73 m2 ( where the minus sign denotes a decrement ) in the telmisartan-treated subjects , as compared with -15.0 ml per minute per 1.73 m2 in the enalapril-treated subjects ; the treatment difference was thus -2.6 ml per minute per 1.73 m2 ( 95 percent confidence interval , -7.1 to 2.0 ml per minute per 1.73 m2)[corrected ] The lower boundary of the confidence interval , in favor of enalapril , was greater than the predefined margin of -10.0 ml per minute per 1.73 m2 , indicating that telmisartan was not inferior to enalapril . The effects of the two agents on the secondary end points were not significantly different after five years . CONCLUSIONS Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes . These findings do not necessarily apply to persons with more advanced nephropathy , but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events",
"Angiotensin-converting enzyme ( ACE ) inhibitors have favourable effects on hypertension and diabetic nephropathy , but persistent use may result in incomplete blockade of the renin-angiotensin system . Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker ( ARB ) telmisartan on blood pressure and albumin excretion rate ( AER ) were evaluated . Patients with type 2 diabetes mellitus , hypertension ( systolic blood pressure [ SBP ] > or=140 mmHg or diastolic blood pressure [ DBP ] > or=90 mmHg ) and microalbuminuria ( AER 30 - 300 mg/24h ) received 20 mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks . Patients were then r and omised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks . Significant ( P SBP ( 11.1 mmHg versus 10.0 mmHg ) , DBP ( 5.6 mmHg versus 5.3 mmHg ) and AER ( 98 mg/24 h versus 80 mg/24 h ) were achieved with lisinopril ( n=95 ) or telmisartan ( n=97 ) , respectively , after 24 weeks . Subsequent treatment with lisinopril plus telmisartan for 28 weeks result ed in further significant reductions ( P SBP , DBP and AER compared with either monotherapy . All treatments were well tolerated . Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy . We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes , hypertension and microalbuminuria",
"Background : Although heart failure with a preserved or normal ejection fraction ( HFNEF or diastolic heart failure ) is common , treatment outcomes on quality of life and cardiac function are lacking . The effect of renin – angiotensin blockade by irbesartan or ramipril in combination with diuretics on quality of life ( QoL ) , regional and global systolic and diastolic function was assessed in HFNEF patients . Methods : 150 patients with HFNEF ( LVEF > 45 % ) were r and omised to ( 1 ) diuretics alone , ( 2 ) diuretics plus irbesartan , or ( 3 ) diuretics plus ramipril . QoL , 6-minute walk test ( 6MWT ) and Doppler echocardiography were performed at baseline , 12 , 24 and 52 weeks . Results : The QoL score improved similarly in all three groups by 52 weeks ( −46 % , 51 % , and 50 % respectively , all p although 6MWT increased only slightly ( average + 3–6 % ) . Recurrent hospitalisation rates were equal in all groups ( 10–12 % in 1 year ) . At 1 year , LV dimensions or LVEF had not changed in any group , though both systolic and diastolic blood pressures were lowered in all three groups from 4 weeks onwards . At baseline both mean peak systolic ( Sm ) and early diastolic ( Em ) mitral annulus velocities were reduced , and increased slightly in the diuretic plus irbesartan ( Sm 4.5 ( SEM 0.17 ) to 4.9 ( SEM 0.16 ) cm/sec ; Em 3.8 ( SEM 0.25 ) to 4.2 ( SEM 0.25 ) cm/sec ) and ramipril ( Sm 4.5 ( SEM 0.24 ) to 4.9 ( SEM 0.20 ) cm/sec ; Em 3.3 ( SEM 0.25 ) to 4.04 ( SEM 0.32 ) cm/sec ) groups ( both p were raised at baseline ( 595 ( SD 905 ) pg/ml ; range 5–4748 ) and fell in the irbesartan ( −124 ( SD 302 ) pg/ml , p = 0.01 ) and ramipril ( −173 ( SD 415 ) pg/ml , p = 0.03 ) groups only . Conclusions : In this typically elderly group of HF patients with normal LVEF , diuretic therapy significantly improved symptoms and neither irbesartan nor ramipril had a significant additional effect . However , diuretics in combination with irbesartan or ramipril marginally improved LV systolic and diastolic longitudinal LV function , and lowered NT-proBNP over 1 year",
"BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure , angiotensin-converting-enzyme ( ACE ) inhibitors reduce mortality and morbidity from cardiovascular causes , but the role of angiotensin-receptor blockers ( ARBs ) in such patients is unknown . We compared the ACE inhibitor ramipril , the ARB telmisartan , and the combination of the two drugs in patients with vascular disease or high-risk diabetes . METHODS After a 3-week , single-blind run-in period , patients underwent double-blind r and omization , with 8576 assigned to receive 10 mg of ramipril per day , 8542 assigned to receive 80 mg of telmisartan per day , and 8502 assigned to receive both drugs ( combination therapy ) . The primary composite outcome was death from cardiovascular causes , myocardial infa rct ion , stroke , or hospitalization for heart failure . RESULTS Mean blood pressure was lower in both the telmisartan group ( a 0.9/0.6 mm Hg greater reduction ) and the combination-therapy group ( a 2.4/1.4 mm Hg greater reduction ) than in the ramipril group . At a median follow-up of 56 months , the primary outcome had occurred in 1412 patients in the ramipril group ( 16.5 % ) , as compared with 1423 patients in the telmisartan group ( 16.7 % ; relative risk , 1.01 ; 95 % confidence interval [ CI ] , 0.94 to 1.09 ) . As compared with the ramipril group , the telmisartan group had lower rates of cough ( 1.1 % vs. 4.2 % , P angioedema ( 0.1 % vs. 0.3 % , P=0.01 ) and a higher rate of hypotensive symptoms ( 2.6 % vs. 1.7 % , P rate of syncope was the same in the two groups ( 0.2 % ) . In the combination-therapy group , the primary outcome occurred in 1386 patients ( 16.3 % ; relative risk , 0.99 ; 95 % CI , 0.92 to 1.07 ) ; as compared with the ramipril group , there was an increased risk of hypotensive symptoms ( 4.8 % vs. 1.7 % , P syncope ( 0.3 % vs. 0.2 % , P=0.03 ) , and renal dysfunction ( 13.5 % vs. 10.2 % , P CONCLUSIONS Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema . The combination of the two drugs was associated with more adverse events without an increase in benefit . ( Clinical Trials.gov number , NCT00153101 [ Clinical Trials.gov ] . )",
"We planned a r and omized , double blind clinical trial to evaluate whether an antihypertensive intervention at the proximal or distal level of the renin – angiotensin – aldosterone system could have different effects on a broad range of innovative cardiovascular risk biomarkers . A total of 288 hypertensive Caucasian patients ( 115 men and 113 women ) , aged ⩾18 years , were enrolled in this study . They were r and omized to take losartan 50 mg per day or ramipril 5 mg per day for 1 month and titrated up to 100 mg per day and 10 mg per day for 13 months , respectively . At baseline , 1 , 2 and 14 months after therapy initiation , we evaluated the following parameters : body weight , body mass index ( BMI ) , systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , fasting plasma glucose ( FPG ) , M-value , adiponectin ( ADN ) , resistin ( r ) , retinol binding protein-4 ( RBP-4 ) , visfatin , vaspin , high-sensitivity C-reactive protein ( Hs-CRP ) , matrix metalloproteinase-2 ( MMP-2 ) and matrix metalloproteinase-9 ( MMP-9 ) . No variation of body weight , BMI , FPG or vaspin was obtained with either treatment . We recorded a similar improvement in SBP , DBP and Hs-CRP with both treatments ; however , losartan also increased M-value , ADN and visfatin , whereas ramipril did not . Furthermore , losartan decreased r , RBP-4 , MMP-2 and MMP-9 , whereas ramipril did not have any effect on these parameters . In conclusion , we observed that short-term treatment with losartan improved several metabolic parameters ( M-value , ADN , RBP-4 , r and visfatin ) and decreased vascular remodeling biomarkers ( MMP-2 and MMP-9 ) in hypertensive subjects , whereas ramipril did not",
"Introduction P-wave dispersion ( PWD ) has been shown to be a non-invasive electrocardiographic predictor for development of atrial fibrillation ( AF ) . Thus , it may be possible to attenuate AF risk through improvement of PWD . In this study , we compared the effects of an angiotensin-converting enzyme ( ACE ) inhibitor , quinapril , and an angiotensin receptor blocker ( ARB ) , irbesartan , on PWD . Methods A total of 38 newly diagnosed hypertensive patients were enrolled in the study . The patients were r and omly assigned to receive treatment with either irbesartan ( 150–300 mg ) or quinapril ( 20–40 mg ) . P-wave duration s and PWD were measured at baseline and after 6 and 12 months of treatment . Echocardiographic examinations were performed at baseline and after 12 months of treatment . Results Both drugs significantly reduced blood pressure to a similar degree ( P . Deceleration time ( both P and isovolumetric relaxation time ( both P=0.007 ) were also significantly reduced , whereas there was no significant change in the early diastolic flow/atrial contraction signal ratio . Both irbesartan and quinapril significantly decreased maximum P-wave duration ( Pmax ) ( P and PWD ( from 68.0±22.1 to 41.0±25.1 msec for irbesartan , and from 70.5±20.4 to 46.6±13.3 msec for quinapril ; both P ) . Baseline and follow-up blood pressure , heart rate , echocardiographic findings , and P-wave values were not significantly different between the irbesartan and quinapril groups . No patient developed AF during follow-up . There was no significant correlation between PWD and blood pressure or diastolic function parameters . Conclusion Antihypertensive treatment with either irbesartan or quinapril is associated with significant reductions in Pmax and PWD ",
"Persistence on treatment affects the efficacy of antihypertensive treatment . We prospect ively investigated the persistence on therapy and the extent of blood pressure ( BP ) control in 347 hypertensive patients ( age 59.4 ± 6 years ) r and omly allocated to a first-line treatment with : angiotensin-converting enzyme ( ACE ) inhibitors , calcium-channel blockers ( CCBs ) , ß-blockers , angiotensin-II receptor blockers ( ARBs ) , or diuretics and followed-up for 24-months . Persistence on treatment was higher in patients treated with ARBs ( 68.5 % ) and ACE inhibitors ( 64.5 % ) vs CCBs ( 51.6 % ; p diuretics ( 34.4 % , p ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher persistence in therapy compared with the other molecules used in each therapeutic class . The rate of persistence was significantly higher in patients treated with lercanidipine vs others CCBs ( 59.3 % vs 46.6 % , p was decreased more successfully in patients treated with ARBs ( −11.2/−5.8 mmHg ) , ACE inhibitors ( −10.5/−5.1 mmHg ) , and CCBs ( −8.5/−4.6 mmHg ) compared with ß-blockers ( −4.0/−2.3 mmHg p diuretics ( −2.3/−2.1 mmHg , p , ACE inhibitor , β-blocker , or diuretic was associated with a higher BP control compared with the other molecules used in each therapeutic class . A trend toward a better BP control was observed in response to lercanidipine vs other CCBs ( p = 0.059 ) . The present results confirm the importance of persistence on treatment for the management of hypertension in clinical practice",
"BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors reduce mortality , myocardial infa rct ion , stroke , heart failure , need for revascularization , nephropathy , and diabetes and its complications . Although angiotensin-II receptor blockers ( ARBs ) have been less extensively evaluated , theoretically they may have \" protective \" effects similar to those of ACE inhibitors , but with better tolerability . Currently , there is uncertainty about the role of ARBs when used alone or in combination with an ACE inhibitor in high-risk population s with controlled hypertension . OBJECTIVES Primary objectives of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial ( ONTARGET ) are to determine if the combination of the ARB telmisartan and the ACE inhibitor ramipril is more effective than ramipril alone , and if telmisartan is at least as effective as ramipril . The Telmisartan R and omized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease ( TRANSCEND ) will determine if telmisartan is superior to placebo in patients who are intolerant of ACE inhibitors . The primary outcome for both trials is the composite of cardiovascular death , myocardial infa rct ion , stroke , or hospitalization for heart failure . METHOD High-risk patients with coronary , peripheral , or cerebrovascular disease or diabetes with end-organ damage are being recruited and followed for 3.5 to 5.5 years in 2 parallel , r and omized , double-blind clinical trials . PROGRESS Recruitment from 730 centers in 40 countries for ONTARGET ( n = 25,620 ) was completed in July 2003 . For TRANSCEND , 5776 patients ( out of a projected total of 6000 ) have been recruited ( by May 10 , 2004 ) . Baseline patient characteristics are comparable to the Heart Outcomes Prevention Evaluation ( HOPE ) trial , the basis of the design of the current study , confirming that patients are at high-risk",
"Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus ( NIDDM ) . However , no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM . Therefore , we have investigated the effect of an angiotensin-converting enzyme inhibitor , enalapril , and a highly selective angiotensin receptor blocker , c and esartan cilexetil , on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM . Eight patients were treated with c and esartan ( 8 to 16 mg per day ) and 7 with enalapril ( 10 to 20 mg per day ) for 1 year . Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment . Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated ; moreover , endothelium-dependent vasodilation to acetylcholine was assessed . A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs . Vascular collagen content was reduced and metalloproteinase-9 was increased by c and esartan , but not by enalapril . Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen . The 2 drugs equally improved endothelial function . In conclusion , antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct , at least in part , alterations in small resistance artery structure in hypertensive patients with NIDDM . C and esartan may be more effective than enalapril in reducing collagen content in the vasculature",
"We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide , c and esartan or lisinopril on urinary albumin excretion , endothelial function and inflammatory activity in hypertensive type II diabetic individuals . A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a r and omized , double-blind , double-dummy design . Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10 % with a diastolic pressure below 85 mmHg . After titration , patients were treated for 12 months . Mean blood pressures changed from 157/93 , 151/94 and 149/93 at baseline to 135/80 , 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide ( n=24 ) , c and esartan ( n=24 ) and lisinopril ( n=22 ) groups . About 70 % reached target blood pressures . However , only 45 % had blood pressures 130/85 mmHg . Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased ( GEE regression coefficients , −2.40 mg/24 h ( P but brachial artery endothelium-dependent and -independent vasodilation and levels of von Willebr and factor and C-reactive protein did not change ( GEE regression coefficients , 0.21 mm ( P=0.07 ) , 0.04 mm ( P=0.43 ) , 0.04 IU/ml ( P=0.33 ) and −1.15 mg/l ( P=0.64 ) ) . No differences in outcome variables between treatment groups were observed . These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult . Aggressive antihypertensive therapy can improve urinary albumin excretion , endothelial function and inflammatory activity in hypertensive type II diabetic individuals , regardless of the type of antihypertensive therapy used",
"The Renoprotection of Optimal Antiproteinuric Doses ( ROAD ) study was performed to determine whether titration of benazepril or losartan to optimal antiproteinuric doses would safely improve the renal outcome in chronic renal insufficiency . A total of 360 patients who did not have diabetes and had proteinuria and chronic renal insufficiency were r and omly assigned to four groups . Patients received open-label treatment with a conventional dosage of benazepril ( 10 mg/d ) , individual uptitration of benazepril ( median 20 mg/d ; range 10 to 40 ) , a conventional dosage of losartan ( 50 mg/d ) , or individual uptitration of losartan ( median 100 mg/d ; range 50 to 200 ) . Uptitration was performed to optimal antiproteinuric and tolerated dosages , and then these dosages were maintained . Median follow-up was 3.7 yr . The primary end point was time to the composite of a doubling of the serum creatinine , ESRD , or death . Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease . Compared with the conventional dosages , optimal antiproteinuric dosages of benazepril and losartan that were achieved through uptitration were associated with a 51 and 53 % reduction in the risk for the primary end point ( P = 0.028 and 0.022 , respectively ) . Optimal antiproteinuric dosages of benazepril and losartan , at comparable BP control , achieved a greater reduction in both proteinuria and the rate of decline in renal function compared with their conventional dosages . There was no significant difference for the overall incidence of major adverse events between groups that were given conventional and optimal dosages in both arms . It is concluded that uptitration of benazepril or losartan against proteinuria conferred further benefit on renal outcome in patients who did not have diabetes and had proteinuria and renal insufficiency",
"OBJECTIVES The goal of this study was to compare myocardial perfusion reserve ( MPR ) before and after long-term treatment with lisinopril and losartan in patients with hypertension and left ventricular hypertrophy ( LVH ) . BACKGROUND Studies have suggested that treatment with angiotensin-converting enzyme inhibitors ( ACEIs ) improves MPR in patients with hypertension by potentiating endogenous bradykinins . Because angiotensin receptor blockers ( ARBs ) lack a direct effect on bradykinins , we hypothesized that they may not improve MPR . METHODS We measured pre- and post-treatment myocardial blood flow ( MBF ) by positron emission tomography in 17 patients ( lisinopril : 9 patients , losartan : 8 patients ) with hypertension and LVH at baseline and after coronary vasodilation with intravenous dipyridamole . In addition , we measured rest and hyperemic blood flow in eight normotensive controls . RESULTS Post-treatment maximal coronary blood flow and MPR in the lisinopril group increased significantly compared with pretreatment values ( 3.5 + /- 1.2 vs. 2.6 + /- 1.1 ml/min/g , p = 0.02 ; 3.7 + /- 1.1 vs. 2.4 + /- 1 ml/min/g , respectively , p = 0.002 , respectively ) . Post-treatment hyperemic flow in the patients treated with lisinopril was not significantly different from corresponding measurements in controls ( 3.5 + /- 1.2 vs. 3.9 + /- 1 ml/min/g , respectively , p = NS ) . In the patients treated with losartan , there was no difference between pre- and post-treatment MBF values and MPR . CONCLUSIONS Myocardial perfusion reserve and maximal coronary flow improved in asymptomatic patients with hypertension-induced LVH after long-term treatment with lisinopril but not with losartan . Thus , ACEIs , but not ARBs , might be effective in repairing the coronary microangiopathy associated with hypertension-induced LVH",
"A total of 501 elderly patients with essential hypertension were r and omized to receive valsartan or lisinopril in this one year multi-center , double-blind , parallel group trial . Patients received valsartan 40 mg ( n = 334 ) or lisinopril 2.5 mg ( n = 167 ) daily for 2 weeks with subsequent titration ( alone or in combination with hydroclorothiazide ) , depending on response to treatment . The primary efficacy variable was the percentage of patients with a response , defined as sitting diastolic blood pressure drop of > or = 10 mmHg from baseline . A high percentage of patients responded to treatment in both valsartan and lisinopril groups : 80 % for both groups at 12 weeks and 81 % and 87 % , respectively , at 52 weeks with no statistically significant difference between treatments ( 12 weeks , p = 0.925 ; 52 weeks , p = 0.148 ) . More patients on lisinopril experienced drug-related cough ( 7.5 % on valsartan , 17.4 % on lisinopril ) . In 5.4 % of lisinopril treated patients , cough led to discontinuation of therapy compared to 0.6 % on valsartan . Valsartan 80 mg daily provides comparable short and long-term antihypertensive efficacy to lisinopril in elderly patients with a lower incidence of drug-related cough",
"Abstract We compared the efficacy of treatment protocol s with an angiotensin converting enzyme ( ACE ) inhibitor alone ( enalapril , 5 mg ) or angiotensin II ( ATII ) receptor blocker ( losartan , 50 mg ) or both enalapril plus losartan in patients with microalbuminuria in a prospect i ve , r and omized clinical trial . Normotensive type 2 diabetic patients with microalbuminuria documented by at least 3 consecutive urinary albumin excretion analyses were recruited for the study . Patients were grouped r and omly into one of the protocol s which consisted of treatment with 5 mg enalapril daily ( group 1 ; n=12 ) , 50 losartan daily ( group 2 ; n=12 ) or both drugs ( group 3 ; n=10 ) . They were reevaluated with regard to HbA1c levels , lipid profiles , blood pressure and urinary albumin excretion rates ( UAER ) at 3-month intervals for 12 months . Mean age , duration of diabetes , body mass index , plasma lipid profiles and blood pressure levels were similar at the initial visit . In group 1 , UAER returned to normal levels in 10 patients . Normalization of UAER occurred in 8 and 7 patients in groups 2 and 3 , respectively . Percentage of reduction in UAERs at the end of 12 months were 58 % , 59 % and 60 % ( p=0.0001 ; p=0.0002 ; p=0.0003 , respectively ) . The amount of reduction in UAER did not differ significantly among the three groups ( p=0.346 ) . ACE inhibitors and angiotensin II receptor blockers have similar efficacy in treating diabetic microalbuminuria , and the combination of the two drugs does not add any further benefit",
"BACKGROUND ACE inhibitors attenuate the detrimental effects of angiotensin II , and improve survival and reduce morbidity in patients with acute myocardial infa rct ion and evidence of heart failure or left-ventricular dysfunction . Selective antagonism of the angiotensin type 1 receptor represents an alternative approach to inhibition of the renin-angiotensin system . We did a multicentre , r and omised trial to test the hypothesis that the angiotensin II antagonist losartan would be superior or non-inferior to the ACE inhibitor captopril in decreasing all-cause mortality in high-risk patients after acute myocardial infa rct ion . METHODS 5477 patients 50 years of age or older ( mean age 67.4 years [ SD 9.8 ] ) , with confirmed acute myocardial infa rct ion and heart failure during the acute phase or a new Q-wave anterior infa rct ion or reinfa rct ion , were recruited from 329 centres in seven European countries . Patients were r and omly assigned and titrated to a target dose of losartan ( 50 mg once daily ) or captopril ( 50 mg three times daily ) as tolerated . The primary endpoint was all-cause mortality . Analysis was by intention to treat . FINDINGS There were 946 deaths during a mean follow-up of 2.7 ( 0.9 ) years : 499 ( 18 % ) in the losartan group and 447 ( 16 % ) in the captopril group ( relative risk 1.13 [ 95 % CI 0.99 - 1.28 ] , p=0.07 ) . The results for the secondary and tertiary endpoints were as follows : sudden cardiac death or resuscitated cardiac arrest 239 ( 9 % ) versus 203 ( 7 % ) , 1.19 ( 0.98 - 1.43 ) , p=0.07 , and fatal or non-fatal reinfa rct ion 384 ( 14 % ) versus 379 ( 14 % ) , 1.03 ( 0.89 - 1.18 ) , p=0.72 . The all-cause hospital admission rates were 1806 ( 66 % ) versus 1774 ( 65 % ) , 1.03 ( 0.97 - 1.10 ) , p=0.37 . Losartan was significantly better tolerated than captopril , with fewer patients discontinuing study medication ( 458 [ 17 % ] vs 624 [ 23 % ] , 0.70 [ 0.62 - 0.79 ] , p total mortality in favour of captopril , ACE inhibitors should remain first-choice treatment in patients after complicated acute myocardial infa rct ion . Losartan can not be generally recommended in this population . However , it was better tolerated than captopril , and was associated with significantly fewer discontinuations . Although the role of losartan in patients intolerant of ACE inhibition is not clearly defined , it can be considered in such patients",
"In this study , telmisartan , a new angiotensin AT ( 1 ) receptor antagonist given as monotherapy and in combination with hydrochlorothiazide ( HCTZ ) , was compared with lisinopril as monotherapy and in combination with HCTZ . This 52-week , r and omized , multicenter , double-blind , double-dummy , parallel-group , dose-titration study of 578 patients with mild-to-moderate essential hypertension ( mean diastolic blood pressure [ DBP ] , > /=95 mm Hg ) , compared the efficacy and safety of telmisartan ( n = 385 ) with lisinopril ( n = 193 ) . Dosage could be increased for both telmisartan ( 40 -- > 80 -- > 160 mg ) and lisinopril ( 10 -- > 20 -- > 40 mg ) at each of the first 2 monthly visits if DBP control ( HCTZ at 12.5 mg or 25 mg was added , when needed , to regain DBP control . At the end of the titration period , DBP control was achieved on monotherapy by 67 % and 63 % of the telmisartan and lisinopril patients , respectively . At the end of the maintenance period , supine DBP was controlled in 83 % and 87 % of the telmisartan and lisinopril patients , respectively , with systolic blood pressure over DBP reductions of 23.8/16.6 mm Hg for telmisartan and 19.9/15.6 mm Hg for lisinopril . Treatment-related side effects occurred in fewer telmisartan-treated patients ( 28 % ) than in lisinopril-treated patients ( 40 % ; P = .001 ) . Significantly fewer patients ( P = .018 ) receiving telmisartan experienced treatment-related cough ( 3 % v 7 % ) , and cough led to discontinuation significantly less often ( P = .007 ) with telmisartan treatment than with lisinopril treatment ( 0.3 % v 3.1 % ) . In addition , two cases of angioedema were observed , both in the lisinopril group . The selective AT ( 1 ) receptor antagonist , telmisartan , is extremely effective in the treatment of mild-to-moderate hypertension both as monotherapy and in combination with HCTZ and is at least comparable in efficacy to lisinopril , with a tolerability profile that may offer advantages in terms of a reduced incidence of adverse events",
"BACKGROUND Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease . We aim ed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker , and monotherapy of each drug at its maximum dose , in patients with non-diabetic renal disease . METHODS 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan . After screening and an 18-week run-in period , 263 patients were r and omly assigned angiotensin-II receptor blocker ( losartan , 100 mg daily ) , angiotensin-converting-enzyme inhibitor ( tr and olapril , 3 mg daily ) , or a combination of both drugs at equivalent doses . Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease . Analysis was by intention to treat . FINDINGS Seven patients discontinued or were otherwise lost to follow-up . Ten ( 11 % ) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 ( 23 % ) of 85 on tr and olapril alone ( hazard ratio 0.38 , 95 % CI 0.18 - 0.63 , p=0.018 ) and 20 ( 23 % ) of 86 on losartan alone ( 0.40 , 0.17 - 0.69 , p=0.016 ) . Covariates affecting renal survival were combination treatment ( hazard ratio 0.38 , 95 % CI 0.18 - 0.63 , p=0.011 ) , age ( 1.30 , 1.03 - 2.29 , p=0.009 ) , baseline renal function ( 1.80 , 1.02 - 2.99 , p=0.021 ) , change in daily urinary protein excretion rate ( 0.58 , 0.24 - 0.88 , p=0.022 ) , use of diuretics ( 0.80 , 0.30 - 0.94 , p=0.043 ) , and antiproteinuric response to tr and olapril ( 0.81 , 0.21 - 0.91 , p=0.039 ) . Frequency of side-effects with combination treatment was the same as with tr and olapril alone . INTERPRETATION Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy . However , since some patients reached the combined primary endpoint on combined treatment , further strategies for complete management of progressive non-diabetic renal disease need to be research ed",
"BACKGROUND The objectives of this study were to compare the effects of the angiotensin II receptor blocker , losartan , to those of the angiotensin-converting enzyme inhibitor , enalapril , on albuminuria and renal function in relationship to clinic and ambulatory blood pressure ( ABP ) in hypertensive type 2 diabetic subjects with early nephropathy . The tolerability of these agents and their effect on the metabolic profile were also evaluated . METHODS The study was a one-year prospect i ve , double-blind trial with losartan and enalapril administered alone or in combination with hydrochlorothiazide and other antihypertensive agents . ABP and renal and biochemical parameters were measured at baseline and after 12 , 28 , and 52 weeks of active treatment . Ninety-two hypertensive type 2 diabetics with early nephropathy completed the study . RESULTS Both losartan and enalapril administered alone or in combination with other agents induced significant reductions in sitting clinic ( P ABP ( P Geometric means for urinary albumin excretion ( UAE ) decreased significantly ( P systolic and diastolic ABP and the decrease in UAE at 52 weeks was seen in both groups . The decline in glomerular filtration rate ( GFR ) was stabilized at the end of therapy and was identical in both treatment groups . Treatment with enalapril was associated with a significantly higher incidence of cough ( P = 0.006 ) and a rise in serum uric acid ( P = 0.002 ) compared with losartan . CONCLUSIONS Our results indicate that a one-year course of antihypertensive therapy with either losartan or enalapril significantly reduces UAE in hypertensive type 2 diabetic patients with early nephropathy . The reduction in UAE with each treatment is similarly related to decrements in ABP . In addition , the rate of decline in GFR is similar in both treatment groups",
"BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infa rct ion complicated by left ventricular systolic dysfunction , heart failure , or both . In a double-blind trial , we compared the effect of the angiotensin-receptor blocker valsartan , the ACE inhibitor captopril , and the combination of the two on mortality in this population of patients . METHODS Patients receiving conventional therapy were r and omly assigned , 0.5 to 10 days after acute myocardial infa rct ion , to additional therapy with valsartan ( 4909 patients ) , valsartan plus captopril ( 4885 patients ) , or captopril ( 4909 patients ) . The primary end point was death from any cause . RESULTS During a median follow-up of 24.7 months , 979 patients in the valsartan group died , as did 941 patients in the valsartan- and -captopril group and 958 patients in the captopril group ( hazard ratio in the valsartan group as compared with the captopril group , 1.00 ; 97.5 percent confidence interval , 0.90 to 1.11 ; P=0.98 ; hazard ratio in the valsartan- and -captopril group as compared with the captopril group , 0.98 ; 97.5 percent confidence interval , 0.89 to 1.09 ; P=0.73 ) . The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality ( P=0.004 ) and with regard to the composite end point of fatal and nonfatal cardiovascular events ( P valsartan- and -captopril group had the most drug-related adverse events . With monotherapy , hypotension and renal dysfunction were more common in the valsartan group , and cough , rash , and taste disturbance were more common in the captopril group . CONCLUSIONS Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infa rct ion . Combining valsartan with captopril increased the rate of adverse events without improving survival",
"We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide , c and esartan or lisinopril on left ventricular mass ( LVM ) index and arterial stiffness in hypertensive type II diabetic individuals . Seventy hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a r and omized , double-blind , double-dummy design . Blood pressure was titrated to levels below 130/85 mm Hg or a decrease in systolic pressure of 10 % with a diastolic pressure below 85 mm Hg . After titration , patients were treated for 12 months . Mean blood pressures were 157/93 , 151/94 and 149/93 mm Hg at baseline in the hydrochlorothiazide ( n=24 ) , c and esartan ( n=24 ) and lisinopril ( n=22 ) groups , and 135/80 , 135/82 and 131/80 mm Hg after titration . About 70 % reached target blood pressures , with the median use of three antihypertensive drugs . Left ventricular mass index and all estimates of arterial stiffness showed significant improvement after 12 months : that is , LVM index ( −11 g/m2 ; −8 % ) ; carotid distensibility coefficient ( DC ; + 2.8 × 10−3 kPa−1 ; + 27 % ) , compliance coefficient ( CC ; + 0.13 mm2/kPa ; + 21 % ) and elastic modulus ( −0.19 kPa ; −16 % ) ; femoral DC ( + 1.6 × 10−3 kPa−1 ; + 50 % ) and CC ( + 0.08 mm2/kPa ; + 26 % ) ; brachial DC ( + 2.1 × 10−3 kPa−1 ; + 39 % ) and CC ( + 0.03 mm2/kPa ; + 27 % ) and total systemic arterial compliance ( + 0.29 ml/mm Hg ; + 16 % ) . No differences in outcome variables between treatment groups were observed . Aggressive antihypertensive treatment , although difficult to achieve , result ed in substantial reductions of LVM index and arterial stiffness in relatively uncomplicated hypertensive type II diabetic individuals . Strategies based on renin – angiotensin system inhibitors were not clearly superior to conventional ( i.e. diuretic-based ) strategies",
"Objective : The objective of this study was to compare valsartan or ramipril addition to amlodipine + hydrochlorothiazide ( HCTZ ) on blood pressure ( BP ) and left ventricular hypertrophy ( LVH ) in hypertensive diabetic patients with LVH . Research design and methods : 293 patients were treated with amlodipine 10 mg + HCTZ 12.5 combination and then r and omized to receive valsartan 160 mg or ramipril 5 mg , in addition to the previous therapy , for 1 year . Main outcome measures : Clinic BP was measured every month ; echocardiographic assessment s were performed at the end of the placebo period , both before the r and omization and after 1-year of triple combination therapy . Results : Both triple regimens similarly reduced SBP/DBP values ( -13.5/10.9 mm Hg in the valsartan group and -13.4/10.4 mm Hg in the ramipril group ) . Triple combination including valsartan better reduced LVMI ( -20.1 % , p interventricular septal thickness ( IVST ) ( -20.3 % , p left ventricular posterior wall thickness ( PWT ) ( -16.3 % , p ramipril ( -14 % , p increase of E/A ratio ( p Valsartan addition to dual therapy with amlodipine + HCTZ was more effective than ramipril addition in reducing LVH",
"OBJECTIVE To investigate the effect of angiotensin converting enzyme inhibition ( ACE-I ) or angiotensin receptor blockade ( ARB ) , and their combination , on both diabetic autonomic neuropathy ( DAN ) and left ventricular ( LV ) diastolic dysfunction ( LVDD ) in asymptomatic patients with diabetes mellitus ( DM ) . MATERIAL S AND METHODS Sixty-two patients ( 34 women ) with long-term DM ( 24 with Type 1 ) and DAN , aged 51.7+/-13.9 years , free of coronary artery disease ( CAD ) or arterial hypertension ( HT ) at baseline , were studied for a 12-month period . Diagnosis of DAN was established if two or more of the st and ard cardiovascular reflex tests ( CRT ) were abnormal . Patients were r and omly allocated to quinapril ( 20 mg/day ) , losartan ( 100 mg/day ) , or quinapril plus losartan ( 20 mg/day+100 mg/day ) . LV systolic and diastolic function was assessed using radionuclide ventriculography ( RNV ) at baseline and after 12 months of treatment . RESULTS In all three treatment groups , abnormal CRT values were improved . In the quinapril group , the first third filling fraction ( 1/3FF , 48.9+/-17.8 % vs. 39.2+/-12.9 % at baseline , P=.005 ) was increased and the atrial contribution to ventricular filling ( 25.1+/-6.3 vs. 30.1+/-7.8 , P=.027 ) was reduced in the losartan group ; the peak filling rate ( PFR ) was improved ( 3.41+/-.62 vs. 3.11+/-.44 volumes/s , P=.05 ) , and in the combination group , the 1/3FF ( 39.4+/-11.8 % vs. 29.6+/-11.9 % , P=.018 ) was markedly increased , while the time to peak filling ( TPF ; 147+/-42 vs. 184+/-33 ms , P=.02 ) and the TPF/filling time ( TPF/FT ; 32.5+/-6.2 % vs. 38.2+/-5.7 % , P=.016 ) were reduced . CONCLUSIONS Early ACE-I or ARB improve both DAN and LVDD in asymptomatic patients with Type 1 or 2 DM , after 1 year of treatment . Their combination may be slightly better than monotherapies on DAN and LVDD . The clinical importance of these effects should be vali date d by larger studies",
"BACKGROUND Blocking the renin-angiotensin system ( RAS ) with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors protects against renal injury in patients with chronic kidney disease ( CKD ) . The aim of this study was to compare the chronic effects of telmisartan and enalapril on proteinuria , urinary liver-type fatty acid-binding protein ( L-FABP ) and endothelin (ET)-1 levels in patients with mild CKD . MATERIAL S AND METHODS Thirty CKD patients with mild to moderate renal insufficiency ( 20 men and 10 women ; mean age , 37 years ; estimated glomerular filtration rate ( eGFR ) > 60 mL min(-1 ) and blood pressure > 130/85 mmHg ) were included in the study . Patients were r and omly assigned to receive telmisartan at 80 mg day(-1 ) ( n = 15 ) or enalapril at 10 mg day(-1 ) ( n = 15 ) . We measured blood pressure , serum creatinine , eGFR , urinary protein , L-FABP and ET-1 before the start of treatment and 6 and 12 months after the start of treatment . RESULTS The blood pressure reduction rate was similar between the two groups . Urinary protein , L-FABP and ET-1 levels were significantly reduced in both groups 6 and 12 months ( P rates were more pronounced in patients receiving telmisartan than in those receiving enalapril ( P Estimated glomerular filtration rate was increased similarly in both groups at 12 months . CONCLUSIONS The study results suggest that telmisartan results in a greater reduction of urinary markers than does enalapril and that this effect occurs by a mechanism independent of blood pressure reduction . It would be needed to investigate whether the differences may be distinct or not the same when other dosages are used",
"BACKGROUND Hemodialysis patients have uremic dyslipidemia , represented by elevated serum intermediate-density lipoprotein cholesterol ( IDL-C ) levels , and an increased cardiovascular mortality rate . This study was performed to determine the low-dose effects of the angiotensin II receptor blocker losartan and the angiotensin-converting enzyme inhibitor tr and olapril on pulse wave velocity ( PWV ) , which predicts cardiovascular morbidity and mortality in hemodialysis patients . METHODS Serum lipid levels and PWV were monitored for 12 months in 64 hemodialysis patients who were administered low doses of losartan or tr and olapril or a placebo . RESULTS At the start of the study , there were no differences in patient characteristics among the 3 groups . PWV tended to increase in the placebo group during the 12-month study period , but decreased significantly in the losartan and tr and olapril groups , and decreases in PWV were similar in the losartan and tr and olapril groups . There were no changes in blood pressure , hematocrit , erythropoietin dose , ankle-brachial index , serum lipid levels , serum 8-isoprostane levels , or serum C-reactive protein levels during the 12-month study period , but there was an increase in serum triglyceride levels in the losartan group and a decrease in serum IDL-C levels in the losartan and tr and olapril groups . CONCLUSION In hemodialysis patients , tr and olapril is as effective as losartan in decreasing PWV independent of its depressor effect and in suppressing elevated IDL-C levels . Long-term blockade of the renin-angiotensin system may have a beneficial effect on the acceleration of atherosclerosis and uremic dyslipidemia",
"Left ventricular hypertrophy ( LVH ) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients , and is highly predictive of future cardiac morbidity and mortality . In patients with hypertension and LVH , both an angiotensin converting enzyme ( ACE ) inhibitor and an angiotensin type 1 receptor ( AT1 ) antagonist regress LVH . However , it remains controversial whether dual blockade of the renin-angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist . Thirty-three type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School , Saitama , Japan between 1999 and 2001 . The study was carried out for 1 year . All patients were assigned r and omly to three groups with equal number : group I , an ACE inhibitor , enalapril 10 mg daily ; group II , an AT1 antagonist , losartan 100 mg daily ; group III , combination of enalapril 10 mg and losartan 100 mg daily . All antihypertensive drugs were given 30 min after the cessation of dialysis therapy . LVH was evaluated by echocardiography before the start of administration of drugs , at 6 months and 12 months after the start of drug therapy . Systolic blood pressure levels less than 140 mmHg were the target for the three groups . Using repeated measures analysis of variance , applied to those with four echocardiograms , there were progressive decreases over time in left ventricular mass index , posterior wall thickness and interventricular septum thickness . There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups ; however , dual blockade induced an additional 28 % reduction in left ventricular mass index compared with any type of monotherapy . Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy . Moreover , combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy",
"BACKGROUND The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients , compared with captopril , an angiotensin-converting-enzyme ( ACE ) inhibitor . We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated . METHODS We undertook a double-blind , r and omised , controlled trial of 3,152 patients aged 60 years or older with New York Heart Association class II-IV heart failure and ejection fraction of 40 % or less . Patients , stratified for beta-blocker use , were r and omly assigned losartan ( n=1,578 ) titrated to 50 mg once daily or captopril ( n=1,574 ) titrated to 50 mg three times daily . The primary and secondary endpoints were all-cause mortality , and sudden death or resuscitated arrest . We assessed safety and tolerability . Analysis was by intention to treat . FINDINGS Median follow-up was 555 days . There were no significant differences in all-cause mortality ( 11.7 vs 10.4 % average annual mortality rate ) or sudden death or resuscitated arrests ( 9.0 vs 7.3 % ) between the two treatment groups ( hazard ratios 1.13 [ 95.7 % CI 0.95 - 1.35 ] , p=0.16 and 1.25 [ 95 % CI 0.98 - 1.60 ] , p=0.08 ) . Significantly fewer patients in the losartan group ( excluding those who died ) discontinued study treatment because of adverse effects ( 9.7 vs 14.7 % , p cough ( 0.3 vs 2.7 % )",
"Background : Hypertension is frequently seen in autosomal dominant polycystic kidney disease ( ADPKD ) , and it has a negative effect on renal progression . Hypertension and left ventricle hypertrophy ( LVH ) are related in terms of pathogenesis and their effects on renal progression . In this study , we aim ed to compare the effects of losartan and ramipril on blood pressure ( BP ) control , LVH , and renal progression in patients with hypertensive ADPKD . Methods : Thirty-two ADPKD patients with ages ranging between 18 and 70 years who were stage 1–2 hypertensive were included in this study . Routine biochemical tests and echocardiography were obtained at first examination of the patients . Following these , the patients were r and omized . One group was given losartan and the other ramipril . They were followed up for 1 year , and their echocardiographies and routine biochemical tests were repeated at the end of the year . Results : BP values decreased in both the groups at the end of the first year ( p in LVH in both the groups at the end of the first year than at the beginning ( losartan , p = 0.007 ; ramipril , p effective BP control was obtained with losartan and ramipril and LVH was found to be regressed significantly in the hypertensive patients with ADPKD . These two groups of antihypertensive drugs may also have beneficial effects on the retardation of renal progression and in reducing cardiovascular mortality in hypertensive patients with ADPKD"
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Testosterone deficiency ( TD ) may induce a series of clinical symptoms . Studies have shown that testosterone supplementation may prevent these unfavourable symptoms and improve patients ’ quality of life . Given the conflicting findings across studies , this systematic review aims to evaluate the effects and risks associated with testosterone supplementation in middle-aged or aging males with TD . Electronic data bases ( MEDLINE , EMBASE , PubMed , and Cochrane . Library were search ed to December 2019 . The risk of bias of individual included studies and the quality of the aggregate evidence were assessed using the GRADE approach . Our primary outcome was bone mineral density ( BMD ) . Meta-analyses were performed . This systematic review was reported according to the PRISMA statement . A total of 52 r and omized controlled trials ( RCTs ) were included . When compared with placebo , testosterone supplementation did not increase total BMD ( short-term : 1081 participants , MD − 0.01 g/cm2 , 95 % CI − 0.02 g/cm2 to 0.01 g/cm2 ; long-term : 156 participants , MD 0.04 g/cm2 , 95 % CI − 0.07 g/cm2 to 0.14 g/cm2 ) , lumbar spine , hip , or femur neck BMD . Furthermore , testosterone supplementation did not decrease the risk of falling or fracture . Lastly , it was found that testosterone supplementation did not increase the risk of cardiovascular events ( 1374 participants , RR 1.28 , 95 % CI 0.62 to 2.64 ) , all-cause mortality ( 729 participants , RR 0.55 , 95 % CI 0.29 to 1.04 ) , or prostatic events . However , testosterone supplementation may improve sexual function and quality of life ( 1328 participants , MD -1.32 , 95 % CI − 2.11 to − 0.52 ) . The effect of testosterone supplementation on BMD and the risk of falls or fracture remains inconclusive . However , supplementation may benefit patients in the areas of sexual function and quality of life without increasing the risk of cardiovascular events , all-cause mortality , or prostatic events . RCTs with a longer follow-up period are still required . We registered our protocol in PROSPERO ( CRD42018109738 )
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"Purpose . We performed a r and omised controlled study regarding the effects of and rogen replacement therapy ( ART ) on lower urinary tract symptoms ( LUTS ) in hypogonadal men with benign prostate hypertrophy ( BPH ) . Methods . Fifty-two patients with hypogonadism and BPH were r and omly assigned to receive testosterone ( ART group ) as 250 mg of testosterone enanthate every 4 weeks or to the untreated control group . We compared International Prostate Symptom Score ( IPSS ) , uroflowmetry data , post-voiding residual volume ( PVR ) and systemic muscle volume at baseline and 12 months after treatment . Results . Forty-six patients ( ART group , n = 23 ; control , n = 23 ) were included in the analysis . At the 12-month visit , IPSS showed a significant decrease compared with baseline in the ART group ( 15.7 ± 8.7 vs. 12.5 ± 9.5 ; p The ART group also showed improvement in maximum flow rate and voided volume ( p controls . PVR showed no significant changes in either group . In addition , the ART group showed significant enhancement of mean muscle volume ( p Conclusion . ART improved LUTS in hypogonadal men with mild BPH",
"Objective . The aim of the present study was to analyse the effect of testosterone therapy on bone mineral density in healthy elderly men who had low levels of total testosterone . Design . R and omized , double-blind , placebo-controlled study . Participants . Forty-eight men over 60 years old with decreased testosterone levels ( ≤320 ng/dL ) comprised the study . Twenty-five out of 48 received intramuscular injections of testosterone enanthate every three weeks during 12 months ; the remaining 23 participants formed the control group . All participants had measurements of bone mineral density ( BMD ) in both lumbar spine and hip before and at the end of the study as well as testosterone and 17-β estradiol levels . Results : Testosterone treated group exhibited a significant ( p g/cm2 ) in lumbar BMD in parallel with a significant ( p ) in testosterone concentrations , whereas no significant change occurred in femoral neck BMD . Conclusions . Testosterone therapy elicited a positive effect only in lumbar BMD in elderly men with diminished testosterone serum levels",
"Aging in men is associated with loss of bone mass , impaired physical function and altered body composition . The objective of this proof‐of‐concept r and omized , double‐blind , placebo‐controlled , parallel‐group , single‐center trial was to determine the relative effects of testosterone ( T ) and estradiol ( E2 ) on bone mineral density , body composition , and physical performance in older men . The primary outcome was lumbar spine bone mineral density ( BMD ) , and secondary outcomes were body composition , muscle strength , gait speed , and sex hormone concentrations . Forty three men ( age range , 65–82 years ; mean age 71 years ) with low total T levels to one of three groups : 5 g transdermal testosterone gel ( TT ) ( N = 16 ) , anastrozole ( AI ) 1 mg ( N = 14 ) or placebo daily ( N = 13 ) for 12 months . Outcomes were assessed at baseline , 3 , 6 , and 12 months . Both TT and AI increased serum TT levels ( > 500 ng/dL , p primary outcome of lumbar spine BMD ( p interventions improved knee strength at 12 months compared to baseline ( p while lean body mass significantly increased only in the AI group at 6 and 12 months ( 1.49 ± 0.38 kg , p TT improved fast gait speed at 3 and 12 months ( p maintaining BMD in older men with low‐T levels . The trial also uncovered the novel finding that aromatization of T is required for improvement in fast gait speed , an observation that needs to be verified in future studies",
"Older men , particularly those with low serum testosterone ( T ) levels , might benefit from T therapy to improve bone mineral density ( BMD ) and reduce fracture risk . Concerns exist , however , about the impact of T therapy on the prostate in older men . We hypothesized that the combination of T and finasteride ( F ) , a 5 alpha-reductase inhibitor , might increase BMD in older men without adverse effects on the prostate . Seventy men aged 65 yr or older , with a serum T less than 12.1 nmol/liter on two occasions , were r and omly assigned to receive one of three regimens for 36 months : T enanthate , 200 mg i m every 2 wk with placebo pills daily ( T-only ) ; T enanthate , 200 mg every 2 wk with 5 mg F daily ( T+F ) ; or placebo injections and pills ( placebo ) . Low BMD was not an inclusion criterion . We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry . Prostate-specific antigen ( PSA ) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate . Fifty men completed the 36-month protocol . By an intent-to-treat analysis including all men for as long as they contributed data , T therapy for 36 months increased BMD in these men at the lumbar spine [ 10.2 + /- 1.4 % ( mean percentage increase from baseline + /- SEM ; T-only ) and 9.3 + /- 1.4 % ( T+F ) vs. 1.3 + /- 1.4 % for placebo ( P hip [ 2.7 + /- 0.7 % ( T-only ) and 2.2 + /- 0.7 % ( T+F ) vs. -0.2 + /- 0.7 % for placebo , ( P increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip . After 6 months of therapy , urinary deoxypyridinoline ( a bone-resorption marker ) decreased significantly compared with baseline in both the T-only and T+F groups ( P PSA increased significantly from baseline in the T-only group ( P Prostate volume increased in all groups during the 36-month treatment period , but this increase was significantly less in the T+F group compared with both the T-only and placebo groups ( P = 0.02 ) . These results demonstrate that T therapy in older men with low serum T increases vertebral and hip BMD over 36 months , both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men . In addition , the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy . These findings have important implication s for the prevention and treatment of osteoporosis in older men with low T levels",
"The objective of this study was to assess the effects of oral testosterone supplementation therapy on glucose homeostasis , obesity and sexual function in middle-aged men with type 2 diabetes and mild and rogen deficiency . Forty-eight middle-aged men , with type 2 diabetes , ( visceral ) obesity and symptoms of and rogen deficiency , were included in this open-label study . Twenty-four subjects received testosterone undecanoate ( TU ; 120 mg daily , for 3 months ) ; 24 subjects received no treatment . Body composition was analyzed by bio-impedance . Parameters of metabolic control were determined . Symptoms of and rogen deficiency and erectile dysfunction were scored by self-administered question naires . TU had a positive effect on ( visceral ) obesity : statistically significant reduction in body weight ( 2.66 % ) , waist-hip ratio ( -3.96 % ) and body fat ( -5.65 % ) ; negligible changes were found in the control group . TU significantly improved metabolic control : decrease in blood glucose values and mean glycated hemoglobin ( HbA1c ) ( from 10.4 to 8.6 % ) . TU treatment significantly improved symptoms of and rogen deficiency ( including erectile dysfunction ) , with virtually no change in the control group . There were no adverse effects on blood pressure or hematological , biochemical and lipid parameters , and no adverse events . Oral TU treatment of type 2 diabetic men with and rogen deficiency improves glucose homeostasis and body composition ( decrease in visceral obesity ) , and improves symptoms of and rogen deficiency ( including erectile dysfunction ) . In these men , the benefit of testosterone supplementation therapy exceeds the correction of symptoms of and rogen deficiency and also includes glucose homeostasis and metabolic control",
"BACKGROUND Testosterone increases lean mass and may help to counter the changes in muscle architecture associated with sarcopenia . This study was design ed to investigate the effects of testosterone replacement therapy on skeletal muscle architecture in intermediate-frail and frail elderly men . METHODS A subgroup of 30 intermediate-frail and frail elderly men ( 65 - 89 years ) with low to borderline-low testosterone levels were enrolled from a single-center r and omized , double-blind placebo-controlled trial . Participants received either a transdermal testosterone ( 50 mg ) or placebo gel daily for 6 months . Architecture ( muscle thickness , fascicle length , and pennation angle ) of the gastrocnemius medialis muscle was assessed by ultrasound imaging at baseline and after 6 months of treatment . RESULTS Serum testosterone increased from 11.6 ± 3.5 to 18.0 ± 8.1 nmol/L by 10 days after r and omization in the active group ( but not the placebo group ) and was maintained throughout the treatment period . Testosterone treatment result ed in a preservation of muscle thickness at 6 months while it decreased in the placebo group ( effect size 1.4 [ 95 % confidence interval = 0.3 - 2.5 ; p = .015 ] ) . There was no significant effect of treatment on fascicle length ( effect size 1.9 mm [ 95 % confidence interval = -1.2 to 5.0 mm ; p = .22 ] ) or pennation angle ( effect size 1.2 ° [ 95 % confidence interval = -1.3 to 3.7 ° ; p = .32 ] ) . CONCLUSIONS Testosterone replacement in intermediate-frail and frail elderly men is associated with preservation of muscle thickness . The results suggest that testosterone mitigates sarcopenia by improving muscle tissue to maintain a state of normality in aging men",
"Background Uncontrolled studies show fatigue , anorexia , depression , and mortality are associated with low testosterone in men with cancer . Testosterone replacement improves quality of life and diminishes fatigue in patients with non-cancer conditions . The primary objective was to evaluate the effect of testosterone replacement on fatigue in hypogonadal males with advanced cancer , by the Functional Assessment of Chronic Illness Therapy-Fatigue subscale ( FACIT-Fatigue ) at day 29 . Methods This is a r and omized , double-blinded placebo-controlled trial . Out patients with advanced cancer , bioavailable testosterone ( BT ) 3/10 on the Edmonton Symptom Assessment Scale were eligible . Intra-muscular testosterone or sesame seed oil placebo was administered every 14 days to achieve BT levels 70–270 ng/dL. Results Sixteen placebo and 13 testosterone-treated subjects were evaluable . No statistically significant difference was found for FACIT-fatigue scores between arms ( −2 ± 12 for placebo , 4 ± 8 for testosterone , p = 0.11 ) . Sexual Desire Inventory score ( p = 0.054 ) and performance status ( p = 0.02 ) improved in the testosterone group . Fatigue subscale scores were significantly better ( p = 0.03 ) in those treated with testosterone by day 72 . Conclusions Four weeks of intramuscular testosterone replacement in hypogonadal male patients with advanced cancer did not significantly improve quality of life . Larger studies of longer duration are warranted",
"Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more",
"BACKGROUND A large proportion of men over 65 years of age have bioavailable testosterone levels below the reference range of young adult men . The impact of this on musculoskeletal health and the potential for improvement in function in this group with testosterone supplementation require investigation . METHODS Sixty-seven men ( mean age 76 + /- 4 years , range 65 - -87 ) with bioavailable testosterone levels below 4.44 nmol/l ( lower limit for adult normal range ) were r and omized to receive transdermal testosterone ( two 2.5-mg patches per day ) or placebo patches for 1 year . All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones ( testosterone , bioavailable testosterone , sex-hormone binding globulin [ SHBG ] , estradiol , and estrone ) , bone mineral density ( BMD ; femoral neck , Ward 's triangle , trochanter , lumbar spine , and total body ) , bone turnover markers , lower extremity muscle strength , percent body fat , lean body mass , hemoglobin , hematocrit , prostate symptoms , and prostate specific antigen ( PSA ) levels . RESULTS Twenty-three men ( 34 % ) withdrew from the study ; 44 men completed the trial . In these men , bioavailable testosterone levels increased from 3.2 + /- 1.2 nmol/l ( SD ) to 5.6 + /- 3.5 nmol/l ( p estradiol levels in either group , estrone levels increased in the testosterone group ( 103 + /- 26 pmol/l to 117 + /- 33 pmol/l ; p femoral neck BMD , whereas the control group lost 1.6 % over 12 months ( p = .015 ) . No significant changes were seen in markers of bone turnover in either group . Improvements in muscle strength were seen in both groups at 12 months compared with baseline scores . Strength increased 38 % ( p = .017 ) in the testosterone group and 27 % in the control group ( p = .06 ) , with no statistical difference between the groups . In the testosterone group , body fat decreased from 26.3 + /- 5.8 % to 24.6 + /- 6.5 % ( p = .001 ) , and lean body mass increased from 56.2 + /- 5.3 kg to 57.2 + /- 5.1 kg ( p = .001 ) , whereas body mass did not change . Men receiving testosterone had an increase in PSA from 2.0 + /- 1.4 microg/l to 2.6 + /- 1.8 microg/l ( p = .04 ) , whereas men receiving placebo had an increase in PSA from 1.9 + /- 1.0 microg/l to 2.2 + /- 1.5 microg/l ( p = .09 ) . No significant differences between groups were seen in hemoglobin , hematocrit , symptoms or signs of benign prostate hyperplasia , or PSA levels . CONCLUSIONS Transdermal testosterone ( 5 mg/d ) prevented bone loss at the femoral neck , decreased body fat , and increased lean body mass in a group of healthy men over age 65 with low bioavailable testosterone levels . In addition , both testosterone and placebo groups demonstrated gains in lower extremity muscle strength , possibly due to the beneficial effects of vitamin D. Testosterone did result in a modest increase in PSA levels but result ed in no change in signs or symptoms of prostate hyperplasia",
"The indication for testosterone therapy in aging hypogonadal men without hypothalamic , pituitary , or testicular disease remains to be eluci date d. The aim of this study was to investigate the effect of testosterone therapy on insulin sensitivity , substrate metabolism , body composition , and lipids in aging men with low normal bioavailable testosterone levels using a predefined cutoff level for bioavailable testosterone . A r and omized , double-blinded , placebo-controlled study of testosterone treatment ( gel ) was done on 38 men , aged 60–78 years , with bioavailable testosterone 94 cm . Insulin-stimulated glucose disposal ( Rd ) and substrate oxidation were assessed by euglycemic hyperinsulinemic clamps combined with indirect calorimetry . Lean body mass ( LBM ) and total fat mass ( TFM ) were measured by dual x-ray absorptiometry , and serum total testosterone was measured by t and em mass spectrometry . Bioavailable testosterone was calculated . Coefficients ( b ) represent the placebo-controlled mean effect of intervention . LBM ( b = 1.9 kg , p = 0.003 ) increased while HDL – cholesterol ( b = −0.12 mmol/l , p = 0.043 ) and TFM decreased ( b = −1.2 kg , p = 0.038 ) in the testosterone group compared to placebo . Basal lipid oxidation ( b = 5.65 mg/min/m2 , p = 0.045 ) increased and basal glucose oxidation ( b = −9.71 mg/min/m2 , p = 0.046 ) decreased in response to testosterone therapy even when corrected for changes in LBM . No significant changes in insulin-stimulated Rd was observed ( b = −0.01mg/min/m2 , p = 0.92 ) . Testosterone therapy increased muscle mass and lipid oxidation in aging men with low normal bioavailable testosterone levels ; however , our data did not support an effect of testosterone on whole-body insulin sensitivity using the euglycemic hyperinsulinemic clamp technique",
"The male aging process brings about declines in hormonal function including a gradual decline in bioavailable testosterone levels . Animal studies suggest that testosterone modulates cognitive function through enhancing acetylcholine release and up-modulation of nicotinic receptors . Tau protein deposition is also affected by and rogen supplementation in animals . We hypothesize that testosterone replacement in elderly hypogonadal males may improve cognition , in particular the visual-spatial domain . Thirty-six male patients with a new diagnosis of Alzheimer 's disease had their total and bioavailable testosterone levels measured . None of the patients had been on acetylcholinesterase inhibitors . Ten of the 36 patients ( 28 % ) were deemed biochemically hypogonadal ( total testosterone testosterone and five to placebo . Initial Alzheimer 's Disease Assessment Scale cognitive subscale ( ADAScog ) and Mini Mental Status Examination ( MMSE ) ranged from 31 to 19 and from 17 to 22 , respectively . The clock drawing test ( CDT ) and the pentagon-tracing portion of the MMSE were used as measures of visual-spatial abilities . Normal prostate-specific antigen ( PSA ) levels were essential before treatment with intramuscular testosterone , 200 mg every 2 weeks . Measurement of testosterone , complete blood count , lipids , PSA and neuropsychological cognitive tests were repeated at 3 , 6 , 9 and 12 months of treatment . In the testosterone-treated group , levels of total testosterone increased from a mean of 126.4 ng/dl to 341 ng/dl or 3.6 nmol/l to 9.7 nmol/l ( p = 0.11 ) . Bioavailable testosterone also increased from a mean of 48.7 ng/dl to 142 ng/dl or 1.39 nmol/l to 4.05 nmol/l ( p = 0.10 ) . PSA levels were also elevated from a mean of 0.98 to 1.37 ng/ml ( p = 0.07 ) . ADAScog improved from a mean of 25 to 16.3 ( p = 0.02 ) ; MMSE improved from a mean of 19.4 to 23.2 ( p = 0.02 ) , CDT also improved from 2.2 to 3.2 ( p = 0.07 ) . One patient stopped treatment because of hypersexual behavior . The placebo-treated group deteriorated gradually . This small pilot study performed in aging male patients suggests that testosterone could indeed improve cognition , including visual-spatial skills in mild to moderate Alzheimer 's disease",
"CONTEXT Aging in men is associated with reduced testosterone ( T ) levels and physiological changes leading to frailty , but the benefits of T supplementation are inconclusive . OBJECTIVE We studied the effects of T supplementation with and without progressive resistance training ( PRT ) on functional performance , strength , and body composition . DESIGN , SETTING , AND PARTICIPANTS We recruited 167 generally healthy community-dwelling older men ( 66 ± 5 years ) with low-normal baseline total T levels ( 200 - 350 ng/dL ) . INTERVENTION Subjects were r and omized to placebo or transdermal T gel [ 2 doses targeting either a lower ( 400 - 550 ng/dL ) or higher ( 600 - 1000 ng/dL ) T range ] and to either PRT or no exercise for 12 months . MAIN OUTCOME MEASURE The primary outcome was functional performance , whereas secondary outcomes were strength and body composition . RESULTS A total of 143 men completed the study . At 12 months , total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group . In the PRT group , function and strength were not different between T- and placebo-treated subjects , despite greater improvements in fat mass ( P = .04 ) and fat-free mass ( P = .01 ) with T. In the non-PRT group , T did not improve function but improved fat mass ( P = .005 ) , fat-free mass ( P = .03 ) , and upper body strength ( P = .03 ) compared with placebo . There were fewer cardiovascular events in the T-treated groups compared with placebo . CONCLUSIONS T supplementation was well tolerated and improved body composition but had no effect on functional performance . T supplementation improved upper body strength only in nonexercisers compared with placebo",
"As men age , their serum testosterone concentrations decrease , as do their bone densities . Because bone density is also low in hypogonadal men , we hypothesized that increasing the serum testosterone concentrations of men over 65 yr to those found in young men would increase their bone densities . We r and omized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch double blindly for 36 months . We measured bone mineral density by dual energy x-ray absorptiometry before and during treatment . Ninety-six men completed the entire 36-month protocol . The mean serum testosterone concentration in the men treated with testosterone increased from 367 + /- 79 ng/dL ( + /-SD ; 12.7 + /- 2.7 nmol/L ) before treatment to 625 + /- 249 ng/dL ( 21.7 + /- 8.6 nmol/L ; P mean bone mineral density of the lumbar spine increased ( P placebo-treated ( 2.5 + /- 0.6 % ) and testosterone-treated ( 4.2 + /- 0.8 % ) groups , but the mean changes did not differ between the groups . Linear regression analysis , however , demonstrated that the lower the pretreatment serum testosterone concentration , the greater the effect of testosterone treatment on lumbar spine bone density from 0 - 36 months ( P = 0.02 ) . This analysis showed a minimal effect ( 0.9 + /- 1.0 % ) of testosterone treatment on bone mineral density for a pretreatment serum testosterone concentration of 400 ng/dL ( 13.9 nmol/L ) , but an increase of 5.9 + /- 2.2 % for a pretreatment testosterone concentration of 200 ng/dL ( 6.9 nmol/L ) . Increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men did not increase lumbar spine bone density overall , but did increase it in those men with low pretreatment serum testosterone concentrations",
"Dysfunction of the muscles of ambulation contributes to exercise intolerance in chronic obstructive pulmonary disease ( COPD ) . Men with COPD have high prevalence of low testosterone levels , which may contribute to muscle weakness . We determined effects of testosterone supplementation ( 100 mg of testosterone enanthate injected weekly ) with or without resistance training ( 45 minutes three times weekly ) on body composition and muscle function in 47 men with COPD ( mean FEV(1 ) = 40 % predicted ) and low testosterone levels ( mean = 320 ng/dl ) . Subjects were r and omized to 10 weeks of placebo injections + no training , testosterone injections + no training , placebo injections + resistance training , or testosterone injections + resistance training . Testosterone injections yielded a mean increase of 271 ng/dl in the nadir serum testosterone concentration ( to the middle of the normal range for young men ) . The lean body mass ( by dual-energy X-ray absorptiometry ) increase averaged 2.3 kg with testosterone alone and 3.3 kg with combined testosterone and resistance training ( p Increase in one-repetition maximum leg press strength averaged 17.2 % with testosterone alone , 17.4 % with resistance training alone , and 26.8 % with testosterone + resistance training ( p tolerated with no abnormalities in safety measures . Further studies are required to determine long-term benefits of adding testosterone supplementation and resistance training to rehabilitative programs for carefully screened men with COPD and low testosterone levels",
"BACKGROUND Sex hormones are known to affect cholesterol levels and vascular tone in women . The effects of testosterone on cholesterol and vascular tone in men are less well understood . Low testosterone levels have been associated with higher cholesterol levels in epidemiologic studies , but testosterone replacement has result ed in variable changes in cholesterol levels . Similarly , clinical studies suggest that testosterone may be vasodilatory , but few studies have directly evaluated the effects of testosterone on vascular tone . METHODS Sixty-seven men ( mean age 76 + /- 4 years , range 65 - 87 ) with bioavailable testosterone levels below 4.44 nmol/l ( lower limit for adult normal range ) were r and omized to receive transdermal testosterone ( 2 - 2.5 mg patches/d ) or placebo patches for 1 year . Twenty-three men ( 34 % ) withdrew from the study ; 44 men completed the trial . RESULTS While total cholesterol , triglyceride , and low-density lipoprotein cholesterol levels did not significantly change during the year of therapy , high-density lipoprotein ( HDL ) levels ( p = .004 ) and , specifically , HDL(2 ) subfraction ( p = .02 ) decreased in men receiving testosterone supplementation . Vascular tone was measured by brachial artery reactivity in 36 men . Endothelium-dependent brachial artery reactivity did not change from baseline measurements in men receiving transdermal testosterone ( 0.3 + /- 6.7 % to 1.6 + /- 4.6 % ; p = .58 ) or in the placebo group ( 3.2 + /- 5.5 % to 0.7 + /- 5.5 % ; p = .23 ) . CONCLUSIONS Transdermal testosterone decreased HDL(2 ) cholesterol but did not affect vascular reactivity in men older than 65 years selected for low testosterone levels . No study to date has addressed the direct relationship between testosterone replacement and cardiovascular events",
"Testosterone ( T ) levels decline as men age , but it is unclear whether this has an effect on cognition . Some studies indicate that lower T levels are associated with memory loss ; thus , maintaining a higher T level could have positive effects on aspects of cognitive function . Concerns exist , however , about the effect of T therapy on the prostate in older men . We hypothesized that T replacement in older men with low T levels would improve aspects of cognitive function and that the addition of finasteride would not affect the T-induced cognitive improvements . Healthy men , 65 to 83 years of age , with baseline total T below 350 ng/dL and no evidence of cognitive impairment were r and omly assigned to 1 of 3 regimens : 200 mg of T every 2 weeks by intramuscular injection with placebo pill daily ( T-only ) , 200 mg of T every 2 weeks by intramuscular injection with 5 mg of finasteride daily ( T+F ) , or placebo injections and pills ( placebo ) . Sixty-nine men completed baseline cognitive testing ; 65 completed at least 4 months , and 46 completed all 36 months of the study . Participants were given a battery of cognitive evaluations at baseline , 4 months , and 36 months , along with measurement of serum hormone levels . Serum total T , bioavailable T , and estradiol levels in the T-only and T+F groups significantly increased throughout the treatment period , whereas these hormone levels did not change in the placebo group . Only minimally significant differences were seen among the 3 groups in any evaluation of cognitive performance , either in the short-term ( 4 months ) or the long-term ( 36 months ) analysis . These results indicate that T replacement , whether given alone or in combination with finasteride , for 36 months in healthy older men without cognitive impairment at baseline has no clinical ly significant effect on tests of cognitive function . Further studies are warranted to determine whether hormone replacement in men with preexisting cognitive impairment is beneficial",
"IMPORTANCE Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown . A recent r and omized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety . OBJECTIVES To assess the association between testosterone therapy and all-cause mortality , myocardial infa rct ion ( MI ) , or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease . DESIGN , SETTING , AND PATIENTS A retrospective national cohort study of men with low testosterone levels ( coronary angiography in the Veterans Affairs ( VA ) system between 2005 and 2011 . MAIN OUTCOMES AND MEASURES Primary outcome was a composite of all-cause mortality , MI , and ischemic stroke . RESULTS Of the 8709 men with a total testosterone level lower than 300 ng/dL , 1223 patients started testosterone therapy after a median of 531 days following coronary angiography . Of the 1710 outcome events , 748 men died , 443 had MIs , and 519 had strokes . Of 7486 patients not receiving testosterone therapy , 681 died , 420 had MIs , and 486 had strokes . Among 1223 patients receiving testosterone therapy , 67 died , 23 had MIs , and 33 had strokes . At 3 years after coronary angiography , the Kaplan-Meier estimated cumulative percentages with events were 19.9%in the no testosterone therapy group vs 25.7%in the testosterone therapy group , with an absolute risk difference of 5.8%(95%CI , -1.4%to 13.1 % ) [corrected].The Kaplan-Meier estimated cumulative percentages with events among the no testosterone therapy group vs testosterone therapy group at 1 year after coronary angiography were 10.1 % vs 11.3 % ; at 2 years , 15.4 % vs 18.5 % ; and at 3 years , 19.9 % vs 25.7 [corrected].There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease ( test for interaction , P = .41 ) . CONCLUSIONS AND RELEVANCE Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level , the use of testosterone therapy was associated with increased risk of adverse outcomes . These findings may inform the discussion about the potential risks of testosterone therapy",
"BACKGROUND Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men . The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied . METHODS Community-dwelling men , 65 years of age or older , with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter ( 3.5 to 12.1 nmol per liter ) or a free serum testosterone level of less than 50 pg per milliliter ( 173 pmol per liter ) were r and omly assigned to receive placebo gel or testosterone gel , to be applied daily for 6 months . Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification . The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group . RESULTS A total of 209 men ( mean age , 74 years ) were enrolled at the time the trial was terminated . At baseline , there was a high prevalence of hypertension , diabetes , hyperlipidemia , and obesity among the participants . During the course of the study , the testosterone group had higher rates of cardiac , respiratory , and dermatologic events than did the placebo group . A total of 23 subjects in the testosterone group , as compared with 5 in the placebo group , had cardiovascular-related adverse events . The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period . As compared with the placebo group , the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load . CONCLUSIONS In this population of older men with limitations in mobility and a high prevalence of chronic disease , the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events . The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy . ( Clinical Trials.gov number , NCT00240981 .",
"This prospect i ve 2-year , single-center , r and omized , placebo-controlled , open-label clinical trial was performed to evaluate the efficacy of low-dose testosterone undecanoate ( TU ) treatment on bone mineral density ( BMD ) and biochemical markers of bone turnover in elderly male osteoporosis with low serum testosterone . A total of 186 elderly male osteoporosis patients with low serum testosterone were r and omized into three groups : low-dose TU ( 20 mg , per day ) , st and ard-dose TU ( 40 mg , per day ) , and placebo group with a 24-month followup . Since the 6th month in st and ard-dose TU group or since the 12th month followup in low-dose TU group and throughout the study , lumbar spine and femoral neck BMD and serum levels of free testosterone , estradiol , and bone alkaline phosphatase significantly increased . There were no significant differences between groups of low-dose TU and st and ard dose TU in the percentage of changes of these data since the 18th month followup and throughout the study . No side effects on prostate gl and s including prostate specific antigen were found . In conclusion , low-dose TU ( 20 mg , per day ) may be a cost effective and safe protocol for treating elderly male osteoporosis with low serum testosterone",
"CONTEXT Prostate safety is a primary concern when aging men receive testosterone replacement therapy ( TRT ) , but little information is available regarding the effects of TRT on prostate tissue in men . OBJECTIVE To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial of 44 men , aged 44 to 78 years , with screening serum testosterone levels lower than 300 ng/dL ( INTERVENTION Participants were r and omly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months . MAIN OUTCOME MEASURES The primary outcome measure was the 6-month change in prostate tissue and rogen levels ( testosterone and dihydrotestosterone ) . Secondary outcome measures included 6-month changes in prostate-related clinical features , histology , biomarkers , and epithelial cell gene expression . RESULTS Of the 44 men r and omized , 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per- protocol analysis ( TRT , n = 21 ; placebo , n = 19 ) . Testosterone replacement therapy increased serum testosterone levels to the mid-normal range ( median at baseline , 282 ng/dL [ 9.8 nmol/L ] ; median at 6 months , 640 ng/dL [ 22.2 nmol/L ] ) with no significant change in serum testosterone levels in matched , placebo-treated men . However , median prostate tissue levels of testosterone ( 0.91 ng/g ) and dihydrotestosterone ( 6.79 ng/g ) did not change significantly in the TRT group . No treatment-related change was observed in prostate histology , tissue biomarkers ( and rogen receptor , Ki-67 , CD34 ) , gene expression ( including AR , PSA , PAP2A , VEGF , NXK3 , CLU [ Clusterin ] ) , or cancer incidence or severity . Treatment-related changes in prostate volume , serum prostate-specific antigen , voiding symptoms , and urinary flow were minor . CONCLUSIONS These preliminary data suggest that in aging men with late-onset hypogonadism , 6 months of TRT normalizes serum and rogen levels but appears to have little effect on prostate tissue and rogen levels and cellular functions . Establishment of prostate safety for large population s of older men undergoing longer duration of TRT requires further study . Trial Registration clinical trials.gov Identifier : NCT00161304",
"OBJECTIVES To To compare testosterone undecanoate versus propionyl-L-carnitine plus acetyl-L-carnitine and placebo in the treatment of male aging symptoms . METHODS A total of 120 patients were r and omized into three groups . The mean patient age was 66 years ( range 60 to 74 ) . Group 1 was given testosterone undecanoate 160 mg/day , the second group was given propionyl-L-carnitine 2 g/day plus acetyl-L-carnitine 2 g/day . The third group was given a placebo ( starch ) . Drugs and placebo were given for 6 months . The assessed variables were total prostate-specific antigen , prostate volume , peak systolic velocity , end-diastolic velocity , resistive index of cavernosal penile arteries , nocturnal penile tumescence , total and free testosterone , prolactin , luteinizing hormone , International Index of Erectile Function score , Depression Melancholia Scale score , fatigue scale score , and incidence of side effects . The assessment was performed at intervals before , during , and after therapy . RESULTS Testosterone and carnitines significantly improved the peak systolic velocity , end-diastolic velocity , resistive index , nocturnal penile tumescence , International Index of Erectile Function score , Depression Melancholia Scale score , and fatigue scale score . Carnitines proved significantly more active than testosterone in improving nocturnal penile tumescence and International Index of Erectile Function score . Testosterone significantly increased the prostate volume and free and total testosterone levels and significantly lowered serum luteinizing hormone ; carnitines did not . No drug significantly modified prostate-specific antigen or prolactin . Carnitines and testosterone proved effective for as long as they were administered , with suspension provoking a reversal to baseline values . Only the group 1 prostate volume proved significantly greater than baseline 6 months after testosterone suspension . Placebo administration proved ineffective . Negligible side effects emerged . CONCLUSIONS Testosterone and , especially , carnitines proved to be active drugs for the therapy of symptoms associated with male aging",
"objectives We have recently shown that , in men with erectile dysfunction ( ED ) , free testosterone ( FT ) directly correlates with penile arterial inflow . This led us to further investigate the effect(s ) of and rogen administration on cavernous arteries in patients failing sildenafil treatment",
"The stimulatory effects of testosterone on erythropoiesis are very well known , but the mechanisms underlying the erythropoietic action of testosterone are still poorly understood , although erythropoietin has long been considered a potential mediator . A total of 108 healthy men > 65 years old with serum testosterone concentration and r and omized to receive a 60‐cm2 testosterone or placebo patch for 36 months . Ninety‐six subjects completed the trial . We used information and stored serum specimens from this trial to test the hypothesis that increasing testosterone increases haemoglobin by stimulating erythropoietin production . We used information of 67 men , 43 in the testosterone group and 24 in the placebo group who had banked specimens available for assays of testosterone , haemoglobin and erythropoietin at baseline and after 36 months . The original r and omized clinical study was primarily design ed to verify the effects of testosterone on bone mineral density . The primary outcome of this report was to investigate whether or not transdermal testosterone increases haemoglobin by increasing erythropoietin levels . The mean age ± SD of the 67 subjects at baseline was 71.8 ± 4.9 years . Testosterone replacement therapy for 36 months , as compared with placebo , induced a significant increase in haemoglobin ( 0.86 ± 0.31 g/dL , p = 0.01 ) , but no change in erythropoietin levels ( −0.24 ± 2.16 mIU/mL , p = 0.91 ) . Included time‐varying measure of erythropoietin did not significantly account for the effect of testosterone on haemoglobin ( Treatment‐by‐time : β = 0.93 , SE = 0.33 , p = 0.01 ) . No serious adverse effect was observed . Transdermal testosterone treatment of older men for 36 months significantly increased haemoglobin , but not erythropoietin levels . The haematopoietic effect of testosterone does not appear to be mediated by stimulation of erythropoietin production ",
"OBJECTIVE Hypogonadism and subthreshold depression are common conditions in elderly men . The objective of this study was to examine the effect of testosterone treatment in older , hypogonadal men with subthreshold depression . METHOD A r and omized , double-blind , placebo-controlled study was conducted at a university-affiliated Veterans Affairs Medical Center among men aged 50 years or older ( N = 33 ) with screening total testosterone levels of Recruitment for the study was conducted from November 2002 through May 2005 . Participants received either 7.5 g of testosterone gel or placebo gel daily for 12 weeks , followed by a 12-week open-label extension phase during which all subjects received 7.5 g of testosterone gel . The primary outcome measure was the change in the Hamilton Rating Scale for Depression ( HAM-D ) score from baseline to the end of the double-blind phase . Secondary outcome measures were remission of subthreshold depression ( defined a priori as a HAM-D score changes in the Hopkins Symptom Checklist depression scale , the Medical Outcomes Study 36-Item Short-Form Health Survey , and the short-form 16-item Quality of Life Enjoyment and Satisfaction Question naire . RESULTS At the end of the double-blind phase , testosterone-treated men had a greater reduction in HAM-D scores ( p = .024 ) and a higher remission rate of subthreshold depression ( 52.9 % vs. 18.8 % , p = .041 ) than did placebo-treated men , but there were no differences in other secondary outcome measures between groups . At the end of the open-label phase , the testosterone group had sustained improvement , the control group improved , and there were no differences between groups in any outcome measures . CONCLUSION These results suggest that testosterone replacement may be efficacious treatment for subthreshold depression in older men with hypogonadism . Larger studies are needed to corroborate these findings . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00202462",
"Growth hormone is the major regulator of growth and body composition . Pulsatile GH secretion declines exponentially with age . Testosterone replacement is being increasingly offered to older men with age-related low testosterone . Testosterone administration has been shown to stimulate GH secretion . However , little is known about the effect of testosterone aromatization to estradiol on GH pulsatility and its impact on IGF-1 in older men . OBJECTIVE This r and omized controlled proof-of-concept trial investigated the relative effects of testosterone and estradiol on GH pulsatility and IGF-1 in older men with low testosterone . DESIGN Thirty-seven men , ≥65years with total testosterone r and omized to 5 g transdermal testosterone gel ( TT ) , 1 mg oral aromatase inhibitor ( AI ) or placebo daily for 12months . Primary outcome was deconvolution and approximate entropy analyses of pulsatile including basal and entropic modes of secretion performed at baseline and 3months . Secondary outcomes included IGF-1 evaluated at baseline , 3 and 6months . RESULTS At 3months , mean GH and in IGF-1 were similar between the three groups . At 6months , IGF-1 significantly increased by Δ 15.3±10.3ng/ml in the TT-group compared to placebo ( P=0.03 ) . Both intervention groups significantly increased GH pulse frequency ( TT-group , P=0.04 ; AI-group , P=0.05 ) compared to placebo . The GH secretory-burst mode ( duration ) significantly decreased in the TT-group ( P=0.0018 ) compared to placebo while it remained unchanged in the AI-group ( P=0.059 ) . CONCLUSIONS In older men , testosterone increases GH pulse frequency while the aromatization to estradiol is involved in the rise of IGF-1 levels",
"INTRODUCTION Addition of testosterone ( T ) may improve the action of phosphodiesterase type 5 inhibitors ( PDE5-Is ) in patients with erectile dysfunction not responding to PDE5-Is with low or low-normal T levels . AIMS To confirm this add-on effect of T in men optimally treated with PDE5-Is and to specify the baseline T levels at which such an effect becomes significant . METHODS A multicenter , multinational , double-blind , placebo-controlled study of 173 men , 45 - 80 years , nonresponders to treatment with different PDE5-Is , with baseline total T levels ≤ 4 ng/mL or bioavailable T ≤ 1 ng/mL. Men were first treated with tadalafil 10 mg once a day ( OAD ) for 4 weeks ; if not successful , they were r and omized in a double-blind , placebo-controlled design to receive placebo or a 1 % hydroalcoholic T gel ( 50 mg/5 g gel ) , to be increased to 10 mg T if results were clinical ly unsatisfactory . Main Outcomes Measures . Mean change from baseline in the Erectile Function Domain Score of the International Index of Erectile Function and rate of successful intercourses ( Sexual Encounter Profile 3 question ) . RESULTS Erectile function progressively improved over a period of at least 12 weeks in both the placebo and T treatment groups . In the overall population with a mean baseline T level of 3.37 ± 1.48 ng/mL , no additional effect of T administration to men optimally treated with PDE5-Is was encountered . The differences between the T and placebo groups were significant for both criteria only in the men with baseline T ≤ 3 ng/mL. CONCLUSIONS The maximal beneficial effects of OAD dosing with 10 mg tadalafil may occur only after as many as 12 weeks . Furthermore , addition of T to this PDE5-I regimen is beneficial , but only in hypogonadal men with baseline T levels ≤ 3",
"Introduction : The clinical significance of low to low-normal testosterone ( T ) levels in men remains debated . Aim : To analyze the effects of raising serum T on lean body mass ( LBM ) , fat mass ( FM ) , total body mass , and health-related quality -of-life ( HRQoL ) . Methods : R and omized , double-blind , placebo-controlled study . Men , aged 50–80 years , with serum total T 36 , received 6 months treatment with transdermal 1 % T gel ( 5–7.5 mg/day ; n = 183 ) or placebo gel ( n = 179 ) , followed by 12 months open-label with T in all . Results : After 6 months , LBM increased in T- treated patients by 1.28 ± 0.15 kg ( mean ± SE ) and FM decreased by 1.16 ± 0.16 kg , with minor changes with placebo ( LBM + 0.02 ± 0.10 kg and FM −0.14 ± 0.12 kg ; all p subgroups of age , baseline total testosterone , and baseline BMI . Total HRQoL improved compared with placebo ( p 1 % T gel improved body composition and HRQoL in symptomatic men with low to low-normal T , with further improvements over the following 12 months",
"We used longitudinal data from the Massachusetts Male Aging Study , a large population -based r and om- sample cohort of men aged 40 - 70 yr at baseline , to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends . Of 1,709 men enrolled in 1987 - 1989 , 1,156 were followed up 7 - 10 yr afterward . By repeated- measures statistical analysis , we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data , the cross-sectional trend between subjects within the follow-up data , and the longitudinal trend within subjects between baseline and follow-up . Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data , whereas both free and albumin-bound T declined at about 2%/yr , all significantly more steeply than within the baseline data . Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data , similarly to baseline . The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T ( 1.6%/yr ) and bioavailable T ( 2 - 3%/yr ) . Dehydroepi and rosterone , dehydroepi and rosterone sulfate , cortisol , and estrone showed significant longitudinal declines , whereas dihydrotestosterone , pituitary gonadotropins , and PRL rose longitudinally . Apparent good health , defined as absence of chronic illness , prescription medication , obesity , or excessive drinking , added 10 - 15 % to the level of several and rogens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends . The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in and rogen levels",
"Clinical studies suggest there may be a threshold concentration of serum testosterone below which replacement will result in skeletal and psychological benefit . We evaluated the response to testosterone in men with borderline hypogonadism . A r and omized double-blind placebo-controlled trial in 39 men over age 40 years presenting with sexual dysfunction and a borderline low testosterone level ( total testosterone Patients were r and omized to Testoderm TTS body patch ( 5 mg/day , n = 20 ) or a placebo patch ( n = 19 ) for 6 months , followed by open-label testosterone replacement for a further 6 months in all patients . During the placebo-controlled phase of the study serum testosterone increased significantly on testosterone vs. placebo treatment ( p = 0.004 ) ; this was associated with a decrease in total body fat mass ( p = 0.019 ) and increase in haemoglobin level ( p = 0.036 ) . There were no significant changes in lean body mass , markers of bone turnover , and measures of bone mineral density ( BMD ) . There was evidence of difference in quality of life according to the Male Erectile Dysfunction Quality of Life question naire ( MEDQoL score , p = 0.017 ) , mainly accounted for by deterioration in the placebo arm . When the active treatment period was combined for placebo and testosterone groups , the within-patient analysis showed a significant effect of testosterone to decrease markers of bone resorption ( uNTX/Cr , p = 0.007 ; iFDPD/Cr , p = 0.0006 ) and to increase lean body mass ( p = 0.001 ) . There was little convincing evidence from this study that testosterone replacement is likely to have major benefit in men over age 40 years with borderline hypogonadism and sexual dysfunction . However , there was evidence of suppression in bone resorption and hence longer and larger studies are needed to examine its effect on BMD",
"The cardiovascular effects of testosterone treatment are debated . Osteoprotegerin ( OPG ) is an independent marker of cardiovascular risk . We investigated the effect of testosterone therapy on OPG levels in aging men with low normal bioavailable testosterone levels . A r and omized , double-blinded , placebo-controlled study of 6 months testosterone therapy ( gel ) in 38 men aged 60 - 78 years with bioavailable testosterone 94 cm was performed . Clinical evaluation , OPG , and C-reactive protein ( CRP ) measurements were carried out . Lean body mass ( LBM ) , total fat mass , and bone mineral density ( BMD ) were established by dual X-ray absorptiometry . Visceral adipose tissue ( VAT ) and subcutaneous adipose tissue ( SAT ) were measured by magnetic resonance imaging . Power calculation was based on an increase in LBM during testosterone therapy and responders were defined as testosterone treated patients with increased LBM ( Δ LBM positive ) , n=14 . Data are presented as median ( interquartile range ) . Testosterone therapy decreased total fat mass and SAT , whereas VAT was unchanged ( n=38 ) . OPG levels decreased during testosterone therapy ( from 2.0 ( 1.9 - 2.5 ) to 1.9 ( 1.6 - 2.2 ) ng/ml , p whereas CRP levels were unchanged ( n=38 ) . In responders to testosterone therapy ( n=14 ) , ΔOPG levels were inversely associated with ΔSAT ( r= - 0.60 , p=0.03 ) and positively associated with ΔVAT ( r=0.56 , p=0.04 ) . OPG levels decreased during testosterone therapy suggesting decreased cardiovascular risk . Decreased OPG levels were associated with changes in regional fat distribution and future studies are needed to further evaluate the association between OPG and regional fat mass distribution",
"A decline in testicular function is recognized as a common occurrence in older men . However data are sparse regarding the effects of hypogonadism on age-associated physical and cognitive declines . This study was undertaken to examine the year-long effects of testosterone administration in this patient population . Fifteen hypogonadal men ( mean age 68 + /- 6 yr ) were r and omly assigned to receive a placebo , and 17 hypogonadal men ( mean age 65 + /- 7 yr ) were r and omly assigned to receive testosterone . Hypogonadism was defined as a bioavailable testosterone placebo or 200 mg testosterone cypionate biweekly for 12 months . The main outcomes measured included grip strength , hemoglobin , prostate-specific antigen , leptin , and memory . Testosterone improved bilateral grip strength ( P hemoglobin ( P testosterone had greater decreases in leptin than those assigned to the control group ( mean + /- SEM : -2.0 + /- 0.9 ng/dL vs. 0.8 + /- 0.7 ng/dL ; P prostate-specific antigen or memory . Three subjects receiving placebo and seven subjects receiving testosterone withdrew from the study . Three of those seven withdrew because of an abnormal elevation in hematocrit . Testosterone supplementation improved strength , increased hemoglobin , and lowered leptin levels in older hypogonadal men . Testosterone may have a role in the treatment of frailty in males with hypogonadism ; however , older men receiving testosterone must be carefully monitored because of its potential risks",
"Muscle wasting in older men may be related to and rogen deficiency . We have assessed the effect of testosterone replacement therapy on muscle function in the upper and lower limbs of older ( age > 60 years ) men with blood testosterone levels received testosterone enanthate 200 mg i.m . or placebo every 2 weeks in a double blind study over a 12-week period and underwent muscle testing every 4 weeks . A significant increase in blood levels of testosterone and a reduction in levels of sex hormone binding globulin occurred in the treatment group . Total body mass , haemoglobin and packed cell volume also increased significantly ( p h and grip strength , isometric strength of knee flexors and extensors or leg extensor power were seen in either group . Wide variability in all measures of muscle function were observed in these elderly men suggesting that very large study groups would be required to determine potential treatment benefits on muscle function",
"Men have a higher incidence of cardiovascular disease ( CVD ) than women of similar age , and it has been suggested that testosterone may influence the development of CVD . Recently , we demonstrated that elderly men with low testosterone levels had lower plasma levels of free tissue factor pathway inhibitor ( TFPI ) Ag associated with shortened tissue factor (TF)-induced coagulation initiation in a population based case-control study . Our hypothesis was that one year of testosterone treatment to physiological levels in elderly men would increase the levels of free TFPI Ag in plasma and have a favorable effect on TF-induced coagulation . Twenty-six men with low testosterone levels ( were r and omly assigned to treatment with intramuscular testosterone depot injections ( testosterone undecanoate 1,000 mg ) or placebo in a double-blinded study . Each participant received a total of five injections , at baseline , 6 , 16 , 28 and 40 weeks , and TF-induced thrombin generation ex vivo and plasma free TFPI Ag were measured after one year . At the end of the study total and free testosterone levels were significantly higher in the testosterone treated group ( 14.9 + /- 4.5 nM vs. 8.1 + /- 2.4 nM ; p Testosterone treatment for one year did neither cause significant changes in TF-induced thrombin generation ex vivo nor changes in plasma levels of free TFPI Ag . In conclusion , normalising testosterone levels by testosterone treatment for 12 months in elderly men did not affect TF-induced coagulation or plasma TFPI levels . The potential antithrombotic role of testosterone therapy remains to be eluci date",
"CONTEXT Physical frailty is associated with reduced muscle strength , impaired physical function , and quality of life . Testosterone ( T ) increases muscle mass and strength in hypogonadal patients . It is unclear whether T has similar effects in intermediate-frail and frail elderly men with low to borderline-low T. OBJECTIVE Our objective was to determine the effects of 6 months T treatment in intermediate-frail and frail elderly men , on muscle mass and strength , physical function , and quality of life . DESIGN AND SETTING We conducted a r and omized , double-blind , placebo-controlled , parallel-group , single-center study . PARTICIPANTS PARTICIPANTS were community-dwelling intermediate-frail and frail elderly men at least 65 yr of age with a total T at or below 12 nmol/liter or free T at or below 250 pmol/liter . METHODS Two hundred seventy-four participants were r and omized to transdermal T ( 50 mg/d ) or placebo gel for 6 months . Outcome measures included muscle strength , lean and fat mass , physical function , and self-reported quality of life . RESULTS Isometric knee extension peak torque improved in the T group ( vs. placebo at 6 months ) , adjusted difference was 8.6 ( 95 % confidence interval , 1.3 - 16.0 ; P = 0.02 ) Newton-meters . Lean body mass increased and fat mass decreased significantly in the T group by 1.08 + /- 1.8 and 0.9 + /- 1.6 kg , respectively . Physical function improved among older and frailer men . Somatic and sexual symptom scores decreased with T treatment ; adjusted difference was -1.2 ( -2.4 to -0.04 ) and -1.3 ( -2.5 to -0.2 ) , respectively . CONCLUSIONS T treatment in intermediate-frail and frail elderly men with low to borderline-low T for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition , quality of life , and physical function . Further investigations are warranted to extend these results",
"BACKGROUND Loss of muscle mass ( sarcopenia ) leads to frailty in older men . The decline in testosterone over the life span may contribute to this muscle loss . We studied the ability of oral testosterone to prevent muscle loss in older men over a 12-month period . METHODS A st and ard dose ( 80 mg twice daily ) of testosterone undecanoate or placebo was administered for 1 year to 76 healthy men aged 60 years or older . All men had a free testosterone index of 0.3 - 0.5 , which represents a value below the normal lower limit for young men ( 19 - 30 years ) , but remains within the overall normal male range . Measurements of body composition , muscle strength , hormones , and safety parameters were obtained at 0 , 6 , and 12 months . RESULTS Lean body mass increased ( p = .0001 ) and fat mass decreased ( p = .02 ) in the testosterone as compared with the placebo-treated group . There were no significant effects on muscle strength . There was a significant increase in hematocrit ( 0.02 % ) in the testosterone-treated group ( p = .03 ) . Plasma triglycerides , total cholesterol , and low-density lipoprotein cholesterol levels were similar in both groups , but there was a decrease in high-density lipoprotein cholesterol ( -0.1 mmol/L ) at 12 months in the testosterone group as compared to the placebo group ( p = 0.026 ) . There were no differences in prostate-specific antigen or systolic or diastolic blood pressure between the groups . CONCLUSION Oral testosterone administration to older relatively hypogonadal men results in an increase in muscle mass and a decrease in body fat",
"IMPORTANCE Testosterone use in older men is increasing , but its long-term effects on progression of atherosclerosis are unknown . OBJECTIVE To determine the effect of testosterone administration on sub clinical atherosclerosis progression in older men with low or low-normal testosterone levels . DESIGN , SETTING , AND PARTICIPANTS Testosterone 's Effects on Atherosclerosis Progression in Aging Men ( TEAAM ) was a placebo-controlled , double-blind , parallel-group r and omized trial involving 308 men 60 years or older with low or low-normal testosterone levels ( 100 - 400 ng/dL ; free testosterone Recruitment took place between September 2004 and February 2009 ; the last participant completed the study in May 2012 . INTERVENTIONS One hundred fifty-six participants were r and omized to receive 7.5 g of 1 % testosterone and 152 were r and omized to receive placebo gel packets daily for 3 years . The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. MAIN OUTCOMES AND MEASURES Co primary outcomes included common carotid artery intima-media thickness and coronary artery calcium ; secondary outcomes included sexual function and health-related quality of life . RESULTS Baseline characteristics were similar between groups : patients were a mean age of 67.6 years ; 42 % had hypertension ; 15 % , diabetes ; 15 % , cardiovascular disease ; and 27 % , obesity . The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group ( mean difference adjusted for age and trial site , 0.0002 mm/year ; 95 % CI , -0.003 to 0.003 , P = .89 ) . The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group ( adjusted mean difference , -10.8 Agatston units/year ; 95 % CI , -45.7 to 24.2 ; P = .54 ) . Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone . Sexual desire , erectile function , overall sexual function scores , partner intimacy , and health-related quality of life did not differ significantly between groups . Hematocrit and prostate-specific antigen levels increased more in testosterone group . CONCLUSIONS AND RELEVANCE Among older men with low or low-normal testosterone levels , testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life . Because this trial was only powered to evaluate atherosclerosis progression , these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00287586",
"Several r and omized trials of and rogen supplementation in older men have been undertaken . However , the relative contributions of testosterone ( T ) and estrogens on bone metabolism in aging men are controversial . Within the setting of two double-blind , placebo-controlled studies , we evaluated the effect of dihydrotestosterone ( DHT ) and recombinant human chorionic gonadotropin ( rhCG ) on bone turnover in healthy , community-dwelling older men with partial and rogen deficiency ( total T In the first study , 35 men ( age 68.3 + /- 6.8 yr ; baseline T , 13.9 + /- 3.3 nmol/liter ) were r and omized to receive either daily transdermal DHT ( n = 17 ) or placebo for 3 months . In the second study , 40 men ( age 67.4 + /- 5.4 yr ; baseline T , 11.4 + /- 2.2 nmol/liter ) were r and omized to receive either rhCG s.c . ( n = 20 ) , two injections weekly , or placebo for 3 months . The following parameters were measured before , monthly during , and 1 month after treatment : serum T , estradiol ( E2 ) , and LH ; markers of bone formation , serum amino-terminal propeptide of type I procollagen ( S-PINP ) and osteocalcin ; markers of bone resorption , serum carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline . Compared with placebo , treatment with DHT significantly increased serum DHT and suppressed LH and T levels , whereas E2 concentrations and markers of bone turnover did not change . In contrast , rhCG therapy significantly increased both T and E2 , with the increases in E2 being supraphysiological . At the same time , rhCG significantly increased S-PINP concentrations with peak levels after 1 month ( Delta40 % ; P = 0.02 compared with placebo ) . In contrast , serum osteocalcin and carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline levels did not change . The change in S-PINP levels correlated with the change in E2 levels ( r = 0.59 ; P = 0.02 ) but not with a change in T. We conclude that in older men with partial age-related and rogen deficiency , rhCG treatment stimulates osteoblastic collagen formation proportionally to increased E2 concentrations but does not alter markers of mature osteoblastic function or bone resorption . In contrast , treatment with a pure , nonaromatizable and rogen ( DHT ) has no effect on bone turnover despite a 20-fold increase in serum levels . Bone resorption was not accelerated during unchanged ( DHT ) or increased ( rhCG ) E2 levels , suggesting that minimal E2 levels are needed to maintain stable resorption , although direct and rogen receptor-mediated effects can not be excluded . If and rogen supplementation is required for aging men , aromatizable and rogens with sufficient endogenous estrogenic activity may have the most beneficial effects on bone",
"And rogen therapy may precipitate obstructive sleep apnea in men . Despite increasing and rogen use in older men , few studies have examined sleep and breathing . R and omized , double-blind , placebo-controlled studies examining effects of testosterone simultaneously on sleep , breathing , and function in older men are not available . Seventeen community-dwelling healthy men over the age of 60 yr were r and omized to receive three injections of i m testosterone esters at weekly intervals ( 500 mg , 250 mg , and 250 mg ) or matching oil-based placebo and then crossed over to the other treatment after 8 wk of washout . Polysomnography , anthropometry , and physical , mental , and metabolic function were assessed at baseline and after each treatment period . Testosterone treatment reduced total time slept ( approximately 1 h ) , increased the duration of hypoxemia ( approximately 5 min/night ) , and disrupted breathing during sleep ( total and non-rapid eye movement respiratory disturbance indices both increased by approximately seven events per hour ) ( all P body composition ( increase in total and lean mass , reduction in fat mass , P bioimpedance method ) , upper airway dimensions did not change ( acoustic reflectometry ) . Driving ability ( computer simulation ) , physical activity ( accelerometry , Physical Activity Scale in the Elderly ) , quality of life ( SF36 , Functional Outcomes of Sleep Question naire ) , mood ( Profile of Mood States Question naire ) , sleepiness ( Epworth , Stanford scales ) , and insulin resistance ( homeostasis model ) also were not changed by treatment . Short-term administration of high-dose testosterone shortens sleep and worsens sleep apnea in older men but did not alter physical , mental , or metabolic function . These changes did not appear to be due to upper airway narrowing . Further study of longer-term lower-dose and rogen therapy on sleep and breathing is needed to evaluate its safety in older men",
"OBJECTIVE The objective of the study was to assess the effect of T treatment on constitutional and sexual symptoms in men with type 2 diabetes ( T2D ) . DESIGN This was a r and omized double-blind , parallel , placebo-controlled trial . SETTING The study was conducted at a tertiary referral center . PATIENTS Men aged 35 - 70 years with T2D , a hemoglobin A1c less than 8.5 % , and a total T level less than 12.0 nmol/L ( 346 ng/dL ) with mild to moderate aging male symptoms and erectile dysfunction . INTERVENTION Eighty-eight participants were r and omly assigned to 40 weeks of i m T undecanoate ( n = 45 ) or matching placebo ( n = 43 ) . MAIN OUTCOME MEASURES Constitutional symptoms using the aging male symptoms ( AMS ) score , sexual desire ( question 17 AMS score ) , and erectile function ( International Index of Erectile Function-5 ) . RESULTS T treatment did not substantially improve aging male symptoms [ mean adjusted difference ( MAD ) in change over 40 weeks across the T and placebo groups in AMS total score , -0.9 ( 95 % confidence interval [ CI ] -4.1 , 2.2 ) , P = .67 ] or sexual desire [ MAD in question 17 AMS , -0.3 ( 95 % CI -0.8 , 0.2 ) , P = .17 ] . Although compared with placebo , erectile function in men assigned to T was reduced [ MAD in International Index of Erectile Function abridged version 5 , -2.0 ( 95 % CI -3.4 , -0.6 ) , P International Index of Erectile Function abridged version 5 scores if both groups were analyzed separately . At baseline , symptoms were worse in men with depression and microvascular complications but did not correlate with T levels . CONCLUSIONS In this trial , T treatment did not substantially improve constitutional or sexual symptoms in obese , aging men with T2D with mild to moderate symptoms and modest reduction in T levels typical for the vast majority of such men",
"BACKGROUND Dehydroepi and rosterone ( DHEA ) and testosterone are widely promoted as antiaging supplements , but the long-term benefits , as compared with potential harm , are unknown . METHODS We performed a 2-year , placebo-controlled , r and omized , double-blind study involving 87 elderly men with low levels of the sulfated form of DHEA and bioavailable testosterone and 57 elderly women with low levels of sulfated DHEA . Among the men , 29 received DHEA , 27 received testosterone , and 31 received placebo . Among the women , 27 received DHEA and 30 received placebo . Outcome measures included physical performance , body composition , bone mineral density ( BMD ) , glucose tolerance , and quality of life . RESULTS As compared with the change from baseline to 24 months in the placebo group , subjects who received DHEA for 2 years had an increase in plasma levels of sulfated DHEA by a median of 3.4 microg per milliliter ( 9.2 micromol per liter ) in men and by 3.8 microg per milliliter ( 10.3 micromol per liter ) in women . Among men who received testosterone , the level of bioavailable testosterone increased by a median of 30.4 ng per deciliter ( 1.1 nmol per liter ) , as compared with the change in the placebo group . A separate analysis of men and women showed no significant effect of DHEA on body-composition measurements . Neither hormone altered the peak volume of oxygen consumed per minute , muscle strength , or insulin sensitivity . Men who received testosterone had a slight increase in fat-free mass , and men in both treatment groups had an increase in BMD at the femoral neck . Women who received DHEA had an increase in BMD at the ultradistal radius . Neither treatment improved the quality of life or had major adverse effects . CONCLUSIONS Neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition , physical performance , insulin sensitivity , or quality of life . ( Clinical Trials.gov number , NCT00254371 [ Clinical Trials.gov ] . )",
"BACKGROUND This study assessed the feasibility of a 12-week program of exercise , with and without intramuscular testosterone supplementation , in male patients with chronic heart failure ( CHF ) and low testosterone status and collected preliminary data for key health outcomes . METHODS Male patients with CHF ( n = 41 , age 67.2 years , range 51 - 84 years ) with mean ± SD testosterone levels of 10.7 ± 2.6 nmol/L ( 309 ± 76 ng/dL ) were r and omly allocated to exercise with testosterone or placebo groups . Feasibility was assessed in terms of recruitment , intervention compliance , and attrition . Outcomes included an incremental shuttle walk test , peak oxygen uptake , muscular strength , echocardiographic measures , N-terminal pro-brain natriuretic peptide , inflammatory markers , depression ( Beck Depression Inventory ) , and health-related quality of life ( Minnesota Living with Heart Failure Question naire and Medical Outcomes Study Short-Form ) . RESULTS Attrition was 30 % but with 100 % compliance to exercise and injections in patients who completed the study . Similar improvements in shuttle walk test ( 18 % vs 19 % ) , body mass ( -1.3 kg vs -1.0 kg ) , and h and grip strength ( 2.1 kg vs 2.5 kg ) from baseline were observed in both groups . The exercise with testosterone group showed improvements from baseline in peak oxygen uptake ( P ( P ( P domains ( P the exercise with placebo group . Echocardiographic measures , N-terminal pro-brain natriuretic peptide , and inflammatory markers were mostly unchanged . CONCLUSIONS This study shows for the first time that testosterone supplementation during a program of exercise rehabilitation is feasible and can positively impact on a range of key health outcomes in elderly male patients with CHF who have a low testosterone status",
"To assess the effect of testosterone treatment on bone remodelling and density in dieting obese men , 100 obese men aged 53 years ( interquartile range 47–60 ) with a total testosterone level were r and omly assigned at baseline to 56 weeks of intramuscular testosterone undecanoate ( n = 49 , cases ) or matching placebo ( n = 51 , controls ) . Pre-specified outcomes were between-group differences ( mean adjusted difference , MAD ) in serum c-telopeptide ( CTx ) , N-terminal propeptide of type 1 procollagen ( P1NP ) and bone mineral density ( BMD ) . At trial end , CTx was significantly reduced in men receiving testosterone compared to placebo , MAD −66 ng/L ( 95 % CI −113 , −18 ) , p = 0.018 , and this was apparent already after the 10 week VLED phase , MAD −63 ng/L ( 95 % CI −108 , −18 ) , p = 0.018 . P1NP was marginally increased after VLED , MAD + 4.2 ug/L ( 95 % CI −0.01 , + 8.4 ) , p = 0.05 but lower at study end , MAD −5.6 ug/L ( 95 % CI −10.1 , −1.1 ) , p = 0.03 . No significant changes in sclerostin , lumbar spine BMD or femoral BMD were seen . We conclude that in obese men with low testosterone levels undergoing weight loss , bone remodelling markers are modulated in a way that may have favourable effects on bone mass",
"OBJECTIVES To investigate the effects of testosterone supplementation on bone , body composition , muscle , physical function , and safety in older men . DESIGN Double-blind , r and omized , placebo-controlled trial . SETTING A major medical institution . PARTICIPANTS One hundred thirty-one men ( mean age 77.1 + /- 7.6 ) with low testosterone , history of fracture , or bone mineral density ( BMD ) T-score less than -2.0 and frailty . INTERVENTION Participants received 5 mg/d of testosterone or placebo for 12 to 24 months ; all received calcium ( 1500 mg/d diet and supplement ) and cholecalciferol ( 1,000 IU/d ) . MEASUREMENTS BMD of hip , lumbar spine , and mid-radius ; body composition ; sex hormones , calcium-regulating hormones ; bone turnover markers ; strength ; physical performance ; and safety parameters . RESULTS Ninety-nine men ( 75.6 % ) completed 12 months , and 62 ( 47.3 % ) completed end therapy ( mean 23 months ; range 16 - 24 months for 62 who completed therapy ) . Study adherence was 54 % , with 40 % of subjects maintaining 70 % or greater adherence . Testosterone and bioavailable testosterone levels at 12 months were 583 ng/dL and 157 ng/dL , respectively , in the treatment group . BMD on testosterone increased 1.4 % at the femoral neck and 3.2 % at the lumbar spine ( P=.005 ) and decreased 1.3 % at the mid-radius ( P lean mass and a decrease in fat mass in the testosterone group but no differences in strength or physical performance . There were no differences in safety parameters . CONCLUSION Older , frail men receiving testosterone replacement increased testosterone levels and had favorable changes in body composition , modest changes in axial BMD , and no substantial changes in physical function",
"OBJECTIVE To investigate the effects of oral testosterone undecanoate ( TU ) on symptoms associated with late-onset hypogonadism ( LOH ) . Design Multicenter , r and omized , double-blind , placebo-controlled . METHODS The study was performed in 14 study centers in seven European countries . Men > or = 50 years ( n=322 ) with symptoms of hypogonadism and testosterone deficiency ( calculated free testosterone and treated for 12 months with placebo or oral TU 80 , 160 or 240 mg/day . Primary outcome was the total score on the Aging Males ' Symptoms ( AMS ) rating scale after six months of treatment . RESULTS Treatment of mild-to-moderate LOH symptoms in subjects with borderline hypogonadism with oral TU result ed in an improved total AMS score at month 6 , but differences between groups were not statistically significant . There was greater improvement in subjects when compared with subjects > or = 60 years ( P=0.001 ) , but baseline testosterone level had no influence on treatment response . The AMS sexual symptoms domain improved with oral TU 160 mg/day at months 6 ( P=0.008 ) and 12 ( P=0.012 ) compared with placebo , but not with 80 and 240 mg/day . Treatment was well-tolerated and there were no between-group differences in adverse events or drop-out rates . CONCLUSIONS In one of the largest placebo-controlled studies of testosterone therapy in LOH , oral TU did not improve total AMS score in subjects with mild-to-moderate symptoms compared with placebo , except the sexual symptom sub-domain where a modest improvement was reported with oral TU 160 mg/day",
"BACKGROUND Erectile dysfunction and low testosterone levels frequently occur together . OBJECTIVE To determine whether addition of testosterone to sildenafil therapy improves erectile response in men with erectile dysfunction and low testosterone levels . DESIGN R and omized , double-blind , parallel , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00512707 ) SETTING Outpatient academic research center . PARTICIPANTS Men aged 40 to 70 years with scores of 25 or less for the erectile function domain ( EFD ) of the International Index of Erectile Function , total testosterone levels less than 11.45 nmol/L ( free testosterone levels less than 173.35 pmol/L ( INTERVENTION Sildenafil dose was optimized , and 140 participants were then r and omly assigned to 14 weeks of daily transdermal gel that contained 10-g testosterone for 70 participants and placebo for the remaining 70 participants . All participants were included in the primary analysis , although 10 in the testosterone group and 12 in the placebo group did not complete the study . RESULTS At baseline , the 2 groups had similar EFD scores . Administration of sildenafil alone was associated with a substantial increase in EFD score ( mean , 7.7 [ 95 % CI , 6.5 to 8.8 ] ) , but change in EFD score after r and omization did not differ between the groups ( difference , 2.2 [ CI , -0.8 to 5.1 ] ; P = 0.150 ) . The findings were similar for other domains of sexual function in younger men , more obese men , and men with lower baseline testosterone levels or an inadequate response to sildenafil alone . Frequency of adverse events was similar for testosterone and placebo groups . LIMITATION Whether testosterone could improve erectile function without sildenafil was not studied . CONCLUSION Sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with erectile dysfunction and low testosterone levels . PRIMARY FUNDING SOURCE National Institute of Child Health and Human Development"
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Antioxidant micronutrients and essential fatty acids supplementation intake appears to have a protective effect in some diseases such as cardiovascular disease , cancer , and asthma . The aim of this study was to perform a systematic review to evaluate the effects of these nutrients on nutritional and clinical outcomes of patients with cystic fibrosis ( CF ) . This is a systematic review of r and omized clinical trials ( RCTs ) in CF . MEDLINE ( via PubMed ) , Embase , and Scopus data bases were search ed for RCTs published from 1948 through February 2019 . Two investigators independently review ed the titles and abstract s and then extracted the data from the included studies using a st and ardized pre design ed form . Two review ers independently performed the quality assessment of the RCTs according to the Cochrane risk of bias tools . A total of 4,792 studies were identified , and 23 were eligible ( 8 antioxidant micronutrient and 15 essential fatty acids ) . The interventions found were beta-carotene , zinc , magnesium , multivitamin , docosahexaenoic acid ( DHA ) , eicosapentaenoic acid ( EPA ) , linoleic acid and lipid matrix with choline supplementation . A significant improvement was observed in : ( a ) pulmonary function with magnesium ( n=1 ) and essential fatty acids ( n=2 ) supplementation ; ( b ) less pulmonary exacerbations with beta-carotene ( n=1 ) , zinc ( n=1 ) , antioxidant-enriched multivitamin ( n=1 ) and essential fatty acids ( n=2 ) supplementation . One study with antioxidant-enriched multivitamin and four studies with EPA/DHA supplementation reported significant reductions in inflammatory markers . Nutritional status was not modified by antioxidants supplementation in any of the studies , while in five studies there was an improvement with fatty acids supplementation . The risk of bias of the majority of the parallel studies was high . The benefits of antioxidants or DHA/EPA supplementation for CF , although observed in some studies , are not consistent enough to recommend routine use of these supplements . The mechanisms of action of these nutrients , dose levels and timing should be further explored in future studies
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"The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis . Such a model could help research ers and clinicians to evaluate therapies , improve the design of prospect i ve studies , monitor practice patterns , counsel individual patients , and determine the best c and i date s for lung transplantation . The authors used information from the Cystic Fibrosis Foundation Patient Registry ( CFFPR ) , which has collected longitudinal data on approximately 90 % of cystic fibrosis patients diagnosed in the United States since 1986 . They developed multivariate logistic regression models by using data on 5,820 patients r and omly selected from 11,630 in the CFFPR in 1993 . Models were tested for goodness of fit and were vali date d for the remaining 5,810 patients for 1993 . The vali date d 5-year survivorship model included age , forced expiratory volume in 1 second as a percentage of predicted normal , gender , weight-for-age z score , pancreatic sufficiency , diabetes mellitus , Staphylococcus aureus infection , Burkerholderia cepacia infection , and annual number of acute pulmonary exacerbations . The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research",
"AIM The aim of this study was to evaluate whether the previously observed changes in the fatty acid profile , as a result of DHA supplementation , could be maintained during longer study trials and to observe its effect on the clinical outcome of cystic fibrosis ( CF ) patients . METHOD A year-long double-blind placebo-controlled study was performed in DeltaF508 homozygous CF patients above the age of 6 . Clinical data , including pulmonary function and number of infections , were collected . Blood for the determination of the fatty acid ( FA ) composition of serum phospholipid , vitamin E , liver enzymes , immunoglobulins , erythrocyte sedimentation rate and coagulation was drawn at the beginning and then every 6 months after the start of the study . RESULTS Seventeen patients were included ; one dropped out . The treatment group was supplemented with an algal DHA-rich oil and the control group with sunflower seed oil . There was no difference between the control and treatment groups for W/H% , caloric intake , FEV1 % and FVC% at the start of the study and after 1 year of supplements . The phospholipid FA composition did not change in the control group . The treatment group had a significant increase in DHA and eicosapentaenoic acid ( EPA ) concentration . A concomitant decrease of dihomo-gammalinolenic acid , arachidonic acid , 22:5 n-6 and Mead acid was observed . The laboratory results showed no changes in vitamin E level , liver enzymes , albumin , erythrocyte sedimentation rate and IgG concentration in either the placebo or the intervention group . CONCLUSION Although DHA-rich oil shifted the serum phospholipid FAs to a less pro-inflammatory profile , no conclusive clinical improvement could be observed so far",
"Essential fatty acid deficiency as a result of inadequate linoleic acid impairs growth in healthy infants and is common in infants with malabsorption due to cystic fibrosis ( CF ) . We investigated the effect of dietary linoleic acid intake on the growth of infants with CF . In this study , predigested formula preparations A and B , with linoleic acid contents of 12 % and 7 % of energy , respectively , were fed before and after 1989 to infants enrolled in the evaluation and treatment protocol of the Wisconsin CF Neonatal Screening Project . Outcome was assessed from height-for-age ( HAZ ) and weight-for-age ( WAZ ) Z scores on follow-up exams during the first year . Baseline characteristics did not differ significantly between groups A ( n = 43 ) and B ( n = 33 ) . At diagnosis , 53 % of the enrolled infants ( n = 76 ) showed low plasma linoleic acid concentrations and 22 % had a high ratio of triene to tetraene . After correcting for the effect of potentially confounding variables , we found that HAZ ( by .27 , P WAZ ( by 0.26 , P = 0.081 ) were higher in group A than in group B. This occurred despite a significantly higher energy intake in group B. This difference was most pronounced between 6 and 9 mo of age . Our results suggest that a high linoleic acid content in formula benefits infants with CF because it optimizes nutrition , growth , and feeding efficiency",
"BACKGROUND Oxidative stress , as measured by 8-iso-prostagl and in F(2)(alpha ) ( 8-iso-PGF(2)(alpha ) ) , and depleted antioxidant defenses were shown in stable cystic fibrosis ( CF ) patients . The plasma fatty acid status of CF patients was linked to oxidative stress after respiratory exacerbations . OBJECTIVE We examined changes in plasma 8-iso-PGF(2)(alpha ) , antioxidant defenses , plasma fatty acid status , and clinical markers result ing from short-term antioxidant supplementation . DESIGN Forty-six CF patients were r and omly assigned to either group A [ low dose of supplement ( 10 mg vitamin E and 500 micro g vitamin A ) ] or group B [ high dose of supplement ( 200 mg vitamin E , 300 mg vitamin C , 25 mg beta-carotene , 90 micro g Se , and 500 micro g vitamin A ) ] . Plasma concentrations of 8-iso-PGF(2)(alpha ) , vitamins E and C , beta-carotene , zinc , selenium , and copper ; plasma fatty acid composition ; erythrocyte glutathione peroxidase ( EC 1.11.1.9 ) and superoxide dismutase ( EC 1.15.1.1 ) activities ; lung function ; and dietary intake were measured before and after 8 wk of supplementation . RESULTS Antioxidant defenses in group B improved , whereas those in group A did not : in groups B and A , the mean ( + /- SEM ) changes ( Delta ) in vitamin E were 10.6 + /- 1.5 and -1.9 + /- 0.9 micro mol/L , respectively ( P peroxidase activity were 1.3 + /- 0.3 and -0.3 + /- 0.6 U/g hemoglobin , respectively ( P = 0.016 ) . There were no significant differences between the groups in Delta8-iso-PGF(2)(alpha ) , (Delta)vitamin C , (Delta)fatty acid composition , (Delta)superoxide dismutase activity , (Delta)lung function , or (Delta)white cell count . Within group B , (Delta)beta-carotene correlated with (Delta)percentage of forced vital capacity ( r = 0.586 , P = 0.005 ) , (Delta)selenium correlated with (Delta)percentage of forced expiratory volume in 1 s ( r = 0.440 , P = 0.046 ) , and (Delta)plasma fatty acid concentrations correlated with (Delta)percentage of forced expiratory volume in 1 s ( r = 0.583 , P = 0.006 ) and Delta8-iso-PGF(2)(alpha ) ( r = 0.538 , P = 0.010 ) . CONCLUSIONS Whereas increased beta-carotene , selenium , and fatty acid concentrations are linked to improved lung function , increased plasma fatty acid concentrations are linked to oxidative stress . If oxidative stress is deemed to be important to the clinical outcome of CF patients , means of reducing oxidative stress while maintaining a high-fat , high-energy diet must be investigated",
"Background It is possible that cross-over studies included in current systematic review s are being inadequately assessed , because the current risk of bias tools do not consider possible biases specific to cross-over design . We performed this study to evaluate whether this was being done in cross-over studies included in Cochrane Systematic Review s ( CSRs ) . Methods We search ed the Cochrane Library ( up to 2013 issue 5 ) for CSRs that included at least one cross-over trial . Two authors independently undertook the study selection and data extraction . A r and om sample of the CSRs was selected and we evaluated whether the cross-over trials in these CSRs were assessed according to criteria suggested by the Cochrane h and book . In addition we reassessed the risk of bias of these cross-over trials by a checklist developed form the Cochrane h and book . Results We identified 688 CSRs that included one or more cross-over studies . We chose a r and om sample of 60 CSRs and these included 139 cross-over studies . None of these CSRs undertook a risk of bias assessment specific for cross-over studies . In fact items specific for cross-over studies were seldom considered anywhere in quality assessment of these CSRs . When we reassessed the risk of bias , including the 3 items specific to cross-over trials , of these 139 studies , a low risk of bias was judged for appropriate cross-over design in 110(79 % ) , carry-over effects in 48(34 % ) and for reporting data in all stages of the trial in 114(82 % ) . Assessment of biases in cross-over trials could affect the GRADE assessment of a review ’s findings . Conclusion The current Cochrane risk of bias tool is not adequate to assess cross-over studies . Items specific to cross-over trials leading to potential risk of bias are generally neglected in CSRs . A proposed check list for the evaluation of cross-over trials is provided",
"OBJECTIVES To compare the absorption of a lysophosphatidylcholine , monoglyceride , and fatty acid matrix ( organized lipid matrix , OLM ) with that of a triacylglycerol (TG)-based fat meal in patients with cystic fibrosis ( CF ) . STUDY DESIGN Five adolescents with CF and 3 control patients were given fat meals supplemented with retinyl palmitate of either OLM or TG at a 2-week interval . In a clinical trial , 73 patients with CF were r and omly assigned to nutritional supplements containing either OLM or TG for a 1-year double-blind trial followed by a 6-month observation period . RESULTS The peak increases and areas under the curve for TG and retinyl palmitate after the fat meal were 10-fold higher after OLM than after the TG fat load and did not differ from values obtained in control patients . OLM led to better clinical outcomes in terms of energy intake from the diet , weight-for-age Z score , essential fatty acid status , vitamin E , and retinol binding protein . Height-for-age Z score and FEV(1 ) only reached statistical significance at the end of the 6-month observation period . CONCLUSIONS These results suggest that OLM is a readily absorbable source of fat and energy in CF and is an effective nutritional supplement",
"Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more",
"BACKGROUND : Children with cystic fibrosis may have a deficiency of micronutrients , including zinc , which may affect their susceptibility to infections . There is a paucity of data on zinc supplementation among children with cystic fibrosis . We hypothesized that a pharmacologic dose of zinc administered daily for 12 months would reduce the need for antibiotics by 50 % . METHODS : This double-blind r and omized placebo-controlled trial was conducted among children with cystic fibrosis to assess the effect of zinc supplementation on the need for antibiotics and pulmonary function tests . The children , age 5–15 y , of either sex , received either 30-mg zinc tablets or similar looking placebo tablets daily in addition to st and ard care . They were followed up every month for a period of 12 months and whenever they had pulmonary exacerbations . Their serum zinc was estimated at baseline and at 12 months of enrollment . During each visit , the children underwent a pulmonary function test and sputum culture . RESULTS : Of a total of 43 children screened , 40 were enrolled , and of them , 37 completed the study . The median ( interquartile range ) number of days of the administration of antibiotics over 12 months of follow-up among the children receiving zinc was 42 ( 14–97 ) d. In the placebo group , it was 38 ( 15–70 ) d ( P = .79 ) . There were no significant differences in the percent-of-predicted FEV1 or change in FEV1 values at 12 months ( P = .44 ) . The number of children in whose respiratory specimens Pseudomonas was isolated was similar for the 2 groups at different time intervals . The adverse events reported were similar in the 2 groups . CONCLUSION : We did not find any significant difference in the need for antibiotics , pulmonary function tests , hospitalization , colonization with Pseudomonas , or the need for antibiotics for children with cystic fibrosis receiving zinc supplementation of 30 mg/d",
"BACKGROUND Magnesium is one of the most important minerals in the body . Although some studies reported that patients with cystic fibrosis ( CF ) lack magnesium , no international study has assessed the importance of oral magnesium supplementation in CF patients . OBJECTIVE We prospect ively investigated the long-term effect of oral magnesium supplementation on respiratory muscle strength by using manuvacuometry and the Shwachman-Kulczycki ( SK ) score among children and adolescents with CF . DESIGN This double-blind , r and omized , placebo-controlled crossover study included 44 CF patients ( aged 7 - 19 y ; 20 males ) who were r and omly assigned to receive magnesium ( n = 22 ; 300 mg/d ) or placebo ( n = 22 ) for 8 wk with a 4-wk washout period between trials . All patients were undergoing conventional treatment of CF . The experimental protocol included clinical evaluation , assessment of urinary concentration of magnesium , and manuvacuometric measurements [ maximal inspiratory pressure ( MIP ) and maximal expiratory pressure ( MEP ) ] . MIP was the primary outcome . RESULTS Urinary magnesium increased after the administration of magnesium ( change : 36.38 mg/d after magnesium compared with 0.72 mg/d after placebo ; P MIP and MEP significantly improved only after magnesium administration ( change in MIP : 11 % predicted after magnesium compared with 0.5 % predicted after placebo ; change in MEP : 11.9 % predicted after magnesium compared with 0.8 % predicted after placebo ; P SK score ( change : 4.48 points after magnesium compared with -1.30 points after placebo ; P SK score and respiratory muscle strength in pediatric patients with CF",
"ABSTRACT Pancreatic enzyme therapy does not normalize dietary fat absorption in patients with cystic fibrosis and pancreatic insufficiency . Efficacy of LYM-X-SORB ( LXS ) , an easily absorbable lipid matrix that enhances fat absorption , was evaluated in a 12-month r and omized , double-blinded , placebo-controlled trial with plasma fatty acids ( FA ) and coefficient of fat absorption ( CFA ) outcomes . A total of 110 subjects ( age 10.4 ± 3.0 years ) were r and omized . Total FA increased with LXS at 3 and 12 months ( + 1.58 , + 1.14 mmol/L ) and not with placebo ( P = 0.046 ) . With LXS , linoleic acid ( LA ) increased at 3 and 12 months ( + 298 , + 175 nmol/mL , P ⩽ 0.046 ) , with a 6 % increase in CFA ( P 0.01 ) . LA increase was significant in LXS versus placebo ( 445 vs 42 nmol/mL , P = 0.038 ) . Increased FA and LA predicted increased body mass index Z scores . In summary , the LXS treatment improved dietary fat absorption compared with placebo as indicated by plasma FA and LA and was associated with better growth status ",
"OBJECTIVE Several studies have reported omega-3 and omega-6 fatty acid imbalances in patients with cystic fibrosis ( CF ) . Whether these imbalances contribute to or are manifestations of the pathophysiology of CF is unknown . The study objective was to determine bioavailability , tissue accretion , and safety of a large dose of an algal source of docosahexaenoic acid ( DHA ) triacylglycerol and to observe effects on lung function in patients with CF . METHODS Twenty subjects with CF ( 8 to 20 y of age ) were r and omly assigned to receive algal oil providing 50 mg of DHA per kilogram per day ( 1 to 4.2 g of DHA per subject per day ) or placebo for 6 mo . Fatty acids , liver enzymes , and lipid soluble antioxidants were measured in blood at baseline and at 1 , 3 , and 6 mo . Rectal biopsy specimens were collected at baseline and at 3 mo for fatty acid analysis . Lung function , anthropometrics , and adverse experiences were monitored throughout the study . RESULTS Compared with placebo , DHA supplementation increased plasma , erythrocyte , and rectal DHA levels four- to five-fold ( P blood arachidonic acid levels and the ratio of arachidonic acid to DHA . Supplementation was well tolerated , with no treatment-related changes in liver enzymes , growth , or antioxidant status . DHA supplementation had no detectable effect on lung function during the course of this study . CONCLUSIONS Algal DHA triacylglycerol oil is readily absorbed , well tolerated , and increases blood and tissue DHA levels in patients with CF . No adverse developments were associated with this large dose of DHA oil . Larger studies of longer duration are needed to determine whether DHA supplementation results in any clinical ly significant benefits in patients with CF",
"BACKGROUND Cystic fibrosis ( CF ) patients are subjected to increased oxidative stress due to chronic pulmonary inflammation and recurrent infections . Additionally , these patients have diminished skeletal muscle performance and exercise capacity . We hypothesize that a mixture of multiple micronutrients could have beneficial effects on pulmonary function and muscle performance . METHODS A double-blind , r and omized , placebo controlled , cross-over trial with a mixture of multiple micronutrients ( ML1 ) was performed in 22 CF patients ( 12.9+/-2.5 yrs ) with predominantly mild lung disease . Anthropometric measures , pulmonary function , exercise performance by bicycle ergometry , muscular strength and vitamins A and E were determined . RESULTS Analysis was performed using the paired Student t-test comparing the change in each parameter during ML1 and placebo . Plasma vitamin E and A levels increased during ML1 when compared to placebo . However , no significant difference between the effect of the ML1 or placebo was observed neither for FEV1 , FVC , anthropometry , nor for the parameters for muscle performance . CONCLUSIONS The micronutrient mixture was not superior to placebo with respect to changes in pulmonary function or muscle performance in pediatric CF patients , despite a significant increase in plasma vitamin E concentrations",
"Much of the lung damage that limits the life of young adults with cystic fibrosis is due to proteases and oxygen metabolites generated by neutrophils , which are recruited into the airway by the interaction between Pseudomonas aeruginosa and pulmonary macrophages . Leukotriene B4 ( LTB4 ) has been proposed as a local mediator of this process ; its production is susceptible to specific modulation with dietary eicosapentaenoic acid ( EPA ) . We carried out a placebo-controlled trial of EPA ( 2.7 g daily for 6 weeks ) to assess its effects on markers of clinical state , peripheral neutrophil function , and lung inflammation in sixteen patients with cystic fibrosis colonised with P aeruginosa . EPA was well tolerated and result ed in a significant reduction in sputum volume ( median change with EPA -10 mL/day , placebo 0 ; p = 0.015 ) , and improvements in Schwachman score ( EPA 5 % , placebo 0 ; p = 0.034 ) , forced expiratory volume in 1 s ( EPA 0.25 L , placebo -0.1 L ; p = 0.006 ) , and vital capacity ( EPA 0.6 L , placebo 0 ; p = 0.011 ) . Relative chemotaxis of circulating neutrophils to LTB4 increased from a subnormal baseline of 4 ( median ; range 0 - 10 ) microns/30 min before treatment , to a near normal value of 11 ( 5 - 18 ) microns/30 min after EPA . Relative chemotaxis to LTB4 of patients taking placebo did not change : the difference in response was highly significant ( p = 0.001 ) . Specific reduction of neutrophil chemotaxis to LTB4 is a sensitive assay of chronic in-vivo exposure to LTB4 . Our results suggest that LTB4 has a pathogenetic role in the lung damage of cystic fibrosis . Longer-term clinical trials of EPA are warranted in a larger number of cystic fibrosis patients",
"The substitution of omega-3 ( n-3 ) fatty acids for omega-6 ( n-6 ) fatty acids generates eicosanoids with diminished inflammatory effects . As the lungs of patients with cystic fibrosis ( CF ) are in a state of chronic inflammation in which increased amounts of eicosanoids are found , n-3 supplementation may reduce this level of inflammation and result in clinical improvement . The absorption and clinical effects of n-3 vs. n-6 fatty acids in CF were measured in a prospect i ve , r and omized , double-blind , crossover study in which 14 patients with CF ( age : 6 - 16 years , mean 10.5 years ; baseline Shwachman-Brasfield scores : 41 - 88 , mean 76.7 ) received 6 weeks of n-3 ethyl ester concentrate from menhaden oil ( 100 - 131 mg/kg/day , mean 112.8 ) or n-6 fatty acids from safflower oil ( 102 - 132 mg/kg/day , mean 113.3 ) , followed by a washout period of 6 weeks , and then 6 weeks of the other supplement . Analysis by gas chromatography showed that n-3 supplementation result ed in increased eicosapentaenoic acid ( 20:5n-3 ) in platelet phospholipids , from 0.14 to 2.16 % , P docosahexaenoic acid ( 22:6n-3 ) , from 1.33 to 3.72 % , P adverse effects were reported or observed . No statistically significant differences were found ( ANOVA , P > 0.05 ) in Shwachman-Brasfield scores , sweat test , weight change , or forced expiratory volume and flow ( FEV1 , FEF25 - 75 % , and FVC ) percentiles . Tumor necrosis factor was not measurable in any serum sample . Serum leukotriene B4 ( LTB4 ) levels were significantly reduced by n-3 fatty acids , mean reduction ( -177 pg/mL ) compared to n-6 fatty acids ( + 63 pg/mL ) P serum LTB4 . No significant clinical differences or adverse effects were found",
"Rationale : Cystic fibrosis ( CF ) is characterized by dietary antioxidant deficiencies , which may contribute to an oxidant‐antioxidant imbalance and oxidative stress . Objectives : Evaluate the effects of an oral antioxidant‐enriched multivitamin supplement on antioxidant concentrations , markers of inflammation and oxidative stress , and clinical outcomes . Methods : In this investigator‐initiated , multicenter , r and omized , double‐blind , controlled trial , 73 pancreatic‐insufficient subjects with CF 10 years of age and older with an FEV1 between 40 % and 100 % predicted were r and omized to 16 weeks of an antioxidant‐enriched multivitamin or control multivitamin without antioxidant enrichment . Endpoints included systemic antioxidant concentrations , markers of inflammation and oxidative stress , clinical outcomes ( pulmonary exacerbations , anthropometric measures , pulmonary function ) , safety , and tolerability . Measurements and Main Results : Change in sputum myeloperoxidase concentration over 16 weeks , the primary efficacy endpoint , was not significantly different between the treated and control groups . Systemic antioxidant ( & bgr;‐carotene , coenzyme Q10 , & ggr;‐tocopherol , and lutein ) concentrations significantly increased in the antioxidant‐treated group ( P whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4 . The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group ( adjusted hazard ratio , 0.50 ; P = 0.04 ) . Lung function and growth endpoints did not differ between groups . Adverse events and tolerability were similar between groups . Conclusions : Antioxidant supplementation was safe and well tolerated , result ing in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks . Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation . Clinical trial registered with www . clinical trials.gov ( NCT01859390 )",
"Low plasma concentrations of docosahexaenoic acid ( DHA ) are reported in unsupplemented cystic fibrosis ( CF ) patients . Forty-one CF patients aged from 6 to 12 years were r and omized to receive high-dose DHA ( 100 mg/kg/day in the first month and 1 g per day thereafter through a 12-month supplementation ) or placebo ( germ oil ) . Primary outcome was percentage change in plasma AA : DHA ratio . Secondary outcomes were changes in the number of pulmonary exacerbations compared to previous year , lung function , BMI , skinfold thicknesses , and body composition assessed by DXA and in serum concentrations of C-reactive protein , cytokines and vitamin ( α-tocopherol and retinol ) . Compared to the control group plasma AA : DHA ratio decreased in the intervention group after 6 months ( median percentage changes : -73 % in the intervention group vs. -10 % in the control group , P=0.001 ) . No differences were detected between groups for secondary outcomes . Despite a decrease of the AA/DHA ratio , DHA supplementation for one year did not induce any significant biochemical and clinical improvement in CF patients",
"Background Patients with cystic fibrosis who have steatorrhea frequently are underweight and have essential fatty acid ( EFA ) depletion , which is associated with a poor clinical course . It has been stated that poor EFA status is difficult to correct in patients with cystic fibrosis , and an impaired EFA metabolism with reduced synthesis of long-chain polyunsaturated fatty acids has been proposed . In this study , the effects of an oral energy supplement rich in linoleic acid were investigated in patients with cystic fibrosis who had a body weight below 95 % of normal for height . Methods Thirty-six patients ( 16 girls ) more than 4 years of age were r and omized either to a control group ( n = 20 , age 13.3 ± 3.8 years , mean ± SD ) receiving intensive dietary counseling only , or an intervention group ( n = 16 , age , 10.4 ± 4.3 years ) treated for 3 months with dietary counseling plus 628 ± 254 mL ( = kcal ) per day of an energy supplement rich in fat ( 31 % of energy ) and linoleic acid ( 16 % of energy ) . Results In contrast to the control group , the patients with supplemented diets achieved significant increases of energy intake ( 2189 ± 731 kcal/day vs. 2733 ± 762 kcal/day ) , weight for height ( 82.8 % ± 8.6 % vs. 84.8 % ± 9.6 % of normal ) , and body fat ( 5.1 ± 1.7 kg vs. 5.8 ± 2.2 kg ) as well as the initially low values of plasma phospholipid linoleic acid ( 11.8 % ± 1.1 % vs. 17.6 % ± 1.6 % of total phospholipid fatty acids ) and its main metabolite arachidonic acid ( 4.4 % ± 0.4 % vs. 5.9 % ± 0.3 % ) . Conclusions Patients with cystic fibrosis with low body weight and poor EFA status benefit from EFA-rich energy supplements and can synthesize arachidonic acid from the precursor linoleic acid",
"BACKGROUND AND AIMS Various anti-inflammatory therapies , including dietary omega-3 polyunsaturated fatty acids ( PUFA ) supplementation , have been investigated in cystic fibrosis ( CF ) patients . To further explore this nutritional approach , biological effects of an omega-3 PUFA oral liquid supplementation were measured in 17 CF patients in a double-blind , r and omized , crossover without a washout period and placebo-controlled study . METHODS CF patients ( age : 18+/-9 year ; weight : 43+/-13 kg ) received a liquid dietary supplementation either enriched or not in omega-3 PUFA ( 390 - 1170 mg/day according to patient weight ) during two 6-month periods . RESULTS Increase in eicosapentaenoic acid was observed in neutrophil membrane following omega-3 PUFA dietary supplementation ( from 0.7+/-0.6 to 1.6+/-0.6 micromol% , P leukotriene B(4 ) ( LTB(4))/leukotriene B(5 ) ( LTB(5 ) ) ratio was decreased ( from 72+/-27 to 24+/-7 , P CF patients taking omega-3 PUFA supplements . In contrast , omega-3 PUFA supplementation affected neither internalization of IL-8 receptors following IL-8 exposure , nor IL-8-induced neutrophil chemotaxis . CONCLUSION Our results show that omega-3 PUFA are incorporated in neutrophil membranes . The subsequent decrease in LTB(4)/LTB(5 ) ratio suggests that , in such conditions , neutrophils may produce less pro-inflammatory mediators from the acid arachidonic pathway . These data indicate that omega-3 PUFA intake may have anti-inflammatory effect that still need to be assessed by long-term studies following large groups of patients",
"A common feature of cystic fibrosis ( CF ) is the functional derangement of the exocrine pancreas , which affects output of pancreatic lipase . This condition results in severe dietary malabsorption due to the poor hydrolysis of triacylglycerol ( TG ) in the lumen of the small intestine . Despite the benefits of pancreatic enzyme supplements , patients with CF present with persistent intestinal fat malabsorption . The aim of the present investigation was to determine whether defects in the intracellular phase of lipid transport occur in this pathophysiology in addition to the known disturbed digestive processes . Our hypothesis was tested by incubating intestinal biopsies from six CF and six healthy subjects with radiolabeled lipid and protein precursors . Lipid esterification and secretion were markedly decreased by 22 - 31 % and 38 - 42 % , respectively , in CF sample s , as noted by the low incorporation of [(14)C]palmitic acid into TGs , phospholipids , and cholesteryl esters in patients ' duodenal explants and culture media compared with controls ( 100 % ) . Accordingly , the output of TG-rich lipoproteins was substantially reduced ( P synthesis of apoB-48 ( 40 % ) and apoA-I ( 30 % ) . Given the critical role of microsomal triglyceride transfer protein in the formation of apoB-containing lipoproteins , its activity was determined and not found to be altered in CF intestinal tissue . Together , these results suggest that CF malabsorption may also be caused by defects in mucosal mechanisms leading to abnormal lipoprotein delivery into the blood circulation",
"Effectiveness of omega-3 supplementation in cystic fibrosis ( CF ) remains controversial . This study sought to evaluate clinical status , exercise tolerance , inflammatory parameters , and erythrocyte fatty acid profile after 1 year of oral omega-3 supplementation in CF patients . Fifteen ΔF508-homozygous patients undergoing chronic azithromycin were r and omized to receive omega-3 fish oil supplementation at a dose of 60mg/Kg/day or placebo . In comparison with the previous year , in the supplemented group , the number of pulmonary exacerbations decreased at 12 months ( 1.7 vs. 3.0 , p duration of antibiotic therapy ( 26.5 days vs. 60.0 days , p increased the levels of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) as early as decreases in arachidonic acid ( AA ) levels . This pilot study suggests that long-term omega-3 supplementation offers several clinical benefits as to the number of exacerbations and duration of antibiotic therapy in CF patients",
"Cystic fibrosis ( CF ) is characterized by abnormal levels of essential fatty acids ( EFA ) in plasma phospholipids . The reduced availability of EFA has been reported to alter patterns of circulating and tissue esterified acids and may determine profound changes in membrane fluidity and cell signaling mechanisms . In the current study , the results of a new strategy aim ed at the realization of a practical , low cost integrator , for daily use in the dietary management of FC subjects , are reported . We investigated the plasma phospholipids and triglycerides fatty acids composition of CF patients subjected to a dietary supplement constituted of a mixture of 50 % extra virgin olive oil and 50 % soybean oil and studied the clinical effects of this supplementation . The study included fourteen young subjects , aged between 6 and 15 years , affected by cystic fibrosis , with pancreatic insufficiency and heterozygotes or homozygotes for the delta F508 mutation . The subjects were matched by age and r and omly assigned to either an oil mixture supplemented ( OM ) group ( n = 7 ) , or to a control ( C ) group ( n = 7 ) . In contrast to the control group , the patients with supplemented diet achieved significant increases of the relative amount of C18:1 in the triglycerides as well as a significant decrease in saturated fatty acids ( C 16:0 , C 17:0 , C 18:0 , C 22:0 ) . Moreover , the ratio between LA acid and AA significantly increased in the triglycerides of the OM group . In the phospholipids of the OM group , the relative amount of C 18:1 and of palmitic acid increased significantly whereas the relative amount of the most important polyunsaturated fatty acids ( PUFA ) decreased . These results show that oleic acid can be absorbed and incorporated into the plasma triglycerides of CF patients receiving pancreatic enzymes , whereas poor incorporation of LA occurs . Despite the reduction in the relative amounts of phospholipid PUFA , the supplemented subjects did not reported adverse effects There were no significant differences between groups in the clinical indexes recorded ( height , weight , BMI , Schwachman-Kulczycki score and FEV 1s ) . The results of this study showed that the supplementation with a mixture of extravirgin olive and soybean oil was safe in seven CF patients treated during a 2-months period and no negative clinical effects were evident . However , further clinical trials will be necessary in order to better evaluate the consequence of the observed changes in plasma fatty acids composition in a longer testing period",
"Dietary supplementation with fish oils high in the omega-3 fatty acids , eicosapentaenoic acid and docosahexaenoic acid , may have an antiinflammatory effect . We determined whether patients with cystic fibrosis ( CF ) could incorporate omega-3 fatty acids into their plasma and cell membrane phospholipids without adverse effects . In this double-blind study , 12 patients with pancreatic insufficiency who have CF ( mean age , 12.2 + /- 5.4 ( SD ) years ) and 13 subjects without CF ( mean age , 13.4 + /- 6.3 ( SD ) years ) were r and omly assigned to ingest 8 gm daily of either encapsulated fish oil ( 3.2 gm of eicosapentaenoic acid and 2.2 gm of docosahexaenoic acid daily ) or olive oil ethyl esters for 6 weeks . Two of seven and two of five patients with CF who received fish and olive oils , respectively , and one of eight and none of five subjects without CF discontinued taking the capsules before 6 weeks because of eructation or diarrhea . Significant incorporation of omega-3 fatty acids into plasma and erythrocyte membrane phospholipids was observed in subjects with and those without CF r and omly assigned to the fish oil treatment . For example , in subjects r and omly assigned to receive fish oil , the eicosapentaenoic acid/arachidonic acid ratio in plasma increased 9.8-fold , from 0.04 + /- 0.02 ( mean + /- SEM ) to 0.39 + /- 0.11 ( p = 0.02 ) , in the patients with CF ( n = 7 ) and 23.0-fold , from 0.04 + /- 0.01 to 0.92 + /- 0.17 ( p = 0.001 ) , in the subjects without CF ( n = 8) who received fish oil ( p = 0.02 , patients with CF vs subjects without CF at 6 weeks ) . No clinical ly or statistically significant changes from baseline were observed in platelet aggregation or levels of vitamin E or A in subjects who received fish oil . Future studies are indicated to determine whether omega-3 fatty acid enrichment provides a clinical ly beneficial antiinflammatory effect in patients with CF",
"BACKGROUND Patients with cystic fibrosis ( CF ) have significantly decreased plasma concentrations of nutrient antioxidant vitamins , especially of β-carotene , which is thought to result from fat malabsorption and chronic pulmonary inflammation . The aim of this double blind , placebo controlled study was to investigate the effect of oral β-carotene supplementation for six months on clinical parameters . METHODS Twenty four patients with CF were r and omised to receive β-carotene 1 mg/kg/day ( maximum 50 mg/day ) for three months ( high dose supplementation ) and 10 mg/day for a further three months ( low dose supplementation ) or placebo . At monthly follow up visits the plasma β-carotene concentration , total antioxidant capacity , malondialdehyde ( MDA ) as a marker of lipid peroxidation , and clinical parameters ( Shwachmann-Kulczycki score , body mass index ( BMI ) , height , and lung function ( FEV1 ) ) were assessed . The number of pulmonary exacerbations requiring antibiotic treatment ( in days ) three months before and during the study were evaluated . RESULTS The plasma concentration of β-carotene increased significantly to the normal range during the three months of high dose supplementation ( baseline 0.08 ( 0.04 ) μmol/l to 0.56 ( 0.38 ) μmol/l ; p Initially raised plasma levels of MDA fell to normal levels and the total antioxidant capacity showed a non-significant trend towards improvement during high dose supplementation . Antibiotic treatment decreased significantly in the supplementation group from 14.5 ( 14.9 ) days/patient during the three months before the study to 9.8 ( 10.3 ) days/patient during high dose supplementation ( p=0.0368 ) and to 10.5 ( 9.9 ) days/patient during low dose supplementation , but increased in the placebo group . The Shwachmann-Kulczycki score , lung function , and BMI did not show any changes in either of the treatment groups . No adverse events were observed during the study period . CONCLUSION Oral β-carotene supplementation in a dose of 1 mg/kg/day only was effective in normalising the plasma concentration of β-carotene and result ed in a decrease in pulmonary exacerbations . These data suggest that patients with CF may benefit clinical ly from supplementation with β-carotene and further studies are warranted",
"Objectives : To obtain a balance in the fatty acid ( FA ) metabolism is important for the inflammatory response and of special importance in cystic fibrosis ( CF ) , which is characterized by impaired FA metabolism , chronic inflammation , and infection in the airways . Nitric oxide ( NO ) has antimicrobial properties and low nasal ( nNO ) and exhaled NO ( FENO ) , commonly reported in CF that may affect bacterial status . The present study investigates the effect of different FA blends on nNO and FENO and immunological markers in patients with CF . Patients and Methods : Forty-three patients with CF and “ severe ” mutations were consecutively enrolled in a r and omized double-blind placebo-controlled study with 3 FA blends containing mainly n-3 or n-6 FA or saturated FA acting as placebo . FENO , nNO , serum phospholipid concentrations of FA , and biomarkers of inflammation were measured before and after 3 months of supplementation . Results : Thirty-five patients in clinical ly stable condition completed the study . The serum phospholipid FA pattern changed significantly in all 3 groups . An increase of the n-6 FA , arachidonic acid , was associated with a decrease of FENO and nNO . The inflammatory biomarkers , erythrocyte sedimentation rate , and interleukin-8 decreased after supplementation with n-3 FA and erythrocyte sedimentation rate increased after supplementation with n-6 FA . Conclusions : This small pilot study indicated that the composition of dietary n-3 and n-6 FA influenced the inflammatory markers in CF . FENO and nNO were influenced by changes in the arachidonic acid concentration , supporting previous studies suggesting that both the lipid abnormality and the colonization with Pseudomonas influenced NO in the airways"
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CONTEXT Selective serotonin reuptake inhibitors ( SSRIs ) are often described as having a delayed onset of effect in the treatment of depression . However , some trials have reported clinical improvement as early as the first week of treatment . OBJECTIVE To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression . DATA SOURCES Trials identified by search ing CENTRAL , The Cochrane Collaboration data base of controlled trials ( 2005 ) , and the reference lists of identified trials and other systematic review s. STUDY SELECTION R and omized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment ( 50 trials from > 500 citations identified ) . Trials were excluded if limited to participants older than 65 years or specific comorbidities . DATA EXTRACTION Data were extracted on trial design , participant characteristics , and outcomes by a single review er . DATA SYNTHESIS Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment . In the primary analysis , the pattern of response seen was tested against alternative models of onset of response . The primary analysis incorporated data from 28 r and omized controlled trials ( n=5872 ) . A model of early treatment response best fit the experimental data . Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use . A secondary analysis indicated an increased chance of achieving a 50 % reduction in Hamilton Depression Rating Scale scores by 1 week ( relative risk , 1.64 ; 95 % confidence interval , 1.2 - 2.25 ) with SSRI treatment compared with placebo . CONCLUSIONS Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use , and the improvement continues at a decreasing rate for at least 6 weeks
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"This study was aim ed at resolving the time course of clinical action of antidepressants ( ADs ) and the type of early behavioral changes that precede recovery in treatment-responsive depressed patients . The first goal was to identify , during the first 2 weeks of treatment , the onset of clinical actions of the selective serotonin reuptake inhibitor ( SSRI ) , paroxetine , and the selective noradrenergic reuptake inhibitor , desipramine ( DMI ) . The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients . The design was a r and omized , parallel group , placebo-controlled , double-blind study for 6 weeks of treatment following a 1-week washout period . The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity . The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days , averaged 13 days for paroxetine , and was 16–42 days for placebo . Furthermore , as hypothesized , the different types of ADs initially impacted different behavioral aspects of the disorder . After 1 week of treatment , DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo , and this difference persisted at the second week of treatment . Early improvement in depressed mood – motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not . Paroxetine initially reduced anxiety more in responders than in nonresponders , and by the second week , significantly improved depressed mood and distressed expression in responders to a greater extent . Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement . Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs , results that could eventually be applied directly to clinical practice",
"OBJECTIVE Antidepressants that inhibit the reuptake of serotonin ( SSRIs ) or norepinephrine ( SNRIs ) are effective in the treatment of disorders such as depression and anxiety . Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders , but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information . The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers . METHOD Forty-two male and female volunteers were r and omly assigned to 7 days of double-blind intervention with the SSRI citalopram ( 20 mg/day ) , the SNRI reboxetine ( 8 mg/day ) , or placebo . On the final day , facial expression recognition , emotion-potentiated startle response , and memory for affect-laden words were assessed . Question naires monitoring mood , hostility , and anxiety were given before and after treatment . RESULTS In the facial expression recognition task , citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear . Citalopram also abolished the increased startle response found in the context of negative affective images . Both antidepressants increased the relative recall of positive ( versus negative ) emotional material . These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety . However , reboxetine decreased subjective ratings of hostility and elevated energy . CONCLUSIONS Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers , reducing the processing of negative relative to positive emotional material . Such effects of antidepressants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders . They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression",
"BACKGROUND Previous comparative studies of the selective serotonin reuptake inhibitors ( SSRIs ) have rarely included a placebo control group and have rarely demonstrated significant between-group differences . The study reported on here was a placebo-controlled comparison of the antidepressant effects of two SSRIs , citalopram and sertraline . METHODS Three hundred twenty-three patients with DSM-IV-defined major depressive disorder were r and omized to 24 weeks of double-blind treatment with citalopram ( 20 - 60 mg/day ) , sertraline ( 50 - 150 mg/day ) , or a placebo . The primary efficacy measure was the Hamilton Depression Rating Scale ( HAMD ) and the primary statistical analysis was an analysis of variance comparing the change from baseline to the last observation carried forward in each treatment group . RESULTS Both citalopram and sertraline produced significantly greater improvement than placebo on the HAMD , the Montgomery-Asberg Depression Rating Scale , and the Clinical Global Impression Scale . Significant improvement was observed at earlier timepoints in the citalopram group than the sertraline group ; however , sertraline treatment was associated with increased gastrointestinal side effects and a tendency toward early discontinuation , and analyses that excluded early dropouts revealed similar acute efficacy for the two active treatments . The Hamilton Anxiety Scale demonstrated a significant anxiolytic effect of citalopram , but not sertraline , relative to placebo . CONCLUSIONS This study confirms the antidepressant efficacy of two SSRIs , citalopram and sertraline . It is hypothesized that the more consistent evidence of antidepressant activity that was observed early in treatment in the citalopram group was related to more pronounced antianxiety effects and better tolerability upon initiation of therapy",
"These data provide evidence for the antidepressant efficacy of paroxetine . Paroxetine- and imipramine-treated patients were significantly different from placebo-treated patients , but little different to each other , on all depressive outcome measures . However , paroxetine appeared to have a possibly greater and earlier beneficial effect on anxiety symptoms associated with depression , when compared with imipramine . Both active therapies were effective in treating patients with severe depression . Side effects for paroxetine were typical of other serotonin ( 5-HT ) uptake inhibitors but different from those of imipramine . In particular , anticholinergic and cardiovascular symptoms were reduced , and premature withdrawal less likely",
"BACKGROUND Citalopram is a racemic selective serotonin reuptake inhibitor ( SSRI ) indicated for the treatment of depression . Citalopram is a racemate and its serotonin reuptake inhibitory activity resides primarily in the single S-isomer , escitalopram , which is now being evaluated for its potential usefulness in the treatment of depression and other psychiatric disorders . RESULTS from placebo-controlled studies that also included citalopram as an active control have shown that escitalopram is effective in treating depression and associated symptoms of anxiety . However , none of these studies was powered sufficiently to detect differences between active treatment groups . The goal of the present analysis is to evaluate the efficacy of escitalopram compared with citalopram in the treatment of major depressive disorder . METHOD Data were pooled from three similarly design ed , r and omized , double-blind , placebo-controlled trials of escitalopram ( 10 - 20 mg/day ) and citalopram ( 20 - 40 mg/day ) . Patients were male or female , greater than or equal to 18 years of age , who met criteria for a major depressive episode with a Montgomery Asberg Depression Rating Scale ( MADRS ) score greater than or equal to 22 at baseline . Efficacy measures included change from baseline in MADRS score and the Clinical Global Impression of Improvement ( CGI-I ) scale . Improvement in associated symptoms of anxiety was measured using the change from baseline in the MADRS inner tension item . RESULTS Both escitalopram and citalopram significantly improved depression and anxiety symptoms compared with placebo , and there were significantly more MADRS responders ( defined as > /=50 % improvement in MADRS scores at end point ) in the escitalopram and citalopram treatment groups . Escitalopram treatment was associated with statistically significant improvements in all efficacy measures relative to placebo after 1 week of treatment , whereas citalopram treatment statistically separated from placebo at the end of week 4 ( CGI-I and MADRS inner tension ) or week 6 ( MADRS ) . Escitalopram treatment also was statistically significantly superior to citalopram treatment at a number of time points . CONCLUSION These data support the effectiveness of escitalopram and citalopram in the treatment of major depressive disorder , and suggest escitalopram may have a faster onset and greater overall magnitude of effect than citalopram in improving symptoms of depression and anxiety in patients with major depressive disorder",
"Escitalopram , a selective serotonin reuptake inhibitor ( SSRI ) , was compared to placebo in a study of patients with major depressive disorder ( DSM-IV ) who had baseline Montgomery – Åsberg Depression Rating Scale ( MADRS ) total scores ≥22 and ≤40 . After a 1-week , single-blind placebo period , patients were r and omized to receive escitalopram 10 mg/day ( n = 191 ) or placebo ( n = 189 ) in an 8-week , double-blind period . The primary efficacy analysis of adjusted mean change in MADRS total score from baseline showed a statistically significantly larger effect for escitalopram than for placebo with a treatment difference at week 8 ( last observation carried forward , LOCF ) of 2.7 points ( SE 0.85;P = 0.002 ) . In further by-week efficacy analyses , the effect of escitalopram was consistently larger than that of placebo ( P ( Clinical Global Impression – Improvement score ) , week 2 ( MADRS score ) or week 3 ( Clinical Global Impression – Severity score ) . Escitalopram was very well tolerated with a low overall withdrawal rate similar to that for placebo . Nausea was the only adverse event reported significantly more in escitalopram-treated patients than in placebo-treated patients , although it was infrequent and transient . Escitalopram 10 mg/day had a statistically significantly better antidepressant effect than placebo as early as week 1 , and was safe and very well tolerated",
"The clinical profile of reboxetine , a selective noradrenaline reuptake inhibitor , was compared with that of the selective serotonin reuptake inhibitor fluoxetine and placebo in a double-blind , multicenter , parallel-group clinical trial of patients with major depression . Among the 381 patients treated with reboxetine 8 to 10 mg/day , fluoxetine 20 to 40 mg/day , or placebo for up to 8 weeks , a statistically significant greater reduction in the mean Hamilton Rating Scale for Depression ( 21-item HAM-D ) total score ( the primary efficacy variable ) was seen for both active treatment groups compared with placebo ( p reboxetine or fluoxetine also achieved a response ( ≥50 % reduction in HAM-D ) or remission ( HAM-D ≤10 points ) than those who received placebo ( p population of severely ill patients , with statistically significantly greater decreases in the mean HAM-D total score between both active treatment groups compared with placebo ( p ( Montgomery-Åsberg Depression Rating Scale , Clinical Global Impression ) reflected the primary efficacy analysis , with both active treatments offering comparable efficacy that was superior to that of placebo . Reboxetine and fluoxetine are more effective than placebo in the treatment of major depression . Futhermore , both antidepressants are well tolerated but possess different adverse event profiles",
"As part of a study in which reduced rapid eye movement latency was used to predict treatment response , fluoxetine and placebo were compared in 89 out patients with major depression with ( n = 52 ) and without ( n = 37 ) DSM-III-R melancholia , to determine whether the presence or absence of melancholia predicted antidepressant and /or placebo response . Following a 2-week , single blind placebo lead-in , men and women were assigned by r and om allocation to double-blind fluoxetine , 20 mg/day , or placebo for 8 weeks . Fluoxetine was statistically significantly superior to placebo in patients with melancholia ( endpoint change in the Montgomery-åsberg Depression Rating Scale [ MADRS ] score , response rates and remission rates ) . A weekly analysis demonstrated statistical superiority of fluoxetine compared with placebo at week 3 and continuing for the remainder of the study . Fluoxetine was statistically significantly more likely to reduce suicidal ideation compared with placebo , using the MADRS item 10 ( suicidal ideation question )",
"CONTEXT Paroxetine controlled release ( CR ) is approved for the treatment of major depressive disorder ( MDD ) in the dosage range of 25 to 62.5 mg daily . However , lower daily doses ( 12.5 mg and 25 mg ) of this formulation have not been investigated in the treatment of MDD . If the 12.5-mg and 25-mg doses are found to be efficacious , these lower doses may well convey a superior tolerability profile for paroxetine CR in the treatment of MDD . OBJECTIVE To evaluate the antidepressant efficacy and tolerability profile of daily doses of paroxetine CR 12.5 mg and 25 mg versus placebo in the treatment of MDD . DESIGN AND SETTING R and omized , double-blind , placebo-controlled clinical trial conducted in 40 clinical investigation centers in the United States . PARTICIPANTS 447 adult ( > or = 18 years of age ) out patients who met DSM-IV criteria for MDD and with a baseline 17-item Hamilton Rating Scale for Depression ( HAM-D ) score of at least 20 comprised the intent-to-treat study population ( mean age = 38.8 years ; 58.4 % female ; 75.6 % white ) . INTERVENTION Eligible patients completing a 1-week single-blind placebo run-in period were r and omly assigned to receive once-a-day study medication ( paroxetine CR 12.5 mg [ N = 156 ] , paroxetine CR 25 mg [ N = 154 ] , or placebo [ N = 149 ] ) in an 8-week , double-blind , parallel cell comparison . MAIN OUTCOME MEASURES The primary efficacy measure was the change from baseline to study endpoint ( week 8) as measured by the HAM-D. Secondary efficacy measures included change from baseline to study endpoint as assessed by both the depressed mood item on the HAM-D and the Clinical Global Impressions ( CGI ) Severity of Illness scale ( CGI-S ) . The proportion of patients considered at study endpoint to be in response ( CGI-Improvement score of 1 or 2 ) or in remission ( HAM-D Quality of life was assessed by the change from baseline in total score of the short form of the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) . Safety observations were made by assessing the proportion of patients who had adverse experiences , including laboratory and electrocardiographic abnormalities , during the treatment period . RESULTS The primary efficacy analysis revealed that both the 12.5-mg and the 25-mg paroxetine CR treatment groups were associated with significant therapeutic effects ( change in HAM-D score ) from baseline to study endpoint ( LOCF : p = .038 , 95 % CI = -3.38 to -0.09 and p = .005 , 95 % CI = -4.06 to -0.74 , respectively ) . Results from the Wilcoxon rank sum test of the depressed mood item of the HAM-D ( p = .011 , 95 % CI = -0.57 to -0.07 ) demonstrated significant efficacy in the 25-mg treatment group but not in the 12.5-mg group . However , LOCF analysis of the CGI-S revealed significant therapeutic effects for both the 12.5-mg ( p = .018 , 95 % CI = -0.61 to -0.06 ) and 25-mg ( p 25-mg paroxetine CR-treated group than in the placebo-treated group met criteria for response ( CGI-Improvement score of 1 or 2 , p = .035 , OR = 1.68 , 95 % CI = 1.04 to 2.73 ) as well as for remission ( HAM-D score HAM-D remission analysis nor CGI responder analysis showed statistical separation from placebo for paroxetine CR 12.5-mg treatment . Quality of life improvements were statistically significant for the 25-mg treatment ( p = .041 , 95 % CI = 0.17 to 8.03 ) on the Q-LES-Q total score . Post hoc LOCF analyses of HAM-D sleep disturbance , psychic anxiety , and anxiety/somatization factors revealed significant improvements from baseline in the paroxetine CR 25-mg and 12.5-mg treatment groups . The types of adverse events reported in the 12.5-mg and 25-mg groups were similar to those reported with paroxetine CR at the customary 25-mg to 62.5-mg range ; however , the lower doses of paroxetine CR were associated with a relatively reduced incident rate of these adverse events and an overall improved tolerability compared with the incident rate and tolerability profile associated with the customary dose range of paroxetine CR ( 25 to 62.5 mg ) . CONCLUSION Paroxetine CR , at 12.5 mg/day and 25 mg/day , demonstrated significant antidepressant effects",
"BACKGROUND Paroxetine is a potent and selective serotonin reuptake inhibitor ( SSRI ) . The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed out patients . METHOD A double-blind , parallel-group study was undertaken in four st and -alone centers . Patients aged 18 - 65 years , meeting DSM-III criteria for major depression , and having a Hamilton Rating Scale for Depression ( HAM-D ) score > or = 18 on the first 17 items of the HAM-D-21 were r and omized to paroxetine or placebo for 6 weeks of treatment . Efficacy outcome variables included the HAM-D , the Montgomery-Asberg Depression Rating Scale , the Clinical Global Impressions Scale ( CGI ) , and the Covi Anxiety Scale . Tolerability was assessed by asking a non-leading question . Routine laboratory safety and vital sign data from all four centers were pooled . The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed . Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables . RESULTS Significant differences ( p paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4 . Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor . Similar results were obtained when an adequate treatment group ( therapy for > or = 28 days ) was considered . A full clinical response ( CGI-severity of illness score 1 or 2 ) was seen in over 40 % of subjects . Adverse events were more common for paroxetine compared with placebo ( p Somnolence was twice more common than nervousness . Dropout due to adverse events was similar between therapies . Paroxetine had no clinical ly significant effect on laboratory safety data or vital signs . CONCLUSION Paroxetine was an effective , well tolerated , and safe antidepressant . Side effects were typical of the SSRI class of drugs . Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects",
"Considerable research shows that serotonin dysfunction is implicated in major depression . Paroxetine is an investigational antidepressant that appears to act by selectively blocking neuronal serotonin uptake . Seventy-two out patients with moderate-to-severe major depression entered this 6-week , double-blind comparison of paroxetine and placebo . The results showed clear and significant superiority of paroxetine on all of the major outcome variables . These included physician-rated measures such as the Hamilton Rating Scale for Depression and its four factor scores , the Clinical Global Impressions scale , the Montgomery and Asberg Depression Rating Scale , and the Raskin Depression Scale . Results on these agreed well with patient-rated measures like the Hopkins Symptom Checklist and Patient Global Evaluation Scale . Paroxetine was also very well tolerated . Nausea and constipation occurred significantly more often with paroxetine , but only 9 % of paroxetine patients dropped out of the study due either in whole or in part to an adverse effect . This compares to 8 % of the placebo patients who were discontinued for the same reason . This study suggests that paroxetine is a safe and effective medication for the treatment of major depression",
"In a double-blind , placebo-controlled study the authors found that fluoxetine , a potent and selective inhibitor of serotonin reuptake , was an effective antidepressant in moderately depressed , ambulatory out patients . Typical adverse effects reported by patients treated with fluoxetine included agitation , nausea , fatigue , and insomnia . Compared to imipramine , fluoxetine was associated with fewer complaints of dry mouth , constipation , and dizziness",
"OBJECTIVE The present study aim ed to 1 ) assess facial expression recognition in subjects with a previous history of major depressive disorder relative to subjects with no history of depression and 2 ) characterize the effects of acute citalopram infusion on recognition performance for both groups . METHOD Unmedicated euthymic women with a history of major depression and matched comparison subjects with no history of depression were given a facial expression recognition task following intravenous infusion of saline or citalopram ( 10 mg ) in a double-blind , between-group design . RESULTS Following saline infusion , subjects with a previous history of depression showed a selectively greater recognition of fear relative to the subjects with no history of depression . The abnormal fear processing observed in the subjects with a previous history of depression was normalized following citalopram infusion , an effect that was opposite to that seen with the subjects with no history of depression . CONCLUSIONS These results suggest that increased recognition of fear is a trait vulnerability marker for depression and that this is normalized following a single dose of citalopram",
"BACKGROUND We conducted a r and omized , double-blind , placebo-controlled study of the efficacy and safety of once-daily venlafaxine extended release ( XR ) and fluoxetine in out patients with major depression and concomitant anxiety . METHOD Patients who met DSM-IV criteria for major depressive disorder and satisfied eligibility criteria were r and omly assigned to once-daily venlafaxine XR , fluoxetine , or placebo for 12 weeks . Efficacy was assessed with the Hamilton Rating Scale for Depression ( HAM-D ) , Hamilton Rating Scale for Anxiety ( HAM-A ) , and Clinical Global Impressions scale . RESULTS Among 359 out patients , venlafaxine XR and fluoxetine were significantly superior ( p placebo on the HAM-D total score beginning at week 2 and continuing to the end of the study . Venlafaxine XR but not fluoxetine was significantly better than placebo at week 2 on the HAM-D depressed mood item . At week 12 , the HAM-D response rate was 43 % on placebo , 67 % on venlafaxine XR , and 62 % on fluoxetine ( p HAM-D remission rate was significantly higher ( p venlafaxine XR and at weeks 8 , 12 , and final evaluation with fluoxetine than with placebo . The HAM-A response rate was significantly higher ( p venlafaxine XR than with fluoxetine at week 12 . The incidence of discontinuation for adverse events was 5 % with placebo , 10 % with venlafaxine XR , and 7 % with fluoxetine . CONCLUSION Once-daily venlafaxine XR is effective and well tolerated for the treatment of major depression and concomitant anxiety and provides evidence for superiority over fluoxetine",
"This research was aim ed at study ing the rate of action of tricyclic drugs in depressive disorders , specifying the behavioural effects associated with recovery , and predicting clinical response . The research design involved comparison of a recovered group with a group treated for the equivalent four weeks , who showed minimal to no response . The findings indicated significant differences in baseline characteristics between responders and non-responders . Further , the drugs were found to act early in the responders , within the first week of treatment . Specific changes at one week which distinguished responder and non-responder groups occurred in the disturbed affects , and in cognitive functioning . Improvements also occurred in somatic symptoms , but these latter changes were general and not associated with later recovery . At 2 1/2 weeks , all facets of the depressed condition showed positive change in the responders . Implication s of the results for assessing rate of tricyclic drug actions , their effects on the interaction of affect and neurochemistry , and the practical application of the results for the clinical situation , are discussed",
"The efficacy and safety of fluvoxamine maleate , a selective serotonin reuptake inhibitor , was compared with placebo and imipramine in patients with major depressive disorder . Previous literature has cited a dose range of 100 to 300 mg/day of fluvoxamine maleate for the treatment of major depression ; however , this study demonstrates that a dose range of 50 to 150 mg/day is as effective as imipramine ( 80 - 240 mg/day ) . After a 1- to 2-week , single-blind , placebo washout phase , 150 depressed out patients were r and omized to double-blind treatment with fluvoxamine maleate ( 50 - 150 mg/day ) , imipramine ( 80 - 240 mg/day ) , or placebo for 6 weeks . Fluvoxamine produced a significant therapeutic benefit over placebo ( p Hamilton Rating Scale for Depression ; imipramine ( 80 - 240 mg/day ) produced similar results . The secondary outcome variables ( i.e. , Clinical Global Impression severity of illness item and 56-Item Hopkins Symptom Checklist depression factor ) also showed significant differences between fluvoxamine maleate and placebo during three of the four final weeks of the study . Both fluvoxamine maleate and imipramine appeared to be safe and well tolerated by the majority of patients . As expected from the pharmacology of these agents , the imipramine groups reported more anticholinergic effects ( dry mouth , dizziness , and urinary retention ) and electrocardiographic effects , whereas the fluvoxamine group reported more nausea , somnolence , and abnormal ejaculation . The majority of these adverse events were mild to moderate and , with the exception of dry mouth ( imipramine ) and abnormal ejaculation ( fluvoxamine ) , were transient . The data clearly demonstrate the antidepressant activity and tolerability of fluvoxamine maleate ( 50 - 150 mg/day ) as compared with placebo ; it is also as effective as the tricyclic antidepressant imipramine ( 80 - 240 mg/day ) in patients with major depressive disorder",
"In a 6-week , r and omized , double-blind , multicenter trial , sertraline 50 mg , 100 mg , or 200 mg , or placebo , was administered once daily to 369 patients with DSM-III-defined major depression . Efficacy variables included changes from baseline scores for total Hamilton Rating Scale for Depression ( HAMD ) , HAMD Bech Depression Cluster , Clinical Global Impressions ( CGI ) Severity , CGI Improvement , and Profile of Mood States Depression/Dejection Factor . For the evaluable- patients analysis , all sertraline groups showed significantly ( p efficacy variables except one when compared with the placebo group . For the all- patients analysis , all efficacy variables in the 50 mg group were statistically significantly ( p placebo . Side effects increased with increasing dosage but were usually mild and well tolerated . The results of this study show that sertraline 50 mg once daily is as effective as higher dosages for the treatment of major depression with fewer side effects and therapy discontinuations",
"This 7- to 8-week , multicenter , r and omized , double-blind , placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder . Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects . The study enrolled 600 out patients , male and female , age 18 - 65 , meeting DSM-III-R criteria for major depressive disorder . A 13-item subscore of the st and ard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score . Secondary efficacy assessment s included the HAM-D retardation factor , HAM-D depressed mood item , CGI-severity of illness item , and SCL depression factor . Fluvoxamine ( 50 - 150 mg/day ) was therapeutically effective and well tolerated during 6 weeks of therapy . Based on the HAM-D depressed mood item , efficacy was dose dependent . The minimum effective dose was 50 mg/day . Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder",
"In any antidepressant study , placebo response in patients assigned active drug is a troubling source of variance . There have been few attempts to identify the patients whose conditions improve as a result of true drug effect , in contrast with improvement that is a result of nonspecific effects . In a previous report we demonstrated that true drug effect seemed to be characterized by a two-week delay in onset and persistence . We described a method of pattern analysis to identify such patients . In this report , we describe the use of pattern analysis to replicate our initial findings . Data from a new sample of 150 nonmelancholic patients support the hypothesis that true drug effect is characterized by a two-week delay in onset and persistence of improvement , once achieved . There was little evidence of the onset of antidepressant effect before two weeks . The theoretical and clinical implication s of this work are discussed",
"The purpose of this study was to develop a method for differentiating specific ( \" true \" ) and nonspecific antidepressant drug response for the individual patient . Patterns of clinical response , based on weekly global ratings of clinical status , were generated for each of 185 patients participating in six-week placebo-controlled drug trials . We hypothesized and found that substantially more patients receiving active than placebo medication displayed treatment response patterns characterized both by two-week or greater delay in onset of initial improvement and nonfluctuating persistence of improvement once achieved . Identification of a distinctive pattern of clinical response to an active drug has both research and clinical applications . Pattern analysis may contribute to underst and ing the nature of drug mechanisms of action , may clarify some ambiguous treatment study outcomes , and in the individual case , may facilitate clinical management",
"1 . The efficacy of fluvoxamine is compared to that of desipramine in a multicenter double blind placebo controlled six-week flexible dose trial of 90 out patients with major depressive disorder . 2 . Although overall drug effects were relatively weak , there were trends suggesting separation of both active drugs from placebo at week six . Both drugs were well tolerated . 3 . Studies of major depression ought to be design ed to last 8 - 10 weeks in order to demonstrate placebo active drug differences and the stability of such a difference should it occur in the first six weeks",
"OBJECTIVE The authors used magnetic resonance spectroscopy ( MRS ) to assess the effect of acute administration of the selective serotonin reuptake inhibitor ( SSRI ) citalopram on cortical levels of gamma-aminobutyric acid ( GABA ) . METHOD Ten healthy volunteers received either intravenous citalopram ( 10 mg ) or saline in a r and omized , double-blind , crossover design . The occipital GABA/creatine ratio was measured with a proton MR spectral editing technique . RESULTS In comparison with saline , citalopram produced a mean increase of 35 % in relative brain GABA concentration in the occipital cortex . CONCLUSIONS These findings extend previous work showing that SSRI treatment increases cortical GABA in depressed patients and suggest that this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement",
"& NA ; Escitalopram was compared to placebo in moderately to severely depressed patients in primary care with citalopram as the active reference . Patients were r and omized to receive flexible doses of 10–20 mg/day escitalopram ( n=155 ) , 20–40 mg/day citalopram ( n=160 ) , or placebo ( n=154 ) over an 8‐week double‐blind period . The primary efficacy parameter was the change from baseline to last assessment in the Montgomery – Asberg Depression Rating Scale total score . Escitalopram produced a statistically significant therapeutic difference of 2.9 points ( P=0.002 ) compared to placebo , and escitalopram was consistently and statistically significantly more efficacious than placebo from week 1 onwards . Analysis of Clinical Global Impression – Severity and Clinical Global Impression – Improvement confirmed the primary efficacy results . By week 8 , significantly more patients had responded to treatment with escitalopram than with citalopram ( P=0.021 ) or placebo ( P=0.009 ) . Escitalopram was as well tolerated as citalopram and had a similar adverse event profile . Both escitalopram‐ and citalopram‐treated patients had placebo‐level adverse event withdrawal rates ( 3 % and 4 % , respectively ) . This study demonstrates the consistent antidepressant efficacy and excellent tolerability of escitalopram 10–20 mg/day in primary care patients with major depressive disorder",
"Paroxetine is a phenylpiperidine compound that selectively inhibits neuronal serotonin uptake in man . In this study , the efficacy of paroxetine was compared with that of placebo in the treatment of 66 out patients with the diagnosis of moderate-to-severe major depression . The research was a 6-week , prospect i ve , double-blind design after a 1-week placebo baseline phase . Paroxetine was associated with a consistent pattern of greater improvement on the primary efficacy scales , but the differences were not statistically significant . Paroxetine did produce significantly greater improvement than placebo for patients whose illness had lasted more than 1 year , and there was a significant reduction in suicidal ideation . Significantly fewer dropouts were due to lack of efficacy in those patients treated with paroxetine compared with those in the placebo group . Paroxetine was well tolerated . There was no difference between paroxetine and placebo in the rate of adverse effects or in the number of patients who dropped out because of adverse effects",
"A double-blind , placebo- and amitriptyline-controlled comparison study was performed to evaluate the antidepressant efficacy of sertraline , a specific serotonin uptake inhibitor . Patients with DSM-III-defined major depression r and omly received either sertraline ( N = 149 ) , amitriptyline ( N = 149 ) , or placebo ( N = 150 ) once daily for the 8-week study period . The mean final daily medication dose for the all- patients group was 145 mg and 104 mg for the sertraline- and amitriptyline-treatment groups , respectively . As measured by the Hamilton Rating Scale for Depression and the Clinical Global Impressions Scale , both the sertraline and amitriptyline treatment groups showed a significantly greater improvement from baseline ( p less than or equal to .001 ) than the placebo group . The sertraline group had a higher proportion of gastrointestinal complaints and male sexual dysfunction than either the amitriptyline or the placebo group . The amitriptyline group showed a higher proportion of anticholinergic and sedative side effects and dizziness compared with patients who received either sertraline or placebo",
"Paroxetine is an investigational antidepressant that acts through selective inhibition of serotonin reuptake at the synapse . In this study , 81 out patients with major depression according to DSM-III criteria were treated with either paroxetine or placebo in a 6-week , r and omized , double-blind study . Paroxetine was significantly superior to placebo on all major efficacy variables , including depression as well as anxiety , cognitive disturbance , insomnia , psychomotor retardation , and sleep disturbance . Significant differences in favor of paroxetine were apparent by Week 2 . Paroxetine was also well tolerated . The results support the efficacy and safety of paroxetine as a treatment for patients with major depression",
"Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 out patients with DSM-III major depression , of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy . Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo . Both imipramine and fluoxetine were significantly superior to placebo on most measures . There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures . Fluoxetine was generally well tolerated . Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant . The results support previous studies which suggest fluoxetine 's superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs"
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BACKGROUND AND OBJECTIVES The precise association between palm oil consumption and lipid-related cardiovascular disease risk remains unclear . A systematic review was thus performed to assess whether palm oil consumption has a negative effect on plasma lipid-related cardiovascular disease marker levels . METHODS AND STUDY DESIGN In June 2018 , the electronic bibliographic data bases PubMed , EMBASE ( Ovid ) , the Cochrane Library ( Ovid ) and the Chinese National Knowledge Infrastructure were search ed and a total of 11 eligible dietary intervention articles involving 961 volunteers were selected . Both r and om and fixed effect models were used to calculate pooled weighted mean differences ( WMD ) . RESULTS A total of 11 articles involving 547 participants met the inclusion criteria . The pooled analysis revealed that palm oil increased the concentration of high-density lipoprotein cholesterol ( WMD : 0.15 mmol/L ; p Palm oil consumption had no significant effects on blood total cholesterol ( WMD : -0.01 mmol/L ; p=0.82 ) and LDL-c ( WMD : -0.05mmol/L ; p=0.10 ) and triglyceride concentrations ( WMD : 0.00 mmol/L ; p=0.96 ) , relative to the effects of unsaturated fatty acid consumption . Subgroup analyses revealed that palm oil has a beneficial effect on High-density lipoprotein cholesterol levels when more than 30 % of total dietary energy was constituted by fat . CONCLUSIONS This review revealed that palm oil does not induce increases in cardiovascular disease risk risk-related biomarkers relative to unsaturated fatty acids . Furthermore , larger-scale sample s of human dietary intervention trials are required to increase the accuracy of meta-analyses
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"Objectives To investigate the association between long term intake of individual saturated fatty acids ( SFAs ) and the risk of coronary heart disease , in two large cohort studies . Design Prospect i ve , longitudinal cohort study . Setting Health professionals in the United States . Participants 73 147 women in the Nurses ’ Health Study ( 1984 - 2012 ) and 42 635 men in the Health Professionals Follow-up Study ( 1986 - 2010 ) , who were free of major chronic diseases at baseline . Main outcome measure Incidence of coronary heart disease ( n=7035 ) was self-reported , and related deaths were identified by search ing National Death Index or through report of next of kin or postal authority . Cases were confirmed by medical records review . Results Mean intake of SFAs accounted for 9.0 - 11.3 % energy intake over time , and was mainly composed of lauric acid ( 12:0 ) , myristic acid ( 14:0 ) , palmitic acid ( 16:0 ) , and stearic acid ( 18:0 ; 8.8 - 10.7 % energy ) . Intake of 12:0 , 14:0 , 16:0 and 18:0 were highly correlated , with Spearman correlation coefficients between 0.38 and 0.93 ( all P hazard ratios of coronary heart disease were 1.07 ( 95 % confidence interval 0.99 to 1.15 ; Ptrend=0.05 ) for 12:0 , 1.13 ( 1.05 to 1.22 ; Ptrend Hazard ratios of coronary heart disease for isocaloric replacement of 1 % energy from 12:0 - 18:0 were 0.92 ( 95 % confidence interval 0.89 to 0.96 ; P risk of coronary heart disease was observed when the most abundant SFA , 16:0 , was replaced . Hazard ratios of coronary heart disease for replacing 1 % energy from 16:0 were 0.88 ( 95 % confidence interval 0.81 to 0.96 ; P=0.002 ) for polyunsaturated fat , 0.92 ( 0.83 to 1.02 ; P=0.10 ) for monounsaturated fat , 0.90 ( 0.83 to 0.97 ; P=0.01 ) for whole grain carbohydrates , and 0.89 ( 0.82 to 0.97 ; P=0.01 ) for plant proteins . Conclusions Higher dietary intakes of major SFAs are associated with an increased risk of coronary heart disease . Owing to similar associations and high correlations among individual SFAs , dietary recommendations for the prevention of coronary heart disease should continue to focus on replacing total saturated fat with more healthy sources of energy",
"Although dietary trans fatty acids can affect plasma lipoproteins negatively in humans , no direct comparison with specific saturated fatty acids has been reported , even though trans fatty acids were design ed to replace saturates in foods and food processing . In this study , dietary trans 18:1 [ elaidic acid at 5.5 % energy ( en ) ] was specifically exchanged for cis 18:1 , 16:0 or 12:0 + 14:0 in 27 male and female subjects consuming moderate fat ( 31 % en ) , low cholesterol ( whole food diets during 4-wk diet periods in a crossover design . The trans-rich fat significantly elevated total cholesterol and LDL cholesterol relative to the 16:0-rich and 18:1-rich fats and uniquely depressed HDL cholesterol relative to all of the fats tested . Trans fatty acids also elevated lipoprotein ( a ) [ Lp(a ) ] values relative to all dietary treatments . Furthermore , identical effects on lipoproteins were elicited by 16:0 and cis 18:1 in these subjects . The current results suggest that elaidic acid , one of the principal trans isomers produced during industrial hydrogenation of edible oils , adversely affects plasma lipoproteins . Thus , the negative effect of elaidic acid on the lipoprotein profile of humans appears to be unmatched by any other natural fatty acid(s )",
"Twenty-one healthy normocholesterolemic young adults , men and women , completed a r and omized 30-d/30-d crossover comparison of the effect of palmolein and olive oil on plasma lipids . The subjects were free-living volunteers who changed to low-fat diets to which one of the test oils was added ( used as a spread , for baking , or for frying ) in turn . Complete food records were kept throughout : the test oils were compared at 17 % of total dietary energy . Under the conditions of this experiment plasma total and low-density-lipoprotein ( LDL ) cholesterol were almost identical with the two oils , so that when the palmitic acid ( 16:0 ) in palm oil replaced oleic acid ( 18:1 ) in olive oil the expected increase in LDL cholesterol was not seen . These results indicate that 16:0 , though saturated , is not always a plasma cholesterol-raising fatty acid . Palmolein is rich in vitamin E , alpha-tocopherol , and especially tocotrienols , but the latter were barely detectable in plasma",
"The degree to which different saturated fatty acids exert their cholesterol-raising effects is still unknown . Therefore , we studied the effect on serum lipids and lipoproteins of diets rich in lauric , palmitic , or oleic acids . Eighteen women and 14 men consumed in r and om order three experimental diets , each for 6 wk . The diets consisted of solid foods and contained 40 % of energy as fat , of which 28 % was supplied by the experimental fats . The fat high in lauric acid was a mixture of palm kernel oil ( 75 % ) and a high-oleic acid sunflower oil ( 25 % ) ; the fat high in palmitic acid consisted of dairy fat ( 55 % ) , palmstearin ( 36 % ) , and sunflower oil ( 9 % ) ; and the fat high in oleic acid consisted of dairy fat ( 37 % ) and sunflower oil ( 63 % ) . The calculated nutrient composition was the same in each diet except for approximately equal to 8.5 % of energy , which was provided by lauric , palmitic , or oleic acids . With the lauric acid diet the subjects ' serum total cholesterol concentration increased by 0.22 mmol/L ( P = 0.0121 ; 95 % CI : 0.02 , 0.41 mmol/L ) as compared with the palmitic acid diet and by 0.48 mmol/L ( P oleic acid diet . Total cholesterol concentrations with the palmitic acid diet were 0.26 mmol/L ( P = 0.0012 ; 95 % CI : 0.07 , 0.46 mmol/L ) higher than with the oleic acid diet . High-density-lipoprotein (HDL)-cholesterol concentrations increased by 0.12 mmol/L ( P = 0.006 ; 95 % CI : 0.04 , 0.20 mmol/L ) with the lauric acid compared with the palmitic acid diet and by 0.14 mmol/L ( P oleic acid diet . HDL-cholesterol concentrations with the palmitic acid and the oleic acid diet were the same . No effects were seen in serum triacylglycerol and lipoprotein(a ) concentrations . We conclude that both lauric and palmitic acids are hypercholesterolemic compared with oleic acid . Lauric acid raises total cholesterol concentrations more than palmitic acid , which is partly due to a stronger rise in HDL cholesterol",
"The effects on serum lipids of palm oil ( PA ) used in Chinese diets were compared with those of soybean oil ( SO ) , peanut oil ( PE ) and lard ( LA ) in normocholesterolemic subjects and with that of PE in hypercholesterolemic subjects . Normocholesterolemic subjects [ 120 men , 18 - 25 y , total cholesterol ( TC ) 2.8 - 5.0 mmol/L ] were assigned to four groups to consume test diets for six consecutive weeks after a run-in period of 3 wk . About 30 % of dietary energy was derived from fat , 75 - 80 % of which came from test oils . In comparison with the entry level , the average serum TC and LDL cholesterol ( LDL-C ) were 6.7 and 13.1 % lower , respectively , in the PA group and 22.8 and 30.7 % higher , respectively , ( P serum TC , LDL-C and the ratio of TC/HDL cholesterol ( HDL-C ) in the PA group were significantly lower than those of the LA group . Hypercholesterolemic subjects ( 31 men , 20 women , 32 - 68 y , TC 5.5 - 7.0 mmol/L ) were divided into two groups . For 6 wk , one group ( 15 men , 10 women ) consumed the PA diet ; another group ( 16 men , 9 women ) consumed the PE diet . After a 3-wk interval , the two groups interchanged diets for another 6 wk . The test diets again contained about 30 % energy from fat , 60 - 65 % of which came from test oils . Compared with entry values , the PA diet caused significant reductions in serum TC , LDL-C and TC/HDL-C during the first 6 wk and also a significant reduction in TC/HDL-C during the second 6 wk . The PE diet had no significant influence on serum lipids in either experimental period",
"BACKGROUND Despite the high content of palmitic acid , palm olein has been shown to have a neutral effect on plasma cholesterol concentrations when compared with olive oil , which is suggested to be attributable to palmitic acid in the sn-1 and sn-3 position . In contrast , palmitic acid is in the sn-2 position in lard . OBJECTIVE The objective was to investigate the effects of a diet rich in palm olein , fractionated palm oil , olive oil , and lard on plasma blood lipids , inflammatory markers , glucose , and insulin . DESIGN A controlled double-blinded , r and omized 3 × 3 wk crossover dietary intervention study included 32 healthy men who daily replaced part of their habitual dietary fat intake with ~ 17 % of energy from palm olein , olive oil , or lard , respectively . RESULTS Compared with intake of olive oil , palm olein and lard increased total cholesterol and LDL cholesterol ( P ) . Palm olein result ed in a lower plasma triacylglycerol concentration than did olive oil ( P in plasma HDL-cholesterol , high-sensitivity C-reactive protein , plasminogen activator-1 , insulin , and glucose concentrations . CONCLUSIONS The current study did not support the previous finding that the effect of palm olein on total plasma cholesterol and LDL cholesterol in healthy individuals with normal plasma cholesterol concentrations is neutral compared with that of olive oil . Thus , sn-positioning was not confirmed to be important with regard to the effect on plasma cholesterol . The relatively lower plasma triacylglycerol concentration after the palm olein diet than after the olive oil diet was unexpected . This trial is registered at clinical trials.gov as NCT00743301",
"The cholesterol-raising effect of dietary saturated fatty acids is largely accounted for by lauric , myristic , and palmitic acids . Dairy fat is a major source of myristic acid , and palm oil is especially rich in palmitic acid . Myristic acid is suspected of being much more cholesterolemic than palmitic acid , but direct comparisons have been lacking . We therefore fed 36 women and 23 men three diets that differed from each other in palmitic , oleic , and myristic acid content by about 10 % of total energy . We used palm oil , high-oleic acid sunflower oil , and a specially produced high-myristic acid fat to achieve these differences . Each diet was consumed for 3 weeks in r and om order . Mean serum cholesterol was 4.53 mmol/L on the high-oleic acid diet , 4.96 mmol/L on the palmitic acid diet , and 5.19 mmol/L on the myristic acid diet ( P acid raised low-density lipoprotein ( LDL ) cholesterol by 0.11 mmol/L , high-density lipoprotein ( HDL ) cholesterol by 0.12 mmol/L , and apolipoprotein ( apo ) A-I by 7.2 mg/dL relative to palmitic acid ; increases relative to oleic acid were 0.50 mmol/L for LDL cholesterol , 0.15 mmol/L for HDL cholesterol , 6.0 mg/dL for apoB , and 8.9 mg/dL for apoA-I ( P HDL cholesterol and apoA-I levels on the palmitic and oleic acid diets were the same . None of the responses differed significantly between woman and men . Myristic acid and palmitic acid both caused high LDL cholesterol and apoB levels and low HDL to LDL ratios . ( ABSTRACT TRUNCATED AT 250 WORDS",
"BACKGROUND AND OBJECTIVES As the most widely produced edible vegetable oil , palm oil is known as to contain a high level of saturated fatty acid , which was thought to adversely affect serum lipid profiles . However , recent studies have shown no influence or benefits of palm oil on serum lipids . The potential nutritional value of palm oil is attributed to the high mono-unsaturation at the crucial sn2-position of the oil 's triacylglycerols , as with the so-called ' healthy ' olive oil ( OO ) . The aim of this study was to further test this hypothesis and evaluate the effects of consuming palm olein versus olive oil on serum lipid profiles in a Chinese population . METHODS AND STUDY DESIGN In total , 120 participants were recruited from a spinnery in Yixing city and r and omly divided into two groups ( palm olein or olive oil ) to conduct a 2 × 2 crossover trial for 2 months ' intervention with 2-week washout periods . Each participant was provided 48 g of test oil per day . At the end of each period , anthropometry , and blood lipid indices were measured to determine the effects of palm olein and olive oil . RESULTS Palm olein and olive oil consumption had no significantly different effect on BMI , on serum total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triacylglycerol ( TG ) , Apo B , fasting glucose , or insulin concentrations ( all p>0.05 ) . CONCLUSIONS In a dietary crossover trial , palm olein and olive oil had no recognisably different effects on body fatness or blood lipids in a healthy Chinese population",
"We previously found no difference in healthy young adults ' plasma cholesterols between palmolein and olive oil as the major dietary lipid , although the former is high in palmitic acid ( 16:0 ) but the latter in oleic acid ( 18:1 cis ) . In the experiment reported here we compared the effects of palmolein against another monounsaturated oil , highly oleic sunflower oil ( HOSO ) , on plasma cholesterol in both young and middle-aged healthy adults . The test oils were provided as frying oil of potato crisps ( 150 g/day in men ; 100 g/day in women ) against low-fat background diets in free-living motivated volunteers . The design was a r and omised double-blind 4-week/3-week crossover trial . Compliance was monitored with continuous dietary diaries and by measuring ( fasting ) plasma lipid fatty-acid pattern . Plasma lipids and vitamin-E compounds were measured at the start and twice at the end of each test period . In combined young plus older subjects ( n = 42 ) mean plasma total and low-density-lipoprotein cholesterol ( LDL-c ) values were both 7 % ( significantly ) lower on HOSO than on palmolein , but because high-density-lipoprotein cholesterol ( HDL-c ) was also 5 % lower , the LDL-c/HDL-c ratio was only 3 % lower on HOSO than on palmolein . The difference between the present results with HOSO and previous results with olive oil both compared against palmolein suggest that olive oil is associated with higher plasma cholesterols than other monounsaturated oils . In both the young and older subgroup , LDL-c was lower on HOSO but because HDL-c moved down too in the young subgroup , the LDL-c/HDL-c ratio was lower on HOSO only in the older subjects . Palmolein has an unusual pattern of E vitamins , with a high content of tocotrienols , notably the gamma-isomer . Unlike alpha-tocopherol however , there was no sign of these tocotrienols in subjects ' plasmas",
"In a controlled 16-week trial we have compared the effects on some risk factors for atherosclerosis of 2 cholesterol-lowering diets , one low in total fat and low in polyunsaturated fat ( LO ) and one moderate in total fat but high in polyunsaturated fat ( MOD ) as recommended by various advisory councils . All 35 volunteers were given diet MOD during a 2.5-week control period . This diet provided 31 % of the daily energy intake ( energy% ) as total fat ; one-third of the fatty acids were polyunsaturated ( PUFA ) . VLDL plus LDL cholesterol decreased by 0.66 mmol/1 during the control period while the HDL cholesterol ( HDL-C ) level was unchanged . Total serum triglycerides decreased by 0.33 mmol/l . After the control period the subjects were r and omized into 2 groups , one of which continued on diet MOD , while the other group received the low-fat diet LO , providing 2.1 energy% as total fat and 4 energy% as PUFA . All food was prepared daily and weighed out for each individual in amounts appropriate to the individual 's energy needs . Nutrient intakes were checked by 7-day records and by chemical analysis of double portions . The diets contained the same amounts of cholesterol , phytosterols , oligosaccharides and other nutrients known to affect serum lipid levels . Total serum cholesterol increased by 0.21 ± 0.41 mmol/l on control diet MOD during the test period of 13 weeks . 0.09 ± 0.11 mmol/l of this was due to HDL-C. Total serum triglycerides remained constant during the test period in group MOD . On diet LO total serum cholesterol remained stable during the test period , but HDL-C was lowered by −0.06 ± 0.20 mmol/1 . The difference in HDL-C between the diet groups was mainly located in HDL2 . Total serum triglycerides increased by + 0.32 ± 0.31 mmol/l in group LO ; the increase in VLDL triglycerides was + 0.22 ± 0.18 mmol/l . The depression of HDL on diet LO was also reflected in the ratio of HDL to total cholesterol which decreased by −0.02 ± 0.05 on diet LO , and was unchanged on diet MOD , and in the ratio of apo A1 to apo B ( 6 % decrease on diet LO and constant on diet MOD ) . Combination of these data with those from a preceding study [ Brussaard et al. , Atherosclerosis , 36 ( 1980 ) 515 ] leads to the following conclusions : 1 . ( 1 ) Both diets lower total serum cholesterol levels when compared with the habitual diets of affluent communities . 2 . ( 2 ) The high-carbohydrate , low-fat diet causes lower HDL and higher fasting VLDL triglyceride levels than the recommended moderate-fat-high-PUFA diet",
"The characteristics of people whose serum cholesterol level is unusually susceptible to consumption of cholesterol were investigated . Thirty-two volunteers from the general population of Wageningen , the Netherl and s , each participated in three controlled dietary trials in 1982 . A low-cholesterol diet was fed during the first half and a high-cholesterol diet during the second half of each trial , and the change ( response ) of serum cholesterol was measured . The responses in the three trials were averaged to give each subject 's mean responsiveness . Fecal excretion of cholesterol and its metabolites were measured in the second trial , and body cholesterol synthesis was calculated . Responsiveness showed a positive correlation with serum high density lipoprotein2 ( HDL2 ) cholesterol ( r = 0.41 , p less than 0.05 ) and with serum total cholesterol level on a high-cholesterol diet ( r = 0.31 , p = 0.09 ) . A negative relation was found with habitual cholesterol consumption ( r = -0.62 , p less than 0.01 ) , with body mass index ( r = -0.50 , p less than 0.01 ) , and with the rate of endogenous cholesterol synthesis ( r = -0.40 , p less than 0.05 ) , but not with the reaction of endogenous cholesterol synthesis rate to an increased intake of cholesterol . No relation was found with age , sex , total caloric needs , or the ratio of primary to secondary fecal steroids . Upon multiple regression analysis , only habitual cholesterol intake and serum total and HDL2 cholesterol levels contributed significantly to the explanation of variance in responsiveness . Thus , a low habitual cholesterol intake , a high serum HDL2 cholesterol level , or a low body weight do not make one less susceptible to dietary cholesterol-induced hypercholesterolemia",
"BACKGROUND Dietary fat type is known to modulate the plasma lipid profile , but its effects on plasma homocysteine and inflammatory markers are unclear . OBJECTIVE We investigated the effects of high-protein Malaysian diets prepared with palm olein , coconut oil ( CO ) , or virgin olive oil on plasma homocysteine and selected markers of inflammation and cardiovascular disease ( CVD ) in healthy adults . DESIGN A r and omized-crossover intervention with 3 dietary sequences of 5 wk each was conducted in 45 healthy subjects . The 3 test fats , namely palmitic acid (16:0)-rich palm olein ( PO ) , lauric and myristic acid ( 12:0 + 14:0)-rich CO , and oleic acid (18:1)-rich virgin olive oil ( OO ) , were incorporated at two-thirds of 30 % fat calories into high-protein Malaysian diets . RESULTS No significant differences were observed in the effects of the 3 diets on plasma total homocysteine ( tHcy ) and the inflammatory markers TNF-α , IL-1β , IL-6 , and IL-8 , high-sensitivity C-reactive protein , and interferon-γ . Diets prepared with PO and OO had comparable nonhypercholesterolemic effects ; the postpr and ial total cholesterol for both diets and all fasting lipid indexes for the OO diet were significantly lower ( P decrease postpr and ial lipoprotein(a ) . CONCLUSION Diets that were rich in saturated fatty acids prepared with either PO or CO , and an OO diet that was high in oleic acid , did not alter postpr and ial or fasting plasma concentrations of tHcy and selected inflammatory markers . This trial was registered at clinical trials.gov as NCT00941837",
"We studied the metabolic effects of stearic acid ( 18:0 ) on plasma lipoprotein levels in 11 subjects during three dietary periods of three weeks each . The three liquid-formula diets , which were used in r and om order , were high in palmitic acid ( 16:0 ) , stearic acid , and oleic acid ( 18:1 ) , respectively . Caloric intakes were the same during the three periods . As compared with the values observed when the subjects were on the high-palmitic-acid diet , plasma total cholesterol decreased by an average of 14 percent during consumption of the high-stearic-acid diet ( P less than 0.005 ) and by 10 percent during consumption of the high-oleic-acid diet ( P less than 0.02 ) . Low-density lipoprotein cholesterol levels fell by 21 percent in subjects on the high-stearic-acid diet ( P less than 0.005 ) and by 15 percent in subjects on the high-oleic-acid diet ( P less than 0.005 ) . No significant differences were observed in the plasma levels of triglycerides or high-density lipoprotein cholesterol among the three diets . Measurements of the intestinal absorption of palmitic , stearic , and oleic acids revealed essentially complete absorption of each during the three dietary periods . The oleic acid content of plasma triglycerides and cholesteryl esters increased significantly during the high-stearic-acid period , suggesting that stearic acid is rapidly converted to oleic acid . We conclude that stearic acid appears to be as effective as oleic acid in lowering plasma cholesterol levels when either replaces palmitic acid in the diet",
"Summary . Partial hydrogenation of oil results in fats containing unusual isomeric fatty acids characterized by cis and trans configurations . Hydrogenated fats containing trans fatty acids increase plasma total cholesterol ( TC ) and LDL-cholesterol while depressing HDL-cholesterol levels . Identifying the content of trans fatty acids by food labeling is overshadowed by a reluctance of health authorities to label saturates and trans fatty acids separately . Thus , it is pertinent to compare the effects of trans to saturated fatty acids using stable isotope methodology to establish if the mechanism of increase in TC and LDL-cholesterol is due to the increase in the rate of endogenous synthesis of cholesterol . Ten healthy normocholesterolemic female subjects consumed each of two diets containing approximately 30 % of energy as fat for a fourweek period . One diet was high in palmitic acid ( 10.6 % of energy ) from palm olein and the other diet exchanged 5.6 % of energy as partially hydrogenated fat for palmitic acid . This fat blend result ed in monounsaturated fatty acids decreasing by 4.9 % and polyunsaturated fats increasing by 2.7 % . The hydrogenated fat diet treatment provided 3.1 % of energy as elaidic acid . For each dietary treatment , the fractional synthesis rates for cholesterol were measured using deuterium-labeling procedures and blood sample s were obtained for blood lipid and lipoprotein measurements . Subjects exhibited a higher total cholesterol and LDL-cholesterol level when consuming the diet containing trans fatty acids while also depressing the HDL-cholesterol level . Consuming the partially hydrogenated fat diet treatment increased the fractional synthesis rate of free cholesterol . Consumption of hydrogenated fats containing trans fatty acids in comparison to a mixtur e of palmitic and oleic acids increase plasma cholesterol levels apparently by increasing endogenous synthesis of cholesterol"
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Objective : To determine the factors associated with physical activity participation in adults with hip or knee osteoarthritis . Methods : A systematic review was conducted including search es of AMED , PsycINFO , CINAHL , MEDLINE , EMBASE , PubMed and the Cochrane Library from inception until October 2013 . Studies presenting quantitative correlates of physical activity in adults with hip and /or knee osteoarthritis were included . Two independent authors conducted the search es , extracted data and completed method ological quality assessment . Correlates were analysed using the summary code approach within the socio-ecological model . Results : A total of 170 correlates were identified from 29 publications analysing 8076 individual people with hip or knee osteoarthritis . Method ological quality was generally good . For knee osteoarthritis , factors consistently negatively associated with physical activity ( reported more than four studies ) were increasing age ( number of participants in studies supporting association = 4558 ) , non-white ethnicity ( n = 3232 ) , increased osteoarthritis symptoms ( n = 2374 ) and female gender ( n = 4816 ) . Greater lower limb function ( n = 1671 ) and faster gait speed were ( n = 4098 ) positively associated with physical activity . Social ( e.g. support from spouse ( n = 141 ) ) and environment ( outdoor temperature ( n = 38 ) ) factors were identified as possible factors that influence physical activity . For hip osteoarthritis , higher body mass index ( n = 99 ) , increased comorbidities ( n = 1021 ) , lower mental health ( n = 189 ) and unemployment ( n = 65 ) were negatively associated with physical activity ; while better social functioning ( n = 1055 ) and health-related quality of life were positively associated with physical activity ( n = 34 ) . Conclusion : Demographic , physical , social , psychological and environmental factors are all important correlates for physical activity for people with knee or hip osteoarthritis . Clinicians should consider these in clinical practice
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"OBJECTIVES To determine whether ethnicity was associated with baseline and 18-month health status within a merged sample of older adults with knee osteoarthritis ( OA ) from the Fitness Arthritis in Seniors Trial and the Arthritis , Diet , and Activity Promotion Trial . DESIGN Cross-sectional and prospect i ve study . SETTING Center-based exercise therapy at two universities . PARTICIPANTS A total of 584 African-American ( n=143 ) and Caucasian-American ( n=441 ) adults aged 60 and older with knee OA were examined for baseline and 18-month health status . MEASUREMENTS Six-minute-walk distance , 36-item Short Form General Health Scale ( SF-36 GHS ) , and Physical Functioning Question naire index score . Ethnicity was obtained via self-report . RESULTS Analyses of covariance testing the effect of ethnicity , adjusted for demographic and health status covariates , revealed significant effects for ethnicity upon baseline 6-minute-walk distance and SF-36 GHS , with Caucasian Americans reporting better scores ( P=.001 ) , although these differences were not significant after 18 months of exercise therapy . CONCLUSION Ethnicity and baseline function are important factors that should not be overlooked in knee OA research involving exercise interventions . Moreover , not only should physical activity be recommended to improve functional outcomes , it may also be a useful strategy in reducing health disparities",
"OBJECTIVE Physical activity improves function in adults with arthritis , but it is unknown if there is a grade d relationship between physical activity and functional benefit . This study was undertaken to examine the cross-sectional and longitudinal relationship between self-reported physical activity and observed functional performance in adults with knee osteoarthritis ( OA ) . METHODS The Osteoarthritis Initiative cohort included 2,589 patients with knee OA ( 2,301 with longitudinal followup data ) who were ages 45 - 79 years at baseline . Prospect i ve annual functional performance was assessed for 2 years using timed 20-meter walk tests . We used linear regression to estimate differences across physical activity quartiles in subsequent function ( baseline and 1-year activity predicts 1-year and 2-year function , respectively ) adjusted for demographic factors ( age , sex , race/ethnicity , education level , and marital status ) and health factors ( OA severity , knee symptoms , knee pain , knee injury , body mass index , comorbidity , depression , smoking , alcohol use , and other joint pain ) . RESULTS Increasing physical activity levels had a significant grade d relationship to functional performance . Adults in physical activity quartile groups from least active to most active had an average gait speed of 4.0 , 4.2 , 4.3 , and 4.5 feet/second , respectively , at baseline ( P for trend physical activity level and better performance in adults with knee OA . These findings support guidelines that encourage patients with arthritis who can not attain minimum recommended physical activity to be as active as possible",
"PURPOSE We present final outcomes from the multiple-component Fit and Strong ! intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of this exercise and behavior-change program followed by home-based reinforcement ( n=115 ) with a wait list control ( n=100 ) at 2 , 6 , and 12 months . Fit and Strong ! combined flexibility , aerobic walking , and resistance training with education and group problem solving to enhance self-efficacy for exercise and maintenance of physical activity . All participants developed individualized plans for long-term maintenance . RESULTS Relative to controls , treatment participants experienced statistically significant improvements in self-efficacy for exercise ( p=.001 ) , minutes of exercise per week ( p=.000 ) , and lower extremity stiffness ( p=.018 ) at 2 months . These benefits were maintained at 6 months and were accompanied by increased self-efficacy for adherence to exercise over time ( p=.001 ) , reduced pain ( p=.040 ) , and a marginally significant increase in self-efficacy for arthritis pain management ( p=.052 ) . Despite a substantially smaller sample size at 12 months , significant treatment-group effects were maintained on self-efficacy for exercise ( p=.006 ) and minutes of exercise per week ( p=.001 ) , accompanied by marginally significant reductions in lower extremity stiffness ( p=.056 ) and pain ( p=.066 ) . No adverse health effects were seen . Effect sizes for self-efficacy for exercise and for maintenance of physical activity were 0.798 and 0.713 , and 0.905 and 0.669 , respectively , in the treatment group at 6 and 12 months . IMPLICATION S This consistent pattern of benefits indicates that this low-cost intervention is efficacious for older adults with lower extremity osteoarthritis",
"IMPORTANCE Knee osteoarthritis ( OA ) , a common cause of chronic pain and disability , has biomechanical and inflammatory origins and is exacerbated by obesity . OBJECTIVE To determine whether a ≥10 % reduction in body weight induced by diet , with or without exercise , would improve mechanistic and clinical outcomes more than exercise alone . DESIGN , SETTING , AND PARTICIPANTS Single-blind , 18-month , r and omized clinical trial at Wake Forest University between July 2006 and April 2011 . The diet and exercise interventions were center-based with options for the exercise groups to transition to a home-based program . Participants were 454 overweight and obese older community-dwelling adults ( age ≥55 years with body mass index of 27 - 41 ) with pain and radiographic knee OA . INTERVENTIONS Intensive diet-induced weight loss plus exercise , intensive diet-induced weight loss , or exercise . MAIN OUTCOMES AND MEASURES Mechanistic primary outcomes : knee joint compressive force and plasma IL-6 levels ; secondary clinical outcomes : self-reported pain ( range , 0 - 20 ) , function ( range , 0 - 68 ) , mobility , and health-related quality of life ( range , 0 - 100 ) . RESULTS Three hundred ninety-nine participants ( 88 % ) completed the study . Mean weight loss for diet + exercise participants was 10.6 kg ( 11.4 % ) ; for the diet group , 8.9 kg ( 9.5 % ) ; and for the exercise group , 1.8 kg ( 2.0 % ) . After 18 months , knee compressive forces were lower in diet participants ( mean , 2487 N ; 95 % CI , 2393 to 2581 ) compared with exercise participants ( 2687 N ; 95 % CI , 2590 to 2784 , pairwise difference [Δ](exercise vs diet ) = 200 N ; 95 % CI , 55 to 345 ; P = .007 ) . Concentrations of IL-6 were lower in diet + exercise ( 2.7 pg/mL ; 95 % CI , 2.5 to 3.0 ) and diet participants ( 2.7 pg/mL ; 95 % CI , 2.4 to 3.0 ) compared with exercise participants ( 3.1 pg/mL ; 95 % CI , 2.9 to 3.4 ; Δ(exercise vs diet + exercise ) = 0.39 pg/mL ; 95 % CI , -0.03 to 0.81 ; P = .007 ; Δ(exercise vs diet ) = 0.43 pg/mL ; 95 % CI , 0.01 to 0.85 , P = .006 ) . The diet + exercise group had less pain ( 3.6 ; 95 % CI , 3.2 to 4.1 ) and better function ( 14.1 ; 95 % CI , 12.6 to 15.6 ) than both the diet group ( 4.8 ; 95 % CI , 4.3 to 5.2 ) and exercise group ( 4.7 ; 95 % CI , 4.2 to 5.1 , Δ(exercise vs diet + exercise ) = 1.02 ; 95 % CI , 0.33 to 1.71 ; P(pain ) = .004 ; 18.4 ; 95 % CI , 16.9 to 19.9 ; Δ(exercise vs diet + exercise ) , 4.29 ; 95 % CI , 2.07 to 6.50 ; P(function ) ) . The diet + exercise group ( 44.7 ; 95 % CI , 43.4 to 46.0 ) also had better physical health-related quality of life scores than the exercise group ( 41.9 ; 95 % CI , 40.5 to 43.2 ; Δ(exercise vs diet + exercise ) = -2.81 ; 95 % CI , -4.76 to -0.86 ; P = .005 ) . CONCLUSIONS AND RELEVANCE Among overweight and obese adults with knee OA , after 18 months , participants in the diet + exercise and diet groups had more weight loss and greater reductions in IL-6 levels than those in the exercise group ; those in the diet group had greater reductions in knee compressive force than those in the exercise group . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00381290"
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The assessment of physical activity in healthy population s and in those with chronic diseases is challenging . The aim of this systematic review was to identify whether available activity monitors ( AM ) have been appropriately vali date d for use in assessing physical activity in these groups . Following a systematic literature search we found 134 papers meeting the inclusion criteria ; 40 conducted in a field setting ( validation against doubly labelled water ) , 86 in a laboratory setting ( validation against a metabolic cart , metabolic chamber ) and 8 in a field and laboratory setting . Correlation coefficients between AM outcomes and energy expenditure ( EE ) by the criterion method ( doubly labelled water and metabolic cart/chamber ) and percentage mean differences between EE estimation from the monitor and EE measurement by the criterion method were extracted . R and om-effects meta-analyses were performed to pool the results across studies where possible . Types of devices were compared using meta-regression analyses . Most validation studies had been performed in healthy adults ( n = 118 ) , with few carried out in patients with chronic diseases ( n = 16 ) . For total EE , correlation coefficients were statistically significantly lower in uniaxial compared to multisensor devices . For active EE , correlations were slightly but not significantly lower in uniaxial compared to triaxial and multisensor devices . Uniaxial devices tended to underestimate TEE ( −12.07 ( 95%CI ; -18.28 to −5.85 ) % ) compared to triaxial ( −6.85 ( 95%CI ; -18.20 to 4.49 ) % , p = 0.37 ) and were statistically significantly less accurate than multisensor devices ( −3.64 ( 95%CI ; -8.97 to 1.70 ) % , p was underestimated during slow walking speeds in 69 % of the lab validation studies compared to 37 % , 30 % and 37 % of the studies during intermediate , fast walking speed and running , respectively . The high level of heterogeneity in the validation studies is only partly explained by the type of activity monitor and the activity monitor outcome . Triaxial and multisensor devices tend to be more valid monitors . Since activity monitors are less accurate at slow walking speeds and information about vali date d activity monitors in chronic disease population s is lacking , proper validation studies in these population s are needed prior to their inclusion in clinical trials
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"The purpose of this study was to develop a new two-regression model relating Actigraph activity counts to energy expenditure over a wide range of physical activities . Forty-eight participants [ age 35 yr ( 11.4 ) ] performed various activities chosen to represent sedentary , light , moderate , and vigorous intensities . Eighteen activities were split into three routines with each routine being performed by 20 individuals , for a total of 60 tests . Forty-five tests were r and omly selected for the development of the new equation , and 15 tests were used to cross-vali date the new equation and compare it against already existing equations . During each routine , the participant wore an Actigraph accelerometer on the hip , and oxygen consumption was simultaneously measured by a portable metabolic system . For each activity , the coefficient of variation ( CV ) for the counts per 10 s was calculated to determine whether the activity was walking/running or some other activity . If the CV was 10 , a lifestyle/leisure time physical activity regression was used . In the cross-validation group , the mean estimates using the new algorithm ( 2-regression model with an inactivity threshold ) were within 0.75 metabolic equivalents ( METs ) of measured METs for each of the activities performed ( P > or= 0.05 ) , which was a substantial improvement over the single-regression models . The new algorithm is more accurate for the prediction of energy expenditure than currently published regression equations using the Actigraph accelerometer",
"This study examined the predictive validity of accelerometers ( ACC ) to estimate physical activity intensity ( PAI ) across age and differences in intensity predictions when expressed in relative and absolute PAI terms . Ninety adults categorized into 3 age groups ( 20 - 29 , 40 - 49 , and 60 - 69 yr ) completed a treadmill calibration study with simultaneous ACC ( 7164 Actigraph ) and oxygen-consumption assessment . Results revealed strong linear relations between ACC output and measured PAI ( R2 = .62-.89 ) across age and similar ACC cut-point ranges across age delineating absolute PAI ranges compared with previous findings . Comparing measured metabolic equivalents ( METs ) with estimated METs derived from previously published regression equations revealed that age did not affect predictive validity of ACC estimates of absolute PAI . Comparing ACC output expressed in relative vs. absolute terms across age revealed substantial differences in PAI ACC count ranges . Further work is warranted to increase the applicability ofACC use relative to PAI differences associated with physiological changes with age",
"Background Underst and ing the relationships between physical activity ( PA ) and disease has become a major area of research interest . Activity monitors , devices that quantify free-living PA for prolonged periods of time ( days or weeks ) , are increasingly being used to estimate PA . A range of different activity monitors br and s are available for investigators to use , but little is known about how they respond to different levels of PA in the field , nor if data conversion between br and s is possible . Methods 56 women and men were fitted with two different activity monitors , the Actigraph ™ ( Actigraph LLC ; AGR ) and the Actical ™ ( Mini-Mitter Co. ; MM ) for 15 days . Both activity monitors were fixed to an elasticized belt worn over the hip , with the anterior and posterior position of the activity monitors r and omized . Differences between activity monitors and the validity of br and inter-conversion were measured by t-tests , Pearson correlations , Bl and -Altman plots , and coefficients of variation ( CV ) . Results The AGR detected a significantly greater amount of daily PA ( 216.2 ± 106.2 vs. 188.0 ± 101.1 counts/min , P a CV were 3.1 and 15.5 % for log-transformed and raw data , respectively . When a conversion equation was applied to convert data sets from one br and to another , the differences were no longer significant , with CV 's of 2.2 and 11.7 % , log-transformed and raw data , respectively . Conclusion Although activity monitors predict PA on the same scale ( counts/min ) , the results between these two br and s are not directly comparable . However , the data are comparable if a conversion equation is applied , with better results for log-transformed data",
"The primary purpose of this study was to investigate the accuracy of the activPAL physical activity monitor in measuring step number and cadence in older adults . Two pedometers ( New-Lifestyles Digi-Walker SW-200 and New-Lifestyles NL2000 ) used in clinical practice to count steps were simultaneously evaluated . Observation was the criterion measure . Twenty-one participants ( 65 - 87 yr old ) recruited from community-based exercise classes walked on a treadmill at 5 speeds ( 0.67 , 0.90 , 1.12 , 1.33 , and 1.56 m/s ) and outdoors at 3 self-selected speeds ( slow , normal , and fast ) . The absolute percentage error of the activPAL was steps and cadence . With the exception of the slowest treadmill speed , the NL-2000 error was step number and cadence . Combined with its ability to identify primary postures , the activPAL might be a useful and versatile device for measuring activity in older adults",
"Objective . To determine whether the energy expenditure recorded with the physical activity monitor SenseWear ™ Pro2 Armb and differs from that recorded with indirect calorimetry . Design . Cross‐sectional comparison of measures of energy expenditure . Setting . A convenient sample recruited from a r and omized controlled trial . Population . Twenty‐nine pregnant women ( 24–43years old ) . Methods . Energy expenditure was recorded with SenseWear ™ Pro2 Armb and and a portable oxygen analyzer for 90minutes while carrying out a variety of activities of different intensities . Main Outcome Measures . Energy expenditure recorded with the physical activity monitor SenseWear ™ Pro2 Armb and . Results . Comparing energy expenditure during free‐living activities , the mean differences and limits of agreements from Bl and –Altman plots was −136±343kJ , giving an underestimation of energy expenditure by 9 % . The intraclass correlation coefficient was 0.85 ( 95 % confidence interval 0.71–0.93 ; p Conclusions . SenseWear ™ Pro2 Armb and is a valid measure of energy expenditure during pregnancy",
"PURPOSE The accuracy of pedometers has not been thoroughly tested with older adult population s. The purpose of the present study was to examine the effects of walking speed and gait disorders on the accuracy of Yamax pedometers with nursing home residents ( NH ) relative to older adults living in the community . METHODS Pedometer accuracy was evaluated against observed steps taken during a self-paced walking test ( slow , normal , and fast speeds ) in 26 NH residents and 28 seniors ' recreation center members ( SC ) . Devices were attached to clothing at the waist . Walking speed was ascertained from the timed walk and a gait assessment was conducted . Percent error was calculated as ( [ pedometer steps - observed steps]/observed steps ) x 100 . RESULTS The walking speeds of both sample s increased across self-selected paces ( P community-dwelling older adults walked significantly faster ( P 0.0001 ) gait assessment scores ( indicating fewer gait problems ) . Gait scores were positively associated with walking speed and pedometer percent error . Pedometers significantly underestimated NH residents ' observed steps taken by 74 % ( slow ) , 55 % ( normal ) , and 46 % ( fast ) paces ( P steps taken , respectively ( P magnitude of the error was greater for NH versus SC older adults ( P pedometers for physical activity measurement in frail seniors , such as NH residents , when worn at the usual attachment site . Pedometers , however , can be confidently used with ostensibly healthy older adult population s for both assessment and motivation purpose",
"We have recently developed a simple algorithm for the classification of household and locomotive activities using the ratio of unfiltered to filtered synthetic acceleration ( gravity-removal physical activity classification algorithm , GRPACA ) measured by a triaxial accelerometer . The purpose of the present study was to develop a new model for the immediate estimation of daily physical activity intensities using a triaxial accelerometer . A total of sixty-six subjects were r and omly assigned into validation ( n 44 ) and cross-validation ( n 22 ) groups . All subjects performed fourteen activities while wearing a triaxial accelerometer in a controlled laboratory setting . During each activity , energy expenditure was measured by indirect calorimetry , and physical activity intensities were expressed as metabolic equivalents ( MET ) . The validation group displayed strong relationships between measured MET and filtered synthetic accelerations for household ( r 0·907 , P highly accurate MET estimation for household and locomotive activities . Results were similar when equations were developed by non-linear regression or sex-specific linear or non-linear regressions . Sedentary activities were also accurately estimated by the specific linear regression classified from other activity counts . Therefore , the use of a triaxial accelerometer in combination with a GRPACA permits more accurate and immediate estimation of daily physical activity intensities , compared with previously reported cut-off classification models . This method may be useful for field investigations as well as for self-monitoring by general users",
"In our study of 125 subjects ( 53 men and 72 women ) for two 24-h periods , we vali date d energy expenditure ( EE ) , estimated by a triaxial accelerometer ( Tritrac-R3D ) , by using a whole-room indirect calorimeter under close-to-normal living conditions . The estimated EE was correlated with the measured total EE for the 2 days ( r = 0 . 925 and r = 0.855 ; P Resting EE formulated by the Tritrac was found to be similar to the measured values [ st and ard errors of estimation ( SEE ) = 0.112 W/kg ; P = 0.822 ] . The Tritrac significantly underestimated total EE , EE for physical activities , EE of sedentary and light-intensity activities , and EE for exercise such as stepping ( all P EE by using the acceleration components from the Tritrac . Predicted EE was significantly improved with both models in estimating total EE , total EE for physical activities , EE in low-intensity activities , minute-by-minute averaged relative difference , and minute-by-minute SEE ( all P EE can be estimated with higher accuracy ( averaged SEE = 0.418 W/kg ) than with the Tritrac model",
"We compared the accuracy of two physical activity recall question naires and a motion detector in 45- to 84-yr-old women ( n = 35 ) and men ( n = 32 ) , using doubly labeled water ( DLW ) in conjunction with indirect calorimetry as the criterion measure . Subjects were administered the Yale Physical Activity Survey ( YPAS ) and Minnesota Leisure Time Physical Activity Question naire ( LTA ) . Physical activity energy expenditure was determined over a 10-day period by using a Caltrac uniaxial accelerometer and DLW in conjunction with indirect calorimetry . In older women , Minnesota LTA ( 386 + /- 228 kcal/day ) and Caltrac ( 379 + /- 162 kcal/day ) underestimated physical activity by approximately 55 % compared with DLW ( 873 + /- 244 kcal/day ) . No difference was observed between daily physical activity measured by the YPAS ( 863 + /- 447 kcal/day ) and DLW in older women . In older men , Minnesota LTA ( 459 + /- 288 kcal/day ) and Caltrac ( 554 + /- 242 kcal/day ) underestimated daily physical activity by approximately 50 - 60 % compared with DLW ( 1,211 + /- 429 kcal/day ) . No difference was found between physical activity measured by the YPAS ( 1,107 + /- 612 kcal/day ) and DLW in older men . Despite no difference in mean physical activity levels between YPAS and DLW in women and men , Bl and and Altman ( Lancet 1 : 307 - 310 , 1986 ) analyses demonstrated poor concordance between DLW and YPAS ( i.e. , limits of agreement = -1,310 - 1,518 kcal/day ) . Our data suggest that the Minnesota LTA recall and Caltrac uniaxial accelerometer may significantly underestimate free-living daily physical activity energy expenditure in older women and men . Although the YPAS compares favorably with DLW on a group basis , its use as a proxy measure of individual daily physical activity energy expenditure may be limited in older women and men",
"Physical activity energy expenditure ( PAEE ) is a determinant of prognosis and fitness in older patients with coronary heart disease ( CHD ) . PAEE and total energy expenditure ( TEE ) are closely related to fatness , physical function , and metabolic risk in older individuals . The goal of this study was to assess effects of resistance training on PAEE , TEE , and fitness in older women with chronic CHD and physical activity limitations ( N = 51 , mean age : 72 + 5 yr ) . The study intervention consisted of a progressive , 6-mo program of resistance training vs. a control group condition of low-intensity yoga and deep breathing . The study interventions were completed by 42 of the 51 participants . The intervention group manifested a 177 + /- 213 kcal/day ( + 9 % ) increase in TEE , pre- to posttraining , measured by the doubly labeled water technique during a nonexercise 10-day period ( P resting metabolic rate measured by indirect calorimetry ( P PAEE ( P upper and lower body strength , but no change in fat-free mass , measured by dual X-ray absorptiometry , or left ventricular function , measured by echocardiography and Doppler . Women in the control group showed no alterations in TEE or its determinants . There were no changes between groups in body composition , aerobic capacity , or measures of mental depression . These results demonstrate that resistance training of 6-mo duration leads to an increase in TEE and PAEE in older women with chronic CHD",
"Background Objective measurement of physical activity remains an important challenge . For wearable monitors such as accelerometer-based physical activity monitors , more accurate methods are needed to convert activity counts into energy expenditure ( EE ) . Purpose The purpose of this study was to examine the accuracy of the refined Crouter 2-Regression Model ( C2RM ) for estimating EE during the transition from rest to walking and walking to rest . A secondary purpose was to determine the extent of overestimation in minute-by-minute EE between the refined C2RM and the 2006 C2RM . Methods Thirty volunteers ( age , 28 ± 7.7 yrs ) performed 15 minutes of seated rest , 8 minutes of over-ground walking , and 8 minutes of seated rest . An ActiGraph GT1 M accelerometer and Cosmed K4b2 portable metabolic system were worn during all activities . Participants were r and omly assigned to start the walking bout at 0 , 20 , or 40 s into the minute ( according to the ActiGraph clock ) . Acceleration data were analyzed by two methods : 2006 Crouter model and a new refined model . Results The 2006 Crouter 2-Regression model over-predicted measured kcal kg-1 hr-1 during the first and last transitional minutes of the 20-s and 40-s walking conditions ( P the average EE for a walking bout ( 4.0 ± 0.5 kcal kg-1 hr-1 ) , compared to both the measured kcal kg-1 hr-1 ( 3.6 ± 0.7 kcal kg-1 hr-1 ) and the refined Crouter model ( 3.5 ± 0.5 kcal kg-1 hr-1 ) ( P prediction of EE during walking",
"The use of movement registration for daily physical activity assessment was evaluated during a 7-day period in 30 free-living subjects . Body movement was registered with a Tracmor motion sensor consisting of a triaxial accelerometer and a data unit for on-line processing of accelerometer output over 1-min intervals . Average Tracmor output was correlated against four different energy estimates : 1 ) average daily metabolic rate ( ADMR ) , determined with doubly labeled water ; 2 ) ADMR-sleeping metabolic rate ( SMR ; determined in a respiration chamber ) ; 3 ) ( ADMR-SMR ) per kilogram of body mass ; and 4 ) the overall physical activity level ( PAL = ADMR/SMR ) . The highest correlation was found for the relationship between Tracmor output and PAL ( r = 0.58 ) . After correction for Tracmor values arising from vibrations produced by transportation means , this correlation was improved to 0.73 . There was no difference between Tracmor output and PAL in discriminating between overall activity levels with \" low \" ( PAL 1.85 ) intensity . It is concluded that the Tracmor can be used in free-living subjects to distinguish among interindividual as well as intraindividual levels of daily physical activity",
"This study assessed the ability of four different activity monitors to discriminate changes in treadmill walking velocity . The relationships between walking velocity and bodily movement and between bodily movement and energy expenditure determined by indirect calorimetry ( IC-EE or METs ) were determined . Twenty-eight subjects walked at 3.2 , 4.0 , 4.8 , 5.6 , and 6.4 km/h ( 0 % grade ) for 30 min on separate occasions . The Tritrac-R3D ( TT ) , Computer Science & Applications , Inc. ( CSA ) , and Mini-Logger ( ML ) activity monitors that measure bodily acceleration in one or three planes , and a Yamax Digiwalker-500 ( YX ) that records footsteps , were secured at the waistline of each subject . CSA monitors were also worn at the wrist and ankle . Walking velocity and bodily movement were significantly related ( r = 0.89 to 0.93 ) for TT , CSA , ML , and YX . Importantly , changing each walking velocity produced significant changes in bodily movement that was detected by each monitor . Bodily movement and IC-EE were significantly related for TT , CSA , ML , and YX ( r = 0.47 to 0.94 ) . Compared to IC-EE , and at all walking speeds , EE was significantly overestimated by the TT , and EE was significantly underestimated by the YX . These results indicate that the activity monitors can differentiate bodily movement associated with walking at slow speeds better than they can estimate energy expenditure associated with walking at slow speeds",
"The ability to relate physical activity to health depends on accurate measurement . Yet , none of the available methods are fully satisfactory due to several factors . This study examined the accuracy of a multi-sensor board ( MSB ) that infers activity types ( sitting , st and ing , walking , stair climbing , and running ) and estimates energy expenditure in 57 adults ( 32 females ) 39.2 ± 13.5 years . In the laboratory , subjects walked and ran on a treadmill over a select range of speeds and grade s for 3 min each ( six stages in r and om order ) while connected to a stationary calorimeter , preceded and followed by brief sitting and st and ing . On a different day , subjects completed scripted activities in the field connected to a portable calorimeter . The MSB was attached to a strap at the right hip . Subjects repeated one condition ( r and omly selected ) on the third day . Accuracy of inferred activities compared with recorded activities ( correctly identified activities/total activities × 100 ) was 97 and 84 % in the laboratory and field , respectively . Absolute accuracy of energy expenditure [ 100 – absolute value ( kilocalories MSB – kilocalories calorimeter/kilocalories calorimeter ) × 100 ] was 89 and 76 % in the laboratory and field , the later being different ( P . Test – retest reliability for energy expenditure was significant in both setting s ( P accurate measures of activity type in laboratory and field setting s and energy expenditure during treadmill walking and running although the device underestimates energy expenditure in the field",
"Resting energy expenditure ( REE ) is often elevated in patients with chronic obstructive pulmonary disease ( COPD ) , but no data are available regarding total energy expenditure in free living conditions . We compared total daily energy expenditure ( TDE ) in eight COPD patients ( FEV1 36 + /- 13 % ) admitted to a pulmonary rehabilitation center and eight independently living healthy subjects , matched for sex , age , and body mass index ( BMI ) . TDE was measured over a 2-wk interval using doubly labeled water in combination with measurement of REE and body composition . The COPD patients had a significantly higher TDE than the healthy subjects ( 2,499 + /- 320 kcal/d and 2,107 + /- 88 kcal/d , respectively , p nonresting component of TDE ( TDE-REE : physical activity and diet-induced thermogenesis [ DIT ] ) was significantly higher in the COPD patients than in the healthy subjects , result ing in a ratio between TDE and REE of 1.7 + /- 0.2 and 1.4 + /- 0.1 , respectively ( p COPD patients exhibit an increased TDE in comparison with healthy subjects . The difference could by attributed to an increase in the nonresting component of TDE , since REE was comparable between the groups",
"PURPOSE This study examined the effects of walking speed on the accuracy and reliability of 10 pedometers : Yamasa Skeletone ( SK ) , Sportline 330 ( SL330 ) and 345 ( SL345 ) , Omron ( OM ) , Yamax Digiwalker SW-701 ( DW ) , Kenz Lifecorder ( KZ ) , New Lifestyles 2000 ( NL ) , Oregon Scientific ( OR ) , Freestyle Pacer Pro ( FR ) , and Walk4Life LS 2525 ( WL ) . METHODS Ten subjects ( 33 + /- 12 yr ) walked on a treadmill at various speeds ( 54 , 67 , 80 , 94 , and 107 m x min-1 ) for 5-min stages . Simultaneously , an investigator determined steps by a h and counter and energy expenditure ( kcal ) by indirect calorimetry . Each br and was measured on the right and left sides . RESULTS Correlation coefficients between right and left sides exceeded 0.81 for all pedometers except OR ( 0.76 ) and SL345 ( 0.57 ) . Most pedometers underestimated steps at 54 m x min-1 , but accuracy for step counting improved at faster speeds . At 80 m x min-1 and above , six models ( SK , OM , DW , KZ , NL , and WL ) gave mean values that were within + /- 1 % of actual steps . Six pedometers displayed the distance traveled . Most of them estimated mean distance to within + /- 10 % at 80 m x min-1 but overestimated distance at slower speeds and underestimated distance at faster speeds . Eight pedometers displayed kilocalories , but except for KZ and NL , it is unclear whether this should reflect net or gross kilocalories . If one assumes they display net kilocalories , the general trend was an overestimation of kilocalories at every speed . If one assumes they display gross kilocalorie , then seven of the eight pedometers were accurate to within + /-30 % at all speeds . CONCLUSION In general , pedometers are most accurate for assessing steps , less accurate for assessing distance , and even less accurate for assessing kilocalories",
"The objective of this work was to evaluate the accuracy and viability of a mobility telemonitoring system , based on the short message service ( SMS ) , to monitor the functional mobility of elderly subjects in an unsupervised environment A clinical trial was conducted consisting of 6 elderly subjects ; 3 male , 3 female ( mean : 81.7 , SD : 5.09 ) . Mobility was monitored using an accelerometer based portable unit worn by each monitored subject for eleven hours . Every 15 minutes the mobility of the subject was summarized and transmitted as an SMS message from the portable unit to a remote server for long term analysis . The activPALtrade Trio Professional physical activity logger was simultaneously used for comparison with the portable unit . On conclusion of the trial each subject completed a question naire detailing their satisfaction with the portable unit and any recommendations for improvements . Overall a percentage difference of 2.31 % was found between the activPALtrade Trio and the portable unit for the detection of sitting . For the combined postures of st and ing and walking the percentage difference was calculated as 2.9 % . A bivariate correlation and regression analysis was performed on the entire data set of one subject . Strong positive correlation 's were found for the detection of sitting ( r = 0.996 ) and for the combined postures of st and ing and walking ( r = 0.994 ) . Subjects suggested that a lighter , smaller and wireless unit would be more effective",
"OBJECTIVE To compare the accuracy of 2 motion sensors ( a pedometer and a multisensor ) in terms of step counting and estimation of energy expenditure ( EE ) in patients with chronic obstructive pulmonary disease ( COPD ) and in healthy elderly . DESIGN In this descriptive study , all participants wore both motion sensors while performing a treadmill walking protocol at 3 different speeds corresponding to 30 % , 60 % , and 100 % of the average speed achieved during a six-minute walk test . As criterion methods , EE was estimated by indirect calorimetry , and steps were registered by videotape . SETTING Research laboratory at a university hospital . PARTICIPANTS Patients with COPD ( n=30 ; 17 men ; mean age + /- SD , 67+/-8 y ; mean forced expiratory volume in the first second [ FEV(1 ) ] predicted + /- SD , 46%+/-17 % ; mean body mass index [ BMI ] + /- SD , 24+/-4 kg.m(2 ) ) and matched healthy elderly ( n=30 ; 15 men ; mean age + /- SD , 68+/-7 y ; mean FEV(1 ) predicted + /- SD , 104%+/-21 % ; mean BMI + /- SD , 25+/-3 kg.m(2 ) ) . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURE Step counting and EE estimation during a treadmill walking protocol . RESULTS The pedometer was accurate for step counting and EE estimation in both patients with COPD and healthy elderly at the higher speed . However , it showed significant underestimation at the 2 slower speeds in both groups . The multisensor did not detect steps accurately at any speed , although it accurately estimated EE at all speeds in healthy elderly and at the intermediate and higher speeds in patients with COPD . CONCLUSIONS In both patients with COPD and healthy elderly , the multisensor showed better EE estimates during most walking speeds than the pedometer . Conversely , for step counting , accuracy is observed only with the pedometer during the higher walking speed in both groups",
"Combining accelerometry with heart rate monitoring has been suggested to improve energy estimates , however , it remains unclear whether the single , currently existing commercially available device combining these data streams ( Actiheart ) provides improved energy estimates compared to simpler and less expensive accelerometry-only devices . The purpose of this study was to compare the validity of the heart rate ( HR ) , accelerometry ( ACC ) , and combined ACC/HR estimates of the Actiheart to the ACC estimates of the Actical during low and moderate intensity activities . Twenty-seven participants ( mean age 26.3 ± 7.3 ) wore an Actical , Actiheart and indirect calorimeter ( K4b2 ) while performing card playing , sweeping , lifting weights , walking and jogging activities . All estimates tended to underestimate energy , sometimes by substantial amounts . Viewed across all activities studied , there was no significant difference in the ability of the waist-mounted Actical and torso-mounted Actiheart ( ACC , HR , ACC/HR ) estimates to predict energy expenditure . However , the Actiheart provided significantly better estimates than the Actical for the activities in which acceleration of the pelvis is not closely related to energy expenditure ( card playing , sweeping , lifting weights ) and the Actical provided significantly better estimates for level walking and level jogging . Similar to a previous study , the ACC component of the Actiheart was found to be the weakest predictor of energy suggesting it may be responsible for the failure of the combined ACC/HR estimate to equal or better the estimates derived solely from a waist mounted ACC device",
"UNLABELLED It is suggested that triaxial accelerometers ( RT3 ) are superior to single-plane accelerometers for predicting energy expenditure ( EE ) . PURPOSE To compare the RT3 uniaxial and triaxial prediction of activity EE ( AEE ) during treadmill activities ( TM ) and activities of daily living ( ADL ) . METHODS Two hundred and twelve subjects ( aged 20 - 60 yr ) completed TM speeds of 1.34 , 1.56 , and 2.23 m x s(-1 ) at 0 % and 3 % grade s , stair ascent/descent , moving a box , and two r and omly assigned ADL . Subjects wore a portable indirect calorimeter to measure EE to calculate AEE by subtracting resting metabolic rate . Acceleration counts in the vertical ( V ) , medial-lateral , and anterior-posterior planes were collected in a single RT3 secured to the hip . Predicted AEE ( RT3AEE ) was estimated from vector magnitude ( VM ) counts using a proprietary algorithm . A paired t-test compared RT3AEE versus AEE . The relationship among V and VM counts and AEE was examined using linear regression analyses . RESULTS RT3 overestimated AEE for all activities combined , overestimated for TM ( 9.0 % ) , and underestimated for ADL ( 34.3 % ; P R2 values between RT3AEE and AEE for TM and ADL were R2 = 0.78 and R2 = 0.15 , respectively . The RT3 underestimated activity with greater upper body movements by 24.4%-64.5 % ( P V and VM counts were similarly related to AEE ( R2 = 0.35 ) and RT3AEE ( R2 = 0.83 - 0.89 ) . CONCLUSIONS Although the RT3 did not accurately predict AEE from accelerometer counts , stronger relationships existed between predicted and measured AEE for TM compared with ADL . Compared with V counts , using VM counts to predict AEE did not significantly improve the relationship between counts and AEE . Analytic techniques beyond linear regression with VM as a covariate or with counts from each axis entering the model separately may improve estimates of AEE from triaxial accelerometers ",
"OBJECTIVE The objective was to evaluate two accelerometers , the RT3 and the TriTrac-R3D for their ability to produce estimates of physical activity-related energy expenditure ( PAEE ) in overweight/obese adults . RESEARCH METHODS AND PROCEDURES PAEE estimates from both accelerometers were obtained in two experiments . In Experiment 1 , 13 overweight/obese subjects ( BMI 34.2+/-6.4 kg/m2 ) were monitored over 2 weeks in everyday life , PAEE being simultaneously measured by the doubly labeled water method ( DLW ) . In Experiment 2 , 8 overweight/obese subjects ( BMI 34.3+/-5.0 kg/m2 ) and 10 normal-weight subjects ( BMI 20.8+/-2.1 kg/m2 ) were monitored during a treadmill walking protocol , PAEE being simultaneously measured by indirect calorimetry . RESULTS In Experiment 1 , there was no significant difference between methods in mean PAEE ( DLW : 704+/-223 kcal/d , RT3 : 656+/-140 kcal/d , TriTrac-R3D 624+/-419 kcal/d ) . The relative difference between methods ( accelerometer vs. DLW ) was -17.1%+/-16.7 % for the RT3 and -20.0+/-44.6 % for the TriTrac-R3D . Correlation for PAEE between RT3 and DLW was higher than between TriTrac-R3D and DLW ( r=0.67 , p 95 % confidence interval ( CI ) ( kcal/d ) of the mean difference between methods was large , amounting to -385 to 145 for the RT3 and -887 to 590 for the TriTrac-R3D . In Experiment 2 , both accelerometers were sensitive to the changes in treadmill speed , with no significant difference in mean PAEE between methods in overweight/obese subjects . CONCLUSIONS Although both accelerometers did not provide accurate estimates of PAEE at individual levels , the data suggest that RT3 has the potential to assess PAEE at group levels in overweight/obese subjects",
"Background —The six-minute walk test ( 6MWT ) and cardiopulmonary exercise testing ( CPET ) are the 2 testing modalities most broadly used for assessing functional limitation in patients with heart failure ( HF ) . A comprehensive comparison on clinical and prognostic validity of the 2 techniques has not been performed and is the aim of the present investigation . Methods and Results —Two hundred fifty-three patients diagnosed with systolic ( n=211 ) or diastolic ( n=42 ) HF ( age : 61.9±10.1 years ; New York Heart Association Class : 2.2±0.78 ) underwent a 6MWT and a symptom-limited CPET evaluation and were prospect ively followed up . During the 4-year tracking period , there were 43 cardiac-related deaths with an annual cardiac mortality rate of 8.7 % . The 6MWT distance correlated with CPET-derived variables ( ie , peak Vo2 , Vo2 at anaerobic threshold , and Ve/Vco2 slope ) and was significantly reduced in proportion with lower peak Vo2 and higher Ve/Vco2 slope classes and presence of an exercise oscillatory breathing ( EOB ) pattern ( P in distance covered between survivors and nonsurvivors ( 353.2±95.8 m versus 338.5±76.4 m ; P = NS ) . At univariate and multivariate Cox proportional analyses , the association of the 6MWT distance with survival was not significant either as a continuous or dicotomized variable ( ≤300 m ) . Conversely , CPET-derived variables emerged as prognostic with the strongest association found for EOB ( systolic HF ) and Ve/Vco2 slope ( entire population with HF and patients with a 6MWT≤300 m ) . Conclusions —The 6MWT is confirmed to be a simple and reliable first-line test for quantification of exercise intolerance in patients with HF . However , there is no supportive evidence for its use as a prognostic marker in alternative to or in conjunction with CPET-derived variables",
"PURPOSE We established accelerometer count ranges for the Computer Science and Applications , Inc. ( CSA ) activity monitor corresponding to commonly employed MET categories . METHODS Data were obtained from 50 adults ( 25 males , 25 females ) during treadmill exercise at three different speeds ( 4.8 , 6.4 , and 9.7 km x h(-1 ) ) . RESULTS Activity counts and steady-state oxygen consumption were highly correlated ( r = 0.88 ) , and count ranges corresponding to light , moderate , hard , and very hard intensity levels were or = 9499 cnts x min(-1 ) , respectively . A model to predict energy expenditure from activity counts and body mass was developed using data from a r and om sample of 35 subjects ( r2 = 0.82 , SEE = 1.40 kcal x min(-1 ) ) . Cross validation with data from the remaining 15 subjects revealed no significant differences between actual and predicted energy expenditure at any treadmill speed ( SEE = 0.50 - 1.40 kcal x min(-1 ) ) . CONCLUSIONS These data provide a template on which patterns of activity can be classified into intensity levels using the CSA accelerometer",
"PURPOSE To compare field measures of average daily energy expenditure ( ADEE ) against criterion data by the doubly labeled water method ( DLW ) in overweight women . METHODS The subject were 20 overweight ( BMI 29.9 + a- 3.0 kg.m-2 ) premenopausal women . Energy expenditure was measured by DLW and by the factorial method ( activity diary , two techniques differing by method to obtain resting energy expenditure , REE ) , heart-rate monitoring ( HR , two techniques differing by the FLEX-point to discriminate sedentary and activity HR ) , accelerometer , and pedometer . RESULTS The ADEE(DLW ) was 10.26 + a- 1.1 MJ.d-1 . The mean bias ( ADEE by the alternative minus ADEE(DLW ) was smallest for the accelerometer ( + 0.08 + a- 1.63 MJ ) and HR-FLEX10 ( + 0.11 + a- 1.67 MJ ) . The HR-FLEX(0 ) technique ( lower FLEX-point ) overestimated ADEE by + 1.18 ( + a- 1.97 MJ ) . However , the r and om error ( SD of bias ) was smaller for both factorial techniques ( REE measured : -0.48 + 2- 0.81 MJ ; REE calculated from the WHO equation : -0.22 + 2- 0.88 MJ ) . CONCLUSION The results show that simple factorial methods may assess ADEE with small r and om errors in population with a rather narrow range of physical activity . The accelerometer and HR with the higher FLEX-point have comparable results with smaller bias but larger r and om error compared with the factorial techniques",
"PURPOSE This study aim ed to predict human energy expenditure and activity type using a miniature lightweight ear-worn inertia sensor and a novel pattern recognition algorithm for activity detection . METHODS This study used a protocol of 11 activities of daily living : lying down , st and ing , computer work , vacuuming , stairs , slow walking , brisk walking , slow running , fast running , cycling , and rowing . Subjects included 25 healthy r and omized subjects ( 18 males and 7 females ) . Each participant wore the ear sensor to record posture and linear acceleration , as well as the Cosmed K4b system for indirect calorimetry . The main outcome measure was the continuous energy expenditure per minute prediction for both task-known and task-blind estimation . RESULTS The values for METs predicted using the proposed algorithm and the measured METs using the K4b showed good agreement with low values for the systematic bias ( lying down=0.01 , st and ing=-0.02 , computer work=-0.04 , vacuuming=-0.17 , stairs=-0.02 , slow walking=0.01 , fast walking=0.04 , slow running=0.14 , fast running=-0.35 , cycling=0.32 , and rowing=0.10 ) . For task-blind prediction , the agreement between predicted and measured METs is also good with low values of the systematic bias ( lying down=0.11 , st and ing=0.14 , computer work=-0.06 , vacuuming=0.47 , stairs=-0.47 , slow walking=0.53 , fast walking=-0.11 , slow running=0.83 , fast running=-1.18 , cycling=0.31 , and rowing=-0.67 ) . Activity is also well predicted ( for task-blind prediction ) with an overall success rate of 88.99 % and individual correct classification rates of lying down=89.62 % , st and ing/computer work=99.10 % , vacuuming=76.60 % , stairs=89.13 % , walking=85.11 % , running=98.96 % , and cycling=79.79 % . CONCLUSIONS The ear-worn sensor presented in this work is a novel lightweight device that can be used to predict energy expenditure for a range of activities without behavior interference or modification"
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AIMS The 6 min walk test ( 6MWT ) is commonly used in clinical trials to assess treatments for heart failure , but its ability to distinguish between effective and ineffective treatments is question able . The aim of this study is to investigate , using a systematic literature review , the utility of the 6MWT as a measure of the effectiveness of treatment in r and omized controlled trials of heart failure . METHODS AND RESULTS A literature search was performed using Medline , EMBASE , CINAHL , and Biological abstract s for r and omized controlled trials that measured 6MWT between 1988 and 31 May 2004 . A significant increase in 6MWT distance was observed in only 9 of 47 r and omized controlled trials of pharmacological therapy ; 2 of 6 trials of ACE-inhibitors ; 3 of 17 trials of beta-blockers ; 1 of 4 trials of digoxin ; one trial of ibopamine ; one trial of l-arginine ; one trial of beriberine ; and one trial showed superiority of captopril over flosequinan . A significant increase in 6MWT was observed in four out of six placebo-controlled trials of cardiac resynchronization . Smaller pharmacological trials with fewer centres were more likely to be positive ; six out of nine positive pharmacological trials had four or less participating centres , raising the possibility of publication bias . Pharmacological trials including patients with more severe heart failure were more likely to show a significant improvement with therapy than trials of milder heart failure . Five out of seven pharmacological trials that reported an improvement in symptoms also reported an improvement in 6MWT distance . Of 30 pharmacological trials , 29 that reported no improvement in symptoms also reported no improvement in 6MWT . Using mean values in these trials , the age of patients appeared a more important determinant of 6MWT distance than New York Heart Association classification . CONCLUSION The 6MWT has not yet been proven to be a robust test for the identification of effective pharmacological interventions although it appears useful for the assessment of cardiac resynchronization therapy . The results of the 6MWT were concordant with changes in symptoms , suggesting that it may be used as supportive evidence for symptom benefit . The test may be of greater value in patients with more advanced heart failure , where it may function as a maximal exercise test
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"BACKGROUND Although digoxin is effective in the treatment of patients with chronic heart failure who are receiving diuretic agents , it is not clear whether the drug has a role when patients are receiving angiotensin-converting-enzyme inhibitors , as is often the case in current practice . METHODS We studied 178 patients with New York Heart Association class II or III heart failure and left ventricular ejection fractions of 35 percent or less in normal sinus rhythm who were clinical ly stable while receiving digoxin , diuretics , and an angiotensin-converting-enzyme inhibitor ( captopril or enalapril ) . The patients were r and omly assigned in a double-blind fashion either to continue receiving digoxin ( 85 patients ) or to be switched to placebo ( 93 patients ) for 12 weeks . Otherwise , their medical therapy for heart failure was not changed . RESULTS Worsening heart failure necessitating withdrawal from the study developed in 23 patients switched to placebo , but in only 4 patients who continued to receive digoxin ( P relative risk of worsening heart failure in the placebo group as compared with the digoxin group was 5.9 ( 95 percent confidence interval , 2.1 to 17.2 ) . All measures of functional capacity deteriorated in the patients receiving placebo as compared with those continuing to receive digoxin ( P = 0.033 for maximal exercise tolerance , P = 0.01 for submaximal exercise endurance , and P = 0.019 for New York Heart Association class ) . In addition , the patients switched from digoxin to placebo had lower quality -of-life scores ( P = 0.04 ) , decreased ejection fractions ( P = 0.001 ) , and increases in heart rate ( P = 0.001 ) and body weight ( P digoxin carries considerable risks for patients with chronic heart failure and impaired systolic function who have remained clinical ly stable while receiving digoxin and angiotensin-converting-enzyme inhibitors",
"BACKGROUND Patients with heart failure have reduced peripheral blood flow at rest , during exercise , and in response to endothelium-dependent vasodilators . Nitric oxide formed from L-arginine metabolism in endothelial cells contributes to regulation of blood flow under these conditions . A r and omized , double-blind crossover study design was used to determine whether supplemental oral L-arginine can augment peripheral blood flow and improve functional status in patients with moderate to severe heart failure . METHODS AND RESULTS Fifteen subjects were given 6 weeks of oral L-arginine hydrochloride ( 5.6 to 12.6 g/d ) and 6 weeks of matched placebo capsules in r and om sequence . Compared with placebo , supplemental oral L-arginine significantly increased forearm blood flow during forearm exercise , on average from 5.1 + /- 2.8 to 6.6 + /- 3.4 mL. min-1 . dL-1 ( P functional status was significantly better on L-arginine compared with placebo , as indicated by increased distances during a 6-minute walk test ( 390 + /- 91 versus 422 + /- 86 m , P scores on the Living With Heart Failure question naire ( 55 + /- 28 versus 42 + /- 26 , P Oral L-arginine also improved arterial compliance from 1.99 + /- 0.38 to 2.36 + /- 0.30 mL/mm Hg ( P circulating levels of endothelin from 1.9 + /- 1.1 to 1.5 + /- 1.1 pmol/L ( P Supplemental oral L-arginine had beneficial effects in patients with heart failure . Further studies are needed to confirm the therapeutic potential of supplemental oral L-arginine and to identify mechanisms of action in patients with heart failure",
"Objective To examine the reproducibility and responsiveness to change of a six minute walk test and a quality of life measure in elderly patients with heart failure . Design Longitudinal within patient study . Subjects 60 patients with heart failure ( mean age 82 years ) attending a geriatric outpatient clinic , 45 of whom underwent a repeat assessment three to eight weeks later . Main outcome measures Subjects underwent a st and ardised six minute walk test and completed the chronic heart failure question naire ( CHQ ) , a heart failure specific quality of life question naire . Intraclass correlation coefficients ( ICC ) were calculated using a r and om effects one way analysis of variance as a measure of reproducibility . Guyatt ’s responsiveness coefficient and effect sizes were calculated as measures of responsiveness to change . Results 24 patients reported no major change in cardiac status , while seven had deteriorated and 14 had improved between the two clinic visits . Reproducibility was satisfactory ( ICC > 0.75 ) for the six minute walk test , for the total CHQ score , and for the dyspnoea , fatigue , and emotion domains of the CHQ . Effect sizes for all measures were large ( > 0.8 ) , and responsiveness coefficients were very satisfactory ( > 0.7 ) . Effect sizes for detecting deterioration were greater than those for detecting improvement . Conclusions Quality of life assessment and a six minute walk test are reproducible and responsive measures of cardiac status in frail , very elderly patients with heart failure",
"OBJECTIVES We sought to assess the efficacy of biventricular pacing with respect to both peak and submaximal measures of exercise in patients with New York Heart Association class III heart failure ( HF ) and intraventricular conduction delay in a r and omized , blinded study . BACKGROUND Submaximal and maximal changes in exercise capacity need evaluating in this patient population with this novel therapy . METHODS Grade d exercise and 6-min walk tests were performed in patients r and omized to three months each of active ( atrio-biventricular ) and inactive pacing . Minute ventilation ( VE ) , oxygen uptake ( VO(2 ) ) , ventilated carbon dioxide ( VCO(2 ) ) and heart rate were measured in patients achieving a respiratory quotient > 1 ( n = 30 ) . Oxygen pulse , anaerobic threshold ( AT ) and ventilatory efficiency ( VE/VCO(2 ) ) were calculated . RESULTS Active biventricular pacing increased peak VO(2 ) ( 15.8 + /- 4.3 vs. 14.4 + /- 4.6 ml/kg/min , p = 0.02 ) , exercise time ( 501 + /- 223 s vs. 437 + /- 233 s , p oxygen pulse ( 9.3 + /- 2.8 vs. 8.1 + /- 3.1 ml/beat , p submaximal measures of exercise capacity significantly increased with active pacing : AT ( 11.2 + /- 4.1 ml/kg/min vs. 9.5 + /- 2.3 ml/kg/min , p = 0.02 ) and 6-min walk ( 414 + /- 94 m vs. 359 + /- 94 m , p = 0.001 ) . Minute ventilation/ventilated carbon dioxide improved ( 32 + /- 9 vs. 36 + /- 11 , p = 0.03 ) with normalization of the VE/VCO(2 ) slope in 59 % of patients ( chi-square test , p = 0.002 ) with active pacing . CONCLUSIONS Biventricular pacing may improve maximal and submaximal exercise capacity in patients with advanced HF and intraventricular conduction delay",
"BACKGROUND The Digitalis Investigation Group ( DIG ) trial was a r and omized double-blind placebo-controlled study that examined the effect of digoxin on mortality in 7,788 patients with heart failure and sinus rhythm . A prespecified sub study evaluated the effect of digoxin therapy on health-related quality of life ( HQOL ) in a subset of these patients . METHODS Patients in the DIG trial had clinical heart failure and were r and omized to either digoxin or placebo in addition to their baseline diuretic and angiotensin-converting enzyme therapy ( n = 7,788 ) . The patients in this sub study had HQOL measured using a self-administered question naire employing scales that measured general health , physical functioning , depression , anger , anxiety , life satisfaction , and disease specific measures . A subjective assessment by the investigator and a 6-minute walk test evaluated functional status . HQOL was measured at baseline and at the 4- and 12-month follow-up visits . RESULTS The baseline characteristics of the patients in the quality of life sub study ( n = 589 ) were comparable to the remaining patients in the study ( n = 7,199 ) by age and other clinical measures , including history of prior myocardial infa rct ion or etiology of heart failure ; heart failure was of shorter duration and the ejection fraction was slightly better than in the main trial . Within the sub study , patients receiving digoxin ( n = 298 ) or placebo ( n = 291 ) were also similar in baseline characteristics . There was no statistically significant difference in any HQOL measure between the digoxin and the placebo groups at baseline . At the 4-month visit , only perceived health was improved in the digoxin group . At 12 months , there was no statistically significant difference in perceived health , physical functioning , Minnesota Living with Heart Failure , depression , anxiety , anger , Ladder of Life , or the 6-minute walk between the digoxin and placebo groups . CONCLUSION In this subset of the DIG population , digoxin therapy had no effect on the HQOL in patients with heart failure in sinus rhythm",
"BACKGROUND A preliminary study suggested that the long-acting late-generation calcium-channel blocker amlodipine has favorable effects on exercise tolerance and is safe to use in heart failure , in contrast to earlier generation agents . The goal of 2 multicenter studies was to assess the effect of adjunctive therapy with amlodipine in addition to st and ard therapy on exercise capacity , quality of life , left ventricular function , and safety parameters in patients with heart failure and left ventricular systolic dysfunction . METHODS Two large multicenter trials examining the effects of amlodipine on these parameters over a 12-week period of therapy were undertaken in patients with mild to moderate heart failure and left ventricular systolic dysfunction . A total of 437 patients with stable heart failure were studied in a r and omized , double-blind , placebo-controlled prospect i ve design . RESULTS Amlodipine at a dose of 10 mg/day in addition to st and ard therapy in such patients was associated with no significant difference in change in exercise tolerance on a Naughton protocol compared with placebo in each trial . Among all patients taking amlodipine , exercise time increased 53 + /- 9 ( SE ) seconds ; exercise time for those taking placebo increased 66 + /- 9 seconds ( P = not significant ) . There were no significant differences in changes of quality of life parameters between amlodipine- and placebo-treated patients , and there were no significant differences in symptom scores or New York Heart Association classification between groups . Left ventricular function ( measured as ejection fraction ) improved 3 . 4 % + /- 0.5 % in amlodipine-treated patients and 1.5 % + /- 0.5 % in placebo-treated patients ( P = .007 ) . There was no statistically significant excess of important adverse events ( episodes of worsening heart failure in 10 % amlodipine-treated vs 6.3 % of placebo-treated patients ) or differences in need for changes in background medication between groups . CONCLUSIONS The addition of 10 mg of amlodipine per day to st and ard therapy in patients with heart failure is associated with no significant improvement in exercise time compared with placebo therapy over a 12-week period , and there was no increased incidence of adverse events . These data suggest that the addition of amlodipine to st and ard therapy in heart failure will not result in additional efficacy per se beyond st and ard therapy",
"Summary Two hundred and nine patients with moderate to severe chronic heart failure , all of whom remained symptomatic despite at least 80 mg of frusemide daily , were r and omized to 12 months treatment with flosequinan or captopril . The patients were stratified into two groups , a treadmill group and a corridor walk test group , depending upon their exercise capability . Sixty-five out of 102 patients r and omized to flosequinan and 43 out of 107 r and omized to captopril ( p mortality : 19 patients died while taking flosequinan and 15 while taking captopril . Both drugs had similar effects on treadmill exercise tolerance ; the mean increase at week 52 was 117 seconds in the flosequinan group and 156 seconds ( p=0.57 ) for the captopril group . For those patients stratified to the corridor walk test only , there was also very little difference in the improvement at 52 weeks ; the mean increase for patients r and omized to flosequinan was 61 meters and captopril was 75 meters ( p=0.65 ) . However , when the walk tests from all patients are examined , captopril produced a significant improvement compared with flosequinan at week 52 ( p=0.015 ) . Flosequinan has similar long-term efficacy to captopril but is associated with a higher incidence of adverse events",
"BACKGROUND Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy ( IDC ) . The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy ( ISCD ) . METHODS AND RESULTS Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties . One hundred forty-one subjects with class II or III heart failure , left ventricular ejection fraction ( LVEF ) were given an initial challenge dose of bucindolol 12.5 mg . One hundred thirty-nine subjects ( 99 with IDC , 40 with ISCDC ) tolerated challenge and were r and omized to treatment with placebo or bucindolol 12.5 mg/d ( low dose ) , 50 mg/d ( medium dose ) , or 200 mg/d ( high dose ) . At the end of 12 weeks , left ventricular function and other parameters were measured and compared with baseline values . There was a dose-related improvement in left ventricular function in bucindolol-treated subjects . In the high-dose bucindolol group , radionuclide-measured LVEF improved by 7.8 EF units ( % ) compared with 1.8 units in the placebo group ( P increase in LVEF by > or = 5 units . In contrast , all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units . CONCLUSIONS In heart failure from systolic dysfunction , beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function",
"OBJECTIVES This study examined the relative merits of digoxin , carvedilol , and their combination for the management of patients with atrial fibrillation ( AF ) and heart failure ( HF ) . BACKGROUND In patients with AF and HF , both digoxin and beta-blockers reduce the ventricular rate , and both may improve symptoms , but only beta-blockers have been shown to improve prognosis . If combined therapy is not superior to beta-blockers alone , treatment of patients with HF and AF could be simplified by stopping digoxin . METHODS We enrolled 47 patients ( 29 males ; mean age 68 years ) with persistent AF and HF ( mean left ventricular ejection fraction [ LVEF ] 24 % ) in a r and omized , double-blinded , placebo-controlled study . In the first phase of the study , digoxin was compared with the combination of digoxin and carvedilol ( four months ) . In the second phase , digoxin was withdrawn in a double-blinded manner in the carvedilol-treated arm , thus allowing a comparison between digoxin and carvedilol ( six months ) . Investigations were undertaken at baseline and at the end of each phase . RESULTS Compared with digoxin alone , combination therapy lowered the ventricular rate on 24-h ambulatory electrocardiographic monitoring ( p LVEF ( p symptom score ( p digoxin alone and carvedilol alone in any variable . The mean ventricular rate rose and LVEF fell when patients switched from combination therapy to carvedilol alone . Six-minute walk distance was not significantly influenced by any therapy . CONCLUSIONS The combination of carvedilol and digoxin appears generally superior to either carvedilol or digoxin alone in the management of AF in patients with HF",
"OBJECTIVES This study was conducted to assess the safety and effectiveness of cardiac resynchronization therapy ( CRT ) when combined with an implantable cardioverter defibrillator ( ICD ) . BACKGROUND Long-term outcome of CRT was measured in patients with symptomatic heart failure ( HF ) , intraventricular conduction delay , and malignant ventricular tachyarrhythmias ( ventricular tachycardia/ventricular fibrillation [ VT/VF ] ) requiring therapy from an ICD . METHODS Patients ( n = 490 ) were implanted with a device capable of providing both CRT and ICD therapy and r and omized to CRT ( n = 245 ) or control ( no CRT , n = 245 ) for up to six months . The primary end point was progression of HF , defined as all-cause mortality , hospitalization for HF , and VT/VF requiring device intervention . Secondary end points included peak oxygen consumption ( VO(2 ) ) , 6-min walk ( 6 MW ) , New York Heart Association ( NYHA ) class , quality of life ( QOL ) , and echocardiographic analysis . RESULTS A 15 % reduction in HF progression was observed , but this was statistically insignificant ( p = 0.35 ) . The CRT , however , significantly improved peak VO(2 ) ( 0.8 ml/kg/min vs. 0.0 ml/kg/min , p = 0.030 ) and 6 MW ( 35 m vs. 15 m , p = 0.043 ) . Changes in NYHA class ( p = 0.10 ) and QOL ( p = 0.40 ) were not statistically significant . The CRT demonstrated significant reductions in ventricular dimensions ( left ventricular internal diameter in diastole = -3.4 mm vs. -0.3 mm , p left ventricular ejection fraction ( 5.1 % vs. 2.8 % , p = 0.020 ) . A subgroup of patients with advanced HF ( NYHA class III/IV ) consistently demonstrated improvement across all functional status end points . CONCLUSIONS The CRT improved functional status in patients indicated for an ICD who also have symptomatic HF and intraventricular conduction delay",
"Little is known concerning the long-term drug management of chronic heart failure ( CHF ) in old patients ( greater than or equal to 75 years ) . Accordingly , this double-blind , placebo-controlled trial compared the long-term ( over 6 months ) effect of captopril ( 37.5 - 75 mg/day ) and of ibopamine ( 150 - 300 mg/day ) on exercise testing , symptoms and subjective feeling of well-being , in 150 CHF elderly patients ( mean age 75 years ) under treatment with digitalis and /or diuretics . During an additional open follow-up of approximately 1.5 years , morbid events and deaths were also recorded . Captopril and ibopamine performed better ( p less than 0.01 ) than placebo , improving the 6-min walking distance ( captopril from 300 to 404 m , ibopamine from 282 to 385 m ; placebo from 283 to 299 m ) . NYHA status , symptom score and patients ' global assessment . The difference between the active study drugs was not statistically significant ( p greater than 0.05 ) . Complicating events , including diuretic use , frequency of hospitalization , worsening of CHF and deaths , were grouped by patient-years . These events were significantly ( p less than 0.01 ) lower ( captopril : 28/75 patient-years ; ibopamine 33/74 patient-years ) in the active treatment groups with respect to placebo ( 58/96 patient-years ) . Captopril and ibopamine showed a different safety profile . Creatinine increase ( 2 patients ) , symptomatic hypotension ( 4 patients ) , hyperkalemia ( 2 patients ) and upper respiratory symptoms were mostly associated with captopril treatment . Gastrointestinal adverse events were observed in 11 patients under ibopamine treatment . The study provides evidence of the clinical usefulness of both captopril or ibopamine in the long-term treatment of CHF in old patients . The safety profile of each drug will suggest the preferred therapeutic application",
"OBJECTIVES This study was performed to compare the long-term clinical efficacy of treatment with metoprolol versus carvedilol in patients with chronic heart failure . BACKGROUND Beta-adrenergic blockade is of proven value in chronic heart failure . Metoprolol , a selective beta-blocker , is widely used , but recent trials suggest carvedilol , a nonselective beta-blocker with alpha-1-receptor antagonist activity and antioxidant activities , is also effective . It is uncertain , however , if these additional properties of carvedilol provide further clinical benefit compared with metoprolol . METHODS In this r and omized double-blind control trial , 51 patients with chronic heart failure and mean left ventricular ( LV ) ejection fraction of 26 % + /- 1.8 % were r and omly assigned treatment with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to st and ard therapy after a four-week dose titration period for a total of 12 weeks . Response was assessed by a quality of life question naire , New York Heart Association class , exercise capacity ( 6-min walk test ) , radionucleotide ventriculography for LV ejection fraction , two-dimensional echocardiography measurement of LV dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate variability . RESULTS Both carvedilol and metoprolol produced highly significant improvement in symptoms ( p exercise capacity ( p LV ejection fraction ( p Carvedilol had a significantly greater effect on sitting and st and ing blood pressure , LV end-diastolic dimension and normalized the mitral E wave deceleration time . CONCLUSIONS Both metoprolol and carvedilol were equally effective in improving symptoms , quality of life , exercise capacity and LV ejection fraction , although carvedilol lowers blood pressure more than metoprolol",
"Although a cornerstone in the treatment of heart failure , angiotensin-converting enzyme inhibitors are under-used , partly due to side effects . If proven at least similarly efficacious to angiotensin-converting enzyme inhibitors , angiotensin-receptor blockers may replace them due to their superior tolerability . We aim ed to compare the efficacy and safety of valsartan and enalapril in heart failure patients stabilised on an angiotensin-converting enzyme inhibitor . We r and omised 141 patients ( mean 68 years , 74 % males ) with stable mild/moderate heart failure and left ventricular ejection fraction 0.45 or less , to valsartan 160 mg q.d . ( n=70 ) or enalapril 10 mg b.i.d . ( n=71 ) for 12 weeks . Changes in 6-min-walk test ( primary efficacy variable ) , patients ' wellbeing and left ventricular size and function did not differ significantly between the treatment groups . Valsartan was significantly non-inferior to enalapril in walk test distance change : least-square means treatment difference + 1.12 m ( 95 % confidence interval -21.9 to 24.1 ) , non-inferiority P Left ventricular size ( P function ( P=0.048 ) improved significantly only in the valsartan group . Fewer patients experienced adverse events in the valsartan group ( 50 % ) than in the enalapril group ( 63 % ) , although statistically non-significant . Valsartan is similarly efficacious and safe to enalapril in patients with stable , mild/moderate heart failure , previously stabilised on an angiotensin-converting enzyme inhibitor and directly switched to study medication",
"Beta blockers are known to suppress renin release in hypertension and in patients taking angiotensin-converting enzyme ( ACE ) inhibitors . This study sought to explore the effect of additional beta blockade on neurohumoral modulation in patients with severe heart failure ( HF ) who received ACE inhibitors . Forty-nine patients with chronic HF who received ACE inhibitors were given metoprolol 50 mg or carvedilol 25 mg twice daily after a 4-week dose titration period in addition to st and ard therapy in a prospect i ve trial . Sample s of plasma renin activity ( PRA ) , aldosterone , aminoterminal B-type natriuretic peptide ( N-BNP ) , and atrial natriuretic peptide ( ANP ) were taken at baseline and at 4 , 12 , and 52 weeks after starting therapy . Treatment with either beta blocker significantly lowered PRA at 4 weeks compared with baseline ( -2.0 + /- 0.6 nmol/L/hour , p = 0.006 ) , but at 12 weeks , PRA had reduced to -1.1 + /- 0.6 nmol/L/hour ( p = 0.08 ) , but at 52 weeks , it was not significantly different from baseline ( + 1.05 + /- 0.6 nmol/L/hour , p = 0.13 ) . Aldosterone levels did not change significantly from baseline at 4 or 12 weeks , although there was a nonsignificant trend for lower levels at 52 weeks ( baseline 232 + /- 154 pmol/L , 52 weeks 192 + /- 100 pmol/L , p = 0.09 ) . There was significant reduction in N-BNP and ANP together with an improvement in symptom and left ventricular systolic function at 1-year follow-up . These results indicate that the suppressive effect of beta blockers on PRA in patients with HF taking ACE inhibitors is temporary , and that there is no significant effect on serum aldosterone levels",
"Background This prospect i ve placebo-controlled trial was design ed to determine whether intravenous immune globulin ( IVIG ) improves left ventricular ejection fraction ( LVEF ) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis . Methods and Results Sixty-two patients ( 37 men , 25 women ; mean age ±SD 43.0±12.3 years ) with recent onset ( ≤6 months of symptoms ) of dilated cardiomyopathy and LVEF ≤0.40 were r and omized to 2 g/kg IVIG or placebo . All underwent an endomyocardial biopsy before r and omization , which revealed cellular inflammation in 16 % . The primary outcome was change in LVEF at 6 and 12 months after r and omization . Overall , LVEF improved from 0.25±0.08 to 0.41±0.17 at 6 months ( P receiving IVIG and those given placebo ( 6 months : IVIG 0.14±0.12 , placebo 0.14±0.14 ; 12 months : IVIG 0.16±0.12 , placebo 0.15±0.16 ) . Overall , 31 ( 56 % ) of 55 patients at 1 year had an increase in LVEF ≥0.10 from study entry , and 20 ( 36 % ) of 56 normalized their ejection fraction ( ≥0.50 ) . The transplant-free survival rate was 92 % at 1 year and 88 % at 2 years . Conclusions These results suggest that for patients with recent-onset dilated cardiomyopathy , IVIG does not augment the improvement in LVEF . However , in this overall cohort , LVEF improved significantly during follow-up , and the short-term prognosis remains favorable",
"It has been proposed that worsening of heart failure with dihydropyridines , such as nicardipine , is related to the activation of the neuroendocrine system . To test this , we evaluated 20 patients with severe heart failure ( mean age , 55 ± 13 years ; New York Heart Association functional class III ; left ventricular ejection fraction , 18 % ± 8 % on maintenance therapy with captopril , digoxin , and diuretics ) who were r and omized to nicardipine ( 60 or 90 mg/d ) or placebo during a 4-month double-blind protocol . The following measurements were obtained at baseline , monthly , and at 4 months or last follow-up visit : rest and exercise radionuclide ventriculography , maximal treadmill time , 6-minute walking test distance , serum norepinephrine and aldosterone concentrations , and plasma renin activity . During the follow-up period , worsening of heart failure occurred in 6 patients in the nicardipine group and in 2 patients in the placebo group ( p = 0.06 ) . The maximal treadmill time for a 6-minute walking distance and exercise radionuclide ejection fraction at the last follow-up visit did not change in patients who did not deteriorate with heart failure in the placebo or nicardipine groups as compared with baseline values . In this study group of patients with severe heart failure receiving therapy with digoxin , captopril , and diuretics , nicardipine was associated with worsening heart failure without an apparent activation of the neurohormones . However , because of the small number of patients and a significant number of patients who deteriorated during the follow-up period , no definitive conclusions can be made",
"OBJECTIVE To determine whether a third generation vasodilating beta blocker ( celiprolol ) has long term clinical advantages over metoprolol in patients with chronic heart failure . DESIGN A double blind placebo controlled r and omised trial . SETTING University teaching Hospital . PATIENTS 50 patients with stable chronic heart failure ( NYHA class II-IV ) due to idiopathic dilated , ischaemic , or hypertensive cardiomyopathy , with left ventricular ejection fraction INTERVENTIONS Celiprolol 200 mg daily ( n = 21 ) , metoprolol 50 mg twice daily ( n = 19 ) , or placebo ( n = 10 ) for three months with a four week dose titration period . After the double blind period , patients entered an open label study ( with placebo group receiving beta blockers ) and were assessed after one year . MAIN OUTCOME MEASURES Clinical response , efficacy , and tolerance were assessed by the Minnesota heart failure symptom question naire six minute walk test , Doppler echocardiography ( systolic and diastolic function ) , radionuclide ventriculography , and atrial and brain natriuretic peptides measured at baseline and after three months . RESULTS In the metoprolol group at 12 weeks v baseline there was a 47 % reduction in symptom score ( p NYHA class ( mean ( SEM ) , 2.6 ( 0.12 ) to 1.9 ( 0.13 ) , p = 0.001 ) , exercise distance ( 1246 ( 54 ) to 1402 ( 52 ) feet , p left ventricular ejection fraction ( 26.9(3.1)% to 31(3.0)% , p = 0.016 ) , and a fall in heart rate ( resting , 79 ( 3 ) to 62 ( 3 ) beats/min , p celiprolol group there was a 38 % reduction in symptom score ( p = 0.02 ) , less improvement in exercise distance ( 1191 ( 55 ) to 1256 ( 61 ) feet , p = 0.05 ) , and no significant changes in NYHA class , left ventricular ejection fraction , or heart rate . Mortality at one year was 11 % in metoprolol and 19 % in the celiprolol group , and symptomatic improvement was maintained in the survivors . CONCLUSIONS Both drugs were well tolerated but the vasodilator properties of celiprolol do not seem to provide any obvious additional benefit in the long term treatment of heart failure",
"OBJECTIVES We assessed the clinical efficacy of single-site left ventricular ( LV ) pacing and determined the impact of baseline conduction delay severity on the magnitude of benefit . BACKGROUND Multisite biventricular pacing can improve heart failure ( HF ) symptoms in patients with an intraventricular conduction delay by resynchronizing abnormal ventricular contractions and improving LV systolic function . METHODS Eighty-six patients with at least New York Heart Association functional class II HF , chronic LV systolic dysfunction , normal sinus rhythm , and a QRS interval over 120 ms were implanted for atrial-synchronized LV pacing . The single-blinded , r and omized , controlled , crossover study stratified patients 1:1 by the baseline QRS interval into long ( QRS > 150 ms ) and short ( QRS 120 to 150 ms ) groups , which were compared during a three-month period of active ( univentricular ) pacing and a three-month period of inactive ( ventricular inhibited ) pacing . The primary end point was peak oxygen consumption ( VO(2 ) ) followed by anaerobic threshold , distance walked in 6 min , and quality -of-life question naire score . PATIENTS Twelve patients were withdrawn before r and omization and 17 could not complete both study periods . The short QRS group did not improve in any end point with active pacing . For the long QRS group , peak VO(2 ) increased 2.46 ml/min/kg ( p anaerobic threshold increased 1.55 ml/min/kg ( p distance walked in 6 min increased 47 m ( p = 0.024 ) , and the quality -of-life score improved 8.1 points ( p = 0.004 ) . CONCLUSIONS Left ventricular pacing significantly improves exercise tolerance and quality of life in patients with chronic HF , LV systolic dysfunction , and a QRS interval over 150 ms",
"OBJECTIVES This study assessed the feasibility of an efficacy trial comparing angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism in heart failure . Patients with moderate or severe heart failure whose condition had previously been stabilized by treatment with a converting enzyme inhibitor were r and omly assigned to receive enalapril or losartan . The study was design ed to detect any signs of clinical deterioration during double-blind treatment . BACKGROUND Losartan is a specific , nonpeptide angiotensin II receptor-1 antagonist with a vasodilator hemodynamic profile similar to that of converting enzyme inhibitors . Although therapy with specific receptor blockade has certain theoretic advantages over nonspecific converting enzyme inhibition , demonstration of a comparable therapeutic effect in patients with congestive heart failure will require a major effort comparing two active agents . METHODS One hundred sixty-six patients with stable heart failure in New York Heart Association functional class III or IV and an ejection fraction were included in a multicenter , double-blind , parallel , enalapril-controlled trial . After a 3-week stabilization period with optimal therapy , including digitalis , diuretic drugs and a converting enzyme inhibitor , patients were r and omly assigned to 8 weeks of therapy with losartan , 25 mg/day ( n = 52 ) ; losartan , 50 mg/day ( n = 56 ) ; or enalapril , 20 mg/day ( n = 58 ) . Patients were assessed with frequent clinical and laboratory evaluation and exercise testing . RESULTS No significant differences between groups in terms of changes in exercise capacity ( 6-min walk test ) , clinical status ( dyspnea-fatigue index ) , neurohumoral activation ( norepinephrine , N-terminal atrial natriuretic factor ) , laboratory evaluation or incidence of adverse experience were observed . CONCLUSIONS The results suggest that losartan and enalapril are of comparable efficacy and tolerability in the short-term treatment of moderate or severe congestive heart failure . A trial design ed to compare the efficacy , tolerability and effect on mortality of long-term angiotensin II receptor blockade with converting enzyme inhibition is both feasible and ethically responsible",
"Abstract This double-blind , placebo-controlled study evaluated the effects of the ACE inhibitor , quinapril , on the functional status of elderly frail heart failure patients with preserved systolic function . Seventy-four elderly patients , mean ( SD ) age 78 ( 7 ) years , with symptomatic heart failure ( NYHA II – III ) and normal or only mildly impaired left ventricular systolic function ( ejection fraction ≥40 % ) were r and omly assigned to receive either quinapril or matched placebo ( titrated to 40 mg/day ) for 6 months . There were no significant differences at baseline in terms of age , cardiac function , aetiology , concomitant treatment , and echocardiographic values between active and placebo groups . Mean 6-minute walk distance increased at six months in the quinapril group [ 241.2 ( 132.0 ) v 267.3 ( 124.0 ) metres , p = 0.04 ] and in the placebo group [ 214.6 ( 114.5 ) v 267.6 ( 117.0 ) metres , p = 0.003 ] . The mean increases between the two groups were not significantly different . There were no significant changes in quality of life scores . The number of adverse drug events was similar in the two groups . Patients in the quinapril group were less likely to have worsening heart failure or to be admitted to hospital but these changes were not statistically significant . Conclusions . The present study confirmed the feasibility of single-centre drug trials in very elderly heart failure patients although recruitment and retention remain problematic . It did not show a beneficial effect of quinapril on exercise tolerance and quality of life in elderly heart failure patients with preserved systolic function",
"OBJECTIVES This study was design ed to determine 1 ) whether 12-week oral administration of losartan , an angiotensin II receptor antagonist , in patients with heart failure is well tolerated ; and 2 ) whether functional capacity and clinical status of patients with heart failure in whom treatment with an angiotensin-converting enzyme ( ACE ) inhibitor is replaced with losartan for 12 weeks will remain similar to that noted in patients in whom treatment with an ACE inhibitor is continued . BACKGROUND Losartan is a specific , nonpeptide angiotensin II receptor antagonist . Although specific receptor blockade with losartan has certain theoretic advantages over nonspecific ACE inhibition , definitive demonstration of comparable effects in patients with congestive heart failure is lacking . METHODS A double-blind , multicenter , r and omized , parallel , enalapril-controlled study was conducted in 116 patients with congestive heart failure ( New York Heart Association functional classes II to IV ) and left ventricular ejection fraction ACE inhibitors and diuretic agents , with or without concurrent digitalis and other vasodilators . After a baseline exercise period , open-label ACE inhibitors were discontinued , and patients were r and omly assigned to 12 weeks of therapy with losartan , 25 mg/day ( n = 38 ) ; losartan , 50 mg/day ( n = 40 ) ; or enalapril , 20 mg/day ( n = 38 ) . Drug efficacy was evaluated by changes in maximal treadmill exercise time ( using a modified Naughton protocol ) , 6-min walk test , left ventricular ejection fraction and dyspnea-fatigue index . Safety was measured by the incidence of clinical and laboratory adverse experiences . RESULTS The treadmill exercise time and the 6-min walk test did not change significantly after replacement of ACE inhibitor therapy with losartan . Similarly , a significant change was not observed in either the dyspnea-fatigue index or left ventricular ejection fraction at the end of double-blind period relative to baseline . CONCLUSIONS Losartan was generally well tolerated and comparable to enalapril in terms of exercise tolerance in this short-term ( 12-week ) study of patients with heart failure . The clinical effects of long-term angiotensin II receptor blockade compared with ACE inhibition remain to be studied",
"BACKGROUND We sought to investigate whether beta-blockers exert a presynaptic effect in the myocardium as measured by 123I-metaiodobenzylguanidine . METHODS The study comprised 59 patients with congestive heart failure , New York Heart Association class II or III , and left ventricular ejection fraction After an open label titration phase , patients were r and omized to their maximal tolerable dose of metoprolol or placebo . Myocardial MIBG uptake was measured before the titration phase and after 6 months of treatment . Other parameters were maximal oxygen consumption , 6-minute walking test , plasma neurohormones , and echocardiographic parameters . RESULTS We found a 21.9 % increase in mean myocardial MIBG uptake after 6 months of treatment with metoprolol . In contrast , MIBG uptake decreased by 7.8 % in the placebo group ( P = 0.03 compared with metoprolol ) . Left ventricular end-diastolic diameter decreased from 74 + /- 11 mm to 67 + /- 10 mm ( P LVEF increased from 25.3 % + /- 7.4 % to 32.6 % + /- 9.6 % ( P metoprolol group . Placebo-treated patients showed no significant changes . Comparison of changes in left ventricular end-diastolic diameter and LVEF between metoprolol and placebo did not reach statistical significance ( P = 0.2 ) . CONCLUSIONS This r and omized , placebo-controlled study demonstrates that metoprolol has a presynaptic effect as measured by myocardial MIBG scintigraphy in both ischemic and nonischemic cardiomyopathy",
"Objective : To evaluate the effects of the angiotensin converting enzyme inhibitor perindopril on six minute walking distance and quality of life in very old patients with left ventricular systolic dysfunction . Design : Prospect i ve , double blind placebo controlled trial . Setting : Medicine for the elderly day hospital . Patients : 66 patients ( average age 81 ) with left ventricular systolic dysfunction identified by echocardiography . Interventions : 10 weeks of treatment with titrated doses of perindopril or placebo . Main outcome measures : Six minute walking distance 10 weeks following treatment , quality of life measurements including the Minnesota living with heart failure question naire and the 36 item short form health survey . Results : In patients with left ventricular systolic dysfunction , six minute walking distance was significantly increased in the treatment group ( 37.1 m ) compared with the placebo group ( −0.3 m , p well tolerated and there were no significant adverse events . Conclusions : Six minute walking distance is improved considerably by treatment with perindopril in older patients with heart failure caused by left ventricular systolic dysfunction",
"Walking tests , frequently used to document effects of treatment on exercise capacity , have never been st and ardised . We studied the effects of encouragement on walking test performance in a r and omised study that controlled for the nature of the underlying disease , time of day , and order effects . We r and omised 43 patients with chronic airflow limitation or chronic heart failure or both to receive or not receive encouragement as they performed serial two and six minute walks every fortnight for 10 weeks . Simple encouragement improved performance ( p less than 0.02 for the six minute walk ) , and the magnitude of the effect was similar to that reported for patients in studies purporting to show beneficial effects of therapeutic manoeuvres . Age and test repetition also affected performance . These results demonstrate the need for careful st and ardisation of the performance of walking tests , and suggest caution in interpreting studies in which st and ardisation is not a major feature of the study design",
"Background — Patients with chronic heart failure ( CHF ) are frequently anemic . An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery . We investigated the effect of erythropoietin ( EPO ) on exercise performance in anemic patients with CHF . Methods and Results —Twenty-six anemic patients aged 57±11 years were r and omized to receive EPO ( 15 000 to 30 000 IU per week ) or placebo for 3 months . Parameters measured at baseline and end therapy included blood parameters ( hemoglobin , hematocrit , plasma volume ) , exercise parameters ( peak oxygen consumption [ & OV0312;o2 ] , exercise duration , 6-minute walk ) , muscle aerobic metabolism ( half-time of & OV0312;o2 and near infrared recovery ) , and forearm vasodilatory function . EPO was well tolerated by all patients . Twelve patients in the EPO group felt improvement versus 1 in the placebo group ( P in hemoglobin ( 11.0±0.5 to 14.3±1.0 g/dL , P and exercise duration ( 590±107 to 657±119 s , P group . Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups . Conclusion —EPO significantly enhances exercise capacity in patients with CHF . One mechanism of improvement in & OV0312;o2 is increased oxygen delivery from increased hemoglobin concentration",
"BACKGROUND Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure , but little is known about their effects in severe heart failure . METHODS We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion , who were clinical ly euvolemic , and who had an ejection fraction of less than 25 percent . In a double-blind fashion , we r and omly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months , during which st and ard therapy for heart failure was continued . Patients who required intensive care , had marked fluid retention , or were receiving intravenous vasodilators or positive inotropic drugs were excluded . RESULTS There were 190 deaths in the placebo group and 130 deaths in the carvedilol group . This difference reflected a 35 percent decrease in the risk of death with carvedilol ( 95 percent confidence interval , 19 to 48 percent ; P=0.00013 , unadjusted ; P=0.0014 , adjusted for interim analyses ) . A total of 507 patients died or were hospitalized in the placebo group , as compared with 425 in the carvedilol group . This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol ( 95 percent confidence interval , 13 to 33 percent ; P cardiac decompensation . Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons ( P=0.02 ) . CONCLUSIONS The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial",
"CONTEXT Cardiac resynchronization therapy ( CRT ) through biventricular pacing is an effective treatment for heart failure ( HF ) with a wide QRS ; however , the outcomes of patients requiring CRT and implantable cardioverter defibrillator ( ICD ) therapy are unknown . OBJECTIVE To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association ( NYHA ) class III or IV congestive HF despite appropriate medical management . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , parallel-controlled trial conducted from October 1 , 1999 , to August 31 , 2001 , of 369 patients with left ventricular ejection fraction of 35 % or less , QRS duration of 130 ms , at high risk of life-threatening ventricular arrhythmias , and in NYHA class III ( n = 328 ) or IV ( n = 41 ) despite optimized medical treatment . INTERVENTIONS Of 369 r and omized patients who received devices with combined CRT and ICD capabilities , 182 were controls ( ICD activated , CRT off ) and 187 were in the CRT group ( ICD activated , CRT on ) . MAIN OUTCOME MEASURES The primary double-blind study end points were changes between baseline and 6 months in quality of life , functional class , and distance covered during a 6-minute walk . Additional outcome measures included changes in exercise capacity , plasma neurohormones , left ventricular function , and overall HF status . Survival , incidence of ventricular arrhythmias , and rates of hospitalization were also compared . RESULTS At 6 months , patients assigned to CRT had a greater improvement in median ( 95 % confidence interval ) quality of life score ( -17.5 [ -21 to -14 ] vs -11.0 [ -16 to -7 ] , P = .02 ) and functional class ( -1 [ -1 to -1 ] vs 0 [ -1 to 0 ] , P = .007 ) than controls but were no different in the change in distance walked in 6 minutes ( 55 m [ 44 - 79 ] vs 53 m [ 43 - 75 ] , P = .36 ) . Peak oxygen consumption increased by 1.1 mL/kg per minute ( 0.7 - 1.6 ) in the CRT group vs 0.1 mL/kg per minute ( -0.1 to 0.8 ) in controls ( P = .04 ) , although treadmill exercise duration increased by 56 seconds ( 30 - 79 ) in the CRT group and decreased by 11 seconds ( -55 to 12 ) in controls ( P left ventricular size or function , overall HF status , survival , and rates of hospitalization . No proarrhythmia was observed and arrhythmia termination capabilities were not impaired . CONCLUSIONS Cardiac resynchronization improved quality of life , functional status , and exercise capacity in patients with moderate to severe HF , a wide QRS interval , and life-threatening arrhythmias . These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function",
"OBJECTIVES We sought to compare the short- and long-term clinical effects of atrial synchronous pre-excitation of one ( univentricular ) or both ventricles ( biventricular ) , that provide cardiac resynchronization therapy ( CRT ) . BACKGROUND In patients with heart failure ( HF ) who have a ventricular conduction delay , CRT improves systolic hemodynamic function . The clinical benefit of CRT is still being investigated . METHODS Forty-one patients were r and omized to four weeks of first treatment with biventricular or univentricular stimulation , followed by four weeks without treatment , and then four weeks of a second treatment with the opposite stimulation . The best CRT stimulation was continued for nine months . Cardiac resynchronization therapy was optimized by hemodynamic testing at implantation . The primary end points were exercise capacity measures . Data were analyzed by two-way repeated- measures analysis of variance . RESULTS The left ventricle was selected for univentricular pacing in 36 patients . The clinical effects of univentricular and biventricular CRT were not significantly different . The results of each method were pooled to assess sequential treatment effects . Oxygen uptake during bicycle exercise increased from 9.48 to 10.4 ml/kg/min at the anaerobic threshold ( p = 0.03 ) and from 12.5 to 14.3 ml/kg/min at peak exercise ( p 6-min walk distance increased from 342 m at baseline to 386 m after the first treatment ( p Cardiac resynchronization therapy produces a long-term improvement in the clinical symptoms of patients with HF who have a ventricular conduction delay . The differences between optimized biventricular and univentricular therapy appear to be small for short-term treatment",
"Objective : To compare clinical and haemodynamic variables between left ventricular and biventricular pacing in patients with severe heart failure ; and to analyse haemodynamic changes during daily life and maximum exercise during chronic left ventricular and biventricular pacing . Design : Prospect i ve single blinded r and omised study with crossover . Setting : University hospital ( tertiary referral centre ) . Patients and methods : 13 patients ( mean ( SD ) age , 62 ( 6 ) years ) with chronic atrial fibrillation , severe heart failure ( mean ejection fraction 24 (8)% ) , and QRS prolongation of ≥ 140 ms had His bundle ablation and installation of a pacemaker providing left ventricular and biventricular pacing . The pacemaker was equipped with a peak endocardial acceleration ( PEA ) sensor . The PEA pattern was used as a haemodynamic marker during exercise as it is highly correlated with left ventricular dP/dt . After a baseline period of right ventricular pacing , all patients had two months of left ventricular pacing and two months of biventricular pacing in r and om order . At the end of each phase , an echocardiogram , a haemodynamic analysis at rest and on exercise during a six minute walk test , and a cardiopulmonary exercise test were performed . Results : PEA values were higher with left ventricular pacing ( 0.58 ( 0.38 ) m/s ) and biventricular pacing ( 0.62 ( 0.24 ) m/s ) than at baseline ( 0.49 ( 0.18 ) m/s ) ( p The six minute walk test showed similar performance in both pacing modes , but patients had more symptoms with left ventricular pacing at the end of the test ( p = 0.035 ) . On cardiopulmonary exercise testing , there was a greater increase in mean percentage variation of PEA with biventricular pacing than with left ventricular pacing ( 125 (18)% v 97 (36)% , respectively ; p = 0.048 ) and better performance figures ( 92 ( 34 ) W v 77 ( 23 ) W ; p = 0.03 ) . Conclusions : During symptom limited and daily life exercise tests , chronic biventricular pacing provides better haemodynamic performance than left ventricular pacing . In heart failure patients with wide QRS complexes , the interventricular dyssynchronisation induced by left ventricular pacing may impair myocardial function during exercise",
"This study was design ed to assess the efficacy and safety of berberine for chronic congestive heart failure ( CHF ) . One hundred fifty-six patients with CHF and > 90 ventricular premature complexes ( VPCs ) and /or nonsustained ventricular tachycardia ( VT ) on 24-hour Holter monitoring were r and omly divided into 2 groups . All patients were given conventional therapy for CHF , consisting of angiotensin-converting enzyme inhibitors , digoxin , diuretics , and nitrates . Patients in the treatment group ( n = 79 ) were also given berberine 1.2 to 2.0 g/day . The remaining 77 patients were given placebo . Symptoms , a 6-minute walk test , left ventricular ( LV ) ejection fraction ( EF ) , frequency and complexity of VPCs , and quality of life were assessed after 8 weeks of treatment and during a mean 24-month follow-up . After treatment with berberine , there was a significantly greater increase in LVEF , exercise capacity , improvement of the dyspnea-fatigue index , and a decrease of frequency and complexity of VPCs compared with the control group . There was a significant decrease in mortality in the berberine-treated patients during long-term follow-up ( 7 patients receiving treatment died vs 13 on placebo , p Proarrhythmia was not observed , and there were no apparent side effects . Thus , berberine improved quality of life and decreased VPCs and mortality in patients with CHF",
"BACKGROUND Although previous studies suggested that TNF may contribute to heart failure progression , it is unclear whether antagonizing TNF is beneficial in heart failure patients . METHODS AND RESULTS Eighteen NYHA class III heart failure patients were r and omized into a double-blind dose-escalation study to examine the safety and potential efficacy of etanercept , a specific TNF antagonist ( Enbrel ) . Patients received placebo ( 6 patients ) or an escalating dose ( 1 , 4 , or 10 mg/m2 ) of etanercept ( 12 patients ) given as a single intravenous infusion . Safety parameters and patient functional status were assessed at baseline and at days 1 , 2 , 7 , and 14 . There were no significant side effects or clinical ly significant changes in laboratory indices . There was , however , a decrease in TNF bioactivity and a significant overall increase in quality -of-life scores , 6-minute walk distance , and ejection fraction in the cohort that received 4 or 10 mg/m2 of etanercept ; there was no significant change in these parameters in the placebo group . CONCLUSIONS A single intravenous infusion of etanercept was safe and well tolerated in patients with NYHA class III heart failure . These studies provide provisional evidence that suggests that etanercept is sufficient to lower levels of biologically active TNF and may lead to improvement in the functional status of patients with heart failure",
"BACKGROUND One third of chronic heart failure patients have major intraventricular conduction and uncoordinated ventricular contraction . Non-controlled studies suggest that biventricular pacing may improve haemodynamics and well-being by reducing ventricular asynchrony . The aim of this trial was to assess the clinical efficacy and safety of this new therapy in patients with chronic atrial fibrillation . METHODS Fifty nine NYHA class III patients with left ventricular systolic dysfunction , chronic atrial fibrillation , slow ventricular rate necessitating permanent ventricular pacing , and a wide QRS complex ( paced width > or=200 ms ) , were implanted with transvenous biventricular-VVIR pacemakers . This single-blind , r and omized , controlled , crossover study compared the patients ' parameters , as monitored during two 3-month treatment periods of conventional right-univentricular vs biventricular pacing . The primary end-point was the 6-min walked distance , secondary end-points were peak oxygen uptake , quality -of-life , hospitalizations , patients ' preferred study period and mortality . RESULTS Because of a higher than expected drop-out rate ( 42 % ) , only 37 patients completed both crossover phases . In the intention-to-treat analysis , we did not observe a significant difference . However , in the patients with effective therapy the mean walked distance increased by 9.3 % with biventricular pacing ( 374+/-108 vs 342+/-103 m in univentricular;P = 0.05 ) . Peak oxygen uptake increased by 13 % ( P=0.04 ) . Hospitalizations decreased by 70 % and 85 % of the patients preferred the biventricular pacing period ( P exercise tolerance in NYHA class III heart failure patients with chronic atrial fibrillation and wide paced-QRS complexes . Further r and omized controlled studies are required to definitively vali date this therapy in such patients",
"BACKGROUND We investigated the effects of c and esartan ( an angiotensin II antagonist ) alone , enalapril alone , and their combination on exercise tolerance , ventricular function , quality of life ( QOL ) , neurohormone levels , and tolerability in congestive heart failure ( CHF ) . METHODS AND RESULTS Seven hundred sixty-eight patients in New York Heart Association functional class ( NYHA-FC ) II to IV with ejection fraction ( EF ) c and esartan ( 4 , 8 , or 16 mg ) , c and esartan ( 4 or 8 mg ) plus 20 mg of enalapril , or 20 mg of enalapril for 43 weeks . There were no differences among groups with regard to 6MWD , NYHA-FC , or QOL . EF increased ( P = NS ) more with c and esartan-plus-enalapril therapy ( 0.025+/-0.004 ) than with c and esartan alone ( 0.015+/-0.004 ) or enalapril alone(0.015+/-0.005 ) . End-diastolic ( EDV ) and end-systolic ( ESV ) volumes increased less with combination therapy ( EDV 8+/-4 mL ; ESV 1+/-4 mL ; P c and esartan alone ( EDV 27+/-4 mL ; ESV 18+/-3 mL ) or enalapril alone ( EDV 23+/-7 mL ; ESV 14+/-6 mL ) . Blood pressure decreased with combination therapy ( 6+/-1/4+/-1 mm Hg ) compared with c and esartan or enalapril alone ( P Aldosterone decreased ( P c and esartan ( 0.7+/-7.8 pg/mL ) or enalapril ( -0.8+/-11 . 3 pg/mL ) . Brain natriuretic peptide decreased with combination therapy ( 5.8+/-2.7 pmol/L ; P c and esartan ( 4 . 4+/-3.8 pmol/L ) and enalapril alone ( 4.0+/-5.0 pmol/L ) . CONCLUSIONS C and esartan alone was as effective , safe , and tolerable as enalapril . The combination of c and esartan and enalapril was more beneficial for preventing left ventricular remodeling than either c and esartan or enalapril alone",
"The safety and benefit of outpatient inotrope infusions in intractable heart failure remains controversial . Accordingly a prospect i ve double blind , crossover r and omization scheme was utilized in stable patients with heart failure but intractable symptoms . A total of 29 patients ( mean age 66 + /- 13 years , with a mean left ventricular systolic function of 18 + /- 9 % , New York Heart Association class 3.6 + /- 0.5 ) met all the inclusion and none of the exclusion criteria to receive intravenous milrinone , dobutamine , or matching placebo . Safety evaluations including routine laboratory studies , physical examinations , electrocardiographic monitoring , vital signs , assessment of quality of life scores using the Minnesota Living with Heart Failure question naire , six-minute walk tests , and echocardiographic assessment s were performed . All 29 patients completed the weaning protocol without adverse events ( mean of 27.3 + /- 11.8 treatments per patient ) . Patients initially assigned to milrinone received fewer treatment sessions ( 19 + /- 8 versus 31 + /- 12 ( dobutamine ) and 33 + /- 10 ( placebo ) ; p milrinone required crossover r and omization compared to 27 % patients assigned to dobutamine and 75 % patients assigned to placebo . A statistically significant reduction in quality of life scores ( 60 + /- 20 versus 35 + /- 18 ; p 6-minute walk test assessment s ( 959 + /- 431 versus 1269 + /- 469 ; p 6-minute walk test scores was noted at the end of the study when compared to baseline scores . In contrast , a reduction of -1 % ( p placebo . Finally , a trend that although did not reached statistical significance was noted in patients assigned to milrinone in terms of improvement in left ventricular systolic function , reduction in the severity of mitral regurgitation and estimated right ventricular systolic pressure . These results demonstrate that outpatient infusion of inotropes appear to be safe and effective in improving heart failure symptoms , reducing need for hospitalizations and emergency room visits . Furthermore , infusion of inotropes result ed in a significant improvement on 6-minute walk test scores than placebo . It also appears that milrinone confers all these benefits sooner than dobutamine",
"UNLABELLED Beta-blocker therapy results in a functional benefit in patients with heart failure ( CHF ) due to idiopathic dilated cardiomyopathy ( DCM ) . This study assessed if similar effects were observed in patients with ischemic heart disease ( CAD ) , NYHA II-III after 6 months of therapy with metoprolol . METHODS AND RESULTS Fifty-two patients with CHF secondary to DCM ( 26 patients ) and CAD ( 26 patients ) and a left ventricular ejection fraction (EF) in the placebo-controlled study . The study medication was titrated over 6 weeks , the mean final dosage was 135 mg/day . Three patients died due to cardiogenic shock , two received placebo and one metoprolol . Eight patients did not complete the study due to non-compliance . Metoprolol significantly reduced heart rate at rest and after submaximal and maximal exercise . Vo(2)-max and Vo(2)-AT as well as the 6-min walk test improved significantly after metoprolol treatment . There was a significant increase in EF at rest ( 27.3 - 35 . 2 % ) , submaximal ( 28.5 - 37.7 % ) and maximal exercise ( 28.7 - 40.9 % ) in the metoprolol-treated patients . No differences were found between patients with CAD and DCM . We also observed reduced left ventricular volumes . CONCLUSION The additional therapy with metoprolol improved cardiac function and the cardiopulmonary exercise capacity in patients with CHF",
"BACKGROUND The safety and efficacy of angiotensin-converting enzyme inhibitors for very old patients with chronic heart failure have been less well documented than for younger patients . METHODS A prospect i ve , r and omized double-blind , placebo-controlled study of captopril , 25 mg twice daily , was design ed . Fifty patients ( mean age 84.2 + /- 5.2 ) participated . The degree of chronic heart failure ( according to the Boston Study Group rating ) , the distance walked in 6 minutes , and the occurrence of uncontrolled heart failure and adverse reactions were used as main outcome measures . RESULTS Significantly more patients receiving placebo developed uncontrolled heart failure than patients receiving captopril ( p = .022 ) . In an intention to treat analysis , the first and last evaluations of the degree of chronic heart failure were compared . A significantly different evolution was observed between the two treatment groups ( p captopril-treated patients ( p distance walked in 6 minutes improved significantly only in the captopril group ( p = .004 ) . The only adverse reaction was rash in two patients receiving captopril . CONCLUSIONS The study gives further evidence that angiotensin-converting enzyme inhibitor treatment for very old patients with chronic heart failure is useful",
"BACKGROUND Clinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure , but the utility and safety of these drugs in patients with advanced disease have not been evaluated . METHODS AND RESULTS We enrolled 56 patients with severe chronic heart failure into a double-blind , placebo-controlled study of the vasodilating beta-blocker carvedilol . All patients had advanced heart failure , as evidence d by a mean left ventricular ejection fraction of 0.16 + /- 0.01 and a mean maximal oxygen consumption of 13.6 + /- 0.6 mL.kg-1.min-1 despite digitalis , diuretics , and an angiotensin-converting enzyme inhibitor ( if tolerated ) . After a 3-week , open-label , up-titration period , 49 of the 56 patients were assigned ( in a double-blind fashion using a 2:1 r and omization ) to receive either carvedilol ( 25 mg BID , n = 33 ) or matching placebo ( n = 16 ) for 14 weeks , while background therapy remained constant . Hemodynamic and functional variables were measured at the start and end of the study . Compared with the placebo group , patients in the carvedilol group showed improved cardiac performance , as reflected by an increase in left ventricular ejection fraction ( P = .005 ) and stroke volume index ( P = .010 ) and a decrease in pulmonary wedge pressure , mean right atrial pressure , and systemic vascular resistance ( P = .003 , .002 , and .017 , respectively ) . In addition , compared with placebo , patients treated with carvedilol benefited clinical ly , as shown by an improvement in symptom scores ( P = .002 ) , functional class ( P = .013 ) , and submaximal exercise tolerance ( P = .006 ) . The combined risk of death , worsening heart failure , and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group ( P = .028 ) , but carvedilol-treated patients had more dizziness and advanced heart block . CONCLUSIONS Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors",
"BACKGROUND The purpose of this study was to examine the effects of exercise training on functional capacity in patients with heart failure . METHODS One hundred eighty-one patients in New York Heart Association class I to III , with ejection fraction were recruited into a r and omized , controlled , single-blind trial comparing 3 months of supervised training , then 9 months of home-based training with usual care . RESULTS There was a significant increase in 6-minute walk distance at 3 and 12 months but no between-group differences . Incremental peak oxygen uptake increased in the exercise group compared with the control group at 3 months ( 0.104 + /- 0.026 L/min vs 0.025 + /- 0.023 L/min ; P = .026 ) and 12 months ( 0.154 + /- 0.074 L/min vs 0.024 + /- 0.027 L/min ; P = .081 ) . Compared with the control group , significant increases were observed in the exercise group for arm and leg strength . No significant changes were observed in cardiac function or quality of life . Adherence to exercise was good during supervised training but reduced during home-based training . CONCLUSIONS Exercise training improves peak oxygen uptake and strength during supervised training . Over the final 9 months of the study , there was little further improvement , suggesting that some supervision is required for these patients . There were no adverse effects on cardiac function or clinical events",
"BACKGROUND Metoprolol provides clinical benefits in patients with congestive heart failure ( CHF ) . In this study , we investigated the effects of controlled-release metoprolol ( metoprolol CR ) on clinical status , on left ventricular ( LV ) volumes and function , and on neurohumoral activation in a large number of patients with CHF of mixed causes . METHODS AND RESULTS Four hundred twenty-six patients with symptomatic CHF were r and omized to receive metoprolol CR or placebo for 24 weeks . Metoprolol CR did not affect 6-minute walk distance , New York Heart Association functional class , or quality of life . However , there was a significant improvement in measures of LV function with an attenuation in the increase in LV end-diastolic ( + 23+/-65 mL [ placebo ] versus + 6+/-61 mL , P=0.01 ) and LV end-systolic ( + 19+/-55 mL [ placebo ] versus -2+/-51 mL , P volumes after 24 weeks of therapy . LV ejection fraction was unchanged ( -0.05 % or -0.005 ) in the placebo group but increased by 2 . 4 % in the metoprolol CR-treated patients ( P=0.001 ) . Patients receiving metoprolol CR had a greater decrease in angiotensin II ( P=0.036 ) and renin ( P=0.032 ) levels but an increase in N-terminal atrial natriuretic peptide and brain natriuretic peptide levels ( P deaths in the group receiving beta-blockers ( 3 . 4 % versus 8.1 % ) , and there was a similar number of patients experiencing the composite outcomes of death or any hospitalization . CONCLUSIONS When added to ACE inhibitors , angiotensin II receptor antagonists , or both , the use of metoprolol CR improves ventricular function , reduces activation of the renin-angiotensin systems , and results in fewer deaths",
"The six-minute walking test ( WT ) is used in trials and clinical practice as an easy tool to evaluate the functional capacity of chronic heart failure ( CHF ) patients . As WT measurements are highly variable both between and within individuals , this study aims at assessing the contribution of the different sources of variation and estimating the reproducibility of the test . A statistical model describing WT measurements as a function of fixed and r and om effects is proposed and its parameters estimated . We considered 202 stable CHF patients who performed two baseline WTs separated by a 30 minute rest ; 49 of them repeated the two tests 3 months later ( follow-up control ) . They had no changes in therapy or major clinical events . Another 31 subjects performed two baseline tests separated by 24 hours . Collected data were analysed using a mixed model methodology . There was no significant difference between measurements taken 30 minutes and 24 hours apart ( p = 0.99 ) . A trend effect of 17 ( 1.4 ) m ( mean ( SE ) ) was consistently found between duplicate tests ( p REML estimates of variance components were : 5189 ( 674 ) for subject differences in the error-free value ; 1280 ( 304 ) for subject differences in spontaneous clinical evolution between baseline and follow-up control , and 266 ( 23 ) for the within-subject error . Hence , the st and ard error of measurement was 16.3 m , namely 4 per cent of the average WT performance ( 403 m ) in this sample . The intraclass correlation coefficient was 0.96 . We conclude that WT measurements are characterized by good intrasubject reproducibility and excellent reliability . When follow-up studies > or = 3 months are performed , unpredictable changes in individual walking performance due to spontaneous clinical evolution are to be expected . Their clinical significance , however , is not known",
"OBJECTIVE To study the potential usefulness of the 6-minute walk test , a self-paced submaximal exercise test , as a prognostic indicator in patients with left ventricular dysfunction . DESIGN Data were collected during a prospect i ve cohort study , the Studies of Left Ventricular Dysfunction ( SOLVD ) Registry Sub study . SETTING Twenty tertiary care hospitals in the United States , Canada , and Belgium . PARTICIPANTS A stratified r and om sample of 898 patients from the SOLVD Registry who had either radiological evidence of congestive heart failure and /or an ejection fraction of 0.45 or less were enrolled in the sub study and underwent a detailed clinical evaluation including a 6-minute walk test . Patients were followed up for a mean of 242 days . OUTCOME MEASURES Mortality and hospitalization . RESULTS During follow-up , 52 walk-test participants ( 6.2 % ) died and 252 ( 30.3 % ) were hospitalized . Hospitalization for congestive heart failure occurred in 78 participants ( 9.4 % ) , and the combined endpoint of death or hospitalization for congestive heart failure occurred in 114 walk-test participants ( 13.7 % ) . Compared with the highest performance level , patients in the lowest performance level had a significantly greater chance of dying ( 10.23 % vs 2.99 % ; P = .01 ) , of being hospitalized ( 40.91 % vs 19.90 % ; P = .002 ) , and of being hospitalized for heart failure ( 22.16 % vs 1.99 % ; P ejection fraction and distance walked were equally strong and independent predictors of mortality and heart failure hospitalization rates during follow-up . CONCLUSION The 6-minute walk test is a safe and simple clinical tool that strongly and independently predicts morbidity and mortality in patients with left ventricular dysfunction",
"Experimentelle Arbeiten und retrospektive Analysen klinischer Studien lassen einen positiven Effekt von Statinen bei Patienten mit Herzinsuffizienz vermuten . Möglicherweise ist hieran eine direkte Wirkung von Statinen auf das Myokard beteiligt . Wir untersuchten daher in einer prospektiven , r and omisierten , doppelblinden Studie ( n = 15 ) den Effekt von Cerivastatin 0,4 mg ( Statin ) oder Placebo auf Patienten mit nichtischämischer Kardiomyopathie . Einschlusskriterien waren der angiographische Ausschluss von Koronarstenosen , stabile Herzinsuffizienz NYHA II-IV und eine etablierte Therapie mit ACE-Hemmern und Betablockern . Die Beh and lungsdauer betrug i m Mittel 20 Wochen . Die Statinbeh and lung führte bei den normo- cholesterinämischen Patienten zu einer Reduktion des LDL um 11,3 mg/dl ( p = n. s. ) . Es zeigte sich eine Verbesserung der Lebensqualität und der körperlichen Belastbarkeit in der Statin- , aber nicht in der Placebo Gruppe . Dies war assoziiert mit einem Trend zu einer verbesserten linksventrikulären Pumpfunktion und einer gesteigerten Endothel-abhängigen Vasodilatation . Die Statin Beh and lung führte i m Vergleich zu Placebo zu einer signifikanten Herabregulation der Plasmakonzentrationen von Troponin T , hochsensitivem CRP , Plasminogen Aktivator Inhibitor und Tumor Nekrose Faktor alpha , dagegen wurden ICAM-1 und IL-10 nicht signifikant reguliert . Statine zeigen positive Effekte bei Patienten mit nicht-ischämischer Kardiomyopathie und verbessern die Lebensqualität und die körperliche Belastbarkeit . Diese Pilotstudie könnte auf eine neue Beh and lungsstrategie für Patienten mit Herzinsuffizienz hinweisen . HMG CoA reductase inhibitors ( statins ) may exert a wide array of cholesterolindependent effects including antihypertrophic effects on the heart . Their role in the treatment of heart failure has not been studied . 15 patients with heart failure NYHA II-III based on non-ischemic dilated cardiomyopathy were r and omized in a double-blind study to 0.4 mg cerivastatin or placebo for an average treatment period of 20 weeks . Quality of life and exercise capacity increased significantly in the statin treatment but not in the placebo group ( Minnesota Living with Heart Failure Question naire , 6 min walking test ) . Concomitantly , there was a trend towards increased left ventricular ejection fraction ( radionuclear ventriculography ) and improved endothelial function ( forearm blood flow ) . Statins decreased plasma concentrations of troponine T , high sensitive C-reactive protein ( hsCRP ) , plasminogen activator inhibitor-1 ( PAI-1 ) and tumor necrosis factor alpha ( TNFα ) . Statins induce benefical effects in patients with non-ischemic cardiomyopathy leading to improvement of quality of life and exercise capacity disclosing a promising novel treatment strategy for patients with heart failure",
"OBJECTIVES The purpose of this study was to determine whether digoxin is effective in patients with chronic , stable mild to moderate heart failure . BACKGROUND Digoxin has been a traditional therapy in heart failure , but method ologic limitations in earlier studies have prevented definitive conclusions regarding its efficacy . METHODS Withdrawal of digoxin ( placebo group , n = 46 ) or its continuation ( digoxin group , n = 42 ) was performed in a prospect i ve , r and omized , double-blind , placebo-controlled multicenter trial of patients with chronic , stable mild to moderate heart failure secondary to left ventricular systolic dysfunction who had normal sinus rhythm and were receiving long-term treatment with diuretic drugs and digoxin . RESULTS Patients withdrawn from digoxin therapy showed worsened maximal exercise capacity ( median change in exercise time -96 s ) compared with that of patients who continued to receive digoxin ( change in exercise time + 4.5 s ) ( p = 0.003 ) . Patients withdrawn from digoxin therapy showed an increased incidence of treatment failures ( p = 0.039 ) ( 39 % , digoxin withdrawal group vs. 19 % , digoxin maintenance group ) and a decreased time to treatment failure ( p = 0.037 ) . In addition , patients who continued to receive digoxin had a lower body weight ( p = 0.044 ) and heart rate ( p = 0.003 ) and a higher left ventricular ejection fraction ( p = 0.016 ) . CONCLUSIONS These data provide strong evidence of the clinical efficacy of digoxin in patients with normal sinus rhythm and mild to moderate chronic heart failure secondary to systolic dysfunction who are treated with diuretics ",
"BACKGROUND Many patients remain markedly symptomatic despite optimal current therapy for heart failure . Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function . METHODS AND RESULTS One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind , placebo-controlled study of the vasodilating beta-blocker carvedilol . All patients had symptomatic , advanced heart failure while on st and ard triple therapy , as evidence d by a mean ejection fraction of 0.22 , marked reduction in distance traveled in a 6-minute corridor walk test , and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Question naire . After a 2-week , open-label test of 6.25 mg twice daily carvedilol , 105 patients were r and omized ( 2:1 ) to receive either carvedilol ( up to 25 mg twice daily , n = 70 ) or matching placebo ( n = 35 ) for 6 months while background therapy with digoxin , diuretics , and an angiotensin-converting enzyme inhibitor remained constant . Ten patients ( 8 % ) did not complete the open-label period because of adverse events and 11.4 % in both the carvedilol and placebo groups dropped out in the double-blind phase . The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved . Quality of life , which was the primary endpoint , improved similarly in the carvedilol and placebo groups , whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol ( P Hospitalization and mortality rate were too low to evaluate a difference , and exercise time and New York Heart Association classification did not change significantly in response to the drug . Left ventricular ejection fraction rose significantly ( + 0.09 ) in the carvedilol group compared with the placebo group ( + 0.02 , P = .004 ) . CONCLUSION The beta-blocker carvedilol can be safely employed in patients with severe heart failure . Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity",
"BACKGROUND Many patients with congestive heart failure do not receive the benefits of angiotensin-converting enzyme ( ACE ) inhibitors because of intolerance . We sought to determine the tolerability of an angiotensin II receptor blocker , c and esartan cilexetil , among patients considered intolerant of ACE inhibitors . METHODS Patients with CHF , left ventricular ejection fraction less than 35 % , and history of discontinuing an ACE inhibitor because of intolerance underwent double-blind r and omization in a 2:1 ratio to receive c and esartan ( n = 179 ) or a placebo ( n = 91 ) . The initial dosage of c and esartan was 4 mg/d ; the dosage was increased to 16 mg/d if the drug was tolerated . A history of intolerance of ACE inhibitor was attributed to cough ( 67 % of patients ) , hypotension ( 15 % ) , or renal dysfunction ( 11 % ) . RESULTS The study drug was continued for 12 weeks by 82.7 % of patients who received c and esartan versus 86.8 % of patients who received the placebo . This 4.1 % greater discontinuation rate with active therapy was not significant ; the 95 % confidence interval ranged from 4.8 % more discontinuation with placebo to 13 % more with c and esartan . Titration to the 16-mg target dose was possible for 69 % of patients who received c and esartan versus 84 % of those who received the placebo . Frequencies of death and morbidity were not significantly different between the c and esartan and placebo groups ( death 3.4 % and 3.3 % , worsening heart failure 8.4 % and 13.2 % , myocardial infa rct ion 2.8 % and 5.5 % , all-cause hospitalization 12.8 % and 18.7 % , and death or hospitalization for heart failure 11.7 % and 14.3 % ) . CONCLUSIONS C and esartan was well tolerated by this population . The effect of c and esartan on major clinical end points , including death , remains to be determined",
"BACKGROUND Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival . Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation ; the drug improves symptoms of heart failure . We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre , r and omised placebo-controlled study . METHODS Patients with advanced severe heart failure ( New York Heart Association classes III and IV ) and evidence of severe left-ventricular disease , who were already receiving optimum treatment for heart failure , were r and omly allocated oral ibopamine 100 mg three times daily or placebo . The primary endpoint was all-cause mortality . The study was design ed to recruit 2200 patients , and the minimum duration of treatment would be 6 months . We did intention-to-treat and on-treatment analyses ; a post-hoc subgroup analysis was also done . FINDINGS After we had recruited 1906 patients the trial was stopped early , because of an excess of deaths among patients in the ibopamine group . 232 ( 25 % ) of 953 patients in the ibopamine group died , compared with 193 ( 20 % ) of 953 patients in the placebo group ( relative risk 1.26 [ 95 % CI 1.04 - 1.53 ] , p = 0.017 ) . The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group . In multivariate analysis , only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients . INTERPRETATION Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy , but the reasons for this increase are not clear . Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important , but exploratory analyses must be interpreted with caution",
"BACKGROUND Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies , but its clinical effects have not been evaluated in large , multicenter trials . METHODS AND RESULTS We enrolled 278 patients with moderate to severe heart failure ( 6-minute walk distance , 150 to 450 m ) and a left ventricular ejection fraction After an open-label , run-in period , each patient was r and omly assigned ( double-blind ) to either placebo ( n = 145 ) or carvedilol ( n = 133 ; target dose , 25 to 50 mg BID ) for 6 months , while background therapy with digoxin , diuretics , and an ACE inhibitor remained constant . Compared with placebo , patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration , as evaluated by changes in the NYHA functional class ( P = .014 ) or by a global assessment of progress judged either by the patient ( P = .002 ) or by the physician ( P carvedilol was associated with a significant increase in ejection fraction ( P combined risk of morbidity and mortality ( P = .029 ) . In contrast , carvedilol therapy had little effect on indirect measures of patient benefit , including changes in exercise tolerance or quality -of-life scores . The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure . CONCLUSIONS These findings indicate that , in addition to its favorable effects on survival , carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin , diuretics , and an ACE inhibitor",
"Clinicians have relied on history and results from physical examinations to guide treatment of patients with advanced congestive heart failure , but these results may not reflect disease severity or hemodynamic status . We assessed how the distance walked in 6 minutes relates to clinical outcomes and symptoms of such patients . We compared the rates of death , hospitalization , and their composite at 1 year by the distance walked in 6 minutes at baseline and at 1 month , and by the change in distance between baseline and 1 month in 440 patients enrolled in a r and omized trial . We also assessed the relations of baseline distance walked to symptom score and New York Heart Association class . The median distance increased from 218 m at baseline to 280 m at 1 month . Of 365 patients able to perform the baseline walk , 121 ( 33 % ) died and 217 ( 60 % ) were hospitalized compared with 46 ( 61 % ) and 34 ( 45 % ) of 75 patients unable to walk at baseline . Baseline distance significantly predicted mortality ( hazard ratio 0.58/100-m increase , 95 % confidence interval 0.50 to 0.68 , p Baseline distance also significantly predicted hospitalization and the composite end point , as did the 1-month distance walked . The change in distance walked from baseline to 1 month did not predict any end point . Baseline distance correlated only moderately with symptom score ( r = -0.385 , p New York Heart Association class ( r = -0.468 , p Distance walked during 6 minutes independently and strongly predicts mortality and hospitalization in patients with advanced congestive heart failure . This may be a simple , noninvasive , objective way to risk-stratify these patients and st and ardize their treatment",
"BACKGROUND Previous studies have suggested that cardiac resynchronization achieved through atrial-synchronized biventricular pacing produces clinical benefits in patients with heart failure who have an intraventricular conduction delay . We conducted a double-blind trial to evaluate this therapeutic approach . METHODS Four hundred fifty-three patients with moderate-to-severe symptoms of heart failure associated with an ejection fraction of 35 percent or less and a QRS interval of 130 msec or more were r and omly assigned to a cardiac-resynchronization group ( 228 patients ) or to a control group ( 225 patients ) for six months , while conventional therapy for heart failure was maintained . The primary end points were the New York Heart Association functional class , quality of life , and the distance walked in six minutes . RESULTS As compared with the control group , patients assigned to cardiac resynchronization experienced an improvement in the distance walked in six minutes ( + 39 vs. + 10 m , P=0.005 ) , functional class ( P quality of life ( -18.0 vs. -9.0 points , P= 0.001 ) , time on the treadmill during exercise testing ( + 81 vs. + 19 sec , P=0.001 ) , and ejection fraction ( + 4.6 percent vs. -0.2 percent , P hospitalization ( 8 percent vs. 15 percent ) or intravenous medications ( 7 percent vs. 15 percent ) for the treatment of heart failure ( P unsuccessful in 8 percent of patients and was complicated by refractory hypotension , bradycardia , or asystole in four patients ( two of whom died ) and by perforation of the coronary sinus requiring pericardiocentesis in two others . CONCLUSIONS Cardiac resynchronization results in significant clinical improvement in patients who have moderate-to-severe heart failure and an intraventricular conduction delay",
"C resynchronization therapy ( CRT ) by atriobiventricular pacing has been proposed to treat severe heart failure in patients with intraventricular conduction delay result ing in ventricular mechanical discoordination . The clinical efficacy of CRT was recently demonstrated in a single-blind , r and omized , crossover trial , namely the MUltisite STimulation In Cardiomyopathies ( MUSTIC ) study .1 The purpose of this sub study was to assess the effect of CRT on heart rate variability ( HRV ) and to analyze its correlation with clinical efficacy . • • • All patients provided written informed consent before enrollment . All had severe heart failure due to idiopathic or ischemic left ventricular systolic dysfunction , left ventricular ejection fraction 35 % , and end-diastolic diameter 60 mm . All patients were in sinus rhythm with a QRS interval 150 ms and no classic indication for pacemaker implantation.2 Patients had been in New York Heart Association ( NYHA ) class III for 1 month before inclusion while receiving individually optimized treatment , including diuretics and angiotensin-converting enzyme inhibitors at the maximum tolerated dose . Exclusion criteria have been already reported.1 The study included a 6-month r and omized crossover phase during which atriobiventricular ( active ) pacing was compared with inhibited ( inactive ) ventricular pacing at the basic rate of 40 beats/min , each for a period of 3 months in r and om order ( Figure 1 ) . Implantation was performed after a 1-month observation period to verify the stability of heart failure . Pacemakers were programmed as inactive after implantation . Patients were r and omly assigned to experimental groups within the following 2 weeks after verification of pacemaker proper performance . Treatment order r and omization followed a block design with stratification according to center . The single-blind , crossover phase was followed by a complementary 6-month period during which the pacing system was programmed according to patients ’ preferences . All leads were implanted transvenously . The left ventricular lead was placed in a tributary of the coronary sinus according to a previously described method .3 Specially design ed electrodes were used . The preferred target site was the lateral wall . The pacemakers were triple-output devices using st and ard dual-chamber technology , with built-in adapters to synchronize pacing in both ventricles . Pacemakers were programmed as either active or inactive at r and omization . The baseline pacing rate was set at 40 beats/min and the upper rate limit at 85 % of the highest predictable heart rate according to patients ’ age and gender . Each patient underwent Doppler echocardiography to determine their optimal atrioventricular delay ( electrical delay between atrial and ventricular excitation ) during atriobiventricular pacing . No modification of medical treatment except diuretic dose adjustment was permitted between enrollment and the end of the crossover phase of the study . Twenty-four-hour ambulatory electrocardiograms with a 2-channel recorder ( ELA Medical , le PlessisRobinson , France ) were obtained in all subjects during normal activity at baseline , at r and omization , at the end of each of the 2 crossover periods , and at the end of each longitudinal follow-up period ( 9 and 12 months ) . Tapes were replayed through a Elatec analyzer ( ELA Medical ) . HRV analysis used specifically vali date d software.4 Ambulatory electrocardiographic recordings that lasted 16 hours and whose analyzable proportion was 90 % were excluded to avoid bias linked to HRV circadian variations . After initial arrhythmia analysis and editing , the remaining normal-to-normal RR intervals in suitable recordings were measured and HRV time-domain analyses were performed according to published guidelines .5 For the purpose s of this study , 4 different time-domain HRV indexes were measured : ( 1 ) the SD of the normal-to-normal ( NN ) interval over the recording duration ( SDNN ) ; ( 2 ) the SD of the 5-minute mean NN interval over the entire recording ( SDANN [ milliseconds ] ) . Because SDANN values are obtained from successive 5-minute periods , they reflect heart rate changes caused by 5-minute cycles . They reflect long-term variations but provide no short-term variability data ; ( 3 ) the square root of the mean squared successive differences between adjacent RR intervals over the entire recording ( rMSSD [ milliseconds ] ) . This correlates more with the parasympathetic ( vagal ) activity ; ( 4 ) proportion of successive interval differences 50 ms as computed over the entire recording ( pNN50 [ percent ] ) . This also reflects parasympathetic activity . From the Departement de Cardiologie et Maladies Vasculaires , Centre Cardio-Pneumologique , Hopital Pontchaillou-CHU , Rennes , France . Dr. Daubert ’s address is : Departement de Cardiologie et Maladies Vasculaires , Centre Cardio-Pneumologique , Hopital PontchaillouCHU , 35033 Rennes Cedex , France . E-mail : jean-claude . [email protected] . Manuscript received August 23 , 2002 ; revised manuscript received and accepted January 23 , 2003",
"BACKGROUND AND METHODS Aldosterone is important in the pathophysiology of heart failure . In a doubleblind study , we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor , a loop diuretic , and in most cases digoxin . A total of 822 patients were r and omly assigned to receive 25 mg of spironolactone daily , and 841 to receive placebo . The primary end point was death from all causes . RESULTS The trial was discontinued early , after a mean follow-up period of 24 months , because an interim analysis determined that spironolactone was efficacious . There were 386 deaths in the placebo group ( 46 percent ) and 284 in the spironolactone group ( 35 percent ; relative risk of death , 0.70 ; 95 percent confidence interval , 0.60 to 0.82 ; P risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes . The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group ( relative risk of hospitalization , 0.65 ; 95 percent confidence interval , 0.54 to 0.77 ; P spironolactone had a significant improvement in the symptoms of heart failure , as assessed on the basis of the New York Heart Association functional class ( P Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone , as compared with 1 percent of men in the placebo group ( P serious hyperkalemia was minimal in both groups of patients . CONCLUSIONS Blockade of aldosterone receptors by spironolactone , in addition to st and ard therapy , substantially reduces the risk of both morbidity and death among patients with severe heart failure",
"Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy . Our large multicentre study aim ed to find out whether metoprolol improves overall survival and morbidity in this disorder . 383 subjects with heart failure from idiopathic dilated cardiomyopathy ( ejection fraction placebo or metoprolol . 94 % were in New York Heart Association functional classes II and III , and 80 % were receiving background treatment . A test dose of metoprolol ( 5 mg twice daily ) was given for 2 - 7 days ; those tolerating this dose ( 96 % ) entered r and omisation . Study medication was increased slowly from 10 mg to 100 - 150 mg daily . There were 34 % ( 95 % CI -6 to 62 % , p = 0.058 ) fewer primary endpoints in the metoprolol than the placebo group ; 2 and 19 patients , respectively , deteriorated to the point of needing transplantation and 23 and 19 died . The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo ( 0.13 vs 0.06 , p Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo ( 5 vs 2 mm Hg , p = 0.06 ) . Exercise time at 12 months was significantly greater ( p = 0.046 ) in metoprolol-treated than in placebo-treated patients . In patients with idiopathic dilated cardiomyopathy , treatment with metoprolol prevented clinical deterioration , improved symptoms and cardiac function , and was well tolerated",
"Because of conflicting results from studies examining the usefulness of digoxin in congestive heart failure ( CHF ) patients in sinus rhythm , a cross-over trial was conducted in which 20 patients received 7 weeks of digoxin titrated to a level of 1.54 to 2.56 nmol/liter and 7 weeks of matched placebo . The order of treatments was determined by r and om allocation and patients , clinicians and research staff were blind to allocation . In patients with deteriorating condition , the treatment period was terminated and outcome measures were obtained . If deterioration occurred during the first period , the patient was crossed over without the code being broken . Seven patients required premature termination of study periods because of increasing symptoms of CHF . All 7 were taking placebo at the time ( p = 0.016 ) . Small differences in dyspnea ( p = 0.044 ) , walking test score ( p = 0.055 ) , clinical assessment of CHF ( p = 0.036 ) and ejection fraction ( p = 0.004 ) favored the digoxin treatment group . Patients with more severe CHF were more likely to benefit from digoxin administration . It was concluded that oral digoxin , in doses titrated to produce a serum level of 1.54 to 2.56 nmol/liter , improved quality of life and functional exercise capacity in some patients with CHF in sinus rhythm",
"Treatment with human recombinant growth hormone ( GH ) has yielded conflicting results in patients with congestive heart failure . We analyzed the baseline somatotrophic axis in 50 patients with dilated cardiomyopathy . Then , a double-blind , r and omized , placebo-controlled study of GH was performed . We r and omly allocated these patients to treatment with subcutaneous GH ( 2 IU daily ) or placebo for a minimum of 12 weeks . The primary end-points were the effect on left ventricular ( LV ) mass and systolic wall stress . The secondary endpoint was LV ejection fraction . Severity of heart failure as determined by cardiac index , LV end-diastolic diameter , and plasma noradrenaline concentrations correlated markedly with baseline serum insulin-like growth factor-1 ( IGF-1 ) levels . Patients in the GH group had an increase in LV mass compared with the placebo group ( p = 0.0001 ) . There was no significant difference in LV systolic wall stress , mean blood pressure , or systemic vascular resistance between the two groups . New York Heart Association ( NYHA ) functional classification and distance in 6-minute walk test remained unchanged . The change in IGF-1 concentrations between GH and placebo group was notably related ( p = 0.0001 ) to the change in LV mass ( p = 0.0001 ) . The GH-induced increase of IGF-1 predicted the changes of ejection fraction ( p ejection fraction of 7 % was observed in patients whose IGF-1 increased by more than the median increase , in comparison to the patients with an increase below the median ( p = 0.03 ) . Serum levels of IGF-1 reflecting GH secretion are diminished in relation to severity of heart failure in patients with dilated cardiomyopathy . GH-induced increases of IGF-1 of more than 80 pg/mL caused notable improvement of ejection fraction . There is a marked increase in LV mass in patients with dilated cardiomyopathy given GH . Changes in LV mass are related to changes in serum IGF-1 concentrations",
"In order to compare directly the efficacy of two different angiotensin-converting enzyme ( ACE ) inhibitors in terms of clinical status and exercise capacity , 443 patients with chronic heart failure ( New York Heart Association classes II-IV ) were r and omized into a 24-week double-blind study to receive cilazapril ( CLZ ) 1 - 2.5 mg once daily ( n = 221 ) , captopril ( CPT ) 25 - 50 mg three times daily ( n = 108 ) , or placebo ( PLA ) for 12 weeks followed by CLZ 2.5 mg ( n = 114 ) in addition to their st and ard heart failure therapy . The majority were New York Heart Association functional class II ( 56 - 62 % ) , and the most frequent etiology of chronic heart failure was coronary heart disease ( 35 - 42 % ) , followed by dilative cardiomyopathy ( approximately 28 % ) . Both ACE inhibitors prolonged the exercise tolerance test duration at all visits , and the effect at week 12 ( CLZ 62.2 + /- 7.5 s ; CPT 73.1 + /- 10.7 s ) was significantly greater than after PLA ( 28.1 + /- 12.2 s ; p = 0.011 and p = 0.005 , respectively ) . Furthermore , the distance walked during 6 min increased at all visits with ACE inhibitors ( NS vs. PLA ) . CLZ was more effective in patients with the most impaired physical ability at baseline as defined by exercise tolerance test duration < or = 6 min ( p = 0.0036 at week 12 and p = 0.0150 at week 24 ) and by walking test < or = 400 m ( p = 0.0004 at week 12 and p = 0.0009 at week 24 ) . Similar results were obtained with CPT for the walking test ( p = 0.0369 at week 12 and p = 0.0142 at week 24 ) . ( ABSTRACT TRUNCATED AT 250 WORDS"
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BACKGROUND Iodine deficiency is the main cause of potentially preventable mental retardation in childhood , as well as causing goitre and hypothyroidism in people of all ages . It is still prevalent in large parts of the world . OBJECTIVES To assess the effects of iodine supplementation overall , and of different forms and dosages of iodine supplementation separately , in the prevention of iodine deficiency disorders in children . SEARCH STRATEGY The Cochrane Library , MEDLINE , EMBASE and reference lists , data bases of ongoing trials and the Internet were search ed . Date of latest search : October 2003 . SELECTION CRITERIA We included r and omised controlled trials and prospect i ve controlled trials not using r and omisation of iodine supplementation in children living in areas of iodine deficiency . DATA COLLECTION AND ANALYSIS Two review ers did the initial data selection and quality assessment of trials independently . As the studies identified were not sufficiently similar and not of sufficient quality , we did not do a meta- analysis but summarised the data in a narrative format . MAIN RESULTS Twenty-six prospect i ve controlled trials were related to our question , assessing a total of 29613 children . Twenty of them were classified as being of low quality , six of moderate quality . Most studies used iodised oil as a supplement , but other supplements were also used . The intervention groups were compared to a non-supplemented control group , different doses or different forms of iodine supplementation . There was a clear tendency towards goitre reduction with iodine supplementation ; this was significant in several studies . Significant differences in physical development were not seen , except in one study . Results for differences in cognitive and psychomotor measures were mixed , with only few studies showing a positive intervention effect . One study suggested that infant mortality was lowered after iodine supplementation . Most studies showed a significant increase in urinary iodine excretion and levels recommended by the WHO were reached in most cases after supplementation . Thyroid-stimulating hormone ( TSH ) levels were significantly reduced in one study . In 1.8 % of the children investigated , adverse effects were found , most of them were minor and transient . REVIEW ERS ' CONCLUSIONS Despite most of the included studies being of low quality , the results suggest that iodine supplementation , especially iodised oil , is an effective means of decreasing goitre rates and improving iodine status in children . Indications of positive effects on physical and mental development and mortality were seen , although results were not always significant . Adverse effects were generally minor and transient . Insufficient evidence was available on non-oil supplements . High quality controlled studies investigating relevant long term outcome measures are needed to address the question of the best form of iodine supplementation in different population groups and setting
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"Iodised oil is traditionally based on the fatty acids ( FAs ) of the poppyseed , an expensive commodity . An equipotent but cheaper vehicle would be welcome . Iodination of rapeseed oil yields a product ( Brassiodol ) with a total iodine content of 376 mg/mL. Brassiodol has been compared with the poppyseed-based Lipiodol in two villages in Chad in the west African goitre belt . A 2 mL dose of Brassiodol is followed by urinary spillover of half the ingested iodine . The other half undergoes tissue sequestration and slow release , allowing protection against iodine deficiency for 9 months and regression of stage I/II goitre for longer than was achieved with Lipiodol . The prolonged protection offered by Brassiodol can be attributed to its unique lipid profile . The urinary output argues that 1 mL should not be exceeded , and at that dose the cost would be only 20 US cents per person per year",
"To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrolment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results",
"Endemic goiter is a health problem in many areas of the world ; in some areas the disease is so severe that cretinism and other defects are found . In many areas geographic , economic , and other factors prevent the use of iodized salt as a preventive measure . Field studies were begun in 1966 to determine the feasibility and effectiveness of parenteral administration of iodized oil in goiter prevention . Studies were carried out in Ecuador and Peru . In Ecuador 2 villages were chosen in which the prevalence of goiter was about 60 % ; in Peru 3 villages were chosen where incidence was about 50 % . Prevalence of goiter decreased for 20 months during the study but then began to rise again with the maximum reduction seen up to age 18 and minimal reduction after 40 years of age . The control groups in the study experienced only slight decreases in rate of incidence . Cretinism has not yet appeared among the progeny of the population injected with iodized oil but several instances have appeared in control groups . The use of iodized oil as a public health procedure for the prevention of endemic goiter and its associated defects is an acceptable measure in regions where salt iodization can not be done",
"BACKGROUND An adequate iodine supply in utero and shortly after birth is known to be crucial to an individual 's physical and mental development . The question of whether iodine supplementation later in life can exert a favorable influence on the mental performance of iodine-deficient population s was addressed in various studies , but with contradictory results . OBJECTIVE The aim of this study was to examine the effect of an improvement in iodine status on mental and psychomotor performance of schoolchildren ( 7 - 11 y ) who were moderately to severely iodine deficient . DESIGN The study , which was originally planned as a double-blind , r and omized , placebo-controlled intervention , was carried out in an iodine-deficient population of schoolchildren ( n = 196 ) in northern Benin . As the population began to have access to iodized salt during the 1-y intervention period , the study population was split post hoc-on the basis of urinary iodine concentrations-into a group with improved iodine status and a group with unchanged iodine status . Changes in mental and psychomotor performance over the intervention period were compared . RESULTS Children with increased urinary iodine concentrations had a significantly greater increase in performance on the combination of mental tests than did the group with no change in urinary iodine concentrations . CONCLUSIONS An improvement in iodine status , rather than iodine status itself , determined mental performance in this population , which was initially iodine deficient . These findings suggest a \" catch-up \" effect in terms of mental performance",
"Iodine deficiency control programs have greatly reduced iodine deficiency disorders worldwide . For monitoring changes in iodine status , different indicators may be used . The aim of this study was to evaluate the suitability of indicators of iodine status and thyroid function , thyroglobulin ( Tg ) , thyroid-stimulating hormone ( TSH ) and free thyroxine ( FT4 ) in serum , thyroid volume and urinary iodine concentration , in iodine-deficient schoolchildren under conditions of increasing iodine supply . The study was established as a double-blind , placebo-controlled oral administration of a single dose of iodized oil to schoolchildren ( 7 - 10 y old ) , living in an iodine-deficient area of Benin , with an observation period of 10 mo . However , 3 - 4 mo after supplementation , iodized salt became available in the area . The study population therefore comprised an iodized oil-supplemented group and a nonsupplemented group , both of which had variable , uncontrolled intakes of iodized salt during the last 6 mo of the study . Initial mean serum concentrations of TSH and FT4 were within the normal range , whereas serum Tg concentration , urinary iodine concentration and thyroid volume were indicative of moderate-to-severe iodine deficiency . At the end of the study , all indicators had improved significantly , except thyroid volume , which had decreased only in the supplemented group . The supplemented group also still had significantly lower serum Tg and higher urinary iodine concentrations than the nonsupplemented group . Serum Tg and urinary iodine concentrations are the indicators most influenced by a changing iodine supply . Current normal reference ranges of serum concentrations of TSH and FT4 are too wide for detecting iodine deficiency in this age group",
"One hundred goitrous school children received 475 mg iodized oil by mouth , while 100 controls received mineral oil , on a double-blind basis . On follow-up 22 months later the urinary iodine had increased and goiter size had decreased in both groups , more strikingly in the iodine-treated children . There were no consistent differences between the two treatment groups in rate of somatic growth or performance on the Stanford-Binet and Bender tests . Because of the complexities introduced by increases in urinary iodine in the controls , we compared goiter reduction with improvement in IQ score in all children , regardless of group , and found a significant relationship ( p = 0.014 ) , particularly in girls ( p = 0.029 ) . We conclude that oral iodized oil is an attractive alternative to its injection but we recommend an approximate doubling of the dose used here for more effective control . Also , while our data are not conclusive , they support the possibility that correction of iodine deficiency may improve mental performance in school age children , particularly girls",
"Iodized salt and iodized oil are the main methods used to prevent iodine deficiency , but sometimes alternative approaches are needed . We tested the efficacy of various regimens for the intermittent administration of potassium iodide in Hwedza , Zimbabwe , an area of known severe iodine deficiency . We divided 304 schoolchildren aged 7 - 13 y into five equal groups that received iodine as a 10 % solution of potassium iodide as follows : 8.7 mg every 2 wk ( group A ) , 29.7 mg every month ( group B ) , 148.2 mg every 3 mo ( group C ) , 382 mg every 6 mo ( group D ) , or 993 mg once ( group E ) . The follow-up period was 13 mo . No adverse effects were encountered with any of these doses . After 6 mo , the median blood spot thyroglobulin concentration had decreased in all groups and had normalized in groups A and B to values found in iodine-sufficient population s. The number of children with elevated thyroid-stimulating hormone concentrations decreased in groups A-C , but the changes were not significant . Urine iodine concentration generally remained low in all groups but increased in group A. After 13 mo , mean thyroid volume measured by ultrasound had decreased in groups A and B to values comparable with those in iodine-sufficient areas , and was unchanged in the other groups . We conclude that oral potassium iodide is effective for the prophylaxis of iodine deficiency if given as a dose of 30 mg I monthly or 8 mg biweekly",
"BACKGROUND Deficiencies of iron , iodine , and vitamin A are prevalent worldwide and can affect the mental development and learning ability of schoolchildren . OBJECTIVE The aim of this study was to determine the effect of micronutrient-fortified biscuits on the micronutrient status of primary school children . DESIGN Micronutrient status was assessed in 115 children aged 6 - 11 y before and after consumption of biscuits ( fortified with iron , iodine , and beta-carotene ) for 43 wk over a 12-mo period and was compared with that in a control group ( n = 113 ) who consumed nonfortified biscuits . Cognitive function , growth , and morbidity were assessed as secondary outcomes . RESULTS There was a significant between-group treatment effect on serum retinol , serum ferritin , serum iron , transferrin saturation , and urinary iodine ( P hemoglobin and hematocrit ( P low serum retinol concentrations ( low serum ferritin concentrations ( anemia ( hemoglobin low urinary iodine concentrations ( cognitive function with the digit span forward task ( short-term memory ) . Fewer school days were missed in the intervention than in the control group because of respiratory- ( P = 0.097 ) and diarrhea-related ( P = 0.013 ) illnesses . The intervention had no effect on anthropometric status [ corrected ] . CONCLUSIONS Fortified biscuits result ed in a significant improvement in the micronutrient status of primary school children from a poor rural community and also appeared to have a favorable effect on morbidity and cognitive function [ corrected ]",
"BACKGROUND In developing countries , many children are at high risk of goiter and iron deficiency anemia . Because iron deficiency can have adverse effects on thyroid metabolism , iron deficiency may influence the response to supplemental iodine in areas of endemic goiter . OBJECTIVE The aim of this study was to determine whether goitrous children with iron deficiency anemia would respond to oral iodine supplementation . DESIGN A trial of oral iodine supplementation was carried out in an area of endemic goiter in western Côte d'Ivoire in goitrous children ( n = 109 ) aged 6 - 12 y. Group 1 ( n = 53 ) consisted of goitrous children who were not anemic . Group 2 ( n = 56 ) consisted of goitrous children who had iron deficiency anemia . At baseline , thyroid gl and volume and urinary iodine , thyrotropin , and thyroxine were measured by using ultrasound . Each child received 200 mg I orally and was observed for 30 wk , during which urinary iodine , thyrotropin , thyroxine , hemoglobin , and thyroid gl and volume were measured . RESULTS The prevalence of goiter at 30 wk was 12 % in group 1 and 64 % in group 2 . The mean percentage change from baseline in thyroid volume 30 wk after administration of oral iodine was -45.1 % in group 1 and -21.8 % in group 2 ( P thyroid volume and hemoglobin concentration ( r(2 ) = 0.65 ) . CONCLUSION The therapeutic response to oral iodine was impaired in goitrous children with iron deficiency anemia , suggesting that the presence of iron deficiency anemia in children limits the effectiveness of iodine intervention programs",
"BACKGROUND In many developing countries , children are at high risk of both goiter and iron deficiency anemia . OBJECTIVE In a series of studies in northern Morocco , we developed and tested a dual-fortified salt ( DFS ) containing iodine and microencapsulated iron . DESIGN To establish the DFS fortification concentration , we measured salt intake by 3-d weighed food records and estimated iron bioavailability from the local diet by using published algorithms . We then formulated a DFS containing 25 micro g iodine/g salt ( as potassium iodide ) and 1 mg iron/g salt ( as ferrous sulfate hydrate encapsulated with partially hydrogenated vegetable oil ) . After storage and acceptability trials , we compared the efficacy of the DFS to that of iodized salt in a 9-mo , r and omized , double-blind trial in iodine-deficient , 6 - 15-y-old children ( n = 377 ) . RESULTS Mean salt intake in school-age children was 7 - 12 g/d , and estimated iron bioavailability from the local diet was 0.4 - 4.3 % . After storage for 20 wk , the DFS and iodized salt were not significantly different in iodine content , and color stability was acceptable when the compounds were added to local meals . During the efficacy trial , urinary iodine concentrations and thyroid volumes improved significantly ( P mean hemoglobin concentrations in the DFS group had increased by 14 g/L ( P serum ferritin , transferrin receptor , and zinc protoporphyrin concentrations were significantly better ( P salt group . The prevalence of iron deficiency anemia in the DFS group decreased from 35 % at baseline to 8 % at 40 wk ( P < 0.001 ) . CONCLUSION A DFS containing iodine and encapsulated iron can be an effective fortification strategy",
"Although reports suggest that infant mortality is increased during iodine deficiency , the effect of iodine supplementation on infant mortality is unknown . A double-masked , r and omized , placebo-controlled , clinical trial of oral iodized oil was conducted in Subang , West Java , Indonesia to evaluate the effect of iodine supplementation on infant mortality . Infants were allocated to receive placebo or oral iodized oil ( 100 mg ) at about 6 wk of age and were followed to 6 mo of age . Six hundred seventeen infants were enrolled in the study . Infant survival was apparently improved , as indicated by a 72 % reduction in the risk of death during the first 2 mo of follow-up ( P mean time to death among infants who died in the iodized oil group compared with infants who died in the placebo group ( 48 days vs. 17.5 d , P = 0.06 ) . Other infant characteristics associated with reduced risk of death included weight-for-age at base line , consumption of solid foods , female gender and recent history of maternal iodine supplementation . Oral iodized oil supplementation had a stronger effect on the mortality of males compared with females . This study suggests that oral iodized oil supplementation of infants may reduce infant mortality in population s at risk for iodine deficiency",
"Objective : Elevated hearing thresholds have been demonstrated in population s afflicted by endemic cretinism as a result of severe iodine deficiency . However , data on the effects of less severe iodine deficiency on hearing thresholds in apparently normal children are scant . This study addresses the question whether there is a relationship among iodine variables , hearing and mental performance in a mildly iodine-deficient population . Design : A r and omized , placebo-controlled intervention trial with an observation period of 11 months . Setting : An iodine-deficient area in northern Benin . Subjects : A total of 197 school children , aged 7–11 y. Interventions : A total of 97 children received an oral dose of iodized oil , containing 540 mg I , while 100 children received a placebo . About 3–4 months after supplementation , the whole population began to have access to iodized salt . Non-verbal mental tests were administered and biochemical indicators ( thyrotropin , free thyroxine , thyroglobulin and urinary iodine ) were measured at the beginning and the end of the study . Hearing was measured at the end of the study in both ears by pure-tone audiometry at seven frequencies . Results : In this mildly iodine-deficient child population children with higher serum thyroglobulin concentrations had significantly higher hearing thresholds in the higher frequency range ( ≥2000 Hz ) than children with lower serum thyroglobulin concentration . Moreover children with lower hearing thresholds performed significantly better on the mental tests used . Conclusions : Even when iodine deficiency is ‘ mild ’ , promotion of adequate iodine intake through salt iodization programs and other means remains crucial . Sponsorship : Nestlé Foundation , Lausanne , Switzerl and ; Wageningen University , Wageningen , The Netherl and s . European Journal of Clinical Nutrition ( 2001 ) 55 ,",
"OBJECTIVE The purpose of this trial was to compare three different iodine interventions . DESIGN School children aged 8 - 10 years were r and omized into one of three groups : group A was provided with iodized salt by research ers with an iodine concentration of 25 ppm ; group B purchased iodized salt from the market ; and group C was similar to group B with the exception that they were given iodized oil capsules containing 400 mg iodine at the beginning of the study . Salt iodine content was measured bimonthly for 18 months and indicators of iodine deficiency were measured at baseline and 6 , 9 , 12 and 18 months after r and omization . RESULTS The prevalence of abnormal thyroid volumes , based on the World Health Organization ( WHO ) body surface area reference > 97th percentile , was 18 % at baseline and declined to less than 5 % by 12 months in groups A and C , and to 9 % after 18 months in group B. Results for goitre by palpation were similar . The median urinary iodine was 94 microg l(-1 ) at baseline and increased in all groups to > 200 microg l(-1 ) at the 6-month follow-up . CONCLUSIONS In this population of school children with initially a low to moderate level of iodine deficiency , the group receiving salt with 25 ppm ( group A ) was not iodine deficient on all indicators after 18 months of study . When the iodine content of the salt varied , such as in group B , by 18 months thyroid sizes had not yet achieved normal status",
"Summary The spontaneous development of thyroid gl and volume ( TGV ) during the first 3 months of life was studied in entirely breast-fed infants ( n = 21 ) and compared to those fed an iodine-supplemented formula ( n = 19 ) , an iodine-free formula ( n = 5 ) , or partially breast-fed in addition to an iodine-free ( n = 4 ) or an iodine-supplemented formula ( n = 16 ) . The TGV of the infants and their mothers was determined sonographically in addition to their urinary iodine concentrations 57 days postpartum and 3 months later . In ten additional lactating mothers the breast milk concentrations of thyroid hormones and iodine were determined . It was shown that at 3 months of age an infant consuming about 1000 ml breast milk per day receives about 2 μg thyroid hormones and 55 μg iodine per day . At the end of their first week of life the infants showed a TGV between 0.28 and 1.5 ml ( median 0.61 ml ) and a urinary iodine concentration between 0.03 and 16.3 μg/dl ( median 3.0 μg/dl ) . At 3 months of age the TGV of the breast-fed infants had decreased by a median of 0.24 ml (= −34 % ; median of percentage changes ) whereas those fed a formula without iodine had increased by a median of 0.26 ml (= + 50 % ; median of percentage changes ) . Those receiving an iodine-supplemented formula showed a TGV reduction of 0.14 ml (= + 2 % ; median of percentage changes ) . The TGV development of the partially breast-fed infants lay between those being exclusively breast or formula fed . It is concluded that with respect to the development of TGV , breast milk is superior even to the feeding of an iodine-supplemented formula",
"The reversibility of thyroid dysfunction in children with endemic cretinism treated with supplemental iodine is unknown . To study this question we conducted a five-month follow-up of 51 patients with cretinism ( age 14 and below ) , who were r and omly assigned to treatment ( 0.5 ml of intramuscular iodized oil ) and control groups . The geometric mean initial serum level of thyrotropin ( 223 microU per milliliter ; SD , 97 to 513 ) and the mean ( + /- SD ) initial serum level of thyroxine ( 1.0 + /- 1.2 micrograms per deciliter ) indicated that all patients had severe hypothyroidism . Within one month after receiving the iodized oil , 13 of 14 of the younger patients ( less than 4 years ) and 1 of 9 of the older patients ( 4 to 14 years ; P less than 0.001 ) had thyrotropin values below 20 microU per milliliter . Five months after treatment , the levels of thyrotropin had decreased and those of thyroxine had increased in all children , but greater changes occurred in the 13 younger patients than in the 14 older patients . The mean levels of thyrotropin were 2 microU per milliliter ( SD , 0.6 to 6 ) vs. 38 microU per milliliter ( SD , 11 to 132 ; P less than 0.001 ) , and the mean ( + /- SD ) levels of thyroxine were 13.1 + /- 2.8 vs. 8.1 + /- 4.6 micrograms per deciliter ( P less than 0.001 ) . In the untreated group , 3 of the 9 younger patients and none of the 15 older patients recovered normal thyroid function within five months . We conclude that iodine supplementation restored a biochemically euthyroid state in all younger children with cretinism but only some of the older children . In addition , some younger patients became euthyroid without iodine supplementation",
"The prevention of iodine deficiency is still a worldwide concern . This study , conducted in Soja in western Sudan , was carried out to evaluate the effects of a dose of iodized oil sufficient enough to give maximum protection against goiter and provide an acceptable iodine supply without side-effects over a sufficiently long period of time . Adult goitrous subjects ( n = 117 ) were r and omly assigned to three groups , A , B , and C , and received a single oral dose of 200 , 400 , or 800 mg iodine , respectively . Urine and blood sample s were collected at the start of the study and monitored for 1 yr . In the 3 groups , mean serum T4 and median urinary iodine and serum TSH values were restored to reference limits , and these were maintained for about 1 yr . In each treatment group , about two thirds of the subjects displayed a reduction in goiter size , and the 400- and 800-mg doses were not more efficient than the 200-mg dose to accomplish normalization of thyroid hormone values . A temporary rise in TSH was noted 1 week after iodine administration in 1 , 3 , and 10 subjects , respectively , and 1 , 0 , and 3 subjects showed biochemical signs of thyrotoxicosis during the year after treatment with the 3 different doses . The data indicate that oral administration of 200 mg iodine is effective and acceptable for treating iodine deficiency in adults for 1 yr . Because of the risks of side-effects and the shortage of medical re sources , higher doses are not recommended",
"In order to reduce the prevalence of goiter in a village of Mali liable to iodine deficiency , an iodized product ( Lipiodol ® Ultra Fluide ) was orally administered to their inhabitants . Taking into account a series of demographic variables and goiter types , a protocol was conducted using Lipiodol at three different dosage levels . Six months after the treatment , the hormone levels regained normal values , whereas only the smallest dose reduces the volume of goiters significantly",
"In Central Africa , all of northern Zaire is very severely deficient in iodine . A peculiar feature of this endemia is that iodine deficiency and the ensuing thyroid gl and stimulation not only leads to goitre formation but also to progressive thyroid involution and to myxoedematous cretinism . An iodine supplementation trial based on oral administration of small doses of iodine was made in 81 schoolchildren . All of them received a small dose of iodine ( 0.1 ml containing 48 mg ) per os and the thyroid status was followed during 4 months . Blood and urine sample s were collected at the start of the study , then 2 weeks , 2 months and 4 months after iodine administration . Before iodine supplementation the mean urinary iodine level was 0.18 + /- 0.02 micromol/l , and 10 % of the subjects had a urinary iodine level below 0.08 micromol/l . Fifty-two percent of the subjects had a serum thyrotropin ( TSH ) level above 10 mU/l . All the subjects responded to the administration of iodine . and all of them recovered a euthyroid status . Most of them were still euthyroid at the end of the study . However . within 4 or even 2 months , some subjects ( 15 % of the total ) reverted to hypothyroidism . At the entry of the study these subjects were all hypothyroid and had elevated TSH and paradoxically low serum thyroglobulin ( TG ) values . In myxoedematous cretins living in the same area , even lower serum TG levels were found . Together with the absence of goitre , a paradoxically low serum TG Suggests a low thyroid reserve , and in the present case a reduced amount of functional thyroid tissue . We show that the serum TG/TSH ratio may be used as a predictive index of thyroid reserve and of positive response to iodine administration . These data further suggest that thyroid damage is not confined to myxoedematous cretins . but is widely distributed in the phenotypically normal population . Widely distributed thyroid damage may render iodine prophylaxis based on oral administration unpredictable",
"BACKGROUND About one billion people worldwide are at risk for iodine deficiency . Despite existing programs of prophylaxis , the prevention of iodine deficiency is still a challenge throughout the developing world . We studied the efficacy of low doses of iodized oil in an area of severe iodine deficiency in Zaire . METHODS Seventy-five subjects with visible goiter were r and omly assigned to receive a single oral dose of placebo or either 0.1 or 0.25 ml of iodized oil , corresponding to 0 , 47 , and 118 mg of iodine , respectively . The mean ages of the subjects in the three groups were 23 , 22 , and 22 years , respectively , and the ratios of males to females were 0.25 , 0.32 , and 0.19 . Efficacy was assessed by evaluating goiter size and measuring urinary iodine and serum thyroid hormone concentrations for 12 months . RESULTS Goiter size decreased in most of the subjects who received either dose of iodized oil . Their urinary iodine concentrations were normal for six to nine months and their serum thyroxine and thyrotropin concentrations were nearly all normal throughout the study period . There were no side effects , even in subjects whose serum thyroxine concentrations had initially been low . In the placebo group , neither goiter size nor any of the biochemical values changed . CONCLUSIONS The oral administration of a single small dose of iodized oil is capable of correcting iodine deficiency for about a year . This method of supplementation is likely to be more effective , efficient , and acceptable than the administration of either intramuscular or large oral doses of iodized oil",
"OBJECTIVES To find how the urinary parameters of iodine excretion evolved in a community with deficiencies , after administering iodine orally and IM in two provinces in Burkina Faso ; to recommend a national strategy to tackle iodine deficits . Design . A longitudinal survey before and after the iodine was given ( 12 months ) . Descriptive analysis of the data . SETTING Provinces of Namentenga and Passoré in Burkina Faso . PARTICIPANTS The general population of the two provinces who satisfied age-sex criteria : males from 0 to 25 , females from 0 - 45 . R and omised two-stage sampling . 423 people in all took part ( 210 in Namentenga and 213 in Passoré ) . INTERVENTIONS The administration of 1 ml of iodised oil ( Lipiodol ) orally in Namentenga and IM in Passoré . MEASUREMENTS AND MAIN RESULTS The urinary parameters of micrograms of iodine per gr . of Creatinine , and micrograms of iodine per dl of urine , were used . Figures for normalisation of the urinary parameters 12 months after iodisation was significantly higher in Passoré province , where iodine was administered IM . CONCLUSIONS The intramuscular pathway has more longlasting effects , but the characteristics of Burkina Faso 's health system and the feasibility of a medium or long-term intervention make it advisable that iodine supplements be administered orally",
"OBJECTIVE To compare the effects of three different iodine interventions on the speed of normalization of enlarged thyroid gl and . METHODS Schoolchildren aged 8 - 10 years were r and omized divided into one of three groups : group A was given iodized salt by research ers with an iodine concentration of 25 mg/kg ; group B used iodized salt purchased from the market ; and group C was similar to group B with additional intake of iodized oil capsules containing 400 mg iodine at the beginning of the study . Salt iodine content was measured bimonthly for 18 months and indicators of iodine deficiency were measured at baseline and 6 , 9 , 12 and 18 months thereafter . RESULTS The prevalence of goiter measured by ultrasound , based on the World Health Organization ( WHO ) body surface area reference > 97(th ) percentile , was 18 % at baseline and declined to less than 5 % by 12 month in groups A and C respectively , and to 9 % after 18 months in group B. Rates of goiter were similar by palpation or by ultrasound . The median urinary iodine was 94 micro g/L at baseline and increased in all groups to > 200 micro g/L at the 6-month follow-up . CONCLUSIONS In this sample of schoolchildren with initially low or moderate level of iodine deficiency , the group receiving salt with 25 mg/kg ( group A ) recovered from iodine deficient on all indicators after 18 months of study . However when the iodine content of salt was floating , as seen in group B , the sizes of thyroid did not yet achieve normal status by 18 months",
" Three And ean villages at altitudes of 3,100 to 3,500 meters above sea level were studied in order to determine the prophylac— ' tic effect of iodized oil administration on endemic goiter \\ and cretinism ( 1 ) . At the time of the study the population in | these villages was approximately 4,000 , with an annual growth ' rate of about three percent . In a group of 3,000 subjects i examined in a house-to-house survey , the visible goiter rate , : as defined in an accompanying paper ( 2 ) , was 55 percent . However , ? when the cccurrence of palpable goiter was considered as well , | the incidence of goiter rose to 83 percent . Fifty percent of * the children in the 0 - 5 yr age group were goitrous and of these , | 20 percent demonstrated visible goiter . Goiter prevalence l increased with age , as did nodularity . An example of this is ‘ shown in Fig. 1 . In some families every member was found with ii goiter as illustrated in Fig. 2 . Goiter was also found among 4 the domestic animals . The percentage of defective persons in the i three villages ranged from 1.0 to 3.6 percent . Although these _ . x villages are accessible by automobile , they are still quite remote * , and isolated",
"This report incorporates the results of an investigation design ed to test the effectiveness of potassium iodide and potassium io date in the control of Himalayan endemic goitre when these compounds are added in small physiological doses to the domestic salt habitually consumed by the people in the endemic belt . In a prospect i ve study lasting five years , a striking reduction in the prevalence of goitre was observed in areas receiving salt fortified with either potassium iodide or potassium io date . During the same period , goitre prevalence remained unchanged in the control zone , which received plain , unfortified salt . The study has an important bearing on the problem of goitre control in developing countries that use moist , coarsely crystalline salt",
"A controlled trial of iodine supplementation comparing oral with intramuscular iodized oil has been carried out in an iodine deficient area of Zaire . Two years after the administration of 2 ml of oral iodized oil to the population of four villages the overall goitre prevalence had fallen from 64 to 54 % . In a further two villages given 2 ml of intramuscular oil the prevalence fell from 65 to 50 % . The effectiveness of supplementation was also assessed by measuring changes in thyroid function in women of reproductive age . Among women in the villages given oral iodized oil , the geometric mean thyroxine concentration , measured in dried bloodspots , rose from 27.2 to 52.6 nmol/L at the two-year follow-up . This was similar to the response of the intramuscularly treated villages in which thyroxine levels rose from 32.1 to 65.4 nmol/L. There was no change in goitre prevalence or thyroid function in two control villages . Oral iodized oil is a cheaper and simpler alternative to the injected form providing effective iodine prophylaxis for up to two years after a single dose",
"BACKGROUND Low levels of circulating thyroid hormones have been associated with poorer general and neurodevelopmental outcome in preterm babies and it has been speculated that the association is causal . Low levels of circulating thyroid hormone have been reported after inadequate intake of iodine in preterm infants being fed milk formula . AIM To investigate whether increased iodine intake from supplemented preterm formula would improve thyroid hormone levels in preterm babies ( this study ) and hence improve neurodevelopmental status ( planned subsequent study ) . METHOD A total of 121 preterm infants were entered into a r and omised controlled trial of st and ard ( 68 μg/l ) versus increased ( 272 μg/l ) iodine in preterm formula . RESULTS The two groups were comparable at recruitment . No evidence of an effect of the intervention on thyroid hormone levels was seen up to 41 weeks after conception . CONCLUSION Calls for increased iodine content of preterm infant formulas are not justified by this study . Key message Increasing milk iodine content in line with the latest recommendations for preterm babies had no effect on thyroid hormone levels in the perinatal",
"A community-based controlled trial of iodine supplementation comparing oral or intramuscular iodized oil with oral potassium iodide has been carried out in 23 severely iodine-deficient villages in Eastern Zaire . The overall goitre prevalence in the population ( n = 5999 ) was 61 % and mean urinary iodine excretion in sample of 57 women 10.9 ( SD 6.8 ) micrograms/g creatinine . All adults in three groups of four villages were given single doses of potassium iodide of 0.5 g , 1.0 g , and 2.0 g respectively . A fourth group was given oral iodized oil ( 2 ml ) and a fifth placebo-treated . A further three villages were given intramuscular iodized oil ( 2 ml ) . The effectiveness of supplementation was assessed by measurements of bloodspot thyroxine ( T4 ) concentration in women of reproductive age in the villages . The effects of iodide were small and inconsistent . Eight months after supplementation with oral iodized oil the distribution of T4 concentrations was similar to that seen with intramuscular oil . We conclude that oral iodized oil is an effective alternative to injected oil and would be feasible for iodine supplementation in remote areas with untrained people",
"The effect of anthropometric status on the efficacy of an oral supplement of iodised oil ( 1 ml Lipiodol Ultrafluide , 490 mg I ; Laboratoire Guerbet , Aulnay-sous-Bois , France ) was examined in 8 - 10-year-old schoolchildren ( n 197 ) of Ntcheu , a severely I-deficient district of Malawi . The study was a controlled trial using the I concentration of casual urine sample s to monitor the I status . The median urinary I concentration increased from 0.15 micromol/l at baseline ( 51.3 % of children total goitre prevalence fell from 63 % to 21 % . Variables of efficacy were estimated from a hyperbolic function describing the longitudinal pattern of urinary I excretion after the dose . The I retention and I elimination rate , and the periods of protection from mild ( deficiency were obtained for groups of children with differing anthropometric status at baseline . Initial height-for-age and mid upper-arm circumference were not significantly related to efficacy . However , both the I retention and I elimination rate were reduced in children with lower initial weight-for-height . Children with lower skinfold thickness at baseline also had reduced I retention , which result ed in shorter protection periods from recurrent moderate and mild I deficiency . The efficacy of the oral iodised-oil supplement was not related to changes in anthropometric status during follow-up , nor was it related to the consumption of a food supplement of 1610 kJ immediately before the iodised-oil dose . Very low ( urinary I concentration , and the presence of goitre at baseline were both associated with higher I retention and elimination rate . Children with goitre at baseline were found to have a prolonged duration of protection against recurrent moderate I deficiency . We conclude that in apparently healthy schoolchildren in I-deficient areas , general anthropometric status has a little influence on the efficacy of oral iodised oil for correcting I deficiency",
"Iodine ( I ) is essential for normal thyroid function , and the majority of subjects tolerate a wide range of dietary levels . However , a subset of individuals upon exposure to normal or elevated levels of I develop thyroid dysfunction and autoimmunity . In this double blind trial , we evaluated efficacy and tolerability of low dose I in adults with euthyroid , diffuse , endemic goiter . Sixty-two subjects were r and omly assigned I ( 0.2 mg/day ) or placebo for 12 months . After termination of therapy , both groups were followed for a further 6 months . Thyroid sonography and determinations of thyroid-related hormones , urinary I excretion per 24 h , and thyroid antibodies were carried out at baseline and at 3 , 6 , 9 , 12 , 15 , and 18 months . Markedly elevated urinary I values were found during therapy in subjects receiving I ( 32 at baseline vs. 213 micrograms/24 h at 12 months ; P = 0.0001 ) compared to placebo ( 34 and 33 micrograms/24 h , respectively ; P thyroid volume ( 29 vs. 18 mL at 12 months ; -38 % ; P = 0.0001 ) , and at 18 months , the therapeutic effect was sustained . In the placebo group , no significant changes were observed . High microsomal and thyroglobulin autoantibody titers were present in 3 of 31 ( 9.7 % ) subjects receiving I , and I-induced hypo- and hyperthyroidism developed in 2 and 1 , respectively . Fine needle biopsy revealed marked lymphocytic infiltration in all 3 cases . After withdrawal of I , thyroid dysfunctions spontaneously remitted , and antibody titers as well as lymphocytic infiltration decreased markedly . Follow-up of these 3 subjects for an additional 2 yr showed normalization of antibody titers in 2 . Thus , among subjects with endemic goiter , low dose I successfully normalized thyroid volume and body I supplementation ; nevertheless , reversible I-induced thyroid dysfunctions and autoimmunity were observed in nearly 10 % of the subjects",
"The availability of iodinated salt containing 20 mg of iodine as io date /kg salt consumed on a voluntary basis enabled us to investigate its effect on goitre prevalence and iodine excretion in urine in a longitudinal , prospect i ve , r and omized study over 4 years . With this salt , under the assumption of a consumption of 5 g salt per day and person , an additional intake of 100 micrograms of iodine can be achieved . The study was performed on initially 334 children ( 168 boys , 166 girls ) at the age of 10 years living in an area of iodine deficiency . After 4 years , 286 children still participated in the study . Initially , goitre prevalence as assessed by palpation was found to be 30.5 % ( 37.4 % in girls and 23.8 % in boys ) . Neck circumference was found to be significantly higher in children with goitre compared with those without ( 30.2 + /- 1.4 vs 29.4 + /- 1.4 cm ; P less than 0.001 ) . Iodine excretion in the urine was significantly lower in children with goitre compared with those without ( 40.4 + /- 16.7 micrograms/g creatinine vs 46.1 + /- 24.9 micrograms/g creatinine ; x + /- SD ; P less than 0.05 ) . The children were r and omly assigned to two different groups : group A ( N = 146 ) was asked to use iodinated salt , group B ( N = 188 ) non-iodinated salt . Over the 4 years , a continuous increase in iodine excretion in urine could be demonstrated in group A. ( ABSTRACT TRUNCATED AT 250 WORDS",
"The effect of oral iodine supplementation on total goitre rate ( % TGR ) and urinary iodine excretion among school children 4 to 16 years of age was studied . In the first group ( n = 57 ) 200 mg oral iodized oil reduced % TGR from 31.6 % to 17.5 % and 33.3 % to 24.6 % in males and females respectively , while in the second group ( n = 53 ) , 400 mg iodine reduced the % TGR from 34.0 % to 20.8 % in males and 35.9 % to 24.5 % in females after 13 months of intervention . This gave a relative indication that the 200 mg is as effective as the 400 mg in goitre reduction . In subsequent tests , the maximum urinary iodine excretion was obtained from the groups which received two doses of iodized oil 24 hours after the intervention . A significant ( p = 0.003 ) greater increase in urinary iodine excretion was noted at 24 hours among both male and female children administered 400 mg than among those who received 200 mg . Measurements after 24 hours showed no significant difference between urinary iodine excretion of the two dose groups . These results suggest that : ( i ) 200 mg is likely equally effective as 400 mg for iodine deficiency disorders control and prevention among children and ( ii ) iodine could be administered annually rather than biannually",
"Objective : To evaluate the long-term efficacy and possible side effects of low doses of iodized oil on iodine nutrition and thyroid function in endemic goiter in Romania . Methods : R and om selection of 214 schoolchildren aged 6–14 years . Serial measurements of urinary iodine , thyroid volume with ultrasound , serum concentrations of thyrotropin , free thyroxine , thyroglobulin and thyroid autoantibodies before and up to 2 years after the oral administration of 200 mg iodine in iodized oil . Results : Urinary iodine concentrations indicated a moderate iodine deficiency before therapy , sharply increased soon after therapy and slowly decreased thereafter but remained within the normal range up to more than 1 year after therapy . The prevalence of goiter was 29 % before the administration of iodized oil and 9 % 1 year later . Thyroid function tests and autoantibodies were normal before and up to 2 years after therapy . Conclusion : A single dose of 200 mg iodine from oral Lipiodol ® appears adequate and safe for correcting moderate iodine deficiency in children"
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Background Research waste can occur when trials are conducted in the wrong population s. Vitamin D deficient population s are most likely to benefit from vitamin D supplementation . We investigated waste attributable to r and omised controlled trials ( RCTs ) of supplementation in population s that were not vitamin D deficient . Methods In December 2015 , we search ed Pubmed , recent systematic review s , and three trial registries for RCTs of vitamin D with clinical endpoints in adults , and 25-hydroxvitamin D ( 25OHD ) survey data relevant to large ( N ≥ 1000 ) RCTs . We investigated the proportion of RCTs that studied vitamin D deficient population s , temporal trends in baseline 25OHD , and whether investigators in large RCTs considered relevant 25OHD survey data or systematic review s in their trial justifications . Results Of 137 RCTs of vitamin D with clinical endpoints , 118 ( 86 % ) reported baseline mean/median 25OHD , which was in 12 ( 10 % ) , 62 ( 53 % ) , 36 ( 31 % ) , and 8 ( 7 % ) RCTs , respectively . In 70 % of RCTs , baseline 25OHD was > 40 nmol/L. Baseline 25OHD increased over time . Before 2006 , 38 % , 62 % , 0 % and 0 % of RCTs had baseline 25OHD with baseline 25OHD vitamin D deficient population , 3 in vitamin D insufficient population s , and 17 had , or probably will have , baseline 25OHD > 40 nmol/L. 44 % ( 8/18 ) of large completed RCTs cited relevant prior population 25OHD data , and only 3/10 ( 30 % ) relevant prior systematic review s. Conclusions Up to 70 % of RCTs of vitamin D with clinical endpoints , 71 % of large completed RCTs , and 100 % of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient
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"Vitamin D insufficiency and low calcium intake contribute to increase parathyroid function and bone fragility in elderly people . Calcium and vitamin D supplements can reverse secondary hyperparathyroidism thus preventing hip fractures , as proved by Decalyos I. Decalyos II is a 2-year , multicenter , r and omized , double-masked , placebo-controlled confirmatory study . The intention-to-treat population consisted of 583 ambulatory institutionalized women ( mean age 85.2 years , SD = 7.1 ) r and omized to the calcium – vitamin D3 fixed combination group ( n= 199 ) ; the calcium plus vitamin D3 separate combination group ( n= 190 ) and the placebo group ( n= 194 ) . Fixed and separate combination groups received the same daily amount of calcium ( 1200 mg ) and vitamin D3 ( 800 IU ) , which had similar pharmacodynamic effects . Both types of calcium-vitamin D3 regimens increased serum 25-hydroxyvitamin D and decreased serum intact parathyroid hormone to a similar extent , with levels returning within the normal range after 6 months . In a subgroup of 114 patients , femoral neck bone mineral density ( BMD ) decreased in the placebo group ( mean = –2.36 % per year , SD = 4.92 ) , while remaining unchanged in women treated with calcium-vitamin D3 ( mean = 0.29 % per year , SD = 8.63 ) . The difference between the two groups was 2.65 % ( 95 % CI = –0.44 , 5.75 % ) with a trend in favor of the active treatment group . No significant difference between groups was found for changes in distal radius BMD and quantitative ultrasonic parameters at the os calcis . The relative risk ( RR ) of HF in the placebo group compared with the active treatment group was 1.69 ( 95 % CI = 0.96 , 3.0 ) , which is similar to that found in Decalyos I ( RR = 1.7 ; 95 % CI = 1.0 , 2.8 ) . Thus , these data are in agreement with those of Decalyos I and indicate that calcium and vitamin D3 in combination reverse senile secondary hyperparathyroidism and reduce both hip bone loss and the risk of hip fracture in elderly institutionalized women",
"RATIONALE Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis . OBJECTIVES To test whether vitamin D supplementation of patients with tuberculosis ( TB ) improved clinical outcome and reduced mortality . METHODS We conducted a r and omized , double-blind , placebo-controlled trial in TB clinics at a demographic surveillance site in Guinea-Bissau . We included 365 adult patients with TB starting antituberculosis treatment ; 281 completed the 12-month follow-up . The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment . MEASUREMENTS AND MAIN RESULTS The primary outcome was reduction in a clinical severity score ( TBscore ) for all patients with pulmonary TB . The secondary outcome was 12-month mortality . No serious adverse effects were reported ; mild hypercalcemia was rare and present in both arms . Reduction in TBscore and sputum smear conversion rates did not differ among patients treated with vitamin D or placebo . Overall mortality was 15 % ( 54 of 365 ) at 1 year of follow-up and similar in both arms ( 30 of 187 for vitamin D treated and 24 of 178 for placebo ; relative risk , 1.19 [ 0.58 - 1.95 ] ) . HIV infection was seen in 36 % ( 131 of 359 ) : 21 % ( 76 of 359 ) HIV-1 , 10 % ( 36 of 359 ) HIV-2 , and 5 % ( 19 of 357 ) HIV-1 + 2 . CONCLUSIONS Vitamin D does not improve clinical outcome among patients with TB and the trial showed no overall effect on mortality in patients with TB ; it is possible that the dose used was insufficient . Clinical trial registered with www.controlled-trials.com/is rct n ( IS RCT N35212132 )",
"BACKGROUND Low serum 25-hydroxyvitamin D ( 25-[OH]D ) levels have been associated with lower FEV(1 ) , impaired immunologic control , and increased airway inflammation . Because many patients with chronic obstructive pulmonary disease ( COPD ) have vitamin D deficiency , effects of vitamin D supplementation may extend beyond preventing osteoporosis . OBJECTIVE To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations . DESIGN R and omized , single-center , double-blind , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00666367 ) SETTING University Hospitals Leuven , Leuven , Belgium . PATIENTS 182 patients with moderate to very severe COPD and a history of recent exacerbations . INTERVENTION 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year . MEASUREMENTS The primary outcome was time to first exacerbation . Secondary outcomes were exacerbation rate , time to first hospitalization , time to second exacerbation , FEV(1 ) , quality of life , and death . RESULTS Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group ( mean between-group difference , 30 ng/mL [ 95 % CI , 27 to 33 ng/mL ] ; P median time to first exacerbation did not significantly differ between the groups ( hazard ratio , 1.1 [ CI , 0.82 to 1.56 ] ; P = 0.41 ) , nor did exacerbation rates , FEV(1 ) , hospitalization , quality of life , and death . However , a post hoc analysis in 30 participants with severe vitamin D deficiency ( serum 25-[OH]D levels exacerbations in the vitamin D group ( rate ratio , 0.57 [ CI , 0.33 to 0.98 ] ; P = 0.042 ) . LIMITATION This was a single-center study with a small sample size . CONCLUSION High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations . In participants with severe vitamin D deficiency at baseline , supplementation may reduce exacerbations . PRIMARY FUNDING SOURCE Applied Biomedical Research Program , Agency for Innovation by Science and Technology ( IWT-TBM )",
"Importance Cohort studies have reported increased incidence of cardiovascular disease ( CVD ) among individuals with low vitamin D status . To date , r and omized clinical trials of vitamin D supplementation have not found an effect , possibly because of using too low a dose of vitamin D. Objective To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population . Design , Setting , and Participants The Vitamin D Assessment Study is a r and omized , double-blind , placebo-controlled trial that recruited participants mostly from family practice s in Auckl and , New Zeal and , from April 5 , 2011 , through November 6 , 2012 , with follow-up until July 2015 . Participants were community-resident adults aged 50 to 84 years . Of 47 905 adults invited from family practice s and 163 from community groups , 5110 participants were r and omized to receive vitamin D3 ( n = 2558 ) or placebo ( n = 2552 ) . Two participants retracted consent , and all others ( n = 5108 ) were included in the primary analysis . Interventions Oral vitamin D3 in an initial dose of 200 000 IU , followed a month later by monthly doses of 100 000 IU , or placebo for a median of 3.3 years ( range , 2.5 - 4.2 years ) . Main Outcomes and Measures The primary outcome was the number of participants with incident CVD and death , including a prespecified subgroup analysis in participants with vitamin D deficiency ( baseline deseasonalized 25-hydroxyvitamin D [ 25(OH)D ] levels myocardial infa rct ion , angina , heart failure , hypertension , arrhythmias , arteriosclerosis , stroke , and venous thrombosis . Results Of the 5108 participants included in the analysis , the mean ( SD ) age was 65.9 ( 8.3 ) years , 2969 ( 58.1 % ) were male , and 4253 ( 83.3 % ) were of European or other ethnicity , with the remainder being Polynesian or South Asian . Mean ( SD ) baseline deseasonalized 25(OH)D concentration was 26.5 ( 9.0 ) ng/mL , with 1270 participants ( 24.9 % ) being vitamin D deficient . In a r and om sample of 438 participants , the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group . The primary outcome of CVD occurred in 303 participants ( 11.8 % ) in the vitamin D group and 293 participants ( 11.5 % ) in the placebo group , yielding an adjusted hazard ratio of 1.02 ( 95 % CI , 0.87 - 1.20 ) . Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes . Conclusions and Relevance Monthly high-dose vitamin D supplementation does not prevent CVD . This result does not support the use of monthly vitamin D supplementation for this purpose . The effects of daily or weekly dosing require further study . Trial Registration clinical trials.gov Identifier :",
"Introduction Osteoporotic fractures in older people are a major and increasing public health problem . We examined the effect of vitamin D supplementation on fracture rate in people living in sheltered accommodation . Methods In a pragmatic double blind r and omised controlled trial of 3 years duration , we examined 3,440 people ( 2,624 women and 816 men ) living in residential or care home . We used four-monthly oral supplementation using 100,000 IU vitamin D2 ( ergocalciferol ) . As a main outcome measure , we used the incidence of first fracture using an intention to treat analysis . This was a multicentre study in 314 care homes or sheltered accommodation complexes in South Wales , UK . Results The vitamin D and placebo groups had similar baseline characteristics . In intention-to-treat analysis , 205 first fractures occurred in the intervention group during a total of 2,846 person years of follow-up ( 7 fractures per 100 people per year of follow-up ) , with 218 first fractures in the control group over 2,860 person years of follow-up . The hazard ratio of 0.95 ( 95 % confidence interval 0.79–1.15 ) for intervention compared to control was not statistically significant . ConclusionS upplementation with four-monthly 100,000 IU of oral vitamin D2 is not sufficient to affect fracture incidence among older people living in institutional care",
"BACKGROUND Maternal vitamin D status has been associated with bone mass of offspring in many , but not all , observational studies . However , maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a r and omised controlled trial . We aim ed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content ( BMC ) at birth than those of mothers who had not received supplementation . METHODS The Maternal Vitamin D Osteoporosis Study ( MAVIDOS ) was a multicentre , double-blind , r and omised , placebo-controlled trial that recruited pregnant women from three study sites in the UK ( Southampton , Oxford , and Sheffield ) . Eligible participants were older than 18 years , with a singleton pregnancy , gestation of less than 17 weeks , and a serum 25-hydroxyvitamin D ( 25[OH]D ) concentration of 25 - 100 nmol/L at 10 - 17 weeks ' gestation . P'articipants were r and omly assigned ( 1:1 ) , in r and omly permuted blocks of ten , to either cholecalciferol 1000 IU/day or matched placebo , taken orally , from 14 weeks ' gestation ( or as soon as possible before 17 weeks ' gestation if recruited later ) until delivery . Participants and the research team were masked to treatment allocation . The primary outcome was neonatal whole-body BMC , assessed within 2 weeks of birth by dual-energy x-ray absorptiometry ( DXA ) , analysed in all r and omly assigned neonates who had a usable DXA scan . Safety outcomes were assessed in all r and omly assigned participants . This trial is registered with the International St and ard R and omised Controlled Trial registry , IS RCT N 82927713 , and the European Clinical Trials Data base , EudraCT 2007 - 001716 - 23 . FINDINGS Between Oct 10 , 2008 , and Feb 11 , 2014 , we r and omly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day . 370 ( 65 % ) neonates in the placebo group and 367 ( 65 % ) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint . Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo ( 61·6 g [ 95 % CI 60·3 - 62·8 ] vs 60·5 g [ 59·3 - 61·7 ] , respectively ; p=0·21 ) . We noted no significant differences in safety outcomes , apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group ( 96 [ 17 % ] of 569 mothers in the placebo group vs 65 [ 12 % ] of 565 mothers in the cholecalciferol group ; p=0·01 ) . No adverse events were deemed to be treatment related . INTERPRETATION Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo , but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete , and it is safe . These findings support current approaches to vitamin D supplementation in pregnancy . Results of the ongoing MAVIDOS childhood follow-up study are awaited . FUNDING Arthritis Research UK , Medical Research Council , Bupa Foundation , and National Institute for Health Research",
"UNLABELLED This study of 9605 community-dwelling residents supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in elderly in a northern European region known to be deficient in vitamin D , especially during winter periods . INTRODUCTION We evaluated the effect of two programs for the prevention of osteoporotic fractures leading to acute hospital admission in a population of elderly community-dwelling residents . MATERIAL S AND METHODS This was a factorial , cluster-r and omized , pragmatic , intervention study . We included 9605 community-dwelling residents aged 66 + years . We offered a prevention program of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU ( 10 microg ) of vitamin D3 to a total of 4957 participants . Another program with evaluation and suggestions for the improvement of the domestic environment was offered to a total of 5063 participants . Both programs included revision of the resident 's current pharmaceutical treatment . We achieved information on osteoporotic fractures in the study population from the Danish Hospital Registration Data base . We defined osteoporotic fractures as low energy fractures of the proximal humerus , distal forearm , vertebral column , pelvis , cervical femur , and intertrochanteric femur . RESULTS Active participation was 50.3 % in the Calcium and Vitamin D Program and 46.4 % in the Environmental and Health Program . We observed a 16 % reduction in fracture incidence rate ( relative risk [ RR ] , 0.84 ; CI , 0.72 - 0.98 ; p female residents offered the Calcium and Vitamin D Program ( intention-to-prevent analysis ) . CONCLUSIONS This study supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in community-dwelling elderly people in a northern European region known to be deficient in vitamin D , especially during winter periods",
"Conflicting data regarding cardiovascular effects of thiazolidinediones ( TZDs ) and extra-skeletal effects of vitamin D supported the need for a definitive trial . The Thiazolidinedione Intervention with vitamin D Evaluation ( TIDE ) trial aim ed to assess the effects of TZDs ( rosiglitazone and pioglitazone ) on cardiovascular outcomes and the effects of vitamin D ( cholecalciferol ) on cancers and mortality . A large multicentre 3 × 2 factorial double-blind placebo-controlled r and omised trial recruited from outpatient primary care and specialty clinics in 33 countries . From June 2009 to July 2010 , 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥50 years whose HbA1c was 6.5–9.5 % ( 48–80 mmol/mol ) when using two or fewer glucose-lowering drugs were r and omised by a central computer system to placebo ( n = 541 ) , rosiglitazone 4–8 mg/day ( n = 399 ) or pioglitazone 30–45 mg/day ( n = 392 ) ; 1,221 participants were r and omised to placebo ( n = 614 ) or vitamin D 1,000 IU/day ( n = 607 ) . Participants and all study personnel were blind to treatment allocation . The primary outcome for the TZD arm was the composite of myocardial infa rct ion , stroke or cardiovascular death , and for the vitamin D arm it was cancer or all-cause death . All r and omised participants were included in the primary analysis . From the study design , 16,000 people were to be followed for approximately 5.5 years . However , the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data . In the TZD arm , the cardiovascular outcome occurred in five participants ( 0.9 % ) in the placebo groups and three participants ( 0.4 % ) in the TZD groups ( two allocated to pioglitazone , one to rosiglitazone ) . In the vitamin D arm , the primary outcome occurred in three participants ( 0.5 % ) in the placebo group and in two participants ( 0.3 % ) receiving vitamin D. Adverse events were comparable in all groups . Uncertainty persists regarding the clinical ly relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial . Clinical Trials.gov NCT00879970 The study was funded by GlaxoSmithKline",
"OBJECTIVE Low serum vitamin D levels have been associated with increased prevalence of the reproductive tract condition bacterial vaginosis ( BV ) . The objective of this trial was to evaluate the effect of high-dose vitamin D supplementation on BV recurrence . STUDY DESIGN This r and omized , placebo-controlled , double-blinded trial enrolled 118 women with symptomatic BV from an urban sexually transmitted disease clinic ( clinical trials.gov registration NCT01450462 ) . All participants received 500 mg of oral metronidazole twice daily for 7 days . Intervention participants ( n = 59 ) also received 9 doses of 50,000 IU of cholecalciferol ( vitamin D3 ) over 24 weeks ; control women ( n = 59 ) received matching placebo . Recurrent BV was assessed via Nugent scoring after 4 , 12 , and 24 weeks . We assessed the effect of the intervention using an intention-to-treat approach , fitting Cox proportional hazards models to evaluate recurrent BV over the follow-up period . RESULTS Most participants ( 74 % ) were black , with a median age of 26 years . Median presupplementation serum 25-hydroxyvitamin D [ 25(OH)D ] was similar across r and omization arms : 16.6 ng/mL in the vitamin D arm and 15.8 ng/mL in the control arm . At trial completion , median 25(OH)D among women receiving vitamin D was 30.5 ng/mL , vs 17.8 ng/mL in control women ; 16 % of women receiving vitamin D and 57 % receiving placebo remained vitamin D deficient ( BV prevalence among women r and omized to vitamin D was very similar to those r and omized to placebo at the 4- and 12-week visits , but by the 24-week visit , BV prevalence was 65 % among women in the vitamin D arm and 48 % among control women . BV recurrence was not reduced by vitamin D supplementation ( intention-to-treat hazard ratio , 1.11 ; 95 % confidence interval , 0.68 - 1.81 ) . Among women experiencing recurrent BV , median time to recurrence was 13.7 weeks in the vitamin D arm and 14.3 weeks in the control arm . CONCLUSION Women receiving vitamin D experienced significant increases in serum 25(OH)D , but this increase was not associated with decreased BV recurrence in this high-risk sexually transmitted disease clinic population",
"BACKGROUND The role of vitamin D in Atopic Dermatitis ( AD ) is ambiguous and clinical trials are needed to assess the role of vitamin D in the treatment of AD . The aim of this clinical trial study to evaluate the effect of vitamin D supplementation on patients with AD . MATERIAL AND METHODS sixty AD patients were included in a r and omized , double-blind , placebo-controlled trial study . They were r and omly divided into two groups and treated for 60 days : group vitamin D ( n=30 ) , and placebo group ( n=30 ) . The two groups were as follows : Group D , 1600 IU cholecalciferol ( vitamin D ) and second group placebo . The severity of AD was evaluated based on SCORAD ( Scoring Atopic Dermatitis ) and TIS ( Three Item Severity score ) value by the same trained physician before and after the trial . RESULTS According to SCORAD and TIS value index in the vitamin D group showed significant improvement in patients with mild , moderate and severe AD ( P placebo , this improvement did n't showed ( P>0.05 ) . CONCLUSION Results mention that supplementation with oral vitamin D dramatically improved disease severity in AD patients",
"CONTEXT Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures ; however , adherence to daily supplementation is typically poor . OBJECTIVE To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture . DESIGN , SETTING , AND PARTICIPANTS A double-blind , placebo-controlled trial of 2256 community-dwelling women , aged 70 years or older , considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were r and omly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years . The study concluded in 2008 . INTERVENTION 500,000 IU of cholecalciferol or placebo . MAIN OUTCOME MEASURES Falls and fractures were ascertained using monthly calendars ; details were confirmed by telephone interview . Fractures were radiologically confirmed . In a sub study , 137 r and omly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels . RESULTS Women in the cholecalciferol ( vitamin D ) group had 171 fractures vs 135 in the placebo group ; 837 women in the vitamin D group fell 2892 times ( rate , 83.4 per 100 person-years ) while 769 women in the placebo group fell 2512 times ( rate , 72.7 per 100 person-years ; incidence rate ratio [ RR ] , 1.15 ; 95 % confidence interval [ CI ] , 1.02 - 1.30 ; P = .03 ) . The incidence RR for fracture in the vitamin D group was 1.26 ( 95 % CI , 1.00 - 1.59 ; P = .047 ) vs the placebo group ( rates per 100 person-years , 4.9 vitamin D vs 3.9 placebo ) . A temporal pattern was observed in a post hoc analysis of falls . The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months ( test for homogeneity ; P = .02 ) . In the sub study , the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3 % of the sub study participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group , 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L , were approximately 90 nmol/L at 3 months , and remained higher than the placebo group 12 months after dosing . CONCLUSION Among older community-dwelling women , annual oral administration of high-dose cholecalciferol result ed in an increased risk of falls and fractures . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12605000658617 ; is rct n.org Identifier : IS RCT N83409867",
"CONTEXT The benefits of high serum levels of 25-hydroxyvitamin D [ 25(OH)D ] are unclear . Trials are needed to establish an appropriate evidence base . OBJECTIVE We plan to conduct a large-scale trial of vitamin D supplementation for the reduction of cancer incidence and overall mortality and report here the methods and results of a pilot trial established to inform its design . DESIGN Pilot D-Health was a r and omized trial carried out in a general community setting with 12 months intervention and follow-up . PARTICIPANTS Participants were 60- to 84-yr-old residents of one of the four eastern Australian states who did not have any vitamin D-related disorders and who were not taking more than 400 IU supplementary vitamin D per day . A total of 644 participants were r and omized , and 615 completed the study ( two persons withdrew because of nonserious adverse events ) . INTERVENTIONS The interventions were monthly doses of placebo or 30,000 or 60,000 IU vitamin D(3 ) . MAIN OUTCOMES The main outcomes were the recruitment rate and changes in serum 25(OH)D. RESULTS Ten percent of those approached were recruited . At baseline , the mean 25(OH)D was 42 nmol/liter in all three study arms . The mean change in 25(OH)D in the placebo group was 0.12 nmol/liter , compared with changes of 22 and 36 nmol/liter in the 30,000- and 60,000-IU groups , respectively . CONCLUSIONS The D-Health pilot has shown that a large trial is feasible in Australia and that a dose of 2000 IU/d will be needed to ensure that a large proportion of the population reaches the target serum 25(OH)D level",
"Abstract Objective : To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community . Design : R and omised double blind controlled trial of 100 000 IU oral vitamin D3 ( cholecalciferol ) supplementation or matching placebo every four months over five years . Setting and participants : 2686 people ( 2037 men and 649 women ) aged 65 - 85 years living in the general community , recruited from the British doctors register and a general practice register in Suffolk . Main outcome measures : Fracture incidence and total mortality by cause . Results : After five years 268 men and women had incident fractures , of whom 147 had fractures in common osteoporotic sites ( hip , wrist or forearm , or vertebrae ) . Relative risks in the vitamin D group compared with the placebo group were 0.78 ( 95 % confidence interval 0.61 to 0.99 , P=0.04 ) for any first fracture and 0.67 ( 0.48 to 0.93 , P=0.02 ) for first hip , wrist or forearm , or vertebral fracture . 471 participants died . The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 ( 0.74 to 1.06 , P=0.18 ) . Findings were consistent in men and women and in doctors and the general practice population . Conclusion : Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community . What is already known in this topic Vitamin D and calcium supplements are effective in preventing fractures in elderly women Whether isolated vitamin D supplementation prevents fractures is not clear What this paper adds Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community Total fracture incidence was reduced by 22 % and fractures in major osteoporotic sites by 33",
"Abstract Objective To assess whether supplementation with calcium and cholecaliferol ( vitamin D3 ) reduces the risk of fracture in women with one or more risk factors for fracture of the hip . Design Pragmatic open r and omised controlled trial . Setting Practice nurse led clinics in primary care . Participants 3314 women aged 70 and over with one or more risk factors for hip fracture : any previous fracture , low body weight ( Intervention Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls , or leaflet only ( control group ) . Main outcome measures Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment , falls , and quality of life ( measured with the SF-12 ) . Results 69 % of the women who completed the follow-up question naire at 24 months were still taking supplements ( 55 % with inclusion of r and omised participants known to be alive ) . After a median follow-up of 25 months ( range 18 to 42 months ) , clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures ( odds ratio for fracture in supplemented group 1.01 , 95 % confidence interval 0.71 to 1.43 ) . The odds ratio for hip fracture was 0.75 ( 0.31 to 1.78 ) . The odds of a woman having a fall at six and 12 months was 0.99 and 0.98 , respectively . Quality of life did not significantly differ between the groups . Conclusion We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture . Registration IS RCT N26118436 , controlled trials registry",
"In a double-blind trial of vitamin D supplements in pregnant Asian women calciferol ( ergocalciferol , 1000 IU/day ) was administered to 59 women and placebo to 67 controls during the last trimester . The two groups had similar distributions of maternal age , height , parity , number of vegetarians , countries of origin , and sex and gestation of the infants . At entry to the trial maternal serum 25-hydroxy vitamin D ( 25-OHD ) concentrations were low in both treatment and control groups and significantly lower in vegetarians than non-vegetarians . Mothers in the treatment group gained weight faster in the last trimester than those in the control group , and at term they and their infants all had adequate plasma 25-OHD concentrations , Mothers and infants in the control group , however , had low plasma concentrations of 25-OHD and calcium and raised plasma alkaline phosphatase ( bone isoenzyme ) activity . Five of these infants developed symptomatic hypocalcaemia . Almost twice as many infants in the control group were small for gestational age ( 29 % v 15 % ) , but there were no significant differences between the two groups of infants in antropometric measurements . Infants in the control group , however , had larger fontanelles , suggesting impaired ossification of the skull . Because of the benefits to mothers and infants in the treatment group and the absence of side effects , vitamin D supplements should be given to all pregnant Asian women in the United Kingdom",
"OBJECTIVES The objective of the present study was to examine the cross-sectional relation between serum 25-hydroxyvitamin D [ 25-(OH ) D ] levels and depression in overweight and obese subjects and to assess the effect of vitamin D supplementation on depressive symptoms . DESIGN Cross-sectional study and r and omized double blind controlled trial of 20,000 or 40,000 IU vitamin D per week versus placebo for 1 year . SETTING A total of 441 subjects ( body mass index 28 - 47 kg m(-2 ) , 159 men and 282 women , aged 21 - 70 years ) recruited by advertisements or from the out-patient clinic at the University Hospital of North Norway . MAIN OUTCOME MEASURES Beck Depression Inventory ( BDI ) score with subscales 1 - 13 and 14 - 21 . RESULTS Subjects with serum 25(OH)D levels depressive traits ) than those with serum 25(OH)D levels > or = 40 nmol L(-1 ) on the BDI total [ 6.0 ( 0 - 23 ) versus 4.5 ( 0 - 28 ) ( median and range ) ] and the BDI subscale 1 - 13 [ 2.0 ( 0 - 15 ) versus 1.0 ( 0 - 29.5 ) ] ( P vitamin D , but not in the placebo group , there was a significant improvement in BDI scores after 1 year . There was a significant decrease in serum parathyroid hormone in the two vitamin D groups without a concomitant increase in serum calcium . CONCLUSIONS It appears to be a relation between serum levels of 25(OH)D and symptoms of depression . Supplementation with high doses of vitamin D seems to ameliorate these symptoms indicating a possible causal relationship",
"Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease ( CVD ) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention . The VITamin D and Omega-A 3 TriaL ( VITAL ) is an ongoing nationwide , r and omized , double-blind , placebo-controlled clinical trial design ed to fill this knowledge gap . The study population consists of 25,874 U.S. adults without cancer or CVD at baseline , who were selected only on age ( men aged ≥50 and women aged ≥55 ) , with an oversampling of African Americans ( n=5,107 ) . In a 2 × 2 factorial design , participants were r and omized to one of four supplement groups : [ 1 ] active vitamin D3 ( cholecalciferol ; 2000 IU/d ) and active marine omega-3 fatty acids ( Omacor ® fish oil , eicosapentaenoic acid [ EPA ] and docosahexaenoic acid [ DHA ] , 1g/d ) ; [ 2 ] active vitamin D and omega-3 placebo ; [ 3 ] vitamin D placebo and active marine omega-3 fatty acids ; or [ 4 ] vitamin D placebo and omega-3 placebo . The mean length of the r and omized treatment period will be 5 years . The r and omization was successful , as evidence d by similar distributions of baseline demographic , health , and behavioral characteristics across treatment groups . The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed . VITAL is expected to provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD",
"Rationale Asthma exacerbations are commonly precipitated by viral upper respiratory infections ( URIs ) . Vitamin D insufficiency associates with susceptibility to URI in patients with asthma . Trials of vitamin D in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking . Objective To conduct a r and omised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI ( co primary outcomes ) . Measurements and methods 250 adults with asthma in London , UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 ( n=125 ) or placebo ( n=125 ) over 1 year . Secondary outcomes included asthma control test and St George 's Respiratory Question naire scores , fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum . Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes . Main results 206/250 participants ( 82 % ) were vitamin D insufficient at baseline . Vitamin D3 did not influence time to first severe exacerbation ( adjusted HR 1.02 , 95 % CI 0.69 to 1.53 , p=0.91 ) or first URI ( adjusted HR 0.87 , 95 % CI 0.64 to 1.16 , p=0.34 ) . No clinical ly important effect of vitamin D3 was seen on any of the secondary outcomes listed above . The influence of vitamin D3 on co primary outcomes was not modified by baseline vitamin D status or genotype . Conclusions Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency . Trial registration number NCT00978315 ( Clinical Trials.gov )",
"BACKGROUND The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal . METHODS We recruited 36,282 postmenopausal women , 50 to 79 years of age , who were already enrolled in a Women 's Health Initiative ( WHI ) clinical trial . We r and omly assigned participants to receive 1000 mg of elemental [ corrected ] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo . Fractures were ascertained for an average follow-up period of 7.0 years . Bone density was measured at three WHI centers . RESULTS Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group ( P calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture ( 95 percent confidence interval , 0.72 to 1.08 ) , 0.90 for clinical spine fracture ( 0.74 to 1.10 ) , and 0.96 for total fractures ( 0.91 to 1.02 ) . The risk of renal calculi increased with calcium plus vitamin D ( hazard ratio , 1.17 ; 95 percent confidence interval , 1.02 to 1.34 ) . Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 ( 95 percent confidence interval , 0.52 to 0.97 ) . Effects did not vary significantly according to prer and omization serum vitamin D levels . CONCLUSIONS Among healthy postmenopausal women , calcium with vitamin D supplementation result ed in a small but significant improvement in hip bone density , did not significantly reduce hip fracture , and increased the risk of kidney stones . ( Clinical Trials.gov number , NCT00000611 . )",
"Abstract The correlation between vitamin D deficiency and depression has recently been put forward and result ed in controversial findings . The present study was conducted to find out the effect of 2 single injections of 150,000 and 300,000 IU of vitamin D on improving the depression in depressed patients with vitamin D deficiency . This clinical trial study was carried out during 2011–2012 in Yazd , Islamic Republic of Iran . A total of 120 patients who had a Beck Depression Inventory II score of 17 + and were affected with vitamin D deficiency were r and omly assigned to 3 groups of 40 . They included G300 , G150 , and NTG . G300 and G150 received an intramuscular single dose of 300,000 and 150,000 IU of vitamin D , respectively , and the NTG group received nothing . After 3 months of intervention , the depression state , serum vitamin D , calcium , phosphorus , and parathormone were measured . The median of serum vitamin D after intervention were 60.2 , 54.6 , and 28.2 nmol/L ( P Percentages of vitamin D deficiency after intervention were 18 , 20 , and 91.2 for the groups , respectively . The serum calcium mean showed a statistically significant increase in just the 2 test groups receiving vitamin D. There was only significant difference in mean of Beck Depression Inventory II test score between G300 and NTG ( P = 0.003).The results of the study revealed that first , the correction of vitamin D deficiency improved the depression state , and second , a single injection dose of 300,000 IU of vitamin D was safe and more effective than a 150,000-IU dose",
"OBJECTIVES To determine whether vitamin D supplementation reduces the risk of fracture or falls in elderly people in care home accommodation . DESIGN A r and omised controlled trial of cluster design . SETTING AND SUBJECTS 223 Residential units ( mainly identical 30-bedded units ) , within 118 homes for elderly people throughout Britain , with 3,717 participating residents ( 76 % women , average age 85 years ) . The units provided mainly or entirely residential care ( 35 % of residents ) , nursing care ( 42 % ) or care for elderly mentally infirm ( EMI ) residents ( 23 % ) . METHODS Participants were r and omly allocated by residential unit ( cluster design ) to a treated group offered ergocalciferol 2.5 mg every 3 months ( equivalent to a daily dose of 1,100 IU ) , or to a control group . Fractures were reported by staff and confirmed in hospital , and routinely collected data on reported falls were obtained . RESULTS After median follow-up of 10 months ( interquartile range 7 - 14 months ) , 64 ( 3.6 % ) of 1,762 vitamin D-treated residents and 51 ( 2.6 % ) of 1,955 controls had one or more non-vertebral fractures , and 24 ( 1.3 % ) and 20 ( 1.0 % ) , respectively , had a hip fracture . The proportion reporting at least one fall was 44 % in vitamin D-treated and 43 % in control residents . The differences between the vitamin D and control groups were not statistically significant . The incidence of all non-vertebral fractures in the care homes ( 3.2 % per year ) and of hip fractures ( 1.1 % per year ) was low , similar to rates in elderly people in sheltered accommodation , and the pre-treatment serum 25-hydroxy vitamin D concentration was high [ median 47 nmol/l , measured in a 1 % ( n = 18 ) sample ] . CONCLUSIONS We found no evidence that vitamin D prevents fractures or falls in elderly people in care home accommodation",
"CONTEXT Observational studies have reported an inverse association between serum 25-hydroxyvitamin D ( 25-OHD ) levels and incidence of upper respiratory tract infections ( URTIs ) . However , results of clinical trials of vitamin D supplementation have been inconclusive . OBJECTIVE To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch , New Zeal and . INTERVENTION Participants were r and omly assigned to receive an initial dose of 200,000 IU oral vitamin D3 , then 200,000 IU 1 month later , then 100,000 IU monthly ( n = 161 ) , or placebo administered in an identical dosing regimen ( n = 161 ) , for a total of 18 months . MAIN OUTCOME MEASURES The primary end point was number of URTI episodes . Secondary end points were duration of URTI episodes , severity of URTI episodes , and number of days of missed work due to URTI episodes . RESULTS The mean baseline 25-OHD level of participants was 29 ( SD , 9 ) ng/mL. Vitamin D supplementation result ed in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study . There were 593 URTI episodes in the vitamin D group and 611 in the placebo group , with no statistically significant differences in the number of URTIs per participant ( mean , 3.7 per person in the vitamin D group and 3.8 per person in the placebo group ; risk ratio , 0.97 ; 95 % CI , 0.85 - 1.11 ) , number of days of missed work as a result of URTIs ( mean , 0.76 days in each group ; risk ratio , 1.03 ; 95 % CI , 0.81 - 1.30 ) , duration of symptoms per episode ( mean , 12 days in each group ; risk ratio , 0.96 ; 95 % CI , 0.73 - 1.25 ) , or severity of URTI episodes . These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels . CONCLUSION In this trial , monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12609000486224",
"OBJECTIVE To assess vitamin D intake and casual exposure to sunshine in relation to serum 25-hydroxyvitamin D ( 25OHD ) levels . DESIGN Cross-sectional study of a population -based , r and om sample of women aged 20 - 92 years , assessed between 1994 and 1997 . SETTING AND PARTICIPANTS 861 women from the Barwon Statistical Division ( population , 218000 ) , which includes the city of Geelong ( latitude 38 degrees south ) in Victoria . MAIN OUTCOME MEASURES Vitamin D intake ; serum 25OHD level ; season of assessment ; exposure to sunshine . RESULTS Median intake of vitamin D was 1.2 microg/day ( range , 0.0 - 11.4 microg/day ) . Vitamin D supplements , taken by 7.9 % of participants , increased intake by 8.1 % to 1.3 microg/day ( range , 0.0 - 101.2 microg/day ) ( P serum 25OHD levels was observed for sunbathing frequency before and after adjusting for age ( P serum 25OHD levels were dependent on vitamin D intake ( partial r2= 0.01 ; P serum 25OHD and vitamin D intake during summer . The prevalences of low concentrations of serum 25OHD were , for vitamin D from dietary sources appears to be insignificant during summer . However , during winter vitamin D status is influenced by dietary intake . Australia has no recommended dietary intake ( RDI ) for vitamin D , in the belief that adequate vitamin D can be obtained from solar irradiation alone . Our results suggest that an RDI may be needed",
"Observational studies have suggested that 25-hydroxyvitamin D ( 25(OH)D ) levels are associated with inflammatory markers . Most trials reporting significant associations between vitamin D intake and inflammatory markers used specific patient groups . Thus , we aim ed to determine the effect of supplementary vitamin D using secondary data from a population -based , r and omised , placebo-controlled , double-blind trial ( Pilot D-Health trial 2010/0423 ) . Participants were 60- to 84-year-old residents of one of the four eastern states of Australia . They were r and omly selected from the electoral roll and were r and omised to one of three trial arms : placebo ( n 214 ) , 750 μg ( n 215 ) or 1500 μg ( n 215 ) vitamin D3 , each taken once per month for 12 months . Post-intervention blood sample s for the analysis of C-reactive protein ( CRP ) , IL-6 , IL-10 , leptin and adiponectin levels were available for 613 participants . Associations between intervention group and biomarker levels were evaluated using quantile regression . There were no statistically significant differences in distributions of CRP , leptin , adiponectin , leptin : adiponectin ratio or IL-10 levels between the placebo group and either supplemented group . The 75th percentile IL-6 level was 2·8 pg/ml higher ( 95 % CI 0·4 , 5·8 pg/ml ) in the 1500 μg group than in the placebo group ( 75th percentiles:11·0 v. 8·2 pg/ml ) , with a somewhat smaller , non-significant difference in 75th percentiles between the 750 μg and placebo groups . Despite large differences in serum 25(OH)D levels between the three groups after 12 months of supplementation , we found little evidence of an effect of vitamin D supplementation on cytokine or adipokine levels , with the possible exception of IL-6",
"Locally produced 1,25-dihydroxyvitamin D3 may have pleiotropic effects outside of bone . Experimental and observational studies suggest that nutritional vitamin D may enhance erythropoiesis in setting s of 25-hydroxy vitamin D ( 25(OH)D ) deficiency . We conducted a double-blind , placebo-controlled , r and omized clinical trial to assess the effects of supplementation with ergocalciferol on epoetin utilization and other secondary outcomes in patients on hemodialysis with serum 25(OH)D In all , 276 patients were r and omized to 6 months of ergocalciferol or placebo . Mean±SD serum 25(OH)D increased from 16.0±5.9 ng/ml at baseline to 39.2±14.9 ng/ml in the ergocalciferol arm and did not change ( 16.9±6.4 ng/ml and 17.5±7.4 ng/ml , respectively ) in the placebo arm . There was no significant change in epoetin dose over 6 months in the ergocalciferol or placebo arms ( geometric mean rate 0.98 [ 95 % confidence interval ( 95 % CI ) , 0.94 to 1.02 ] versus 0.99 [ 95 % CI , 0.95 to 1.03 ] , respectively ) and no difference across arms ( P=0.78 ) . No change occurred in serum calcium , phosphorus , intact parathyroid hormone , or C-reactive protein levels , cinacalcet use , or phosphate binder or calcitriol dose in either study arm . Rates of all-cause , cardiovascular , and infection-related hospitalizations did not differ by study arm , although statistical power was limited for these outcomes . In conclusion , 6 months of supplementation with ergocalciferol increased serum 25(OH)D levels in patients on hemodialysis with vitamin D insufficiency or deficiency , but had no effect on epoetin utilization or secondary biochemical and clinical outcomes",
"Specific receptors for vitamin D have been identified in human muscle tissue . Cross-sectional studies show that elderly persons with higher vitamin D serum levels have increased muscle strength and a lower number of falls . We hypothesized that vitamin D and calcium supplementation would improve musculoskeletal function and decrease falls . In a double-blind r and omized controlled trial , we studied 122 elderly women ( mean age , 85.3 years ; range , 63 - 99 years ) in long-stay geriatric care . Participants received 1200 mg calcium plus 800 IU cholecalciferol ( Cal+D-group ; n = 62 ) or 1200 mg calcium ( Cal-group ; n = 60 ) per day over a 12-week treatment period . The number of falls per person ( 0 , 1 , 2 - 5 , 6 - 7 , > 7 falls ) was compared between the treatment groups . In an intention to treat analysis , a Poisson regression model was used to compare falls after controlling for age , number of falls in a 6-week pretreatment period , and baseline 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations . Among fallers in the treatment period , crude excessive fall rate ( treatment - pretreatment falls ) was compared between treatment groups . Change in musculoskeletal function ( summed score of knee flexor and extensor strength , grip strength , and the timed up&go test ) was measured as a secondary outcome . Among subjects in the Cal+D-group , there were significant increases in median serum 25-hydroxyvitamin D ( + 71 % ) and 1,25-dihydroxyvitamin D ( + 8 % ) . Before treatment , mean observed number of falls per person per week was 0.059 in the Cal+D-group and 0.056 in the Cal-group . In the 12-week treatment period , mean number of falls per person per week was 0.034 in the Cal+D-group and 0.076 in the Cal-group . After adjustment , Cal+D-treatment accounted for a 49 % reduction of falls ( 95 % CI , 14 - 71 % ; p crude average number of excessive falls was significantly higher in the Cal-group ( p = 0.045 ) . Musculoskeletal function improved significantly in the Cal+D-group ( p = 0.0094 ) . A single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49 % compared with calcium alone . Over this short-term intervention , recurrent fallers seem to benefit most by the treatment . The impact of vitamin D on falls might be explained by the observed improvement in musculoskeletal function",
"BACKGROUND Observational data suggested that supplementation with vitamin D could reduce risk of infection , but trial data are inconsistent . OBJECTIVE We aim ed to examine the effect of oral vitamin D supplementation on antibiotic use . DESIGN We conducted a post hoc analysis of data from pilot D-Health , which is a r and omized trial carried out in a general community setting between October 2010 and February 2012 . A total of 644 Australian residents aged 60 - 84 y were r and omly assigned to receive monthly doses of a placebo ( n = 214 ) or 30,000 ( n = 215 ) or 60,000 ( n = 215 ) IU oral cholecalciferol for ≤12 mo . Antibiotics prescribed during the intervention period were ascertained by linkage with pharmacy records through the national health insurance scheme ( Medicare Australia ) . RESULTS People who were r and omly assigned 60,000 IU cholecalciferol had nonsignificant 28 % lower risk of having antibiotics prescribed at least once than did people in the placebo group ( RR : 0.72 ; 95 % CI : 0.48 , 1.07 ) . In analyses stratified by age , in subjects aged ≥70 y , there was a significant reduction in antibiotic use in the high-dose vitamin D compared with placebo groups ( RR : 0.53 ; 95 % CI : 0.32 , 0.90 ) , whereas there was no effect in participants aged lower risk of infection , particularly in older adults . The trial was registered at the Australian New Zeal and Clinical Trials Registry ( anzctr.org.au ) as ACTRN12609001063202",
"OBJECTIVES Low trauma fractures in older people incur enormous physical , social and economic costs . Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group . This strategy requires validation in a population setting . METHODS R and omized , double-blind , placebo-controlled trial of 300,000 IU intramuscular ( i.m . ) vitamin D2 ( ergocalciferol ) injection or matching placebo every autumn over 3 years . 9440 people ( 4354 men and 5086 women ) aged 75 yrs and over were recruited from general practice registers in Wessex , Engl and . Primary outcome measure was all non-vertebral fracture . Secondary outcomes were hip and wrist fractures , and all falls . RESULTS 585 subjects had incident non-spine fractures ( hip 110 , wrist 116 , ankle 37 ) . Hazard ratios ( HRs ) for fracture in the vitamin D group were : 1.09 [ 95 % confidence interval ( CI ) 0.93 - 1.28 , P = 0.29 ] for any first fracture , 1.49 ( 95 % CI 1.02 - 2.18 , P = 0.04 ) for hip and 1.22 ( 95 % CI 0.85 - 1.76 , P = 0.28 ) for wrist . There was no effect on falls : HR 0.98 ( 0.93 - 1.04 ) . No protective effect was observed in any subgroup when the cohort was stratified by sex , age , previous fracture or mobility . CONCLUSIONS An annual i.m . injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population",
"BACKGROUND AND OBJECTIVES Vitamin D ( 25-hydroxyvitamin D ; 25[OH]D ) deficiency is common in patients initiating long-term hemodialysis , but the safety and efficacy of nutritional vitamin D supplementation in this population remain uncertain . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS This r and omized , placebo-controlled , parallel-group multicenter trial compared two doses of ergocalciferol with placebo between October 2009 and March 2013 . Hemodialysis patients ( n=105 ) with 25(OH)D levels ≤32 ng/ml from 32 centers in the Northeast United States were r and omly assigned to oral ergocalciferol , 50,000 IU weekly ( n=36 ) or monthly ( n=33 ) , or placebo ( n=36 ) for a 12-week treatment period . The primary endpoint was the achievement of vitamin D sufficiency ( 25[OH]D > 32 ng/ml ) at the end of the 12-week treatment period . Survival was assessed through 1 year . RESULTS Baseline characteristics were similar across all arms , with overall mean±SD 25(OH)D levels of 21.9±6.9 ng/ml . At 12 weeks , vitamin D sufficiency ( 25[OH]D > 32 ng/ml ) was achieved in 91 % ( weekly ) , 66 % ( monthly ) , and 35 % ( placebo ) ( P was significantly higher in both the weekly ( 49.8±2.3 ng/ml ; P 27.4±2.3 ng/ml ) . Calcium , phosphate , parathyroid hormone levels , and active vitamin D treatment did not differ between groups . All-cause and cause-specific hospitalizations and adverse events were similar between groups during the intervention period . Lower all-cause mortality among ergocalciferol-treated participants was not statistically significant ( hazard ratio , 0.28 ; 95 % confidence interval , 0.07 to 1.19 ) . CONCLUSIONS Oral ergocalciferol can increase 25(OH)D levels in incident hemodialysis patients without significant alterations in blood calcium , phosphate , or parathyroid hormone during a 12-week period",
"Data from laboratory studies , observational research , and /or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease ( CVD ) , but primary prevention trials with adequate dosing in general population s ( i.e. , unselected for disease risk ) are lacking . The ongoing VITamin D and OmegA-3 TriaL ( VITAL ) is a large r and omized , double-blind , placebo-controlled , 2 x 2 factorial trial of vitamin D ( in the form of vitamin D(3 ) [ cholecalciferol ] , 2000 IU/day ) and marine omega-3 fatty acid ( Omacor fish oil , eicosapentaenoic acid [EPA]+docosahexaenoic acid [ DHA ] , 1g/day ) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥ 50 and women aged ≥ 55 . The mean treatment period will be 5 years . Baseline blood sample s will be collected in at least 16,000 participants , with follow-up blood collection in about 6000 participants . Yearly follow-up question naires will assess treatment compliance ( plasma biomarker measures will also assess compliance in a r and om sample of participants ) , use of non- study drugs or supplements , occurrence of endpoints , and cancer and vascular risk factors . Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment , and deaths will be ascertained through national registries and other sources . Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance ; hypertension ; cognitive decline ; depression ; osteoporosis and fracture ; physical disability and falls ; asthma and other respiratory diseases ; infections ; and rheumatoid arthritis , systemic lupus erythematosus , thyroid diseases , and other autoimmune disorders",
"Vitamin D deficiency is common in the elderly and may lead to secondary hyperparathyroidism , cortical bone loss , and hip fractures . The effect of vitamin D supplementation for 1 yr was studied in 72 people living in a nursing home and 70 people living in an aged people 's home . The subjects were r and omized into 3 groups : control , and 400 or 800 IU vitamin D3/day . The initial vitamin D status of each subject was classified as deficient or borderline [ serum 25-hydroxyvitamin D ( 25OHD ) less than 30 nmol/L ] in 79 % and adequate ( serum 25OHD greater than or equal to 30 nmol/L ) in 21 % . Serum 25OHD concentrations increased about 3-fold in both groups receiving vitamin D supplementation . Serum 1,25-dihydroxyvitamin D [ 1,25-(OH)2D ] concentrations increased slightly but significantly , and the increase was inversely related to the initial serum 25OHD concentration . Serum intact PTH-(1 - 84 ) concentrations decreased about 15 % during supplementation in both nursing home and aged people 's home residents , whereas serum osteocalcin significantly decreased in the nursing home residents only . We conclude that a vitamin D3 supplement of 400 IU/day adequately improves vitamin D status in elderly people and increases 1,25-(OH)2D concentrations in those with vitamin D deficiency . Supplementation decreases parathyroid function and may depress bone turnover to some degree",
"Antifracture efficacy of high-dose vitamin D ( 800 IU ) and calcium ( 1000 mg ) remains controversial . To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures , we r and omized 3432 women of the population -based Osteoporosis Risk Factor and Prevention ( OSTPRE ) Study cohort ( ages 65 to 71 years ) living in the region of northern Savonia , Finl and ( latitude 62 degrees to 64 degrees N ) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo . The main outcome measure was incident fractures . Fracture data were collected in telephone interviews and vali date d. Data on 3195 women , 1586 in the intervention group and 1609 in the control group , were available for analysis . In adjusted Cox proportional hazards models , the risk of any fracture decreased in the vitamin D and calcium group by 17 % [ adjusted hazard ratio ( aHR ) = 0.83 ; 95 % confidence interval ( CI ) 0.61 - 1.12 ] , and the risk of any nonvertebral fracture decreased by 13 % ( aHR = 0.87 ; 95 % CI 0.63 - 1.19 ) . The risk of distal forearm fractures decreased by 30 % ( aHR = 0.70 ; 95 % CI 0.41 - 1.20 ) , and the risk of any upper extremity fractures decreased by 25 % ( aHR = 0.75 ; 95 % CI 0.49 - 1.16 ) , whereas the risk of lower extremity fractures remained essentially equal ( aHR = 1.02 ; 95 % CI 0.58 - 1.80 ) . None of these effects reached statistical significance . In conclusion , this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women",
"Multiple sclerosis ( MS ) is an inflammatory disease in which the myelin sheaths around the axons of the central nervous system are damaged . The damage leads to demyelination and scarring as well as a broad spectrum of signs and symptoms . The epidemiological data suggest a possible influence of vitamin D as an immunomodulatory agent on multiple sclerosis susceptibility as well as on clinical course of the disease . We investigated the effects of short-term vitamin D3 therapy on Iranian patients with MS . In a prospect i ve r and omized controlled trial study , 62 MS patients received 300,000 IU/month vitamin D3 or placebo as intramuscular injection for 6 months . Our results showed no significant difference between the treatment and the control groups in the exp and ed disability status scale scores and number of gadolinium-enhancing lesions during the 6-month treatment period . After 6 months , the levels of cell proliferation in the vitamin D treatment group were significantly lower than the control group . Also , the levels of transforming growth factor-beta and interleukin-10 in the vitamin D treatment group were significantly higher than the control group . This result suggests that vitamin D therapy may help prevent the development of MS and could be a useful addition to the therapy",
"Objective . Systemic lupus erythematosus ( SLE ) is a chronic multisystem inflammatory autoimmune disease . Vitamin D has potent immunomodulatory properties that support its use in the treatment of autoimmune conditions , including SLE . We assessed vitamin D status in patients with SLE and determined alterations in inflammatory and hemostatic markers and disease activity before and after vitamin D supplementation . Methods . Patients with SLE ( n = 267 ) were r and omized 2:1 to receive either oral cholecalciferol 2000 IU/day or placebo for 12 months . Outcome measures included assessment of alterations in levels of proinflammatory cytokines and hemostatic markers , and improvement in disease activity before and after 12 months of supplementation . Disease activity was measured by the SLE Disease Activity Index . Vitamin D levels were measured by Liaison immunoassay ( normal 30–100 ng/ml ) . Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency and levels mean 25(OH)D level at baseline was 19.8 ng/ml in patients compared to 28.7 ng/ml in controls . The overall prevalence of suboptimal and deficient 25(OH)D serum levels among patients with SLE at baseline was 69 % and 39 % , respectively . Lower 25(OH)D levels correlated significantly with higher SLE disease activity . At 12 months of therapy , there was a significant improvement in levels of inflammatory and hemostatic markers as well as disease activity in the treatment group compared to the placebo group . Conclusion . Vitamin D supplementation in patients with SLE is recommended because increased vitamin D levels seem to ameliorate inflammatory and hemostatic markers and show a tendency toward subsequent clinical improvement . Clinical Trial Registry NCT01425775",
"BACKGROUND Tuberculosis , including multidrug-resistant tuberculosis ( MDR-TB ) , is a major global health problem . Individuals with tuberculosis disease commonly exhibit vitamin D deficiency , which may adversely affect immunity and the response to therapy . OBJECTIVE We determined whether adjunctive high-dose vitamin D3 supplementation improves outcomes in individuals with pulmonary tuberculosis disease . DESIGN The study was a double-blind , r and omized , placebo-controlled , intent-to-treat trial in 199 individuals with pulmonary tuberculosis disease in Tbilisi , Georgia . Subjects were r and omly assigned to receive oral vitamin D3 [ 50,000 IUs ( 1.25 mg ) thrice weekly for 8 wk and 50,000 IU every other week for 8 wk ] or a placebo concomitant with st and ard first-line antituberculosis drugs . The primary outcome was the time for the conversion of a Mycobacterium tuberculosis ( Mtb ) sputum culture to negative . RESULTS Baseline characteristics between groups were similar . Most subjects ( 74 % ) were vitamin D deficient ( plasma 25-hydroxyvitamin D [ 25(OH)D ] concentration With vitamin D3 , plasma 25(OH)D concentrations peaked at ∼250 nmol/L by 8 wk and decreased to ∼125 nmol/L at week 16 . Adverse events and plasma calcium concentrations were similar between groups . In 192 subjects with culture-confirmed tuberculosis , an adjusted efficacy analysis showed similar median culture-conversion times between vitamin D3 and placebo groups [ 29 and 27 d , respectively ; HR : 0.86 ; 95 % CI : 0.63 , 1.18 ; P = 0.33 ) . Eight-week culture-conversion rates were also similar ( 84.0 % and 82.1 % for vitamin D3 and placebo , respectively ; P = 0.99 ) . CONCLUSION A high-dose vitamin D3 regimen safely corrected vitamin D deficiency but did not improve the rate of sputum Mtb clearance over 16 wk in this pulmonary tuberculosis cohort . This trial was registered at clinical trials.gov at NCT00918086",
"R and omized controlled trials have shown that a combination of vitamin D and calcium can prevent fragility fractures in the elderly . Whether this effect is attributed to the combination of vitamin D and calcium or to one of these nutrients alone is not known . We studied if an intervention with 10 microg of vitamin D3 per day could prevent hip fracture and other osteoporotic fractures in a double-blinded r and omized controlled trial . Residents from 51 nursing homes were allocated r and omly to receive 5 ml of ordinary cod liver oil ( n = 569 ) or 5 ml of cod liver oil where vitamin D was removed ( n = 575 ) . During the study period of 2 years , fractures and deaths were registered , and the principal analysis was performed on the intention-to-treat basis . Biochemical markers were measured at baseline and after 1 year in a sub sample . Forty-seven persons in the control group and 50 persons in the vitamin D group suffered a hip fracture . The corresponding figures for all nonvertebral fractures were 76 persons ( control group ) and 69 persons ( vitamin D group ) . There was no difference in the incidence of hip fracture ( p = 0.66 , log-rank test ) , or in the incidence of all nonvertebral fractures ( p = 0.60 , log-rank test ) in the vitamin D group compared with the control group . Compared with the control group , persons in the vitamin D group increased their serum 25-hydroxyvitamin D concentration with 22 nmol/liter ( p = 0.001 ) . In conclusion , we found that an intervention with 10 microg of vitamin D3 alone produced no fracture-preventing effect in a nursing home population of frail elderly people",
"OBJECTIVE The objective of the study was to determine whether vitamin D ( vitD ) supplementation during pregnancy affects obstetric and neonatal outcomes . SETTING The study was conducted at a university hospital in Karachi , Pakistan . METHODS The study was a single-center , open-label , r and omized , controlled trial of routine care ( group A , 200 mg ferrous sulfate and 600 mg calcium daily ) vs vitD supplementation ( group B , 4000 IU vitamin D3 daily ) , started at 20 weeks and continued till delivery . Maternal serum sample s of 25-hydroxyvitamin D ( 25OHD ) were collected at baseline and delivery . Neonatal vitD status was assessed in cord blood or in neonatal serum sample s within 48 hours of birth . Obstetric outcomes included gestational hypertension , gestational diabetes , and preterm labor , and neonatal well-being included small for gestational age , birth weight , length , head circumference , and 1- and 5-minute Apgar scores . RESULTS Of 207 gravidae enrolled , 193 completed the trial . Maternal age , vitD status , and gestational age at enrollment were comparable between the two groups . At delivery , maternal 25OHD was increased in group B ( 18.3 ± 11 ng/dL vs 8.82 ± 11.84 ng/dL ( P = .001 ) compared with group A ( 6.9 ± 7.0 ng/dL vs 6.32 ± 3.97 ng/dL , P = .06 ) . The obstetric outcomes were comparable between the two groups ( P > .05 ) . Neonatal 25OHD levels were significantly higher in group B compared with group A ( 19.22 ± 12.19 ng/dL vs 6.27 ± 5.2 ng/dL ) . There was positive correlation between maternal and neonatal 25OHD levels ( r = 0.83 , P = .001 ) . One- and 5-minute Apgar scores were significantly higher in group B ( 7.10 ± 0.66 vs 6.90 ± 0.50 , P = .026 , and 8.53 ± 0.68 vs 8.33 ± 0.81 , P = .051 , respectively ) . Neonatal anthropometric parameters were comparable between the two groups ( P > .05 ) . CONCLUSION Maternal vitD supplementation improved maternal and neonatal vitD status ",
"BACKGROUND Elderly people who have a fracture are at high risk of another . Vitamin D and calcium supplements are often recommended for fracture prevention . We aim ed to assess whether vitamin D3 and calcium , either alone or in combination , were effective in prevention of secondary fractures . METHODS In a factorial- design trial , 5292 people aged 70 years or older ( 4481 [ 85 % ] of whom were women ) who were mobile before developing a low-trauma fracture were r and omly assigned 800 IU daily oral vitamin D3 , 1000 mg calcium , oral vitamin D3 ( 800 IU per day ) combined with calcium ( 1000 mg per day ) , or placebo . Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months . Analysis was by intention-to-treat and the primary outcome was new low-energy fractures . FINDINGS 698 ( 13 % ) of 5292 participants had a new low-trauma fracture , 183 ( 26 % ) of which were of the hip . The incidence of new , low-trauma fractures did not differ significantly between participants allocated calcium and those who were not ( 331 [ 12.6 % ] of 2617 vs 367 [ 13.7 % ] of 2675 ; hazard ratio ( HR ) 0.94 [ 95 % CI 0.81 - 1.09 ] ) ; between participants allocated vitamin D3 and those who were not ( 353 [ 13.3 % ] of 2649 vs 345 [ 13.1 % ] of 2643 ; 1.02 [ 0.88 - 1.19 ] ) ; or between those allocated combination treatment and those assigned placebo ( 165 [ 12.6 % ] of 1306 vs 179 [ 13.4 % ] of 1332 ; HR for interaction term 1.01 [ 0.75 - 1.36 ] ) . The groups did not differ in the incidence of all-new fractures , fractures confirmed by radiography , hip fractures , death , number of falls , or quality of life . By 24 months , 2886 ( 54.5 % ) of 5292 were still taking tablets , 451 ( 8.5 % ) had died , 58 ( 1.1 % ) had withdrawn , and 1897 ( 35.8 % ) had stopped taking tablets but were still providing data for at least the main outcomes . Compliance with tablets containing calcium was significantly lower ( difference : 9.4 % [ 95 % CI 6.6 - 12.2 ] ) , partly because of gastrointestinal symptoms . However , potentially serious adverse events were rare and did not differ between groups . INTERPRETATION The findings do not support routine oral supplementation with calcium and vitamin D3 , either alone or in combination , for the prevention of further fractures in previously mobile elderly people",
"BACKGROUND Epidemiologic and pre clinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia . To further study the chemopreventive potential of these nutrients , we conducted a r and omized , double-blind , placebo-controlled trial of supplementation with vitamin D , calcium , or both for the prevention of colorectal adenomas . METHODS We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy . We r and omly assigned 2259 participants to receive daily vitamin D3 ( 1000 IU ) , calcium as carbonate ( 1200 mg ) , both , or neither in a partial 2 × 2 factorial design . Women could elect to receive calcium plus r and om assignment to vitamin D or placebo . Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations , according to the endoscopist 's recommendation . The primary end point was adenomas diagnosed in the interval from r and omization through the anticipated surveillance colonoscopy . RESULTS Participants who were r and omly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter , relative to participants given placebo . Overall , 43 % of participants had one or more adenomas diagnosed during follow-up . The adjusted risk ratios for recurrent adenomas were 0.99 ( 95 % confidence interval [ CI ] , 0.89 to 1.09 ) with vitamin D versus no vitamin D , 0.95 ( 95 % CI , 0.85 to 1.06 ) with calcium versus no calcium , and 0.93 ( 95 % CI , 0.80 to 1.08 ) with both agents versus neither agent . The findings for advanced adenomas were similar . There were few serious adverse events . CONCLUSIONS Daily supplementation with vitamin D3 ( 1000 IU ) , calcium ( 1200 mg ) , or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years . ( Funded by the National Cancer Institute ; Clinical Trials.gov number , NCT00153816 . )",
"Background Research waste is estimated to be very common , but assessment s of its prevalence and scope are rare . As an example , we assessed research waste in clinical research on calcium intake ( assessing study design and endpoint type ) and vitamin D supplementation ( assessing endpoint type ) . Methods We examined 404 r and omised controlled trials ( RCTs ) and observational studies of calcium intake ( diet or supplements ) and bone mineral density ( BMD ) or fracture , and 547 RCTs of vitamin D supplements , and assessed the proportion of studies that used surrogate or clinical endpoints . For studies with BMD or fracture as an endpoint , we estimated when the ‘ tipping ’ point occurred indicating the need for RCTs with fracture as an endpoint ( based on cumulative meta-analyses of BMD RCTs , and chronological review of observational studies ) , and whether each study published at least 5y after the tipping point was novel , added new clinical knowledge or was research waste . Results Observational studies of calcium intake and BMD or fracture outnumbered RCTs by 3.3–4.5 times . For both calcium intake and vitamin D supplements , studies using surrogate endpoints outnumbered studies using clinical endpoints by 1.6–3 times . Of 41 RCT publications of calcium intake and BMD or fracture published at least 5y after the tipping point in 1994 , we considered that 19 ( 46 % ) lacked novelty , another 13 ( 32 % ) added no new clinical knowledge , and 30 ( 73 % ) were research waste . Of 204 observational study publications of calcium intake and BMD or fracture , 197 ( 96 % ) lacked novelty , another 5 ( 2 % ) added no new clinical knowledge , and 202 ( 99 % ) were research waste . Of 39 RCTs of vitamin D supplementation and BMD or fracture published at least 5y after the tipping point in 1999 , 14 ( 36 % ) lacked novelty , another 13 ( 33 % ) added no new clinical knowledge , and 27 ( 69 % ) were research waste . Conclusions A high proportion of studies of calcium intake since 2000 ( 95 % ) and trials of vitamin D supplements since 2005 ( 69 % ) on BMD or fracture represent research waste",
"BACKGROUND AND OBJECTIVE Supplements of calcium and vitamin D ( Ca/VitD ) could help prevent falls , although it is unknown whether the effect differs according to the level of physical activity or baseline 25-OH-vitamin D3 . The objective is to determine the effect of Ca/VitD supplements in reducing falls and the musculoskeletal function in elderly over 65 years living in the community , who do not have osteoporosis or vitamin D deficiency . MATERIAL AND METHOD R and omized double-blinded clinical trial . A total of 508 patients were selected from 35 Family Medicine consultations . The treatment was administered to 398 subjects ( Ca/VitD 188 and placebo 210 ) . The efficacy parameters were : incidence of falls , changes in muscle strength in dominant h and and changes in musculoskeletal function . RESULTS The cumulative incidence of falls in the group Ca/VitD was 27.7 % ( 95 % confidence interval [ 95 % CI ] : 21.0 to 34.3 ) and 30.5 % in the placebo group ( 95 % CI : 24.0 to 36.9 ) ( P=.537 ) . The difference was not significant in the subgroup analysis : male/female , active/inactive physically and level of 25-OH-vitamin D3 higher/less than 32 ng/ml . There was no difference in muscle strength in subjects of both groups . The proportion of adverse effects was higher in the Ca/VitD group ( 14.4 versus 7.1 % , P=.019 ) . CONCLUSIONS The results contradict the recommendation to provide supplements , and it is not an effective and well tolerated strategy . Although they may reduce the risk of falls when there are very low levels of vitamin D , the results are unsatisfactory when elders do not have this deficiency , and it is necessary to consider the possibility of adverse effects",
"IMPORTANCE Knee osteoarthritis ( OA ) , a disorder of cartilage and periarticular bone , is a public health problem without effective medical treatments . Some studies have suggested that vitamin D may protect against structural progression . OBJECTIVE To determine whether vitamin D supplementation reduces symptom and structural progression of knee OA . DESIGN , SETTING , AND PATIENTS A 2-year r and omized , placebo-controlled , double-blind , clinical trial involving 146 participants with symptomatic knee OA ( mean age , 62.4 years [ SD , 8.5 ] ; 57 women [ 61 % ] , 115 white race [ 79 % ] ) . Patients were enrolled at Tufts Medical Center in Boston between March 2006 and June 2009 . INTERVENTION Participants were r and omized to receive either placebo or oral cholecalciferol , 2000 IU/d , with dose escalation to elevate serum levels to more than 36 ng/mL. MAIN OUTCOME MEASURES Primary outcomes were knee pain severity ( Western Ontario and McMaster Universities [ WOMAC ] pain scale , 0 - 20 : 0 , no pain ; 20 , extreme pain ) , and cartilage volume loss measured by magnetic resonance imaging . Secondary end points included physical function , knee function ( WOMAC function scale , 0 - 68 : 0 , no difficulty ; 68 , extreme difficulty ) , cartilage thickness , bone marrow lesions , and radiographic joint space width . RESULTS Eighty-five percent of the participants completed the study . Serum 25-hydroxyvitamin D levels increased by a mean 16.1 ng/mL ( 95 % CI , 13.7 to 18.6 ) in the treatment group and by a mean 2.1 mg/mL ( 95 % CI , 0.5 to 3.7 ) ( P Baseline knee pain was slightly worse in the treatment group ( mean , 6.9 ; 95 % CI , 6.0 to 7.7 ) than in the placebo group ( mean , 5.8 ; 95 % CI , 5.0 to 6.6 ) ( P = .08 ) . Baseline knee function was significantly worse in the treatment group ( mean , 22.7 ; 95 % CI , 19.8 to 25.6 ) than in the placebo group ( mean , 18.5 ; 95 % CI , 15.8 to 21.2 ) ( P = .04 ) . Knee pain decreased in both groups by a mean -2.31 ( 95 % CI , -3.24 to -1.38 ) in the treatment group and -1.46 ( 95 % CI , -2.33 to -0.60 ) in the placebo group , with no significant differences at any time . The percentage of cartilage volume decreased by the same extent in both groups ( mean , -4.30 ; 95 % CI , -5.48 to -3.12 vs mean , -4.25 ; 95 % CI , -6.12 to -2.39 ) ( P = .96 ) . There were no differences in any of the secondary clinical end points . CONCLUSION AND RELEVANCE Vitamin D supplementation for 2 years at a dose sufficient to elevate 25-hydroxyvitamin D plasma levels to higher than 36 ng/mL , when compared with placebo , did not reduce knee pain or cartilage volume loss in patients with symptomatic knee OA . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00306774",
"IMPORTANCE Low vitamin D status is linked to increased mortality and morbidity in patients who are critically ill . It is unknown if this association is causal . OBJECTIVE To investigate whether a vitamin D3 treatment regimen intended to restore and maintain normal vitamin D status over 6 months is of health benefit for patients in ICUs . DESIGN , SETTING , AND PARTICIPANTS A r and omized double-blind , placebo-controlled , single-center trial , conducted from May 2010 through September 2012 at 5 ICUs that included a medical and surgical population of 492 critically ill adult white patients with vitamin D deficiency ( ≤20 ng/mL ) assigned to receive either vitamin D3 ( n = 249 ) or a placebo ( n = 243 ) . INTERVENTIONS Vitamin D3 or placebo was given orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months . MAIN OUTCOMES AND MEASURES The primary outcome was hospital length of stay . Secondary outcomes included , among others , length of ICU stay , the percentage of patients with 25-hydroxyvitamin D levels higher than 30 ng/mL at day 7 , hospital mortality , and 6-month mortality . A predefined severe vitamin D deficiency ( ≤12 ng/mL ) subgroup analysis was specified before data unblinding and analysis . RESULTS A total of 475 patients were included in the final analysis ( 237 in the vitamin D3 group and 238 in the placebo group ) . The median ( IQR ) length of hospital stay was not significantly different between groups ( 20.1 days [ IQR , 11.1 - 33.3 ] for vitamin D3 vs 19.3 days [ IQR , 11.1 - 34.9 ] for placebo ; P = .98 ) . Hospital mortality and 6-month mortality were also not significantly different ( hospital mortality : 28.3 % [ 95 % CI , 22.6%-34.5 % ] for vitamin D3 vs 35.3 % [ 95 % CI , 29.2%-41.7 % ] for placebo ; hazard ratio [ HR ] , 0.81 [ 95 % CI , 0.58 - 1.11 ] ; P = .18 ; 6-month mortality : 35.0 % [ 95 % CI , 29.0%-41.5 % ] for vitamin D3 vs 42.9 % [ 95 % CI , 36.5%-49.4 % ] for placebo ; HR , 0.78 [ 95 % CI , 0.58 - 1.04 ] ; P = .09 ) . For the severe vitamin D deficiency subgroup analysis ( n = 200 ) , length of hospital stay was not significantly different between the 2 study groups : 20.1 days ( IQR , 12.9 - 39.1 ) for vitamin D3 vs 19.0 days ( IQR , 11.6 - 33.8 ) for placebo . Hospital mortality was significantly lower with 28 deaths among 98 patients ( 28.6 % [ 95 % CI , 19.9%-38.6 % ] ) for vitamin D3 compared with 47 deaths among 102 patients ( 46.1 % [ 95 % CI , 36.2%-56.2 % ] ) for placebo ( HR , 0.56 [ 95 % CI , 0.35 - 0.90 ] , P for interaction = .04 ) , but not 6-month mortality ( 34.7 % [ 95 % CI , 25.4%-45.0 % ] for vitamin D3 vs 50.0 % [ 95 % CI , 39.9%-60.1 % ] for placebo ; HR , 0.60 [ 95 % CI , 0.39 - 0.93 ] , P for interaction = .12 ) . CONCLUSIONS AND RELEVANCE Among critically ill patients with vitamin D deficiency , administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay , hospital mortality , or 6-month mortality . Lower hospital mortality was observed in the severe vitamin D deficiency subgroup , but this finding should be considered hypothesis generating and requires further study . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01130181",
"AIMS To compare depressive symptoms in participants with low and high serum 25-hydroxyvitamin D ( 25(OH)D ) levels and to examine whether supplementation with vitamin D(3 ) would improve symptoms in those with low serum 25(OH)D levels . METHOD Participants with low 25(OH)D levels were r and omised to either placebo or 40 000 IU vitamin D(3 ) per week for 6 months . Individuals with high serum 25(OH)D levels were used as nested controls . Depressive symptoms were evaluated with the Beck Depression Inventory , Hospital Anxiety and Depression Scale , Seasonal Pattern Assessment Scale and Montgomery-Åsberg Depression Rating Scale . The study was registered at Clinical Trials.gov ( NCT00960232 ) . RESULTS Participants with low 25(OH)D levels ( n = 230 ) at baseline were more depressed ( P participants with high 25(OH)D levels ( n = 114 ) . In the intervention study no significant effect of high-dose vitamin D was found on depressive symptom scores when compared with placebo . CONCLUSIONS Low levels of serum 25(OH)D are associated with depressive symptoms , but no effect was found with vitamin D supplementation"
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There existed systematic review on studies investigating the association between hip fractures and external risk factors including meteorological factors . Albeit the fact that most serious common fall injury is a hip fracture , it can not account for all injuries forms of fall . There was a lack of systematic review covering all fall-related injury or deaths to thoroughly summarise meteorological aspects of fall . This study aim ed to systematic ally review epidemiological studies of fall and fall-related circumstances without restriction to hip fracture . A systematic search in three data bases , namely PubMed , CINAHL Plus and EMBASE , was performed . Search es in two Chinese data bases named the Wanfang Med Online and the China Journal Net were done in addition . A total of 29 studies were identified . The study site , fall cases identification , meteorological factors and findings of all the selected studies were being extracted . The quality of the studies was critically appraised . We identified some of the environmental risk factors to fall among those studies . Ranging from the lower ambient temperature , the presence of snow cover , seasonal factors , and time of the day to location of fall , these factors have different levels of impact related to higher incidence or mortality of fall . To conclude , a better underst and ing of injury mechanisms is a prerequisite for preventive interventions
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"Climatic conditions may affect the incidence of fractures and fall deaths . Analysis of national fatality data shows that among white women , those living in colder climates have higher rates of fall deaths . Fall deaths increase in winter in all regions , but especially so in colder states . In a prospect i ve cohort study of 96,506 predominantly white female nurses 35 - 59 years of age , we found that , after controlling for personal and lifestyle characteristics , those women residing in colder climate also had a higher incidence of hip and forearm fracture . In colder states , fracture rates were substantially higher in winter than in summer . A cold climate appears to be a significant risk factor for both fractures and fall deaths among white women , particularly as they age",
"Objectives . Falls among old people is a well-documented phenomenon ; however , falls among people living in the community and receiving home help services have been under- research ed . The aim of this study was to investigate the incidence , including possible seasonal variation , circumstances and injuries related to falls among community living home help receivers , and to investigate whether fall incidence is associated with the type and amount of home help services received . Study design . Prospect i ve cohort study . Methods . All 614 persons aged 65 and over who were living in a particular northern Swedish community and receiving municipality home help were included . Data on age , sex and home help service use were collected from home help service records , and falls were reported by staff on report forms specifically design ed for the study . Results . A total number of 264 falls were recorded among 122 participants . The overall fall incidence was 626 per 1,000 PY , and incidence rate ratios were significantly correlated to the total amount of services used ( p&0.001 ) , as well as to the degree of help for I-ADL needs ( p&0.001 ) , P-ADL needs ( p&0.001 ) and escort service ( p=0.007 ) . The proportion of falls reported as result ing in injury was 33 % . The monthly fall incidence was significantly associated to daylight photoperiod , however it was not associated to temperature . Conclusions . Fall incidence among home help receivers aged 65 and over seems correlated to the amount of services they receive . This is probably explained by the fact that impairments connected to ADL limitations and home help needs also are connected to an increased risk of falls . This implies that fall prevention should be considered when planning home help care for old people with ADL limitations . Further research on the connection between daylight photoperiod and fall incidence in population s at different latitudes is needed",
"Objective —To investigate seasonal variations in the incidence of fall related fractures among people 65 years and older . Population and methods —A prospect i ve , population based cohort study was performed on people aged 65 years and older followed up from 1990 to 1997 , a total of 459 904 person years . Cases were identified through a prospect i ve registration system . Results —There were 10 992 ( 2390 per 100 000 person years ) fall related fractures . The risk was higher in the colder seasons ( October through March ) among people aged 65–79 years ( relative risk ( RR ) = 1.39 , 95 % confidence interval ( CI ) 1.32 to 1.47 ) and in people aged 80 years and older ( RR = 1.17 , 95 % CI 1.09 to 1.22 ) . For arm fractures , the RR was 1.69 ( 95 % CI 1.56 to 1.83 ) among people aged 65–79 years and 1.30 ( 95 % CI 1.13 to 1.43 ) among those aged 80 years and older . The RR for hip fractures was 1.27 ( 95 % CI 1.15 to 1.37 ) among people aged 65–79 years and 1.08 ( 95 % CI 1.00 to 1.15 ) for people aged 80 years and older . Slipping on ice and snow seems to entirely explain the excessive incidence of hip and arm fractures during winter months . Conclusion —Season affects the incidence of all types of fractures in elderly people . Slipping on ice and snow seems to be a causal mechanism behind the seasonal effect . Preventive measures targeting this causal mechanism are likely to reduce the risk of fracture , but the size of the effect is difficult to estimate with certainty",
"The type of environmental hazards implicated in the aetiology of a consecutive series of 787 hip-fracture patients was prospect ively studied . Most falls occurred between 09 h 00 and midday and there was no seasonal variation . Fifty-one different environmental hazards were implicated in the aetiology of the fall for 58 % of patients . The nature of environmental hazards was diverse , implying that measures to reduce the risk of falls due to these factors are unlikely to lead to a significant reduction in the incidence of hip fractures",
"BACKGROUND knowledge of the circumstances and consequences of falls in older adults is important for underst and ing the aetiology of falls as well as for effective clinical assessment and design of fall prevention strategies . Such data , however , are relatively scarce , especially in community-dwelling elders . METHOD accidental falls ( including their circumstances and consequences ) occurring in 96 male and female participants between 60 and 88 years of age were monitored prospect ively for 1 year . After the monitoring period , participants were divided into three groups based on fall status : non-fallers ( n = 46 ) , one-time fallers ( n = 27 ) and recurrent fallers ( n = 23 ) . Frequency distributions were created for selected circumstances and consequences of falls and the prevalence of these consequences were examined . RESULTS 50 participants ( 52 % ) fell during the 1 year period , amassing 91 falls . Trips and slips were the most prevalent causes of falls , accounting for 59 % of falls . Falls most often occurred during the afternoon and while subjects walked on level or uneven surfaces . Fallers most commonly attributed falls to hurrying too much . Fractures result ed from five of the 91 falls and eight other falls result ed in soft tissue injuries that required treatment by a physician . There were no differences between one-time and recurrent fallers in the circumstances and consequences of falls . However , several notable differences were found between men ( n = 20 ) and women ( n = 30 ) who fell . Falls by men most often result ed from slips whereas falls by women most often result ed from trips . Moreover , women and men differed in the time of the year in which falls occurred , with men falling most often during winter and women during summer . CONCLUSIONS the results of this study provide insight into the circumstances and consequences of falls among independent community-dwelling older adults and suggest some possible ways of preventing falls . Preventive services , however , should not solely target recurrent fallers , nor should the type of services necessarily differ for one-time and recurrent fallers",
"INTRODUCTION This is the first prospect i ve longitudinal study carried out in a Chinese elderly population with the objective of identifying the incidence and predictors of falls . MATERIAL S AND METHODS This is a population -based cohort study in Hong Kong with 1517 ambulatory elderly Chinese recruited using a multi-stage sampling method . Baseline data on demographic , comorbid diseases , drugs , Activities of Daily Living ( ADL ) [ Barthel Index and Lawton 's Instrumental Activities of Daily Living ( IADL ) ] , Geriatric Depression Scale ( GDS-15 ) , cognitive assessment by the Abbreviated Mental Test ( AMT ) , fear of falling , self-perceived mobility problem , h and grip strength , lower limb power , balance and gait tests were performed . Every subject was followed up for 1 year . RESULTS Four hundred and one falls occurred in 294 fallers ( 19.3 % ) over 1 year of follow-up . The prevalence of falls and recurrent falls were 19.3 % and 4.75 % , respectively . The incidences of falls ( i.e. , the fall events ) were 220 , 324 and 270 per 1000 person-years for men , women and both gender , respectively . The independent predictors of falls were previous history of falls , advancing age , Parkinson 's disease , knee extension power and gait speed . The independent predictors of recurrent falls were previous history of falls , self-perceived mobility problem , the knee extension strength and the Total Mobility Score of the Tinetti Balance and Gait Evaluation . CONCLUSIONS The incidence of falls in the Chinese elderly was 270 per 1000 person-years . History of falls , old age , Parkinson 's disease , decreased lower limb power and impairment in balance and gait function were important independent predictors of falls or recurrent falls in the Chinese elderly . Effective fall prevention programmes targeted at improving these risk factors for falls should be developed for the Chinese elderly in Hong Kong and Asia",
"A prospect i ve analysis was performed on 832 patients to determine the circumstances surrounding falls leading to hip fracture within a homogenous , elderly urban population . Special emphasis was placed on the season of year , time of day , location of fall , and other circumstances in which the fracture occurred . All patients were community dwelling , cognitively intact , previously ambulatory elderly who sustained a femoral neck or intertrochanteric fracture . Most fractures occurred at home , particularly in patients who were older , less healthy , and poorer ambulators . More than 75 % of fractures result ed from a fall while the patient was st and ing or walking . Most falls occurred during daylight hours with a peak seen in the afternoon . No seasonal variation in the incidence of hip fractures was observed",
"BACKGROUND Although the circumstances surrounding falls among community-dwelling elderly people have been described by numerous studies , there are few that have reported falls in the northern regions of Japan , such as Hokkaido , that experience a severe winter with heavy snow . As a preliminary study , we surveyed the circumstances of falls among community-dwelling elderly people in Hokkaido with a self-administered question naire . METHODS Residents living in private homes throughout Hokkaido were r and omly contacted by telephone and those aged over 65 years were recruited for this study . In all , 1000 subjects participated in the survey . A question naire was used to obtain the histories of falls , including the number of falls , the season and place of occurrence , and the cause of the falls in the year prior to the survey . RESULTS Of the 1000 subjects , 849 ( 436 men and 413 women ; mean age , 73.0 years ) completed the question naire . Among the 849 subjects , 277 ( 32.6 % ) fell at least once during the year of the survey . Of these 277 subjects , 155 subjects ( 56.0 % ) experienced two or more falls in the year . Approximately 60 % of the falls occurred during the winter . The most common location where falls occurred was on roads or sidewalks , and slipping was the most prevalent cause . CONCLUSION Our findings revealed several aspects regarding the circumstances surrounding falls among community-dwelling elderly people in Hokkaido",
"Six hours of mild surface cooling in moving air at 24 degrees C with little fall in core temperature ( 0.4 degree C ) increased the packed cell volume by 7 % and increased the platelet count and usually the mean platelet volume to produce a 15 % increase in the fraction of plasma volume occupied by platelets . Little of these increases occurred in the first hour . Whole blood viscosity increased by 21 % ; plasma viscosity usually increased , and arterial pressure rose on average from 126/69 to 138/87 mm Hg . Plasma cholesterol concentration increased , in both high and low density lipoprotein fractions , but values of total lipoprotein and lipoprotein fractions were unchanged . The increases in platelets , red cells , and viscosity associated with normal thermoregulatory adjustments to mild surface cooling provide a probable explanation for rapid increases in coronary and cerebral thrombosis in cold weather . The raised arterial pressure and possibly cholesterol concentration may contribute to slower components of the increased thrombosis",
"Mean deep body temperature fell by 0.4 + /- 0.1 ( SD ) degrees C in five sedentary , clothed 63 - 70 year old men and by 0.1 + /- 0.1 degrees C in four young adults after 2 h exposure in still air at 6 degrees C ( P less than 0.001 ) . The mean increase in systolic and diastolic pressure was significantly greater ( P less than 0.002 ) in the older subjects ( 24 + /- 4 mmHg systolic , 13 + /- 4 mmHg diastolic ) than in the young ( 14 + /- 6 mmHg systolic , 7 + /- 3 mmHg diastolic ) after 2 h at 6 degrees C. A small rise in blood pressure occurred in the older men at 12 degrees C , but there was no increase in either group at 15 degrees C. The association of variables is particularly marked between systolic blood pressure and core temperature changes at 6 degrees C. There were no appreciable cold-adaptive changes in blood pressure or thermoregulatory responses after 7 - 10 days repeated exposure to 6 degrees C for 4 h each day . Blood pressure elevation in the cold was slower but more marked in the older men . These changes in blood pressure may provide a possible basis for delineating low domestic limiting temperature conditions",
"As the elderly population increases and they lead more active and healthy lifestyles , their exposure to the threats of injury multiply . Undoubtedly , the geriatric population will comprise a growing percentage of trauma patients . The role of alcohol and drug use in geriatric trauma has not been clearly defined . The purpose of this study is to determine the incidence of alcohol and illicit drug use in association with mechanism of injury in all elderly trauma patients presenting to level I and II trauma centers in the State of Illinois over 3 years . A retrospective analysis was performed on 3 years of data ( January 1 , 1994 to December 31 , 1996 ) , provided by the Illinois Department of Public Health as the Illinois Trauma Registry , which describes consecutive trauma patients presenting to level I and II trauma facilities in the State of Illinois . During the study period , there were a total of 134,846 trauma patient entries . Of these 32,382 ( 24.0 % ) were for patients 65 years of age or older . In those patients 65 and older , 1699 ( 5.2 % ) were tested for the presence of alcohol and 845 ( 49.7 % ) tested positive . Of the elderly patients who tested positive for alcohol , 71.8 % were considered intoxicated ( BAC > 80 mg/dL ) . Urine toxicology screens were performed on 1785 ( 5.5 % ) elderly trauma patients , and 208 ( 11.6 % ) were positive . Besides alcohol , benzodiazipines and opiates were the most frequently detected drugs . For elderly patients under the influence of alcohol falls ( 49.5 % ) and motor vehicle crashes ( 36.7 % ) were the most common mechanism of injury . For geriatric patients testing negative for alcohol , motor vehicle crashes were a much more common mechanism of injury than falls ( 65.0 % v 25.1 % ) . Falls were a much more common cause of injury in elderly patients using alcohol than in those not using alcohol . Alcohol and substance abuse are possibly significant factors in geriatric trauma . Although only 5 % of elderly trauma patients were tested for alcohol , nearly half had alcohol present on presentation to a trauma center , and the majority of these patients were intoxicated . Prospect i ve studies are needed to determine the true incidence of alcohol use/abuse in the geriatric trauma population and the need for routine alcohol screening of these patients . Detection of alcohol abuse in elderly trauma patients could help identify individuals in need of counseling and rehabilitative treatment . It may also reduce future injuries in these patients",
"In a prospect i ve study of falls in 761 subjects 70 years and over an increase in the rate of falls in winter was observed in women but not men . When the daily minimum temperature fell to 1 degrees C or less the relative risk of falling in women increased to 1.53 ( 95 % confidence intervals 1.21 - 1.84 ) . We discuss measures to decrease this seasonal increase in the rate of falls"
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Endometriosis is a chronic gynecological disease characterized by sustained painful symptoms that are responsible for a decline in the quality of life of sufferers . Conventional treatment includes surgical and pharmacological therapy aim ing at reducing painful symptoms . This study aim ed to evaluate pain levels in women with endometriosis , focusing on the influence of conventional treatment in controlling this variable . To do so , a literature search was conducted in the Medline / Pubmed data bases , with 119 scientific articles found . After applying the inclusion and exclusion criteria , 27 were selected for reading and elaboration of this review . Thus , 9 studies evaluated the contribution of surgery , 17 the use of drugs to reduce pain levels in patients with endometriosis and one assessed surgical and medical treatment . The main results of these search es are presented and discussed in this revision . Surgery and the use of drugs provided reduced pain scores in patients with endometriosis but nevertheless exhibit disadvantages , such as risk of recurrence and side effects , respectively . Treatment of endometriosis is , therefore , a challenge for gynecologists and patients , as they must select the best therapeutic approach for this disease . However , improved quality of life in these patients has been obtained with the use of conventional treatment
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"OBJECTIVE Up to now limited attention has been given to the medical treatment of bowel endometriosis . This study evaluates the efficacy of aromatase inhibitors and norethisterone acetate in treating pain and gastrointestinal symptoms caused by bowel endometriosis . STUDY DESIGN This prospect i ve pilot study included six women with colorectal endometriosis ; all women had intestinal nodules infiltrating at least the muscularis propria of the bowel and did not have a stenosis of the bowel lumen > 60 % ; the patients suffered from pain and intestinal symptoms . The study subjects received letrozole ( 2.5 mg/day ) and norethisterone acetate ( 2.5 mg/day ) continuously for 6 months . The presence and intensity of symptoms were evaluated before starting the treatment , and after 3 and 6 months of treatment . RESULTS The double-drug regimen improved pain , non-menstrual pelvic pain , deep dyspareunia , dyschezia , symptoms mimicking diarrhoea-predominant irritable bowel syndrome , intestinal cramping , abdominal bloating and passage of mucus in the stools , and 67 % of the patients declared that the treatment improved their gastrointestinal symptoms . CONCLUSIONS The administration of letrozole and norethisterone acetate reduces pain and gastrointestinal symptoms of women with colorectal endometriosis , particularly when patients suffer from symptoms mimicking diarrhoea-predominant irritable bowel syndrome",
"OBJECTIVE To examine the effect on pain and quality of life for women with all stages of endometriosis undergoing laparoscopic surgery compared with placebo surgery . DESIGN A r and omized , blinded , crossover study . SETTING A tertiary referral unit in a district general hospital . PATIENT(S ) Thirty-nine women with histologically proven endometriosis completed the 12-month study . INTERVENTION(S ) Women were r and omized to receive initially either a diagnostic procedure ( the delayed surgical group ) or full excisional surgery ( the immediate surgery group ) . After 6 months , repeat laparoscopy was performed , with removal of any pathology present . MAIN OUTCOME MEASURE(S ) The end points were changes from baseline values of visual analogue pain scores , vali date d quality -of-life instruments ( EQ-5D and SF-12 ) , and sexual activity question naire scores . Patients and assessors of outcomes were blinded to the treatment-group assignment . RESULT ( S ) Significantly more of the 39 women operated on according to protocol reported symptomatic improvement after excisional surgery than after placebo : 16 of 20 ( 80 % ) vs. 6 of 19 ( 32 % ) ; chi(2)(1 ) = 9.3 . Other aspects of quality of life were also significantly improved 6 months after excisional surgery but not after placebo . Progression of disease at second surgery was demonstrated for women having only an initial diagnostic procedure in 45 % of cases , with disease remaining static in 33 % and improving in 22 % of cases . Nonresponsiveness to surgery was reported in 20 % of cases . CONCLUSION ( S ) Laparoscopic excision of endometriosis is more effective than placebo at reducing pain and improving quality of life . Surgery is associated with a 30 % placebo response rate that is not dependent on severity of disease . Approximately 20 % of women do not report an improvement after surgery for endometriosis",
"Background When aromatase inhibitors are used to treat premenopausal women with endometriosis , additional drugs should be used to effectively down-regulate gonadal estrogen bio synthesis . This r and omized prospect i ve open-label study compared the efficacy in treating pain symptoms and the tolerability of letrozole combined with either norethisterone acetate or triptorelin . Methods Women with pain symptoms caused by rectovaginal endometriosis were treated with letrozole ( 2.5 mg/day ) and were r and omized to also receive either oral norethisterone acetate ( 2.5 mg/day ; group N ) or intramuscular injection of triptorelin ( 11.25 mg every 3 months ; group T ) . The scheduled length of treatment was 6 months . A visual analogue scale and a multidimensional categorical rating scale were used to assess the severity of pain symptoms . The volume of the endometriotic nodules was estimated by ultrasonography using virtual organ computer-aided analysis . Adverse effects of treatment were recorded . Results A total of 35 women were r and omized between the two treatment protocol s. Significantly more patients in group N rated their treatment as satisfactory or very satisfactory ( 64.7 % ) as compared to group T ( 22.2 % ; p = 0.028 ) . The intensity of both non-menstrual pelvic pain and deep dyspareunia significantly decreased during treatment in both study groups , though no statistically meaningful difference between the two groups was apparent . Reduction in the volume of endometriotic nodules was significantly greater in group T than in group N. Interruption of treatment due to adverse effects significantly differed between the groups , with 8 women in group T ( 44.4 % ) and 1 woman in group N ( 5.9 % ) interrupting treatment ( p = 0.018 ) . Similarly , 14 women included in group T ( 77.8 % ) and 6 women included in group N ( 35.3 % ) experienced adverse effects of treatment ( p = 0.018 ) . During treatment , mineral bone density significantly decreased in group T but not in group N. Conclusions Aromatase inhibitors reduce the intensity of endometriosis-related pain symptoms . Combining letrozole with oral norethisterone acetate was associated with a lower incidence of adverse effects and a lower discontinuation rate than combining letrozole with triptorelin",
"This open-label prospect i ve study evaluated the efficacy of letrozole ( 2.5 mg/day ) combined with norethisterone acetate ( 2.5 mg/day ) in the treatment of pain symptoms related to the presence of rectovaginal endometriosis . The treatment significantly and quickly decreased the intensity of symptoms , but pain recurred at 3-month follow-up ; five women underwent surgery during the follow-up , and histologic examination of rectovaginal nodules revealed the presence of active endometriotic lesions",
"BACKGROUND The objective of this multicentre r and omized , controlled clinical trial was to compare the efficacy of a levonorgestrel-releasing intrauterine system ( LNG-IUS ) and a depot-GnRH-analogue in the control of endometriosis-related pain over a period of six months . METHODS Eighty-two women , 18 to 40 years of age ( mean 30 years ) , with endometriosis , dysmenorrhoea and /or CPP , were r and omized using a computer-generated system of sealed envelopes into either LNG-IUS ( n = 39 ) or GnRH analogue ( n = 43 ) treatment groups at three university centres . Daily scores of endometriosis-associated CPP were evaluated using the Visual Analogue Scale ( VAS ) , daily bleeding score was calculated from bleeding calendars , and improvement in quality of life was evaluated using the Psychological General Well-Being Index Question naire ( PGWBI ) . The pain score diary was based on the VAS in which women recorded the occurrence and intensity of pain on a daily basis . A monthly score was calculated from the result of the sum of the daily scores divided by the number of days in each observation period . RESULTS CPP decreased significantly from the first month throughout the six months of therapy with both forms of treatment and there was no difference between the groups ( P > 0.999 ) . In both treatment groups , women with stage III and IV endometriosis showed a more rapid improvement in the VAS pain score than women with stage I and II of the disease ( P LNG-IUS users had a higher bleeding score than GnRH-analogue users at all time points of observation with 34 % and 71 % of patients in the LNG-IUS and GnRH-analogue groups , respectively , reporting no bleeding during the first treatment month , and 70 % and 98 % reporting no bleeding during the sixth month . No difference was observed between groups with reference to improvement in quality of life . CONCLUSIONS Both , the LNG-IUS and the GnRH-analogue were effective in the treatment of CPP-associated endometriosis , although no differences were observed between the two treatments . Among the additional advantages of the LNG-IUS is the fact that it does not provoke hypoestrogenism and that it requires only one medical intervention for its introduction every 5 years . This device could therefore become the treatment of choice for CPP-associated endometriosis in women who do not wish to conceive",
"INTRODUCTION Deep infiltrating endometriosis ( DIE ) is a form of endometriosis in which the lesion penetrates for more than 5 mm under the peritoneal surface . It is a chronic disease which can impair women 's sexual function . There is a growing body of evidence supporting combined surgical/medical treatment in the management of DIE . AIMS The aims of this article are to evaluate the impact of the laparoscopic full excision of endometriosis and postoperative combined oral contraceptives ( COC ) administration on sexual function in patients with DIE and to compare sexual function outcomes of women su bmi tted to intestinal resection and nodule excision . METHODS It is a prospect i ve cohort study in a tertiary care university hospital on 106 sexually active women , with histologically confirmed DIE , managed by laparoscopy and subsequent COC therapy for 6 months . Patients filled preoperatively and 6-month postoperatively a quality of sexual life question naire , the Sexual Health Outcomes in Women Question naire ( SHOW-Q ) and they ranked their symptom intensity using a 10-point visual analogue scale ( VAS ) . MAIN OUTCOME MEASURES Sexual function was measured through the SHOW-Q scores and pain symptoms through VAS scores . Intraoperative details , type of intervention and perioperative complications were noted . RESULTS Six months after surgery and postoperative COC treatment , a significant improvement was observed in the SHOW-Q domains of pelvic problem interference , sexual satisfaction and desire ( P orgasm area of the sexual functioning ( P=0.7 ) . No significant difference was found in SHOW-Q scores between patients su bmi tted to intestinal resection and patients su bmi tted to intestinal nodule excision ( P>0.05 ) . CONCLUSIONS Sexual desire , satisfaction with sex and pelvic problem interference with intercourse are significantly improved after 6 months from laparoscopic excision of DIE combined with postoperative COC therapy . No difference in sexual outcomes was detected between patients su bmi tted to intestinal resection and nodule excision ",
"OBJECTIVE To assess the impact of endometriosis on health-related quality of life ( HRQoL ) and work productivity . DESIGN Multicenter cross-sectional study with prospect i ve recruitment . SETTING Sixteen clinical centers in ten countries . PATIENT(S ) A total of 1,418 premenopausal women , aged 18 - 45 years , without a previous surgical diagnosis of endometriosis , having laparoscopy to investigate symptoms or to be sterilized . INTERVENTION(S ) None . MAIN OUTCOME MEASURE(S ) Diagnostic delay , HRQoL , and work productivity . RESULT ( S ) There was a delay of 6.7 years , principally in primary care , between onset of symptoms and a surgical diagnosis of endometriosis , which was longer in centers where women received predominantly state-funded health care ( 8.3 vs. 5.5 years ) . Delay was positively associated with the number of pelvic symptoms ( chronic pelvic pain , dysmenorrhoea , dyspareunia , and heavy periods ) and a higher body mass index . Physical HRQoL was significantly reduced in affected women compared with those with similar symptoms and no endometriosis . Each affected woman lost on average 10.8 hours ( SD 12.2 ) of work weekly , mainly owing to reduced effectiveness while working . Loss of work productivity translated into significant costs per woman/week , from US$ 4 in Nigeria to US$ 456 in Italy . CONCLUSION ( S ) Endometriosis impairs HRQoL and work productivity across countries and ethnicities , yet women continue to experience diagnostic delays in primary care . A higher index of suspicion is needed to expedite specialist assessment of symptomatic women . Future research should seek to clarify pain mechanisms in relation to endometriosis severity",
"Background Deep infiltrating endometriosis ( DIE ) can affect importantly patients ' quality of life ( QOL ) . The aim of this study is to evaluate the impact of the laparoscopic management of DIE on QOL after six months from treatment . Methods It is a prospect i ve cohort study . In a tertiary care university hospital , between April 2008 and December 2009 , 100 patients underwent laparoscopic management of DIE and completed preoperatively and 6-months postoperatively a QOL question naire , the short form 36 ( SF-36 ) . Quality of life was measured through the SF-36 scores . Intra-operative details of disease site , number of lesions , type of intervention , period of hospital stay and peri-operative complications were noted . Results Six months postoperatively all the women had a significant improvement in every scale of the SF-36 ( p Among patients with intestinal DIE , significant differences in postoperative scores of SF-36 were not detected between patients su bmi tted to nodule shaving and segmental resection ( p > 0.05 ) . There was no significant difference in the SF-36 scores at 6 months from surgery between patients who received postoperative medical treatment and patients who did not ( p > 0.05 ) . Conclusions Laparoscopic excision of DIE lesions significantly improves general health and psycho-emotional status at six months from surgery without differences between patients su bmi tted to intestinal segmental resection or intestinal nodule shaving ",
"BACKGROUND This pilot study evaluates the efficacy of norethisterone acetate in treating pain and gastrointestinal symptoms of women with colorectal endometriosis . METHODS This prospect i ve study included 40 women with colorectal endometriosis , who had pain and gastrointestinal symptoms . Patients received norethisterone acetate ( 2.5 mg/day ) for 12 months ; in case of breakthrough bleeding , the dose of norethisterone acetate was increased by 2.5 mg/day . The degree of patient satisfaction with treatment ( primary end-point ) and the changes in symptoms ( secondary end-point ) were evaluated . Side effects of treatment were recorded . RESULTS Norethisterone acetate determined a significant improvement in the intensity of chronic pelvic pain , deep dyspareunia , dyschezia . Treatment determined the disappearance of symptoms related to the menstrual cycle ( dysmenorrhea , constipation during the menstrual cycle , diarrhoea during the menstrual cycle and cyclical rectal bleeding ) . The severity of diarrhoea , intestinal cramping and passage of mucus significantly improved during treatment . On the contrary , the administration of norethisterone acetate did not determine a significant effect on constipation , abdominal bloating and feeling of incomplete evacuation after bowel movements . At the completion of treatment , 57 % of the patients with diarrhoea or diarrhoea during the menstrual cycle continued the treatment with norethisterone acetate compared with 17 % of the patients with constipation or constipation during the menstrual cycle . CONCLUSIONS In some patients with bowel endometriosis , the administration of norethisterone acetate may determine a relief of pain and gastrointestinal symptoms . This therapy has greater benefits in patients with gastrointestinal symptoms related to the menstrual cycle , diarrhoea and intestinal cramping",
"Objective . Limited attention has been focused on the medical treatment of bowel endometriosis . This study evaluates the efficacy of administration of a continuous low‐dose oral contraceptive in treating pain and other symptoms associated with colorectal endometriotic nodules , as evaluated by rectal endoscopic ultrasonography . Design . Prospect i ve observational study . Setting . Academic Department of San Raffaele Scientific Institute , Obstetrics and Gynecology Unit . Population . Symptomatic women of reproductive age ( n=26 ) with colorectal nodules infiltrating at least the bowel muscularis propria and without a stenosis > 50 % . In 31 % of the patients , endoscopic ultrasonography permitted diagnosis of nodules located more than 10 cm from the anal rim . Methods . Patients received a continuous low‐dose oral contraceptive containing 15 μg ethinylestradiol and 60 μg gestodene for 12 months . Subjective symptoms were prospect ively evaluated , and nodule volumes were monitored using endoscopic ultrasonography . Main outcome measures . Nodule measurements were performed at baseline and after 12 months of treatment . Symptoms at the start and after 12 months were evaluated . Results . A significant improvement in the intensity of all the considered symptoms ( dysmenorrhea , non‐menstrual pelvic pain , deep dyspareunia and painful defecation ) was seen when evaluated by a visual analog scale . A reduction in terms of both diameter ( mean reduction 26 % ) and volume of the nodules ( mean reduction 62 % ) was observed after a 12 month period . Conclusions . A continuous low‐dose oral contraceptive therapy may reduce bowel endometriosis‐associated symptoms . In addition , this therapy induces a significant volumetric reduction of colorectal plaques when evaluated by endoscopic ultrasonography",
"BACKGROUND This study investigates the outcomes for women up to 5 years after laparoscopic excision of endometriosis . METHODS In this prospect i ve observational cohort study , 254 women with chronic pelvic pain were referred to two units specializing in minimal access surgical management of endometriosis . Of these , 216 women underwent surgical assessment and 176 were confirmed to have endometriosis . Question naires and visual analogue scale ( VAS ) scores for dysmenorrhoea , non-menstrual pelvic pain , dyspareunia and dyschesia as well as quality of life instruments ; the EQ-5Dindex and EQ-5Dvas , Short-Form 12 ( SF-12 ) and sexual activity question naires were completed pre-operatively . Intra-operative details of revised American Fertility Society ( rAFS ) stage , site of disease , associated tests , duration of surgery and complications were noted . Follow-up was performed by postal question naire and chart review . For women who had further surgery , rAFS stage , site of disease , other procedures and histology were all recorded . RESULTS Pain scores were all significantly reduced at 2 - 5 years for dysmenorrhoea ( median VAS baseline versus follow-up 2 - 5 years ) ; 9 versus 3.3 ( P non-menstrual pelvic pain 8 versus 3 ( P dyspareunia 7 versus 0 ( P dyschesia 7 versus 2 ( P Quality of life was improved for the EQ-5Dindex ( P = 0.008 and the EQ-5Qvas ( P = 0.03 ) and for sexual function with pleasure ( P = 0.001 ) and habit ( P = 0.012 ) being improved and discomfort being decreased ( P = 0.001 ) . The chance of requiring further surgery as determined by the Kaplan-Meier survival curve was 36 % . A rAFS score of > 70 was predictive of requiring further surgery ( P = 0.03 ) . Of women who had further surgery , endometriosis was found histologically in 68 % . CONCLUSIONS Laparoscopic excision of endometriosis significantly reduces pain and improves quality of life for up to 5 years . The probability of requiring further surgery is 36 % . Return of pain following laparoscopic excision is not always associated with clinical evidence of recurrence",
"BACKGROUND This study aim ed to calculate costs and health-related quality of life of women with endometriosis-associated symptoms treated in referral centres . METHODS A prospect i ve , multi-centre , question naire-based survey measured costs and quality of life in ambulatory care and in 12 tertiary care centres in 10 countries . The study enrolled women with a diagnosis of endometriosis and with at least one centre-specific contact related to endometriosis-associated symptoms in 2008 . The main outcome measures were health care costs , costs of productivity loss , total costs and quality -adjusted life years . Predictors of costs were identified using regression analysis . RESULTS Data analysis of 909 women demonstrated that the average annual total cost per woman was € 9579 ( 95 % confidence interval € 8559-€10 599 ) . Costs of productivity loss of € 6298 per woman were double the health care costs of € 3113 per woman . Health care costs were mainly due to surgery ( 29 % ) , monitoring tests ( 19 % ) and hospitalization ( 18 % ) and physician visits ( 16 % ) . Endometriosis-associated symptoms generated 0.809 quality -adjusted life years per woman . Decreased quality of life was the most important predictor of direct health care and total costs . Costs were greater with increasing severity of endometriosis , presence of pelvic pain , presence of infertility and a higher number of years since diagnosis . CONCLUSIONS Our study invited women to report re source use based on endometriosis-associated symptoms only , rather than drawing on a control population of women without endometriosis . Our study showed that the economic burden associated with endometriosis treated in referral centres is high and is similar to other chronic diseases ( diabetes , Crohn 's disease , rheumatoid arthritis ) . It arises predominantly from productivity loss , and is predicted by decreased quality of life ",
"OBJECTIVE To compare the efficacy of leuprolide and continuous oral contraceptives in the treatment of endometriosis-associated pain . DESIGN Prospect i ve , r and omized , double-blind controlled trial . SETTING Academic medical centers in Rochester , New York , and Boston , Massachusetts . PATIENT(S ) Forty-seven women with endometriosis-associated pelvic pain . INTERVENTION(S ) Forty-eight weeks of either depot leuprolide , 11.25 mg IM every 12 weeks with hormonal add-back using norethindrone acetate 5 mg orally , daily ; or a generic monophasic oral contraceptive ( 1 mg norethindrone + 35 mg ethinyl estradiol ) given daily . MAIN OUTCOME MEASURE(S ) Biberoglu and Behrman ( B&B ) pain scores , numerical rating scores ( NRS ) , Beck Depression Inventory ( BDI ) , and Index of Sexual Satisfaction ( ISS ) . RESULT ( S ) Based on enrollment of 47 women r and omized to continuous oral contraceptives and to leuprolide , there were statistically significant declines in B&B , NRS , and BDI scores from baseline in both groups . There were no significant differences , however , in the extent of reduction in these measures between the groups . CONCLUSION ( S ) Leuprolide and continuous oral contraceptives appear to be equally effective in the treatment of endometriosis-associated pelvic pain",
"STUDY OBJECTIVE To describe the effect of fertility-sparing laparoscopic excision of endometriosis and bowel resection on clinical and quality -of-life outcomes . DESIGN Prospect i ve observational cohort study ( Canadian Task Force classification II-2 ) . SETTING Australian tertiary referral center for the surgical treatment of endometriosis . PATIENTS Seven consecutive patients with known endometriosis involving the bowel . INTERVENTION Laparoscopic resection of all endometriosis , including laparoscopic bowel resection with end-to-end anastomosis with or without temporary ileostomy . MEASUREMENTS AND MAIN RESULTS Preoperative and 12-month postoperative data were collected by use of visual analogue scores for dysmenorrhea , nonmenstrual pelvic pain , dyspareunia , and dyschezia . Vali date d research tools ( SF12 , EuroQOL , and Sexual Activity Question naire ) also assessed quality of life . Reduction in median pain scores at baseline was demonstrated and at 12 months after operation for dysmenorrhea 71 ( interquartile range 43 - 85 ) versus 5 ( 0 - 10 ) ; p=.028 , nonmenstrual pelvic pain 74 ( 48 - 85 ) versus 11 ( 0 - 18 ) ; p=.046 , dyspareunia 66 ( 0 - 98 ) versus 5 ( 0 - 8 ) ; p=.080 , and dyschezia 48 ( 20 - 64 ) versus 20 ( 0 - 40 ) ; p=.173 . All measures of quality of life were improved at 12 months after surgery , although not reaching statistical significance because of the small sample size . All three women wishing to conceive after operation have been successful , result ing in three live births at term . There were few complications associated with this surgery . CONCLUSION Fertility-sparing laparoscopic excision of endometriosis with bowel resection results in improvements in all aspects of pain and quality of life . Results appear to parallel published data for conservative resection of endometriosis not involving bowel . For women with severe endometriosis involving bowel , this surgical treatment provides a viable alternative to pelvic clearance and successfully maintains fertility",
"BACKGROUND The available data on effectiveness of aromatase inhibitors in treating pain symptoms related to endometriosis is limited . We compared the efficacy and tolerability of the aromatase inhibitor letrozole combined with norethisterone acetate versus norethisterone acetate alone in treating pain symptoms . METHODS This prospect i ve , open-label , non-r and omized trial included 82 women with pain symptoms caused by rectovaginal endometriosis . Patients received either a combination of letrozole and norethisterone acetate ( group L ) or norethisterone acetate alone ( group N ) for 6 months . Changes in pain symptoms during treatment and in the 12 months of follow-up were evaluated . Side effects of each treatment protocol were recorded . RESULTS Intensity of chronic pelvic pain and deep dyspareunia significantly decreased during treatment ( P intensity of chronic pelvic pain ( P deep dyspareunia ( P satisfied with treatment compared with 56.1 % in group L ( P = 0.49 ) . Pain symptoms recurred after the completion of treatment ; at 6-month follow-up no difference was observed in the intensity of pain symptoms between the groups . Adverse effects were more frequent in group L than in group N ( P = 0.02 ) . CONCLUSIONS The combination drug regimen was more effective in reducing pain and deep dyspareunia than norethisterone acetate ; however , letrozole caused a higher incidence of adverse effects , cost more and did not improve patients ' satisfaction or influence recurrence of pain",
"STUDY OBJECTIVE To estimate the quality of life of patients undergoing laparoscopic resection of a segment of the rectosigmoid for the treatment of deep infiltrating endometriosis with bowel involvement . DESIGN Prospect i ve application of the SF-36 Health Status Question naire to 151 women before and 1 year after surgical intervention ( Canadian Task Force Design Classification II ) . SETTING Department of Obstetrics and Gynecology , University of São Paulo Medical School , and Samaritano Hospital , São Paulo , Brazil . PATIENTS A total of 151 women ( mean age 34.05 ± 5.65 years ) with deep infiltrating endometriosis underwent resection of a segment of the rectosigmoid by laparoscopy between 2002 to 2009 . INTERVENTIONS All the patients had historical data collected and underwent clinical examination and transvaginal ultrasonography with prior bowel preparation for resection of a segment of the rectosigmoid by laparoscopy indicated for patients with symptoms ( pelvic pain ) with 1 or more lesions of more than 3 cm in length or multifocal lesions . MEASUREMENTS AND MAIN RESULTS Wilcoxon signed rank test verified differences between the degrees of the symptoms and the SF-36 scores before and 1 year after laparoscopic treatment . There was a significant improvement ( p in all pain-related symptoms , as well as a significant increase ( p in scores in all the SF-36 domains and in the sum of the components comprising both physical and mental health . CONCLUSION Laparoscopic segmental resection of the rectosigmoid fulfills its essential objective of treating endometriosis with bowel involvement and improving patients ' QoL to a significant extent",
"OBJECTIVE The purpose of this study was a quantification of changes in endometriosis-associated pain and quality of life during the stimulatory phase of gonadotropin-releasing hormone agonist therapy . STUDY DESIGN One hundred twenty women with significant endometriosis-associated pain participated in a 1-month double-blind , r and omized , placebo-controlled trial . Pain was measured at baseline and at 2 and 4 weeks with visual analog scales and the Endometriosis Symptom Severity score . Quality of life was measured with the SF-36 instrument . Group means and SEMs were calculated . Paired t tests were used after determination of data normality . RESULTS Compared with placebo-treated control subjects women treated with gonadotropin-releasing hormone agonist had a statistically ( P pain and a concomitant decrease in quality of life . CONCLUSION The stimulatory phase of gonadotropin-releasing hormone agonist therapy is associated with an increase in endometriosis-associated pain and a decrease in quality of life",
"Objective . To evaluate sexual function , quality of life and pelvic pain after endometriosis surgery including vaginal resection . Design . Prospect i ve observational study with 12 months follow up . Setting . Regional central hospital and university hospital . Population . Twenty‐two patients with deep endometriotic nodules in the posterior fornix of the vagina undergoing complete excision of endometriosis , including vaginal resection . Methods . Sexual functioning was measured with the McCoy Female Sexuality Question naire , quality of life with a generic question naire ( 15D ) and pain with a 10‐point visual analog scale . Question naires were completed before and 12 months after the surgery . Main outcome measures . Changes in sexual function scores , quality ‐of‐life scores and pain . Results . Twelve months after surgery , the sexual satisfaction score was higher ( p= 0.03 ) and the sexual problems score lower ( p= 0.04 ) compared with baseline values . Health‐related quality ‐of‐life scores for discomfort and symptoms ( p= 0.001 ) , distress ( p= 0.04 ) , vitality ( p= 0.03 ) and sexual activity ( p= 0.001 ) , and the overall 15D score ( p all studied types of pain was significantly decreased ( p Complete excision of endometriosis , including vaginal resection , seems to offer a significant improvement in sexual functioning , quality of life and pelvic pain in symptomatic patients with deeply infiltrating endometriotic nodules in the posterior fornix of the vagina . This surgery may be associated with complications and adverse new‐onset symptoms , and should be performed only after thorough consultation with the patient",
"BACKGROUND Implanon has been reported to be effective in the treatment of dysmenorrhea . We compared the therapeutic efficacies of depot medroxyprogesterone acetate ( DMPA ) and Implanon with regard to pain relief in women with endometriosis . STUDY DESIGN In a clinical research center at a university hospital , 41 patients with dysmenorrhea , nonmenstrual pelvic pain and dyspareunia associated with histologically proven endometriosis were included in an open , prospect i ve , r and omized , controlled clinical trial . Twenty-one women were assigned by computer-generated r and omization to receive Implanon , and 20 women to receive DMPA . As main outcome measures of this pilot study , we evaluated pain improvement quantified according to visual analog scale score , side effects , vaginal bleeding patterns , withdrawal rate and overall degree of satisfaction . RESULTS During a follow-up period of 1 year , we ascertained a clear improvement in pain intensity for both treatment options . After 6 months , the average decrease in pain was 68 % in the Implanon group and 53 % in the DMPA group . The side-effects profile and the overall degree of satisfaction after study termination were comparable for both treatment options . CONCLUSION Concerning pain relief , the therapeutic efficacy of the contraceptive implant Implanon is not inferior to that of DMPA in symptomatic endometriosis"
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AIMS To summarize and evaluate our knowledge of the relationship between heavy cannabis use , Cannabis Use Disorder ( CUD ) , and the brain . METHODS Narrative review of relevant literature identified through existing systematic review s , meta-analyses and a PubMed search . Epidemiology , clinical representations , potential causal mechanisms , assessment s , treatment and prognosis are discussed . RESULTS Although causality is unclear , heavy and dependent cannabis use is consistently associated with a high prevalence of comorbid psychiatric disorders and learning and memory impairments that seem to recover after a period of abstinence . Evidence regarding other cognitive domains and neurological consequences including cerebrovascular events is limited and inconsistent . Abstinence after treatment is only achieved in a minority of cases ; treatment targeted at reduction in use appears have some success . Potential moderators of the impact of CUD on the brain include age of onset , heaviness of use , CUD severity , the ratio of ∆9-tetrahydrocannabinol to cannabidiol , and severity of comorbid disorders . CONCLUSIONS Current evidence of long-term effects of daily cannabis use and cannabis use disorder on brain-related outcomes is suggestive rather than conclusive but use is associated with psychiatric morbidity and with cognitive impairments that recover after a period of abstinence
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"Craving is a major motivator underlying drug use and relapse but the neural correlates of cannabis craving are not well understood . This study sought to determine whether visual cannabis cues increase cannabis craving and whether cue-induced craving is associated with regional brain activation in cannabis-dependent individuals . Cannabis craving was assessed in 16 cannabis-dependent adult volunteers while they viewed cannabis cues during a functional MRI ( fMRI ) scan . The Marijuana Craving Question naire was administered immediately before and after each of three cannabis cue-exposure fMRI runs . FMRI blood-oxygenation-level-dependent ( BOLD ) signal intensity was determined in regions activated by cannabis cues to examine the relationship of regional brain activation to cannabis craving . Craving scores increased significantly following exposure to visual cannabis cues . Visual cues activated multiple brain regions , including inferior orbital frontal cortex , posterior cingulate gyrus , parahippocampal gyrus , hippocampus , amygdala , superior temporal pole , and occipital cortex . Craving scores at baseline and at the end of all three runs were significantly correlated with brain activation during the first fMRI run only , in the limbic system ( including amygdala and hippocampus ) and paralimbic system ( superior temporal pole ) , and visual regions ( occipital cortex ) . Cannabis cues increased craving in cannabis-dependent individuals and this increase was associated with activation in the limbic , paralimbic , and visual systems during the first fMRI run , but not subsequent fMRI runs . These results suggest that these regions may mediate visually cued aspects of drug craving . This study provides preliminary evidence for the neural basis of cue-induced cannabis craving and suggests possible neural targets for interventions targeted at treating cannabis dependence",
"Rationale Long-term heavy cannabis use can result in memory impairment . Adolescent users may be especially vulnerable to the adverse neurocognitive effects of cannabis . Objectives and methods In a cross-sectional and prospect i ve neuropsychological study of 181 adolescents aged 16–20 ( mean 18.3 years ) , we compared performance indices from one of the most widely used measures of learning and memory — the Rey Auditory Verbal Learning Test — between cannabis users ( n = 52 ; mean 2.4 years of use , 14 days/month , median abstinence 20.3 h ) , alcohol users ( n = 67 ) and non-user controls ( n = 62 ) matched for age , education and premorbid intellectual ability ( assessed prospect ively ) , and alcohol consumption for cannabis and alcohol users . Results Cannabis users performed significantly worse than alcohol users and non-users on all performance indices . They recalled significantly fewer words overall ( p impaired learning ( p retention ( p retrieval ( p impairment was associated with the duration , quantity , frequency and age of onset of cannabis use , but was unrelated to alcohol exposure or other drug use . No gender effects were detected and the findings remained after controlling for premorbid intellectual ability . An earlier age of onset of regular cannabis use was associated with worse memory performance after controlling for extent of exposure to cannabis . Conclusions Despite relatively brief exposure , adolescent cannabis users relative to their age-matched counterparts demonstrated similar memory deficits to those reported in adult long-term heavy users . The results indicate that cannabis adversely affects the developing brain and reinforce concerns regarding the impact of early exposure",
"BACKGROUND Evidence regarding the association between cannabis use and depression remain conflicting , especially as studies have not typically adopted a longitudinal design with a follow-up period that was long enough to adequately cover the risk period for onset of depression . METHOD Males from the Cambridge Study in Delinquent Development ( CSDD ) ( N = 285 ) were assessed seven times from age 8 to 48 years to prospect ively investigate the association between cannabis use and risk of major depressive disorder ( MDD ) . A combination of multiple analyses ( logistic regression , Cox regression , fixed-effects analysis ) was employed to explore the strength and direction of effect within different developmental stages . RESULTS Multiple regression analyses revealed that early-onset cannabis use ( before age 18 ) but not late-onset cannabis use ( after age 27 ) was associated with a higher risk and shorter time until a subsequent MDD diagnosis . This effect was present in high-frequency [ ( odds ratio ( OR ) 8.83 , 95 % confidence interval ( CI ) 1.29 - 70.79 ] ; [ hazard ratio ( HR ) 8.69 , 95 % CI 2.07 - 36.52 ) ] and low-frequency early-onset users ( OR 2.41 , 95 % CI 1.22 - 4.76 ; HR 2.09 , 95 % CI 1.16 - 3.74 ) . Effect of increased frequency of cannabis use on increased risk of subsequent MDD was observed only for use during adolescence ( age 14 - 18 ) but not at later life stages , while controlling for observed and non-unobserved time-invariant factors . Conversely , MDD in adulthood ( age 18 - 32 ) was linked to a reduction in subsequent cannabis use ( age 32 - 48 ) . CONCLUSIONS The present findings provide evidence implicating frequent cannabis use during adolescence as a risk factor for later life depression . Future studies should further examine causality of effects in larger sample",
"Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health . Concomitantly , adolescents are initiating cannabis use at younger ages , and more adolescents are using cannabis on a daily basis . The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users . Participants were members of the Dunedin Study , a prospect i ve study of a birth cohort of 1,037 individuals followed from birth ( 1972/1973 ) to age 38 y. Cannabis use was ascertained in interviews at ages 18 , 21 , 26 , 32 , and 38 y. Neuropsychological testing was conducted at age 13 y , before initiation of cannabis use , and again at age 38 y , after a pattern of persistent cannabis use had developed . Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning , even after controlling for years of education . Informants also reported noticing more cognitive problems for persistent cannabis users . Impairment was concentrated among adolescent-onset cannabis users , with more persistent use associated with greater decline . Further , cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users . Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents",
"Worldwide cannabis dependence is increasing , as is the concentration of Δ9-tetrahydrocannabinol ( THC ) in street cannabis . At the same time , the concentration of the second most abundant cannabinoid in street cannabis , cannabidiol ( CBD ) , is decreasing . These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory . No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans . A total of 94 cannabis users were tested 7 days apart , once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures . Using an unprecedented methodology , a sample of cannabis ( as well as saliva ) was collected from each user and analyzed for levels of cannabinoids . On the basis of CBD : THC ratios in the cannabis , individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs , explicit liking , and implicit attentional bias to drug stimuli . When intoxicated , smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC . Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days . Our findings suggest that CBD has potential as a treatment for cannabis dependence . The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders",
"In light of exp and ing legalization of cannabis and swelling debate about the potential risks , particularly for younger users , underst and ing acute cannabis effects among adolescents and emerging adults is more important than ever . Contemporary models of addiction development identify subjective drug responses as central to the developmental unfolding of drug use disorders . Despite this , surprisingly little is known about cannabis ’s acute subjective effects in human youths . This research utilized ecological momentary assessment ( EMA ) in the natural environment to identify the typical situational context of cannabis use among 85 frequent cannabis users , ages 15–24 years ( M = 19.8 , SD = 2.0 ; 48.2 % female ) . Study aims were to ( a ) characterize momentary changes in several subjective states ( i.e. , stimulation , sedation , tension , craving , and high ) when not using , just before cannabis use , and after use , and ( b ) evaluate whether cannabis responses varied with cannabis use disorder ( CUD ) severity or across the transition from adolescence to emerging adulthood in a correlational manner . Use of cannabis produced measurable reductions in craving and tension , as well as increases in stimulation , sedation , and “ high . ” Participants with more CUD symptoms reported greater relief of craving and increased stimulatory response and high following use . In contrast , emerging adults reported diminished stimulatory response and high following use , relative to adolescents . Results highlight the utility of EMA for characterizing cannabis response as this behavior unfolds in daily life , during a key developmental timeframe in the pathogenesis of cannabis-use pathology",
"BACKGROUND Few effective treatment options exist for cannabis-using youth . This pilot study aim ed to test Approach-Avoidance Training to reduce cannabis use with non-treatment-seeking adolescents . METHODS Eighty cannabis-using non-treatment-seeking adolescents ( average age 19 ) were recruited from San Diego , California and Charleston , South Carolina , and r and omized to complete either six sessions of Cannabis Approach-Avoidance Task Training ( CAAT-training ) design ed to reduce automatic approach biases for cannabis cues or CAAT-sham training . Change in two primary outcome variables was examined : 1 ) cannabis approach bias and 2 ) percent cannabis use days over study enrollment . Change in percent alcohol use days over study enrollment was explored as a secondary outcome . RESULTS A mixed models repeated measures analysis confirmed the group by time interaction effect for approach bias failed to reach statistical significance ( p = .06 ) . Significant group by time interaction effects ( ps days of cannabis and alcohol use over study enrollment . Participants r and omized to the avoid cannabis condition ( CAAT-training ) reported 7 % fewer days of cannabis use compared to 0 % change for sham ; unexpectedly , those in the avoid cannabis condition reported 10 % percent more alcohol use days compared to 3 % more for sham . CONCLUSIONS Computerized cognitive bias modification paradigms may have utility in reducing adolescent cannabis use . Future work should consider developing a paradigm that addresses both cannabis and alcohol , as well as alternative computerized approaches for coping with addictive behavior in conjunction with bias modification",
"CONTEXT Cannabis use can both increase and reduce anxiety in humans . The neurophysiological substrates of these effects are unknown . OBJECTIVE To investigate the effects of 2 main psychoactive constituents of Cannabis sativa ( Delta9-tetrahydrocannabinol [ Delta9-THC ] and cannabidiol [ CBD ] ) on regional brain function during emotional processing . DESIGN Subjects were studied on 3 separate occasions using an event-related functional magnetic resonance imaging paradigm while viewing faces that implicitly elicited different levels of anxiety . Each scanning session was preceded by the ingestion of either 10 mg of Delta9-THC , 600 mg of CBD , or a placebo in a double-blind , r and omized , placebo-controlled design . PARTICIPANTS Fifteen healthy , English-native , right-h and ed men who had used cannabis 15 times or less in their life . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygenation level-dependent response ) , electrodermal activity ( skin conductance response [ SCR ] ) , and objective and subjective ratings of anxiety . RESULTS Delta9-Tetrahydrocannabinol increased anxiety , as well as levels of intoxication , sedation , and psychotic symptoms , whereas there was a trend for a reduction in anxiety following administration of CBD . The number of SCR fluctuations during the processing of intensely fearful faces increased following administration of Delta9-THC but decreased following administration of CBD . Cannabidiol attenuated the blood oxygenation level-dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing intensely fearful faces , and its suppression of the amygdalar and anterior cingulate responses was correlated with the concurrent reduction in SCR fluctuations . Delta9-Tetrahydrocannabinol mainly modulated activation in frontal and parietal areas . CONCLUSIONS Delta9-Tetrahydrocannabinol and CBD had clearly distinct effects on the neural , electrodermal , and symptomatic response to fearful faces . The effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety , whereas the anxiogenic effects of Delta9-THC may be related to effects in other brain regions",
"OBJECTIVES To determine risk factors of incident onset of use , abuse and dependence of cannabis in a community sample of adolescents and young adults . METHODS Risk factors were examined in a prospect i ve longitudinal design across 4 years in a representative sample ( N = 2,446 ) aged 14 - 24 at the outset of the study ( EDSP ) . Patterns of DSM-IV defined cannabis use , abuse and dependence were assessed with the Composite International Diagnostic Interview ( M-CIDI ) . Potential risk factors were assessed at baseline . Incident cannabis use , abuse and dependence at second follow-up ( on average 42 months after baseline ) were the main outcome measures in this study . Associations were analyzed with logistic and negative binomial regressions . RESULTS Using 11 of a total of 56 variables examined , the predictive value of the final multiple logistic regression for incident cannabis use was moderately good ( area under the ROC curve = 0.78 ) . Cannabis use frequency was predicted in the final model by 18 variables , cannabis abuse by two variables in the younger sub sample and nine factors in the older group , and dependence by eight variables ( dependence : ROC curve area = 0.97 ) . Incident cannabis use was predicted mainly by availability of drugs , peers ' drug use , a more ' positive ' attitude towards future drug use , and regular previous use of licit drugs , while cannabis dependence was predicted primarily by parental death before age 15 , deprived socio-economic status , and baseline use of other illicit drugs . CONCLUSION Different factors predict the onset or severity of cannabis use and the progression to abuse and dependence . In addition to well-documented risk factors such as peer group pressure , drug availability , and low self-esteem , findings suggest that family history ( e.g. parental mental disorders , early parental death ) , and prior experiences with legal drugs play a significant role in the initiation of cannabis consumption and the transition to cannabis use disorders in adolescents and young adults . Findings suggest that early intervention and prevention might be improved by better targeted treatment",
"Background The present study assessed psychomotor function in chronic , daily cannabis smokers during 3 weeks continuously monitored abstinence on a secure research unit . We hypothesized that psychomotor performance would improve during abstinence of chronic , daily cannabis smokers . Methodology /Principal Findings Performance on the critical tracking ( CTT ) and divided attention ( DAT ) tasks was assessed in 19 male chronic , daily cannabis smokers at baseline and after 8 , 14–16 and 21–23 days of continuously monitored abstinence . Psychomotor performance was compared to a control group of non-intoxicated occasional drug users . Critical frequency ( λc ) of the CTT and tracking error and control losses of the DAT were the primary outcome measures . Results showed that chronic cannabis smokers ’ performance on the CTT ( p the DAT ( p group . Psychomotor performance in the chronic cannabis smokers improved over 3 weeks of abstinence , but did not recover to equivalent control group performance . Conclusions / Significance Sustained cannabis abstinence moderately improved critical tracking and divided attention performance in chronic , daily cannabis smokers , but impairment was still observable compared to controls after 3 weeks of abstinence . Between group differences , however , need to be interpreted with caution as chronic smokers and controls were not matched for education , social economic status , life style and race",
"BACKGROUND The association between cannabis use and mood disorders is well documented , yet evidence regarding causality is conflicting . This study explored the association between cannabis use , major depressive disorder ( MDD ) and bipolar disorder ( BPD ) in a 3-year prospect i ve study . METHODS Data was drawn from waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions ( NESARC ) . MDD and BPD were controlled at baseline and defined as meeting full criteria in the 12 months prior to the follow-up . Initiation of cannabis use was defined as any cannabis used by former lifetime abstainers in the time period between baseline and follow-up . RESULTS Cannabis use was not significantly associated with increased incidence of MDD ( Adjusted Odds Ratio ( AOR ) for daily use=0.58(0.22 - 1.51 ) ) . Weekly to almost daily cannabis use was associated with increased incidence of BPD ( ( AOR for weekly to daily use=2.47(1.03 - 5.92 ) ) ; daily use was not ( AOR=0.52(0.17 - 1.55 ) ) . Baseline MDD was associated with initiation of cannabis use ( AOR=1.72(1.1 - 2.69 ) ) . A crude association between baseline BPD and incidence of cannabis use was not maintained in adjusted models ( AOR=0.61(0.36 - 1.04 ) ) . LIMITATIONS Lack of information regarding frequency of cannabis use at follow-up and limitations regarding generalization of the results . CONCLUSIONS Our findings do not support a longitudinal association between cannabis use and incidence of MDD . Results regarding the association between cannabis use and incidence of BPD are conflicting and require further investigation . Baseline MDD , but not BPD , may be associated with future initiation of cannabis use . This may have implication s for clinical , social and legislative aspects of cannabis use",
"Recent advances in the underst and ing of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis . In a 3-day , double-blind , r and omized , and counterbalanced study , the behavioral , cognitive , and endocrine effects of 0 , 2.5 , and 5 mg intravenous delta-9-tetrahydrocannabinol ( Δ-9-THC ) were characterized in 22 healthy individuals , who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder . Prospect i ve safety data at 1 , 3 , and 6 months post study was also collected . Δ-9-THC ( 1 ) produced schizophrenia-like positive and negative symptoms ; ( 2 ) altered perception ; ( 3 ) increased anxiety ; ( 4 ) produced euphoria ; ( 5 ) disrupted immediate and delayed word recall , sparing recognition recall ; ( 6 ) impaired performance on tests of distractibility , verbal fluency , and working memory ( 7 ) did not impair orientation ; ( 8) increased plasma cortisol . These data indicate that Δ-9-THC produces a broad range of transient symptoms , behaviors , and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses . These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders",
"Human performance studies have usually relied on low-potency marijuana ( 4 % THC ) for determining THC-induced impairment . The present study was design ed to assess the effects of high-potency marijuana ( 13 % THC ) on human performance . In all , 20 recreational users of marijuana participated in a double-blind , placebo controlled , three way cross-over study . The treatments consisted of single doses of 0 , 250 , and 500 μg/kg THC . Performance tests were conducted at regular intervals between 15 min and 6 h postsmoking and included measures of motor control ( Critical tracking task ) , executive function ( Tower of London ) motor impulsivity ( Stop signal task ) , and risk taking ( Iowa gambling task ) . THC significantly impaired performance in the Critical tracking task and decreased the number of correct decisions in the Tower of London task . In addition , THC significantly increased stop reaction time and the proportions of commission and omission errors in the Stop signal task . THC-induced impairments lasted up to 6 h postsmoking as indicated by the absence of a THC × Time after smoking interaction . Effect sizes for performance impairments produced by THC 250 μg/kg were relatively low but generally increased by a factor of two in case of THC 500 μg/kg . These data suggest that high potency marijuana consistently impairs executive function and motor control . Use of higher doses of THC in controlled studies may offer a reliable indication of THC induced impairment as compared to lower doses of THC that have traditionally been used in performance studies",
"Rationale Marijuana is believed to increase impulsivity and risk taking , but the processes whereby it affects such behaviors are not understood . Indeed , either the pharmacologic effect of delta-9-tetrahydrocannabinol ( THC ) or the expectancy of receiving it may lead to deficits in cognitive processing and increases in risk taking . Objectives and methods We examined the relative effects of expecting to receive active marijuana and the pharmacological drug effects using a balanced placebo design . Young adult regular marijuana users ( N = 136 ) were r and omly assigned into one of four groups in a two × two instructional set ( Told THC vs. Told no THC ) by drug administration ( smoked marijuana with 2.8 % THC vs. placebo ) design . Dependent measures included subjective intoxication , behavioral impulsivity , and decision-making related to risky behaviors . Results Active THC , regardless of expectancy , impaired inhibition on the Stop Signal and Stroop Color-Word tasks . Expectancy of having smoked THC , regardless of active drug , decreased impulsive decision-making on a delay discounting task among participants reporting no deception and increased perception of sexual risk among women , consistent with a compensatory effect . Expectancy of smoking THC in combination with active THC increased negative perceptions from risky alcohol use . Active drug and expectancy independently increased subjective intoxication . Conclusions Results highlight the importance of marijuana expectancy effects as users believing they are smoking marijuana may compensate for expected intoxication effects when engaged in deliberate decision-making by making less impulsive and risky decisions . Effects of marijuana on impulsive disinhibition , by contrast , reflect direct pharmacologic effects for which participants did not compensate",
"As more states legalize the sale and consumption of marijuana , the number of Americans using it continues to rise ( 1 , 2 ) . This increase in the use of marijuana highlights the need for a better underst and ing of its risks and benefits . One area of importance is its effect on cardiovascular disease , the number one cause of morbidity and mortality worldwide ( 3 ) . Marijuana may affect cardiovascular health in several ways . Like other psychoactive drugs , it may have hemodynamic effects that can precipitate events ( 4 ) . The active ingredient in marijuana is 9-tetrahydrocannabinol ( THC ) ( 5 ) , which is responsible for the psychoactive effects of marijuana through its interaction with cannabinoid receptors . These receptors are ubiquitous in the brain and its vasculature and present throughout the body , including the myocardium , coronary endothelium , and smooth muscle cells ( 6 , 7 ) . In vitro and animal studies have reported that THC can modulate cannabinoid receptors on human cardiomyocytes and vascular smooth muscles , result ing in ischemia ( 7 , 8) . In vitro studies also have demonstrated that THC influences the regulation of glucose and lipid metabolism , suggesting a possible effect on vascular risk factors ( 9 , 10 ) . At the cellular level , THC may cause inflammatory cytokine release , alteration in lipid metabolism ( 11 , 12 ) , and reactive oxygen species formation ( 13 ) . These effects may potentiate the progression of vascular disease . Marijuana smoking , the predominant method of use , causes a 5-fold increase in the blood carboxyhemoglobin level and a 3-fold increment in the quantity of tar inhaled compared with tobacco ( 14 ) . Studies on secondh and marijuana smoke have found endothelial dysfunction in rats after exposure ( 15 ) . Given the myriad ways in which marijuana might potentiate vascular disease , we conducted a systematic review to assess the effect of regular marijuana use on cardiovascular outcomes and their associated risk factors . Methods The protocol was registered at PROSPERO ( CRD42016051297 ) ( 16 ) at the start of our investigation . This review focuses on studies examining marijuana use and cardiovascular risk factors and outcomes ; our protocol also includes search es and a review of hemodynamic changes associated with marijuana use that are not reported here . Data Sources and Search es We search ed several online data bases ( PubMed , MEDLINE , EMBASE , PsycINFO , and the Cochrane Library ) for titles and abstract s between 1 January 1975 and 30 September 2017 . We chose a 1975 start date because that was the year the Alaska Supreme Court ruled that the Alaska constitution 's right to privacy protects an adult 's ability to use and possess a small amount of marijuana in the home for personal use ( 17 ) . We also conducted reference and author tracking to identify additional articles and search ed Clinical Trials.gov and the National Institutes of Health Research Portfolio ( NIH RePORTER ) for ongoing or completed studies not reported in the literature . For search terms and details , see Supplement 1 . Supplement . Supplementary Material Study Selection All titles and abstract s were independently screened by 2 review ers ( M.G. and D.R. ) . We included observational studies ( cohort , casecontrol , cross-sectional ) and interventional studies ( r and omized controlled trials , experimental studies ) that enrolled participants older than 12 years and were published in English . The exposure criterion was any form of marijuana ( plant or pharmaceutical ) . The main outcomes of interest were cardiovascular risk factors and outcomes . We excluded case reports , case series , review articles , editorials , and in vitro and animal studies . The same 2 investigators independently review ed the full texts of selected articles to identify those that met our inclusion criteria . Disagreements regarding inclusion were resolved by a third review er ( S.K. ) . Interrater reliability for the abstract selection process and the concurrent decision to include the article in the review was excellent ( Cohen , 0.87 ) . For the selection process , see Supplement 2 . Data Extraction and Quality Assessment For each included study , the review ers collected information on study design ( observational or experimental ) , the study population ( for example , healthy volunteers , regular users , or hospitalized patients ) , age distribution , cannabis make-up ( plant based or pharmaceutical ) , route of exposure ( smoking , vaporizing , eating , or injecting ) , exposure duration , and funding source . Four investigators ( D.R. , M.G. , S.K. , and D.K. ) independently rated study quality as low , moderate , or high risk of bias ( ROB ) . We assessed ROB for outcomes in trials with the Cochrane Risk of Bias Tool ( 18 ) , and for outcomes in observational studies with the Newcastle-Ottawa scale ( 19 ) . Disagreements were resolved by consensus . Risk-of-bias tools and scoring are available in Supplement 3 . Data Synthesis and Analysis We performed a qualitative assessment and synthesis of evidence . Because of the heterogeneity of outcomes and lack of reporting of effect sizes , we did not pool any data . Through group discussion , we grade d the overall strength of the evidence for each outcome as insufficient , low , moderate , or high on the basis of methods outlined by the Agency for Healthcare Research and Quality ( 20 ) . Role of the Funding Source The NIH had no role in the design , analysis , interpretation of data , preparation or approval of the manuscript , or decision to su bmi t the manuscript for publication . Results Literature Search Our search yielded 3006 abstract s , 1669 of which were selected for further evaluation . Among these , 140 were selected for full-text review . Another 7 articles were added via author and reference tracking . Of these 147 papers , 24 met our inclusion criteria ( Figure ) . Figure . Evidence search and selection . Study Characteristics The evidence included 9 prospect i ve cohort studies , 3 retrospective cohort studies , 2 casecontrol studies , 2 interventional studies ( 1 experimental study and 1 r and omized trial ) , 7 cross-sectional studies , and 1 case-crossover study . Thirteen studies assessed cardiovascular risk factors , and 11 examined cardiovascular diseases . Most studies ( n= 16 ; 66.7 % ) did not report the chemical constitution ( for example , THC vs. cannabidiol ) of the marijuana used in the study . Among articles that specified the form of marijuana used , the plant-based form was predominant ( n= 7 ) . Among those that specified the route of exposure , smoking was predominant ( n= 11 ) , followed by oral use ( n= 2 ) . Eleven papers did not report the specific route or form of marijuana administration ( such as edible or smoked ) . Tables 1 to 4 of Supplement 3 detail the quality assessment s for individual studies . Cardiovascular Risk Factors Metabolic Parameters : Lipid and Glucose Levels and Diabetes Eleven studies provided data on 1 or more metabolic parameter outcomes , including hyperglycemia , dyslipidemia , and diabetes ( Appendix Table 1 ) . Appendix Table 1 . Studies That Examined Exposure to MJ and CVD Five cross-sectional studies ( 3 low and 2 high ROB ) examined the association between marijuana use and hyperglycemia , dyslipidemia , metabolic syndrome , or diabetes ( 2125 ) . Marijuana use was measured by self-report in all studies . Four studies were based on 3 different waves of the NHANES ( National Health and Nutrition Examination Survey ; 1988 to 1994 , 2005 to 2010 , and 2005 to 2012 ) ( 2123 , 25 ) . Three of the 4 used multivariable analysis to examine the association between marijuana use and metabolic parameters after adjustment for baseline characteristics . All 3 studies reported that marijuana use had different favorable associations , including a lower prevalence of diabetes ( 22 ) , lower glucose levels ( 25 ) , or higher high-density lipoprotein cholesterol concentrations ( 21 , 22 , 25 ) . The fourth NHANES study ( 2005 to 2012 ) used both regression models and an instrumental variable analysis to examine associations ( 23 ) . Marijuana use was associated with a beneficial metabolic effect in the regression model evaluation ; no such effect was seen in the instrumental variable analysis . The final cross-sectional study was an exploratory analysis based on a small sample of 30 persons who were heavy marijuana users and 30 control participants matched for age , sex , ethnicity , and body mass index ( BMI ) ( 24 ) . The authors identified no differences between groups in glucose tolerance or fasting glucose , total cholesterol , or triglyceride levels . Three prospect i ve studies ( 1 low , 1 moderate , and 1 high ROB ) examined the association of marijuana use with risk factors ( 2628 ) . Two were based on the CARDIA ( Coronary Artery Risk Development in Young Adults ) cohort study , which examined the development and determinants of clinical and sub clinical cardiovascular disease and its risk factors ( 26 , 28 ) . The CARDIA study began in 1985 to 1986 with 5113 black and white men and women aged 18 to 30 years . It included comprehensive in-person baseline and outcome data ( sociodemographic characteristics ; fasting glucose levels ; BMI ; diet and physical activity ; and use of tobacco , alcohol , and other substances ) and several exposure assessment s during a long follow-up . Questions pertaining to marijuana use lacked detail on the form used , and exposure was quantified differently in each study . The low-ROB CARDIA-based study reported no associations between marijuana use and changes in glucose , high-density lipoprotein cholesterol , or triglyceride levels among heavy users ( > 1800 days of use ) compared with nonusers during 15 years of follow-up ( 26 ) . The moderate-ROB CARDIA-based study examined the association between marijuana use and diabetes and prediabetes ( 28 ) . Marijuana use was ascertained in year 7 of the prospect i ve cohort , and exposure was very limited : The highest category of use was a lifetime frequency of more than 100 times . Incidence of diabetes and prediabetes assessed at 4 subsequent follow-up examinations over 18 years was based on laboratory assessment ( oral glucose",
"BACKGROUND Frequent cannabis users are at high risk of dependence , still most ( near ) daily users are not dependent . It is unknown why some frequent users develop dependence , whereas others do not . This study aims to identify predictors of first-incidence DSM-IV cannabis dependence in frequent cannabis users . METHODS A prospect i ve cohort of frequent cannabis users ( aged 18 - 30 , n=600 ) with baseline and two follow-up assessment s ( 18 and 36 months ) was used . Only participants without lifetime diagnosis of DSM-IV cannabis dependence at baseline ( n=269 ) were selected . Incidence of DSM-IV cannabis dependence was established using the Composite International Diagnostic Interview version 3.0 . Variables assessed as potential predictors of the development of cannabis dependence included sociodemographic factors , cannabis use variables ( e.g. , motives , consumption habits , cannabis exposure ) , vulnerability factors ( e.g. , childhood adversity , family history of mental disorders or substance use problems , personality , mental disorders ) , and stress factors ( e.g. , life events , social support ) . RESULTS Three-year cumulative incidence of cannabis dependence was 37.2 % ( 95 % CI=30.7 - 43.8 % ) . Independent predictors of the first incidence of cannabis dependence included : living alone , coping motives for cannabis use , number and type of recent negative life events ( major financial problems ) , and number and type of cannabis use disorder symptoms ( impaired control over use ) . Cannabis exposure variables and stable vulnerability factors did not independently predict first incidence of cannabis dependence . CONCLUSIONS In a high risk population of young adult frequent cannabis users , current problems are more important predictors of first incidence cannabis dependence than the level and type of cannabis exposure and stable vulnerability factors",
"Heavy use of marijuana is cl aim ed to damage critical skills related to short-term memory , visual scanning and attention . Motor skills and driving safety may be compromised by the acute effects of marijuana . The aim of this study was to investigate the acute effects of 13 mg and 17 mg Δ 9-tetrahydrocannabinol ( THC ) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana . Fourteen regular users of marijuana were enrolled . Each subject was tested on two separate days . On each test day , subjects smoked two low-nicotine cigarettes , one with and the other without THC . Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day . The sequence of cigarette types was unknown to the subject . During smoking , heart rate and blood pressure were monitored , and the subjects performed a virtual reality maze task requiring attention and motor coordination , followed by 3 other cognitive tasks ( Wisconsin Card Sorting Test ( WCST ) , a “ gambling ” task and estimation of time and distance from an approaching car ) . After smoking a cigarette with 17 mg THC , regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC ; this effect was not seen in patients after they smoked cigarettes with 13 mg THC . Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC . Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC , but not with 13 m THC . Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction , drug “ effect ” and drug “ high ” . These findings imply that smoking of 17 mg THC results in impairment of cognitive — motor skills that could be important for coordinated movemen and driving , whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana",
"Aim of this paper is to investigate the psychobiological reactions to experimentally induced negative emotional states in active marijuana-dependent smokers and whether changes in emotional reactivity were reversed by prolonged abstinence . Twenty-eight patients were r and omly included into group A ( fourteen active marijuana-dependent smokers ) or group B ( fourteen abstinent marijuana-dependent subjects ) . Emotional response evaluation of group B subjects was assessed after 6 months of abstinence . Fourteen healthy volunteers , matched for age and sex , were used as controls . Psychometric and emotional response evaluations were performed by administering Symptoms Check List-90 and State-Trait Anxiety Inventory Y-1 ( STAI ) . Neutral and unpleasant set of pictures selected from the international affective picture system and the Self-Assesment Manikin procedure ( SAM ) have been used to determine ratings of pleasure and arousal . Before and after the experimental session , blood sample s were collected to determine ACTH and cortisol plasma levels . Active cannabis users displayed significantly higher levels of pleasantness SAM scores and lower levels of arousal SAM scores compared to abstinent cannabis users and controls in response to emotional task . In a close parallel with psychological data , hormonal findings indicate a persistent hyperactivity of hypothalamus – pituitary – adrenal ( HPA ) axis in cannabis users , particularly among active marijuana smokers , and an impaired hormonal reaction to negative emotions , in comparison with healthy subjects . The capacity of the HPA axis to respond to stressful stimuli/negative emotions seems to be only partially recovered after 6 months of abstinence . Ours findings , although obtained in a small number of subjects , suggest an association between active cannabis use , subjective reduced sensitivity to negative emotions and threat and HPA axis dysfunction",
"AIMS To describe the empirical construction and initial validation of the Cannabis Use Problems Identification Test ( CUPIT ) , a brief self-report screening instrument for detection of currently and potentially problematic cannabis use . DESIGN In a three-phase prospect i ve design an item pool of c and i date questions was generated from a literature review and extensive expert consultation . The CUPIT internal structure , cross-sectional and longitudinal psychometric properties were then systematic ally tested among heterogeneous past-year users . PARTICIPANTS Volunteer participants were 212 high-risk adolescents ( n = 138 ) and adults ( n = 74 ) aged 13 - 61 years from multiple community setting s. MEASUREMENTS The comprehensive assessment battery included several established measures of cannabis-related pathology for CUPIT validation , with DSM-IV/ICD-10 diagnoses of cannabis use disorders as criterion st and ard . FINDINGS Sixteen items loading highly on two subscales derived from principal components analysis exhibited good to excellent test-retest ( 0.89 - 0.99 ) and internal consistency reliability ( 0.92 , 0.83 ) , and highly significant ability to discriminate diagnostic subgroups along the severity continuum ( non-problematic , risky , problematic use ) . Twelve months later , baseline CUPIT scores demonstrated highly significant longitudinal predictive utility for respondents ' follow-up diagnostic group membership . Receiver operating characteristic ( ROC ) analysis identified a CUPIT score of 12 to be the optimal cut-point for maximizing sensitivity for both currently diagnosable cannabis use disorder and those at risk of meeting diagnostic criteria in the following 12 months . CONCLUSIONS The CUPIT is a brief cannabis screener that is reliable , valid and acceptable for use across diverse community setting s and consumers of all ages . The CUPIT has clear potential to assist with achievement of public health goals to reduce cannabis-related harms in the community",
"BACKGROUND Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders . METHODS In a 3-day , double-blind , r and omized , placebo-controlled study , the behavioral , cognitive , motor , and endocrine effects of 0 mg , 2.5 mg , and 5 mg intravenous Delta-9-tetrahydrocannabinol ( Delta-9-THC ) were characterized in 13 stable , antipsychotic-treated schizophrenia patients . These data were compared with effects in healthy subjects reported elsewhere . RESULTS Delta-9-tetrahydrocannabinol transiently increased 1 ) learning and recall deficits ; 2 ) positive , negative , and general schizophrenia symptoms ; 3 ) perceptual alterations ; 4 ) akathisia , rigidity , and dyskinesia ; 5 ) deficits in vigilance ; and 6 ) plasma prolactin and cortisol . Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects . There were no serious short- or long-term adverse events associated with study participation . CONCLUSIONS Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia . These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis . Furthermore , Delta-9-THC might differentially affect schizophrenia patients relative to control subjects . Finally , the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia",
"The impact of regular marijuana use on executive cognitive abilities , including decision making , is not well understood . While cross-sectional studies have suggested that substance abusers exhibit impaired decision making , as assessed by the Iowa Gambling Task , the direct role of marijuana use in the Gambling Task performance of marijuana smokers has not been well defined . In this report , we present data on performance on a modified Gambling Task in experienced marijuana users after they had smoked marijuana under controlled laboratory conditions . A total of 36 marijuana users , who reported smoking approximately 24 marijuana cigarettes per week , completed this 3-session outpatient study . During each session , these volunteers completed the Gambling Task once at baseline and 3 times after smoking a single marijuana cigarette ( 0.0 , 1.8 , or 3.9 % Δ9-THC ) . Marijuana cigarettes were administered in a double-blind fashion , and the sequence of Δ9-THC concentration was balanced across volunteers . Marijuana increased the time required to complete the task . However , advantageous card selection and money earned on the task were not disrupted by marijuana . These data are consistent with previous findings that indicated that speed of performance on tests of executive function , but not accuracy , is disrupted in experienced marijuana users during marijuana intoxication",
"Literature on impulsivity regularly cl aims inhibitory control deficits underlie impulsive behavior . The current study investigated whether taxing inhibitory control will increase reflection ( decision making under conditions of uncertainty ) , temporal ( delay of gratification ) , and motor impulsivity ( behavioral disinhibition ) . Inhibitory control was challenged , via a r and om letter generation task presented during responding to three impulsivity measures : the Information Sampling Task ( IST ) , Single Key Impulsivity Paradigm , and the Stop Signal Task ( SST ) . Participants ( n = 33 ) were assigned to the inhibitory control challenging ( experimental ) condition , or to a control condition in which inhibitory control was not challenged . The SST was affected by the inhibitory control challenge : participants in the experimental condition displayed increased motor impulsivity , evidence d in longer stop signal reaction times ( SSRTs ) compared to the control group . The manipulation did not affect reflection- or temporal- impulsivity measures . These data support the suggestion that the mechanisms underlying the motor subtype of impulsivity are dissociable from the temporal and reflection subtypes , and that engagement of inhibitory control is not necessary to prevent impulsive decision making",
"BACKGROUND In a recent paper , we reported the efficacy of a modular cognitive-behavioral intervention for treating adolescents and adults with cannabis use disorders ( CUD ) . In this study , we examine the outcome of this intervention after translating it into clinical practice . METHODS A multi-site , r and omized controlled trial of 279 treatment seekers with ICD-10 cannabis use disorders aged 16- 63 years was conducted in 11 outpatient addiction treatment centers in Germany . Patients were r and omly assigned to an Active Treatment ( AT , n=149 ) or Delayed Treatment Control ( DTC , n=130 ) . Treatment consisted of 10 sessions of fully manualized individual psychotherapy that combined Cognitive-Behavioral Therapy , Motivational EnhancementTherapy and problem-solving training . Assessment s were conducted at baseline , during each therapy session , at post-treatment and at three and six month follow-ups . RESULTS At post assessment 53.3 % of AT patients reported abstinence ( 46.3 % negative urine screenings ) compared to 22 % of DTC patients ( 17.7 % negative drug screenings ) ( p frequency of cannabis use , number of cannabis dependence criteria , severity of dependence , as well as number and severity of cannabis-related problems . Effect sizes were moderate to high . While abstinence rates in the AT group decreased over the 3-month ( negative urine screenings : 32.4 % ) and 6-month ( negative urine screenings : 35.7 % ) follow-up periods , the effects in secondary outcomes were maintained . CONCLUSIONS The intervention can successfully be translated to and applied in clinical practice . It has the potential to improve access to evidence -based care for chronic CUD patients",
"Cognitive-behavioral therapy ( CBT ) depends on adequate cognitive functioning in patients , but prolonged cocaine use may impair cognitive functioning . Therefore , cognitive impairment may impede the ability of cocaine abusers to benefit from CBT . To begin to address this issue , we investigated the relationship between cognitive impairment and two treatment outcomes , therapy completion and abstention . Eighteen carefully screened non-depressed cocaine-dependent patients in a psychopharmacological clinical trial were administered the MicroCog computerized battery to assess cognitive performance at treatment entry . T-tests were used to compare cognitive functioning between completers ( patients remaining in treatment at least 12 weeks ) and dropouts . The results indicated that treatment completers had demonstrated significantly better cognitive performance at baseline than patients who dropped out of treatment . Cognitive domains that significantly distinguished between treatment completers and dropouts were attention , mental reasoning and spatial processing . This study provides preliminary evidence that cognitive impairments may decrease treatment retention and abstinence in CBT of cocaine dependence",
"A milestone in cannabis research is the establishment of a clinical ly relevant cannabis withdrawal syndrome , yet little is known about the underlying mechanisms . We investigated the predictive role of mental health and cognitive factors in withdrawal severity during an active attempt to cut down , relative to uninterrupted cannabis use . Ninety heavy cannabis users were r and omly assigned to an experimental or control group . The experimental group was asked to cut down substance use for 1 week . Past week substance use , substance use-related problems , depressive symptoms , cravings , and cognitive control were assessed at baseline . Past week substance use and withdrawal severity were assessed at follow-up . The experimental group reduced their cannabis use more and experienced more withdrawal than the control group . Hierarchical regression analysis per predictor indicated that cannabis use-related problems , depressive symptoms , and cannabis craving , but not cognitive control , predicted stronger withdrawal . Craving uniquely predicted withdrawal in the experimental group . A combined hierarchical regression indicated that only depressive symptoms and cannabis use-related problems uniquely predicted withdrawal across groups . These results suggest that depressive symptoms and cannabis use-related problems are generally indicative of cannabis withdrawal severity , whereas craving specifically predicts cannabis withdrawal during an active attempt to cut-down cannabis use",
"The main active ingredient in cannabis , delta-9-tetrahydrocannabinol ( THC ) , can acutely induce psychotic symptoms and impair episodic and working memory . Another major constituent , cannabidiol ( CBD ) , may attenuate these effects . This study aim ed to determine the effects of THC and CBD , both alone and in combination on psychotic symptoms and memory function . A r and omised , double-blind crossover design compared the effects of ( i ) placebo , ( ii ) THC 8 mg , ( iii ) CBD 16 mg and ( iv ) THC 8 mg + CBD 16 mg administered by inhalation through a vaporiser . Using an experimental medicine approach to predict treatment sensitivity , we selected 48 cannabis users from the community on the basis of ( 1 ) schizotypal personality question naire scores ( low , high ) and ( 2 ) frequency of cannabis use ( light , heavy ) . The Brief Psychiatric Rating Scale ( BPRS ) , Psychotomimetic States Inventory ( PSI ) , immediate and delayed prose recall ( episodic memory ) , 1- and 2-back ( working memory ) were assessed on each day . Results indicated that THC increased overall scores on the PSI , negative symptoms on BPRS , and robustly impaired episodic and working memory . Co-administration of CBD did not attenuate these effects . CBD alone reduced PSI scores in light users only . At a ratio of 2:1 , CBD does not attenuate the acute psychotic and memory impairing effects of vaporised THC . Frequent cannabis users may show a blunted anti- psychotic response to CBD , which is of concern due to the high rates of cannabis use disorders in patients with schizophrenia",
"BACKGROUND Cannabis is one of the most widely used drugs worldwide . Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment . There are no approved pharmacological treatments for cannabis use disorder . One approach is to potentiate endocannabinoid signalling by inhibiting fatty acid amide hydrolase ( FAAH ) , the enzyme that de grade s the endocannabinoid an and amide . We aim ed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal and cannabis use in men who were daily cannabis users . METHODS We did a double-blind , placebo-controlled , parallel group phase 2a trial at one site in men aged 18 - 55 years with cannabis dependence according to DSM-IV criteria ( equivalent to cannabis use disorder in DSM-5 ) . After baseline assessment s , participants were r and omly assigned ( 2:1 ) to receive PF-04457845 ( 4 mg per day ) or placebo using a fixed block size of six participants , stratified by severity of cannabis use and desire to quit . Participants were admitted to hospital for 5 days ( maximum 8 days ) to achieve abstinence and precipitate cannabis withdrawal , after which they were discharged to continue the remaining 3 weeks of treatment as out patients . The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission , and week 4 ( end of treatment ) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population . The study is registered at Clinical Trials.gov , number NCT01618656 . FINDINGS Between Sept 12 , 2012 , and Jan 18 , 2016 , 46 men were r and omly assigned to PF-04457845 and 24 to placebo . Adherence to study medication was 88 % , as confirmed by video-calling and pill count , and corroborated by corresponding drug and an and amide concentrations in blood . Relative to placebo , treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal ( first day of treatment mean symptom score 11·00 [ 95 % CI 7·78 - 15·57 ] vs 6·04 [ 4·43 - 8·24 ] ; difference 4·96 [ 0·71 - 9·21 ] ; padj=0·048 ; second day of treatment 11·74 [ 8·28 - 16·66 ] vs 6·02 [ 4·28 - 8·47 ] ; difference 5·73 [ 1·13 - 10·32 ] ; padj=0·035 ) and related mood symptoms during the inpatient phase . Additionally , treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks ( mean 1·27 joints per day [ 95 % CI 0·82 - 1·97 ] vs 0·40 [ 0·25 - 0·62 ] ; difference 0·88 [ 0·29 - 1·46 ] ; p=0·0003 ) and lower urinary THC-COOH concentrations ( mean 657·92 ng/mL [ 95 % CI 381·60 - 1134·30 ] vs 265·55 [ 175·60 - 401·57 ] ; difference 392·37 [ 17·55 - 767·18 ) ] ; p=0·009 ) . Eight ( 17 % ) patients in the PF-04457845 group and four ( 17 % ) in the placebo group discontinued during the treatment period . During the 4-week treatment phase , 20 ( 43 % ) of 46 participants in the PF-04457845 group and 11 ( 46 % ) of 24 participants in the placebo group had an adverse event . There were no serious adverse events . INTERPRETATION PF-04457845 , a novel FAAH inhibitor , reduced cannabis withdrawal symptoms and cannabis use in men , and might represent an effective and safe approach for the treatment of cannabis use disorder . FUNDING United States National Institute of Drug Abuse ( NIDA )",
"ABSTRACT Adolescent cannabis use is associated with working memory impairment . The present r and omized controlled trial assigned adolescents ages 14 to 21 enrolled in cannabis use treatment to receive either working memory training ( experimental group ) or a control training ( control group ) as an adjunctive treatment . Cognitive function , drug use , and other outcomes were assessed before and after training . We observed few differences in cognitive , functional , or self-reported drug use outcomes as a function of training group , although tetrahydrocannabinol ( THC ) urinalysis results favored the experimental group . These findings are similar to previous studies in substance users , which have shown limited transfer effects for working memory training",
"We conducted a review of systematic review s ( SRs ) and r and omized-controlled trials ( RCTs ) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders . Five data bases were systematic ally search ed ( 2006—August 2018 ) ; 4 SRs ( of 11 RCTs ) and 14 RCTs ( 1629 participants ) were included . Diagnoses were : dementia , cannabis and opioid dependence , psychoses/schizophrenia , general social anxiety , posttraumatic stress disorder , anorexia nervosa , attention-deficit hyperactivity disorder , and Tourette`s disorder . Outcome variables were too heterogeneous to conduct a meta- analysis . A narrative synthesis method was applied . The study quality was assessed using the risk-of-bias tool and SIGN-checklists . THC- and CBD-based medicines , given as adjunct to pharmaco- and psychotherapy , were associated with improvements of several symptoms of mental disorders , but not with remission . Side effects occurred , but severe adverse effects were mentioned in single cases only . In order to provide reliable treatment recommendations , more and larger RCTs with follow-up assessment s , consistent outcome measures and active comparisons are needed",
"Cannabis is the most frequently used illicit drug worldwide , but little is known about the mechanisms underlying continued cannabis use . Cue-reactivity ( the physical , psychological , behavioural and neural reaction to substance-related cues ) might be related to continued cannabis use . In this 3-year prospect i ve neuroimaging study we investigated whether cannabis cue-induced brain activity predicted continued cannabis use and associated problem severity 3 years later . In addition , baseline brain activations were compared between dependent and non-dependent cannabis users at follow-up . Analyses were focussed on brain areas known to be important in cannabis cue-reactivity : anterior cingulate cortex , orbitofrontal cortex , ventral tegmental area , amygdala and striatum . At baseline , 31 treatment-naive frequent cannabis users performed a cue-reactivity functional magnetic resonance imaging task . Of these participants , 23 completed the 3-year follow-up . None of the cue-induced region of interest activations predicted the amount of cannabis use at follow-up . However , cue-induced activation in the left striatum ( putamen ) significantly and independently predicted problem severity at follow-up ( p ly dependent cannabis users at follow-up showed higher baseline activation at trend level in the left striatum compared with non-dependent users . This indicates that neural cue-reactivity in the dorsal striatum is an independent predictor of cannabis use-related problems . Given the relatively small sample size , these results are preliminary and should be replicated in larger sample s of cannabis users"
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Postmenopausal hormone replacement therapy ( HRT ) is one of the most commonly prescribed drug regimens in the United States . This pattern of use reflects a large number of postmenopausal women , many of whom choose to take HRT to treat symptoms of menopause . Also contributing to the high prevalence of use has been significant publicity aim ed at physicians and women regarding the effect of HRT on intermediate biological outcomes , such as lipid levels ( 1 ) and bone density , and its potential effect in decreasing cardiovascular disease ( CVD ) as well as several other serious diseases , such as Alzheimer disease and colon cancer . Cardiovascular disease , primarily coronary artery disease ( CAD ) , is the leading cause of death among women in the United States . Many observational studies and analyses have suggested that HRT protects against CVD . However , in the past 4 years , three secondary prevention trials ( 2 - 4 ) and , most relevantly , the Women 's Health Initiative ( WHI ) primary prevention study ( 5 ) have shown no benefit or increased rates of CVD events among women r and omly assigned to HRT . These results were surprising to many because of the benefit shown in many observational studies and because estrogen use is associated with many effects that could have favorable effects on CVD , including lower low-density lipoprotein cholesterol levels ( 6 ) , lower lipoprotein(a ) levels ( 7 ) , and increased high-density lipoprotein cholesterol levels ( 8) . However , HRT is also associated with potentially unfavorable effects , including increased levels of triglycerides ( 6 ) , factor VII , and C-reactive protein ( 8) and decreased levels of antithrombin III ( 6 ) . Given the mix of intermediate biological outcomes , limitations of observational data , and recent trial results , we conducted this systematic review and meta- analysis to examine the value of HRT for the primary prevention of CVD . We were particularly interested in whether bias might explain discordant results between recent trials and the observational literature . Our review is one of several that will serve as background for the Third U.S. Preventive Services Task Force ( USPSTF ) recommendations on HRT and the prevention of chronic diseases . Methods We search ed the topic of HRT and CVD and CAD in the MEDLINE and Cochrane data bases from 1966 to December 2000 . We also used bibliographies of original research and other publications to identify studies for review . Criteria for inclusion in the systematic review were evaluation of HRT and the primary prevention of CVD , CAD , or both among postmenopausal women and availability of an English- language abstract for review . We included r and omized , controlled trials , and cohort and casecontrol studies if they evaluated CVD or CAD incidence or mortality . We did not review cross-sectional studies because they are limited by prevalence bias . Two investigators review ed all abstract s to identify papers for full-text review . We abstract ed study data and created evidence tables organized by study type . Definitions of current , past , recent , never , and ever use were taken directly from the individual studies ( Appendix Tables 1 and 2 ) . Hormone use was classified in each study as unopposed estrogen replacement therapy or estrogen plus progesterone combined therapy when it was specified , which was infrequent . When the type of estrogen or progesterone therapy was not specified , the exposure was categorized as HRT . Definitions of CVD and CAD events were taken directly from the review ed studies . Most often , CVD mortality was defined by International Classification of Disease codes or World Health Organization criteria or included any death result ing from any type of CVD or CVD-related procedure , including stroke , CAD , sudden cardiac death , congestive heart failure , peripheral vascular disease , coronary artery bypass graft surgery , or percutaneous transluminal coronary angioplasty . Coronary artery disease is a subset of CVD . For the purpose s of this review , CAD deaths included all fatal myocardial infa rct ions , sudden cardiac deaths , or both attributed to CAD ; CAD events included myocardial infa rct ion , coronary artery bypass graft surgery , percutaneous transluminal coronary angioplasty , and , in some studies , angina . In an effort to measure a global effect on CVD , as well as a more specific effect on CAD , we evaluated CVD and CAD separately when the data allowed . Two investigators independently rated the quality of each study based on criteria created by the Third USPSTF ( 9 ) ; discrepancies were adjudicated by a third review er . These criteria are shown in Table 1 . Appendix Tables 1 and 2 show each study 's rating by quality . In ranking the quality of observational studies , we gave significant weight to adequate control of potential CVD risk factors because of known differences in risk profiles among women who use HRT and those who do not ( 10 , 11 ) . Table 1 . U.S. Preventive Services Task Force Categories for Rating Internal Validity of Studies After review ing and rating the studies , we limited our formal review and meta-analyses to only studies rated as fair or good quality and included r and omized , controlled trials ; population -based , casecontrol studies ; and cohort studies with internal controls and at least 3 years of follow-up . In studies with multiple publications from the same cohort or population , only data from the most recent publication were included in the meta-analyses , with reference in the text to older publications if they presented unique findings . To evaluate each study 's control of confounding variables that might explain their results , for each outcome and each study providing data relevant to the outcome , we listed potential CVD risk factors included in the multivariable models determining relative risk . These included age , diabetes , hypertension , smoking , lipid levels , family history , exercise , socioeconomic status , education level , alcohol use , body mass index , and others . Definitions for the presence or absence of these factors , as well as their assessment , are taken directly from the included studies . This research was funded by the U.S. Agency for Healthcare Research and Quality under a contract to support the work of the USPSTF . Agency for Healthcare Research and Quality staff and USPSTF members participated in the initial design of the study and review ed interim analyses and the final manuscript . Since our report was prepared for the Third USPSTF , it was distributed for review to 15 content experts and revised accordingly before preparation of this manuscript . For each outcome , a meta-analytic model was fitted , stratifying by HRT exposure status : current , past , and ever ( if the study did not report results for current and past use separately ) . The model also allowed for a global effect of HRT to be estimated ; this is referred to as the effect of any HRT exposure ( current , ever , or past ) . Our primary analysis compared event rates in patients with any HRT use ( current , past , or ever use ) to those who had never used HRT . We also compared event rates in current , past , or ever HRT use groups to never use to further evaluate variable findings among the studies . Results by category of use are shown in Table 2 . All relative risk estimates are compared with never use . Estimation was made by using the Bayesian data analytic framework , in which the analogue to the confidence interval is the credible interval ( CrI ) ( 16 ) . Further details of the meta- analysis are given in the Appendix . Table 2 . Meta- Analysis Summary Table Results Scope of Literature The MEDLINE search identified 3035 abstract s of papers evaluating primary prevention published between 1966 and December 2000 . From them , 24 cohort studies ; 18 casecontrol studies ; one very small r and omized , controlled trial ; and one meta- analysis were review ed . After the quality of the studies was rated , 20 observational studies ; one r and omized , controlled trial conducted among institutionalized women ; and 1 meta- analysis that combined data from 23 r and omized , controlled trials of HRT for outcomes other than CVD ( such as bone density or lipid levels ) were included in our meta-analyses . Data from studies grade d as poor quality were not included in the meta-analyses . Our search results are shown in the Appendix Figure . We review ed 18 casecontrol studies and rated 6 as poor quality , generally because of very small size , poor evaluation of CVD risk factors , or potential bias in selection of controls ( 17 - 22 ) . We excluded 1 study ( 23 ) because data were provided in an up date d study . Five of the excluded studies did not report risk estimates , 2 suggested decreased risk , and 1 suggested increased risk ( Appendix Table 3 ) . The major difference between studies rated as good or fair quality was in adjustment for CVD risk factors . Twenty-four cohort studies were review ed for inclusion in the meta-analyses , and 11 were excluded because of poor quality ( 24 - 34 ) , usually because they had little or no adjustment for CVD risk factors , they used external controls , or the entire cohort was exposed to HRT . Four studies were excluded because the data were up date d ( 35 - 37 ) or published in another form ( 38 ) . Qualitatively , fair- quality studies had relative risks similar to those of good- quality studies ( range , 0.21 to 1.94 ) . However , all of the poor- quality cohort studies had relative risks or st and ardized mortality ratios significantly below 1 ( range , 0.27 to 0.79 ) ( Appendix Table 3 ) . Cardiovascular and Coronary Artery Disease Mortality All of the studies contributing to our mortality analyses were prospect i ve cohort studies , except for a nested casecontrol study from the Nurses ' Health Cohort . There was little variation among the cohort studies and this study ; therefore , these studies were combined . Similarly , when stratified by study quality ( fair or good ) in the meta-analyses , the findings were similar and the results were combined . More details about the studies are presented in Appendix Tables 4 and 5 . Among 8 observational studies
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"OBJECTIVES This study explored the association between the initiation of hormone replacement therapy ( HRT ) and early cardiac events ( women with a recent myocardial infa rct ion ( MI ) . BACKGROUND Observational studies have linked postmenopausal hormone use with a reduced risk of death from heart disease . However , a recent r and omized trial of HRT found no long-term benefit , primarily due to an increase in cardiac events in the first year . METHODS The Coumadin Aspirin Reinfa rct ion Study ( CARS ) data base contains information on HRT use and menopausal status for women with a recent MI . We classified the 1,857 postmenopausal women in CARS as prior/current HRT users if they took HRT before enrollment , new users if they began HRT during the study period or never users . We assessed the incidence of cardiac events ( death , MI , unstable angina [ UA ] ) during follow-up . RESULTS In our cohort , 28 % ( n = 524 ) used HRT at some point . Of these , 21 % ( n = 111 ) began HRT after their MI . New users had a higher incidence of death/MI/UA ( 41 % vs. 28 % , p = 0.001 ) during follow-up than never users , largely due to a higher incidence of UA ( 39 % vs. 20 % , p = 0.001 ) . After adjustment , new users still had a significantly higher risk of death/MI/UA than never users during follow-up ( relative risk [ RR ] = 1.44 [ 1.05 - 1.99 ] ) . Prior/current users had no excess risk of the composite end point after adjustment . Users of estrogen/progestin had a lower incidence of death/MI/UA during follow-up than users of estrogen only ( RR = 0.56 [ 0.37 - 0.85 ] ) . CONCLUSIONS Postmenopausal women who initiated HRT after a recent MI had an increased risk of cardiac events largely due to excess UA during follow-up",
"OBJECTIVE To examine the relationship between adherence to a medical regimen and mortality following a myocardial infa rct ion in women . DESIGN Analysis of the female cohort entered into a r and omized double-blind multicenter trial . SETTING National Heart , Lung , and Blood Institute beta-Blocker Heart Attack Trial . PARTICIPANTS The 602 women , aged 30 to 69 years , enrolled in the beta-Blocker Heart Attack Trial . INTERVENTION R and om assignment to propranolol hydrochloride or placebo 5 to 21 days following a myocardial infa rct ion . MEASUREMENTS Adherence for each patient was calculated as the mean of all quarterly adherence estimates during the course of the trial ( median follow-up , 26 months ) . Adherence was classified as good ( taking > or = 75 % of medication ) or poor ( taking death from all causes occurring at any time during the trial , adjusted for treatment category and other clinical and sociodemographic features . RESULTS Adherence data were available on 505 women , of whom 32 ( 6.3 % ) died . Death occurred in 13.6 % of poor adherers compared with 5.6 % of good adherers ( relative risk , 2.4 ; 95 % confidence interval , 1.1 to 5.6 ) . The effect of adherence on mortality remained undiminished after adjustment for treatment category ( propranolol or placebo ) , age , severity of myocardial infa rct ion , congestive heart failure , smoking history , marital status , educational level , and race ( adjusted relative risk of death for poor adherers , 2.5 to 3.0 ; P mortality following a myocardial infa rct ion in women is clinical ly substantial , statistically significant , and similar in magnitude to that reported earlier for men",
"BACKGROUND Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events . In contrast , in a recent clinical trial of women with coronary disease , a subgroup analysis demonstrated increased risk during the early months of therapy . Because higher levels of inflammation factors predict vascular disease outcomes , the effect of hormones on these factors is of interest . METHODS AND RESULTS Four inflammation-sensitive factors , C-reactive protein , soluble E-selectin , von Willebr and factor antigen , and coagulation factor VIIIc were measured at baseline , 12 , and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions ( PEPI ) Trial , a r and omized , placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors . Compared with placebo , all 4 active preparations result ed in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin ( P=0.0001 ) . There were no effects of treatment on concentrations of von Willebr and factor or factor VIIIc . There were no differences in effects among treatment arms . Relative to placebo , when combining active treatment arms , final concentrations of C-reactive protein were 85 % higher whereas E-selectin was 18 % lower compared with baseline . CONCLUSIONS Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein . Such an effect may be related to adverse early effects of estrogen therapy . In contrast , hormones reduced the concentration of soluble E-selectin , and this might be considered an anti-inflammatory effect . Because PEPI was not design ed to assess clinical endpoints , studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed",
"The relation of treatment adherence to mortality after a myocardial infa rct ion was investigated among 2175 participants in the Beta Blocker Heart Attack Trial , which had data for measures of treatment adherence , clinical severity , and the psychological and social features that may influence post-infa rct ion mortality . Overall , patients who did not adhere well to treatment regimen ( ie , who took less than or equal to 75 % of prescribed medication ) were 2.6 times more likely than good adherers to die within a year of follow-up ( 95 % confidence interval , 1.2 , 5.6 ) . Poor adherers had an increased risk of death whether they were on propranolol ( OR = 3.1 ) or placebo ( OR = 2.5 ) . Furthermore , this increased risk of death for poor adherers was not accounted for by measures of the severity of myocardial infa rct ion , sociodemographic features ( eg , race , marital status , education ) , smoking , or psychological characteristics ( high life-stress or social isolation )",
"Whether to take hormone therapy is one of the most difficult medical decisions that healthy postmenopausal women face . The apparent coronary benefits ( 1 ) of hormone use are an important part of that decision . Although the data appear consistent in suggesting long-term coronary benefits , the Heart and Estrogen/progestin Replacement Study ( 2 ) showed an increased risk for coronary events during the first year of therapy in women with existing heart disease ; we also found such an elevated risk in an examination of secondary prevention in the Nurses ' Health Study ( 3 ) . More recently , a report from the Women 's Health Initiative , an ongoing r and omized clinical trial of hormone therapy for primary prevention of cardiovascular disease , suggested similar findings in healthy women ( National Institutes of Health . Press release ) . However , additional data on short-term effects of hormone use in women without previous cardiovascular disease are sparse . Many further questions also remain . Among them is the cardiovascular effect of daily doses lower than the st and ard 0.625 mg of oral conjugated estrogen . Recent studies suggest that lower doses of hormone therapy provide bone benefits ( 4 ) and , compared with higher doses , might decrease the risk for thromboembolism ( 5 ) and reduce endometrial hyperplasia ( 4 ) . However , few data are currently available on the relation between low-dose estrogen and primary prevention of heart disease and stroke . In an earlier report , we examined the relation between postmenopausal hormone therapy and primary prevention of cardiovascular disease based on 16 years of follow-up from the Nurses ' Health Study ( 6 ) . In the current analysis , we have almost 50 % more follow-up time among women taking daily doses less than 0.625 mg and more than 800 additional cases of cardiovascular disease , allowing more precise assessment of specific associations . Thus , we now report on the relation among low-dose estrogen , short-term hormone use , and cardiovascular events in 70 533 postmenopausal women with no previous cardiovascular disease who were followed for up to 20 years . We also provide additional information on the effects of estrogen combined with progestin . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about their postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . We up date information with biennial follow-up question naires . Dietary and physical activity question naires were added in 1980 . Cohort follow-up is greater than 90 % . Ascertainment of Hormone Use In 1976 , women were asked about use and duration of hormone therapy after menopause . Beginning in 1978 , we collected information on type of hormones taken , and starting in 1980 , we asked about the dose of oral conjugated estrogen . All information is up date d biennially . Identification of Cardiovascular Disease We identified first occurrences of nonfatal myocardial infa rct ion , fatal coronary disease , and fatal and nonfatal stroke between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion or stroke were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met World Health Organization criteria ( 7 ) ( symptoms plus either elevated levels of cardiac enzymes or diagnostic electrocardiograms ) . Infa rct ions that required hospitalization and were corroborated by interview or letter but for which medical records were unobtainable were included as probable . Infa rct ions of indeterminate age discovered on routine examination were excluded . Nonfatal strokes were confirmed by review of medical records if they were characterized by a typical neurologic deficit , were rapid in onset , lasted at least 24 hours , and met the criteria of the National Survey of Stroke ( 8) . We classified strokes as ischemic ( thrombotic or embolic occlusion of a cerebral artery ) , subarachnoid hemorrhage , or intraparenchymal hemorrhage . We excluded subdural hematomas and strokes caused by infection or neoplasia . Strokes that required hospitalization and were corroborated by letter or interview but for which medical records were unavailable were included as probable . Most deaths were reported by the participants ' families . We search ed the National Death Index to identify deaths among nonrespondents to each 2-year question naire ; mortality follow-up was more than 98 % complete ( 9 ) . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered to be due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . We also included coronary disease listed on the death certificate as the underlying cause without another , more plausible cause , if the nurse was known ( from hospital records , family , or other sources ) to have had coronary disease before death . In no case was the cause listed on the death certificate used as the sole criterion for coronary death . Sudden death within 1 hour of the onset of symptoms in participants with no other plausible cause of death besides coronary disease was also included . Fatal strokes were documented by autopsy or hospital records or if stroke was listed as the underlying cause on the death certificate . The category of major coronary heart disease combines nonfatal myocardial infa rct ion and coronary death ; similarly , total stroke includes nonfatal and fatal cases . The category of combined cardiovascular disease includes major coronary heart disease and stroke . Confirmed and probable cases in each category were analyzed together ( 80 % of major coronary events and 73 % of strokes were confirmed ) . In this and previous analyses ( 6 ) , results for probable cases were similar to those for confirmed cases . The investigators conducted all interviews and record review s without knowledge of participants ' hormone use status . Population for Analysis Women who reported stroke , myocardial infa rct ion , angina , coronary revascularization , or cancer ( except nonmelanoma skin cancer ) on the 1976 question naire were excluded because their disease may have caused them to alter their hormone use . Similarly , women who reported such diagnoses on a subsequent question naire were excluded from further analysis . Thus , at the start of each 2-year interval , the base population included no women reporting these diagnoses . Our own studies ( 6 , 10 ) and other studies ( 11 ) have suggested that hormone therapy may differentially affect incident and fatal strokes ; thus , we separately examined deaths due to stroke . In these analyses , we excluded women with cancer and cardiovascular disease at baseline but did not up date the exclusions because the women who develop cardiovascular disease during follow-up are those most likely to die of stroke . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy . Women who underwent hysterectomy without bilateral oophorectomy were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) . In this cohort , the women 's reports of age at menopause ( 12 ) and type of menopause ( 13 ) were highly accurate . In 1976 , 21 947 postmenopausal women entered the analysis , and 48 586 women were added during follow-up as they became postmenopausal , for a total of 70 533 participants ; 808 825 person-years of follow-up were accrued from 1976 to 1996 . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the 1976 data and were up date d every 2 years ( for estrogen dose , follow-up began in 1980 ) . For analyses of type of hormone therapy , we assigned the regimen reported on the 1978 question naire to women who reported hormone use in 1976 . Analyses of type of hormone therapy were limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate , since these were the most common hormone regimens . If no data were available on hormones in a given time period , women were assigned to a missing category for that time period . To maintain the prospect i ve nature of the study , hormone use ( including duration ) during each 2-year period was established from women 's reports at the start of the period ; thus , we probably underestimate duration of use by an average of 1 year . Follow-up for a participant ended at the first diagnosis of cardiovascular disease , death , or 1 June 1996 , whichever came first . The primary analysis is based on incidence rates for which person-months of follow-up were used as the denominator . We used relative risk as the measure of association , defined as the incidence of cardiovascular events among women in various categories of hormone use divided by the incidence among women who never used hormones . We computed age-specific rates by using 5-year categories ( 14 ) and age-adjusted relative risks by using MantelHaenszel rate ratios ( 15 ) with 95 % CIs ( 16 ) . We used pooled logistic regression across the ten 2-year time periods to adjust simultaneously for potential confounding factors ( 17 ) . In this approach , independent blocks of person-time are pooled for regression analysis , and time-varying covariates are readily accommo date d by assigning successive blocks of person-time to the covariate values at the start of each follow-up cycle . The dependence of the incidence rates on time is modeled nonparametrically with indicator variables . Simulation studies have established the asymptotic equivalence of pooled logistic regression to Cox regression with time-dependent covariates ( 18 ) . The necessary conditions for this equivalence include relatively short time intervals and small probability of the outcome during each interval , both",
"The increasing use of oestrogen replacement therapy in women has focussed attention on the cardioprotective properties it has demonstrated . Historically , it has been shown that women enjoy a certain protection from heart disease , a phenomenon , however , which has not been studied extensively . Women at every age have less coronary artery disease ( CAD ) than men , even when various risk factors are accounted for , although the presence of diabetes carries equal mortality for both sexes . However , women who do develop CAD have a greater risk of mortality than men with CAD . Other gender differences include a later age of onset of CAD for women , and a difference in the type of atherosclerotic lesions developed . Most striking is the fact that , in women , high-density lipoprotein ( HDL ) seems to be a more potent predictor of major cardiovascular events than low-density lipoprotein ( LDL ) , or total cholesterol . The Postmenopausal Oestrogen and Progesterone Interventions ( PEPI ) Trial looked at changes in HDL , fibrinogen , blood pressure and serum insulin result ing from oestrogen use . Four regimens were compared against placebo in 875 women . The results showed that HDL was increased significantly , LDL decreased significantly , fibrinogen levels decreased significantly , and blood pressure and serum insulin levels were essentially unaffected by oestrogen and oestrogen/progestin interactions . The Heart and Oestrogen/Progestin Replacement ( HERS ) Study , currently underway , is a secondary prevention trial testing the protective effect of hormone therapy in women with documented CAD . This trial may definitively answer the question of whether hormones protect against CAD . After HERS , it may be unethical to continue conducting placebo-controlled trials in a therapy that has such documented cardioprotective benefit",
"OBJECTIVE Our purpose was to investigate whether selection of healthy women for postmenopausal estrogen therapy may confound observational studies of estrogen use and cardiovascular disease risk . STUDY DESIGN Data were obtained from baseline ( 1981 to 1984 ) and follow-up ( 1990 to 1992 ) health surveys of two cohorts r and omly selected from communities in southeastern New Engl and . At follow-up postmenopausal women > or = 40 years old were categorized as current users ( n = 70 ) or nonusers ( n = 772 ) of noncontraceptive estrogen . Users and nonusers were compared on both prior characteristics from the baseline surveys and current characteristics measured at follow-up by use of analysis of covariance . RESULTS Prior levels of total and high-density lipoprotein cholesterol , body mass index , and blood pressure were similar for estrogen users and nonusers . Estrogen users were less likely to have smoked and more likely to have had their cholesterol checked and to exercise regularly . These differences were more pronounced for current characteristics than for baseline characteristics . CONCLUSIONS Selection of healthy women for treatment may not fully explain the apparent protective effect of estrogen replacement on cardiovascular risk . However , more healthy profiles among estrogen users may inflate the apparent benefit of treatment in observational studies",
"Studies that report on the risk for coronary heart disease in women who use estrogen replacement therapy alone are numerous , and information on this topic has been summarized in four published quantitative overviews or meta-analyses [ 1 - 4 ] . Although these overviews conclude that the risk for coronary heart disease is lower in estrogen users , the lack of experimental studies of estrogen use limits the ability to draw definitive conclusions about cause and effect . Fewer studies have examined the association between estrogen-progestogen therapy and coronary heart disease [ 5 - 10 ] . Several ongoing large r and omized trials are now examining the relation of estrogen and estrogen-progestogen with coronary heart disease , but the results of these studies may not be available for several years . Until publication of the results of r and omized trials examining the relation between hormone use and myocardial infa rct ion , data from nonexperimental studies will be useful in guiding clinical policy . The primary goal of this casecontrol study was to estimate the odds ratio for incident acute myocardial infa rct ion in relation to current use of estrogen and estrogen-progestogen in a population with a high prevalence of estrogen and estrogen-progestogen use . We used the exposure odds ratio to estimate the degree of risk . The secondary goals of this study were to estimate the odds ratios for incident myocardial infa rct ion in 1 ) current users of estrogen or estrogen-progestogen in relation to the duration of current use and 2 ) past users of estrogen or estrogen-progestogen . These topics have not been examined closely in previous studies . We also estimated the odds ratio for incident myocardial infa rct ion in current users of estrogen or estrogen-progestogen , considering many potentially confounding variables . Methods All case- patients were women 45 to 74 years of age who were hospitalized for myocardial infa rct ion in any of 10 medical centers of the Kaiser Permanente Medical Care Program ( KPMCP ) , Northern California region , between November 1991 and November 1994 . Start and finish date s differed by facility so that the number of months of case ascertainment was different at each facility ( mean , 33.4 months ) . Sources used to identify case- patients included daily admission logs containing admitting diagnoses and information about visits to KPMCP emergency departments . We also regularly review ed the discharge diagnoses from a computerized data base of all overnight hospitalizations in KPMCP , Northern California , centers . The medical records of all case- patients were abstract ed by medical abstract ers and review ed by the medically trained project coordinators ( one was a registered nurse who had research experience in cardiovascular disease studies ; the other was a physician ) , who consulted with one of the physician-investigators as needed . Case- patients who had a history of coronary heart disease before the date of symptom onset , as ascertained by medical record review done before the study interview , were excluded in an attempt to limit the study to persons with incident coronary heart disease . This was done because the presence of coronary heart disease might influence clinical decision making with regard to the use of estrogen or estrogen-progestogen . In addition , a personal history of coronary heart disease was obtained from all interviewed participants ( case- patients and controls ) and was included as an adjustment variable in the analysis . Diagnostic criteria for myocardial infa rct ion were adapted from those of the American Heart Association Council on Epidemiology [ 11 ] . These criteria use presence or absence of chest pain , results of cardiac enzyme tests , and electrocardiograms to classify events as definite myocardial infa rct ion , probable myocardial infa rct ion , suspected myocardial infa rct ion , or not myocardial infa rct ion . Like investigators in other epidemiologic studies of myocardial infa rct ion defined by using these criteria , we included events categorized as definite or probable cases of myocardial infa rct ion . According to these criteria , the presence of cardiac pain and abnormal enzyme test results are sufficient to categorize an event as a definite or probable myocardial infa rct ion , making it unnecessary to have the electrocardiogram examined by an independent expert . For women who could not be categorized as having definite or probable myocardial infa rct ion on the basis of the presence of chest pain and abnormal enzyme test results , electrocardiograms were sent for coding to the Minnesota ECG Coding Center at the University of Minnesota . This information was used to categorize events as definite myocardial infa rct ion , probable myocardial infa rct ion , suspected myocardial infa rct ion , or not myocardial infa rct ion . For each case-patient , an attempt was made to interview one control , matched for year of birth and facility of usual care . To do this , three potential controls were selected at r and om from among all female members of the KPMCP . If the first potential control could not be located , declined to participate , or did not speak English or Spanish , an attempt was made to enroll the second potential control , and , if necessary , the third , in order to obtain one interviewed control per case-patient . Controls were identified for 98.2 % of confirmed case- patients , and 79.6 % of controls were the first of the three potential c and i date s. Eligible case- patients and controls were interviewed in person by trained interviewers who used a st and ardized instrument . All participants were interviewed as soon as possible after the events in the case-patient occurred . The mean interval between the index date and the interview date was 71.8 days for case- patients and 78.5 days for controls . If a case-patient died or was unable to communicate verbally , an attempt was made to interview a proxy . Interview information from proxies and the corresponding controls was excluded from this analysis because 1 ) the prevalence of both current and past hormone replacement therapy ascertained by proxy interview was much lower than that ascertained in direct interviews and 2 ) a comparison of proxy responses with medical records showed substantial underreporting of documented hormone use . We did not use information from medical records for the analysis because use on a particular date and long-term past use could not be reliably ascertained from these records . All interview questions were asked in relation to an index date , which was the date of symptom onset for each case-patient and the same date for each matched control . Information about the lifetime use of estrogen and estrogen-progestogen preparations was obtained by using the calendar method , in which information on use of hormone replacement therapy is gathered by structuring questions in relation to significant life events . Visual aids , consisting of actual pills for commonly used preparations and a color chart with pictures of all hormone replacement preparations ever marketed in the United States , was used to facilitate recall of the formulation of hormone replacement preparations used currently and in the past . A study participant was defined as having hypertension , diabetes , or a high cholesterol level if she answered yes to questions about whether she was taking medication for these risk factors ( she was also defined as having a high cholesterol level if she reported that a physician had told her that she had high cholesterol levels ) . A participant was defined as a nonsmoker if she answered no to the question , Have you ever smoked cigarettes ? If she answered yes to this question , she was categorized as a current regular , occasional , or former smoker on the basis of her answer to the question , On [ index date ] , were you still smoking regularly ? ( Regularly was defined as at least 5 cigarettes per week almost every week . ) Body mass index ( kg/m2 ) was determined by using participant-reported height and weight . A participant was defined as having a previous self-reported history of coronary heart disease if she stated that a physician had told her that she had had a heart attack or angina . The analysis was restricted to postmenopausal women . A study participant was categorized as postmenopausal if she had undergone bilateral oophorectomy or if she had not had a hysterectomy and reported that she had ceased having menstrual periods . Women who have undergone both hysterectomy and unilateral oophorectomy do not know whether they are pre- or postmenopausal on the basis of menstrual function ; thus , we excluded such women if they were younger than 55 years of age because they could not be classified with certainty as postmenopausal . These exclusions were applied to both case- patients and controls . Among women who used replacement therapy , most who had had hysterectomy used estrogen ( 50.6 % used estrogen ; 1.2 % used estrogen-progestogen ) and most women who had not had hysterectomy used estrogen-progestogen ( 18.4 % used estrogen-progestogen ; 3.0 % used estrogen ) . For this reason , estimates of the odds ratios for myocardial infa rct ion in users of estrogen who did not have hysterectomy and the odds ratios for myocardial infa rct ion in users of estrogen-progestogen who had had hysterectomy were highly unstable statistically . Thus , we excluded from this analysis women who had had hysterectomy and used estrogen-progestogen , women who had not had hysterectomy and used estrogen , and women of unknown hysterectomy status ( n = 3 ) who used either estrogen-progestogen or estrogen . Women who used only progestogen were also excluded as both case- patients and controls because there were few women in this group and valid estimates of risk in relation to exposure to progestogen only could not be derived . These exclusion criteria were applied to both case- patients and controls . Conditional logistic regression was used in the main analyses . For these analyses , we defined an exposure variable-current hormone use-as yes for women who had had",
"The Heart and Estrogen/progestin Replacement Study ( HERS ) is a r and omized , double-blind , placebo-controlled trial design ed to test the efficacy and safety of estrogen plus progestin therapy for prevention of recurrent coronary heart disease ( CHD ) events in women . The participants are postmenopausal women with a uterus and with CHD as evidence d by prior myocardial infa rct ion , coronary artery bypass graft surgery , percutaneous transluminal coronary angioplasty , or other mechanical revascularization or at least 50 % occlusion of a major coronary artery . Between February 1993 and September 1994 , 20 HERS centers recruited and r and omized 2763 women . Participants ranged in age from 44 to 79 years , with a mean age of 66.7 ( SD 6.7 ) years . Most participants were white ( 89 % ) , married ( 57 % ) , and had completed high school or some college ( 80 % ) . As expected , the prevalence of coronary risk factors was high : 62 % were past or current smokers , 59 % had hypertension , 90 % had serum LDL-cholesterol of 100 mg/dL or higher , and 23 % had diabetes . Each woman was r and omly assigned to receive one tablet containing 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate daily or an identical placebo . Participants will be evaluated every 4 months for an average of 4.2 years for the occurrence of CHD events ( CHD death and nonfatal myocardial infa rct ion ) . We will also assess other major CHD endpoints , including revascularization and hospitalization for unstable angina . The primary analysis will compare the rate of CHD events in women assigned to active treatment with the rate in those assigned to placebo . The trial was design ed to have power greater than 90 % to detect a 35 % reduction in the incidence of CHD events , assuming a 50 % lag in effect for 2 years and a 5 % annual event rate in the placebo group . The design , analysis , and conduct of the study are controlled by the Steering Committee of Principal Investigators and coordinated at the University of California , San Francisco . HERS is the largest trial of any intervention to reduce the risk of recurrent CHD events in women with heart disease and is the first controlled trial to seek evidence of the efficacy and safety of postmenopausal hormone therapy to prevent recurrent CHD events",
"Observational epidemiologic studies suggest that the incidence of cardiovascular disease is reduced by about 50 % in users of unopposed estrogens , but the reduction may have been overestimated because of a greater tendency for women at lower risk to use estrogens . To minimize bias due to such behavior , the authors conducted a case-control study of first myocardial infa rct ion among Massachusetts women aged 45 - 69 years during 1986 - 1990 , in which each of 858 cases was age-matched with a control from the same geographic area , and important correlates of estrogen use and myocardial infa rct ion were controlled by conditional logistic regression . The estimated relative risk was 0.9 for ever use of unopposed estrogen ( 95 % confidence interval 0.7 - 1.2 ) ; the estimate decreased with increasing duration of use to 0.6 for 5 or more years of use ( p for trend = 0.08 ) . The association with long-term use was stronger for recent use ( p for trend estrogens taken together with progestins . The results suggest that unopposed estrogen use may reduce the risk of first myocardial infa rct ion , that the reduction is related to the duration and recency of use , and that it may be smaller than previously believed . Despite efforts to control confounding , observational studies can not rule out the possibility that a tendency for women at lower risk for myocardial infa rct ion to use estrogens has contributed to the reduced risk in estrogen users , and r and omized trials are needed",
"Observational studies have demonstrated that women who have used postmenopausal estrogen replacement therapy ( ERT ) are at reduced risk of coronary heart disease . The authors examined whether premenopausal women who subsequently elected to use ERT during menopause had a better cardiovascular risk factor profile prior to use than did nonusers . A total of 541 premenopausal women had their cardiovascular risk factors and psychosocial characteristics evaluated at study entry . After approximately 8 years , 355 women had become postmenopausal , and 157 women reported ERT use during the follow-up period ( mean = 93.4 months ) . The authors compared the premenopausal characteristics of users with those of nonusers . Relative to nonusers , ERT users were better educated ( 63 vs. 81 % with at least some college ) , and prior to the use of ERT had higher levels of high density lipoprotein ( HDL ) cholesterol ( 1.49 vs. 1.59 mmol/liter ) , HDL2 ( 0.50 vs. 0.57 mmol/liter ) , HDL3 ( 0.98 vs. 1.02 mmol/liter ) , leisure physical activity ( 5 , 122 vs. 7,158 Kjoules ) , and alcohol intake ( 7.5 vs. 9.7 g/day ) , and lower levels of apolipoprotein B ( 0.97 vs. 0.90g/liter ) , systolic blood pressure ( 112.1 vs. 107.1 mmHg ) and diastolic blood pressure ( 73.8 vs. 71.4 mmHg ) , weight ( 68.5 vs. 64.2 kg ) , and fasting insulin ( 9.10 vs. 7.66 microU/liter ) . Prior to use of ERT , in comparison with nonusers , subsequent users reported on st and ardized question naires that they often exhibited Type A behavior , more aware of their feelings , motives , and symptoms , and had more symptoms of stress . Women who elect to use ERT have a better cardiovascular risk factor profile prior to the use of ERT than do women who subsequently do not use this treatment during the menopause , which supports the hypothesis that part of the apparent benefit associated with the use of ERT is due to preexisting characteristics of women who use ERT . This study underscores the widely recognized importance of r and omized clinical trials to estimate the direct benefit of postmenopausal ERT for protecting women from cardiovascular disease",
"BACKGROUND There is little information about whether an increasing duration of estrogen replacement therapy is associated with a declining risk for myocardial infa rct ion in postmenopausal women . OBJECTIVE To conduct a population -based , case-control study among enrollees of the Group Health Cooperative ( GHC ) of Puget Sound , Seattle , Wash. SUBJECTS AND METHODS Case subjects were all post-menopausal women who were enrolled in the GHC with an incident fatal or nonfatal myocardial infa rct ion from July 1986 through December 1993 . Control subjects were a stratified r and om sample of postmenopausal women who were enrolled in the GHC without myocardial infa rct ion and matched to case subjects by age and calendar year . We review ed the medical records of the 850 case subjects and 1974 control subjects and conducted telephone interviews with consenting survivors . Use of estrogen or estrogen and progestin was assessed using GHC 's computerized pharmacy data base . RESULTS Among women who were currently using estrogen , a longer duration of use was inversely associated with a risk for myocardial infa rct ion after adjustment for age , year of identification , diabetes mellitus , angina , and smoking . For categories of increasing duration of estrogen use ( never , > 0- or = 8.2 years ) , the odds ratios for myocardial infa rct ion were 1.00 ( reference ) , 0.91 , 0.70 , 0.65 , and 0.55 ( for trend among the current users , P = .05 ) . Among women who had used estrogen in the past , there was no evidence of decreasing risk with increasing duration of estrogen use . CONCLUSION In this study , a long duration of hormone replacement therapy among women currently using estrogen was associated with a reduced risk for first myocardial infa rct ion",
"Hormone replacement therapy ( HRT ) has been shown to increase the relative risk of idiopathic venous thromboembolism ( VTE ) about threefold in several observational studies and one r and omised controlled trial . Whether or not this relative risk is higher in women with underlying thrombophilia phenotypes , such as activated protein C ( APC ) resistance , is unknown . We therefore restudied the participants in a case-control study of the relationship between the use of HRT and the occurrence of idiopathic VTE in women aged 45 - 64 years . After protocol exclusions , 66 of the cases in the original study and 163 of the controls were studied . Twenty haematological variables relevant to risk of VTE were analysed , including thrombotic states defined from the literature . The relative risk of VTE showed significant associations with APC resistance ( OR 4.06 ; 95 % CI 1.62 , 10.21 ) ; low antithrombin ( 3.33 ; 1.15 , 9.65 ) or protein C ( 2.93 ; 1.06 , 8.14 ) ; and high coagulation factor IX ( 2.34 ; 1.26 , 4.35 ) , or fibrin D-dimer ( 3.84 ; 1.99 , 7.42 ) . HRT use increased the risk of VTE in women without any of these thrombotic states ( OR 4.09 ; 95 % CI 1.26 , 13.30 ) . A similar effect of HRT use on the relative risk of VTE was also found in women with prothrombotic states . Thus for example , the combination of HRT use and APC resistance increased the risk of VTE about 13-fold compared with women of similar age without either APC resistance or HRT use ( OR 13.27 ; 95 % CI 4.30 , 40.97 ) . We conclude that the combination of HRT use and thrombophilias ( especially if multiple ) increases the relative risk of VTE substantially ; hence women known to have thrombophilias ( especially if multiple ) should be counselled about this increased risk prior to prescription of HRT . However , HRT increases the risk of VTE about fourfold even in women without any thrombotic abnormalities : possible causes are discussed",
"CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue",
"The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of postmenopausal hormone use in 2763 women ( 1 ) . Unlike previous observational studies , it included only women with previous coronary heart disease , and hormone therapy was exclusively oral conjugated estrogen plus progestin . In HERS , overall rates of recurrent coronary heart disease did not differ between the treated and nontreated groups . However , in additional , unplanned analyses , the results of HERS were not uniformly None . A marked and statistically significant trend toward decreasing risk was observed with increasing duration of hormone use ( 1 ) ; in the first year , the rate of major coronary events was 52 % higher in the treatment group . In the second year , rates were equal , but during the final fourth and fifth years , women assigned to hormone therapy had a 33 % lower risk for coronary events . The overall results of HERS and the apparent changes in risk over time were both unexpected . Since no previous investigations have examined the relation between duration of hormone use or combined hormone treatment to secondary prevention of coronary heart disease events , it remains unclear whether the time trend was authentic and whether the observations in HERS are limited to that hormone regimen ( 2 ) . In addition , we were interested in underst and ing how women 's use of hormone therapy before their initial coronary disease event might affect the outcome of their hormone use after that event . In HERS , duration of hormone therapy before trial entry was necessarily disregarded ( although 23 % of participants had previously taken hormones ) ; thus , it remains unknown how , or whether , to account for hormone use or duration of use before a patient 's initial coronary event . To further examine the effects of duration of hormone therapy and to explore the effect of different hormone regimens , we investigated the relation between postmenopausal hormone use and secondary prevention of major coronary events in 2489 women with established coronary disease in the Nurses ' Health Study , a large observational cohort . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 , when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . Every 2 years , we mail follow-up question naires to the original participants to up date information on risk factors and to identify newly diagnosed cases of major illnesses . The total follow-up for the cohort to date exceeds 92 % . Sample for Analysis For this analysis , we limited the cohort to postmenopausal women who reported a previous myocardial infa rct ion or documented coronary atherosclerosis ( coronary artery bypass graft surgery , percutaneous coronary revascularization , or angiographic evidence of 70 % occlusion of one or more major coronary arteries ) . Such women were identified on the baseline question naire in 1976 ; postmenopausal women who reported one of these conditions on a subsequent follow-up question naire were added to the sample at that time . Women ranged in age from 34 to 73 years at entry into the sample for analysis ; 60 % of women had a natural menopause . These criteria closely parallel those used in HERS ( 1 ) ; however , in HERS , women with hysterectomy were excluded , occlusion was defined as at least 50 % , and participants ranged in age from 44 to 79 years . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy . Women who underwent hysterectomy without bilateral oophorectomy were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) ( 3 ) . The women 's reports of age at menopause and type of menopause were highly accurate ( 4 ) . In HERS , women with a history of breast or endometrial cancers were excluded . In the current study , we excluded women who reported stroke or cancer ( except nonmelanoma skin cancer ) on the 1976 baseline question naire at the outset and excluded women from further follow-up if they reported these diseases on a subsequent biennial question naire . This was done to avoid potential bias , in which major diseases such as stroke or cancer may have caused women to alter their hormone use and may be related to risk for coronary heart disease . This type of bias could not have occurred in a r and omized trial , such as HERS . Two hundred forty-eight postmenopausal women with coronary disease entered the analysis in 1976 , and 2241 postmenopausal women were added during follow-up as they reported heart disease ; thus , 17 239 person-years accrued during up to 20 years of follow-up from 1976 to 1996 . Ascertainment of Hormone Use In 1976 , women were asked about current and past use and duration of hormone therapy ; this information was up date d on each biennial question naire . Beginning in 1978 and on each subsequent question naire , we collected information on type of hormone used . For the period 19761978 , we assigned women to the type of hormone reported on the 1978 question naire . If no data were available on hormone therapy for a given 2-year period , those women were assigned to a missing category for that period . In the HERS trial , women who had taken hormones in the 3 months before their screening visit were excluded ( although 23 % to 24 % of the enrolled participants had previously used hormones ) . Because this study is observational , we could not impose a 3-month washout period ; thus , we could not duplicate that aspect of the HERS protocol . We analyzed duration of hormone use in two different ways . In the main analysis , we performed a HERS replication and used a method similar to that in HERS to calculate duration of use . In HERS , duration of hormone therapy began to accrue at r and omization ( regardless of previous hormone use ) ; r and omization occurred sometime after the participant 's initial coronary disease event . Therefore , in our main analysis , we began accruing duration of hormone use for each participant immediately after her initial coronary disease event ( regardless of hormone use before this event ) . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 4 years . In an alternative analysis , we considered the women 's full experience with hormone therapy ( both before and after the initial coronary disease event ) . Thus , duration of hormone use accumulated continuously from start to termination of therapy . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 6 years . Similar to HERS participants , 29 % of the nurses had taken hormones before their first coronary disease event . Identification of Second Coronary Disease Events Similar to HERS , in our study the category of recurrent major coronary heart disease included nonfatal myocardial infa rct ion and fatal coronary disease that occurred between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met the World Health Organization criteria ( 5 ) ( symptoms , plus either elevated cardiac enzyme levels or diagnostic electrocardiograms ) . Infa rct ions requiring hospitalization and corroborated by interview or letter , but for which medical records were unobtainable , were included as probable . Most deaths were reported by the participants ' families . Every 2 years , we search the National Death Index ( 6 ) to identify deaths among nonrespondents ; follow-up for death remains more than 98 % complete to date . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . Cases in which coronary disease was listed on the death certificate as the underlying cause of death and another , more plausible cause could not be discerned were included as probable cases , since the nurse was known to have had coronary disease before death . The investigators conducted all interviews and medical record review s without knowledge of participants ' hormone use status . In separate analyses , results for probable cases of coronary disease ( 20 % ) were almost identical to those for confirmed cases ( 80 % ) ; thus , we present data from analyses in which confirmed and probable cases are combined . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the baseline data and were up date d every 2 years according to information received on follow-up question naires . Examination of type of hormone therapy was limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate , as this was the most common hormone regimen . If information on hormone use was missing during a follow-up period , then person-time was assigned to a missing category for that time period . So that the study would be prospect i ve , we established hormone status during each 2-year follow-up period from women 's reports at the start of the time period ; thus , we probably underestimate duration of use by an average of 1 year in both the main analysis and the alternate analysis . Follow-up for a participant ended with diagnosis of myocardial infa rct ion , death , or 1 June 1996 , whichever came first . The analysis is based on incidence rates , using person-months of follow-up as the denominator . We used relative risk as the measure of association , defined as the incidence of second major coronary events among women in various categories of hormone use divided by the rate among women who never used hormones",
"We examined the relation between menopausal estrogen use and all-cause and cause-specific mortality in a cohort of over 49,000 women followed between 1979 and 1989 in the Breast Cancer Detection Demonstration Project ( BCDDP ) Follow-Up Study . We found a lower all-cause mortality rate among women who took estrogens [ rate ratio ( RR ) = 0.7 ; 95 % confidence interval ( CI ) = 0.7–0.8 ] , particularly current users ( RR = 0.3 ; 95 % CI = 0.2–0.4 ) , than among women who never took them . Additional analyses , however , revealed that women who had recently stopped taking estrogens had a higher all-cause mortality rate than women who had never taken them ( RR = 1.4 ; 95 % CI = 1.2–1.7 ) . Women who had recently stopped taking estrogens also had higher mortality rates from circulatory disease ( RR = 1.3 ; 95 % CI = 1.0–1.8 ) and cancer ( RR = 1.6 ; 95 % CI = 1.2–2.2 ) than women who never took them . The most likely explanation for these results is that women stop taking estrogens when they develop symptoms of serious illness . As a consequence of this “ healthy estrogen user survivor effect , ” nonexperimental studies are susceptible to overestimating the benefits of menopausal estrogen use , particularly current use , on mortality ",
"CONTEXT Estrogens are known to be prothrombotic , and findings from the Heart and Estrogen/progestin Replacement Study suggest that in women with clinical ly recognized heart disease , hormone replacement therapy ( HRT ) may be associated with early harm and late benefit in terms of coronary events . OBJECTIVE To assess whether , as hypothesized , prothrombotic mutations modify the association between HRT use and incidence of first myocardial infa rct ion ( MI ) . DESIGN AND SETTING Population -based , case-control study conducted in a Seattle-based health maintenance organization . PARTICIPANTS Cases were 232 postmenopausal women aged 30 to 79 years who had their first nonfatal MI between 1995 and 1998 . Controls were a stratified r and om sample of 723 postmenopausal women without MI who were frequency-matched to cases by age , calendar year , and hypertension status . MAIN OUTCOME MEASURE Risk of first nonfatal MI based on current use of HRT and the presence or absence of coagulation factor V Leiden and prothrombin 20210 G-->A variants among cases and controls , stratified by hypertension . RESULTS One hundred eight MI cases and 387 controls had hypertension and 124 MI cases and 336 controls did not . Among hypertensive women , the prothrombin variant was a risk factor for MI ( odds ratio [ OR ] , 4.32 ; 95 % confidence interval [ CI ] , 1.52 - 12.1 ) and , in this stratum , there was also a significant interaction between use of HRT and presence of the prothrombin variant on risk of MI . Compared with nonusers of HRT with wild-type genotype , women who were current users and who had the prothrombin variant ( n = 8) had a nearly 11-fold increase in risk of a nonfatal MI ( OR , 10.9 ; 95 % CI , 2.15 - 55.2 ) . The interaction with the prothrombin variant was more pronounced in analyses assuming 100 % compliance than in those assuming 80 % compliance with HRT . The interaction was absent among nonhypertensive women and was less pronounced if hypertensive and nonhypertensive women were combined into 1 group . No interaction was found for factor V Leiden in either hypertensive or nonhypertensive women . Among hypertensive women , the estimates were affected only in trivial ways by adjustment , and the interaction with the prothrombin variant was specific to HRT . CONCLUSIONS Our results suggest that among postmenopausal hypertensive women , the association between HRT use and MI risk differed between those with and without the prothrombin 20210 G-->A variant . If these findings are confirmed in other studies , screening for the prothrombin variant may permit a better assessment of the risks and benefits associated with HRT in postmenopausal women",
"To assess the long-term effects of estrogen replacement therapy ( ERT ) in 157 postmenopausal women , a prospect i ve , nonr and omized , cohort study was conducted from 1964 to 1989 . ERT consisted of 0.625 mg of conjugated equine estrogen daily for the first 25 days of each month without oral progesterone from 1964 to 1984 . From 1984 to 1989 5 mg of medroxyprogesterone was added from day 14 to 25 of every sixth month in subjects with an intact uterus . The mean loss of height was significantly less among the ERT subjects after age 65 years and remained at 0.08 cm/year from age 56 to 80 years , whereas the loss of height accelerated among the control subjects to 0.19 cm/year from age 66 to 70 , to 0.22 cm/year from age 71 to 75 , and to 0.30 cm/year from age 76 to 80 . The mean cortical bone density at the distal third of the radius was significantly greater among the ERT subjects compared to the control subjects with the difference representing a 12.0 % higher bone density with ERT . The risk of both vertebral compression and peripheral fractures was significantly reduced in the ERT group ( relative risk 0.28 ) . The mean serum LDL cholesterol was 21 % lower and the mean HDL cholesterol , 37 % higher among ERT subjects compared to control subjects . Both ERT and total serum cholesterol had independent effects on the development of cardiovascular disease ( myocardial infa rct ion and stroke ) in a multivariate analysis"
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BACKGROUND ageing and sedentary behaviour cause negative changes in the neuromuscular systems of healthy older adults result ing in a decrease in physical functioning . Exercising in water ( aquatic exercise , AE ) has been shown to be effective at improving physical functioning in this population ; however , no systematic review with meta- analysis has been published . PURPOSE to investigate the effect of AE on physical functioning in healthy older adults compared to control or l and -based exercise ( LE ) through a systematic review with meta- analysis of r and omised controlled trials . DATA SOURCES Medline , Embase , Cinahl , PEDro , SPORTD iscus , Web of Science , Cochrane Library , published before 31st December 2015 . STUDY SELECTION in total , 28 studies met the inclusion criteria and were included in the systematic review ; 24 studies with 1,456 subjects ( 89 % female ) and with mean age 66.4 years were included in the meta- analysis . DATA EXTRACTION data were extracted and checked for accuracy by three independent review ers . DATA SYNTHESIS size of treatment effect was measured using the st and ardised mean difference with 95 % confidence intervals ( CIs ) . RESULTS compared to control interventions , AE had a moderate positive effect on physical functioning 0.70 [ 95 % CI 0.48 to 0.92 ] . Compared to LE , AE had a small positive effect on physical functioning 0.39 [ 0.12 to 0.66 ] . LIMITATIONS there is a high risk of bias and low method ological quality in the studies particularly when comparing AE to LE with possible over estimation of the benefit of AE . CONCLUSIONS AE may improve physical functioning in healthy older people and is at least as effective as LE
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"The aim of this study was to assess the effectiveness of a 24-week exercise protocol carried out in geothermal spring water to improve overall physical function and muscle mass in a group of healthy elderly subjects . A further aim was to compare this water-based protocol with a l and -based protocol and a control group . For this purpose , 59 subjects were recruited and r and omly allocated to three groups : aquatic group ( AG ) , l and group ( LG ) , and control group ( CG ) . AG and LG followed a 6-month , twice-weekly , multimodality exercise intervention . AG underwent the protocol in hot-spring water ( 36 ° C ) while LG did it in a l and -based environment . After the intervention , knee-extension strength was maintained in AG and LG . The 8-foot up- and -go test showed a reduction in both exercise groups ( AG −19.3 % , P greater decrease in AG . The back-scratch test revealed an improvement only in AG ( 25.8 % ; P the sit- and -reach test improved in all groups . Finally , AG reduced fat mass by 4 % ( P and dominant forearm fat decreased by 9.2 % ( P addition , calf muscle density increased by 1.8 % ( P water- and l and -based activities were beneficial in maintaining strength and in improving lower-body flexibility . Aquatic exercise appeared a better activity to improve dynamic balance . Thermal swimming pools and the use of rating of perceived exertion as a method of exercise monitoring should be considered potentially useful tools to enhance physical performance and body composition in healthy elderly",
"CONTEXT The Consoli date d St and ards for Reporting of Trials ( CONSORT ) statement was developed to help improve the quality of reports of r and omized controlled trials ( RCTs ) . To date , a paucity of data exists regarding whether it has achieved this goal . OBJECTIVE To determine whether use of the CONSORT statement is associated with improvement in the quality of reports of RCTs . DESIGN AND SETTING Comparative before- and -after evaluation in which reports of RCTs published in 1994 ( pre-CONSORT ) were compared with RCT reports from the same journals published in 1998 ( post-CONSORT ) . We included 211 reports from BMJ , JAMA , and The Lancet ( journals that adopted CONSORT ) as well as The New Engl and Journal of Medicine ( a journal that did not adopt CONSORT and was used as a comparator ) . MAIN OUTCOME MEASURES Number of CONSORT items included in a report , frequency of unclear reporting of allocation concealment , and overall trial quality score based on the Jadad scale , a 5-point quality assessment instrument . RESULTS Compared with 1994 , the number of CONSORT checklist items in reports of RCTs increased in all 4 journals in 1998 , and this increase was statistically significant for the 3 adopter journals ( pre-CONSORT , 23.4 ; mean change , 3.7 ; 95 % confidence interval [ CI ] , 2.1 - 5.3 ) . The frequency of unclear reporting of allocation concealment decreased for each of the 4 journals , and this change was statistically significant for adopters ( pre-CONSORT , 61 % ; mean change , -22 % ; 95 % CI , -38 % to -6 % ) . Similarly , 3 of the 4 journals showed an improvement in the quality score for reports of RCTs , and this increase was statistically significant for adopter journals overall ( pre-CONSORT , 2.7 ; mean change , 0.4 ; 95 % CI , 0.1 - 0.8 ) . CONCLUSION Use of the CONSORT statement is associated with improvements in the quality of reports of RCTs",
"The aim of the present study was to evaluate the effects of an AAG on BMD , osteocalcin and functional autonomy in older women . The sample consisted of eighty-two post-menopausal women with low BMD , r and omly divided into two groups : the Aquatic Aerobics Group [ AAG ; n=42 ; age : 66.8±4.2years ] , su bmi tted to two weekly sessions over eight months , and the Control Group ( GC ; n=42 ; age : 66.9±3.2years ) , which did not participate in regular exercise . BMD was measured by Dual Energy X-ray Absorptiometry [ DXA ] of the lumbar and femur , and serum osteocalcin was measured using electrochemiluminescence . A functional autonomy assessment protocol ( GDLAM , 2004 ) was also applied . Statistical analyses used were repeated measures ANOVA and Tukey 's post hoc tests . The results showed a significant improvement in tests following the GDLAM protocol : 10 meters walk ( 10mw ) -p=0.003 ; rising from a ventral decubitus position ( RVDP ) - Δ%=0.78 , p rising from a chair and moving around the house ( RCMH ) -p autonomy index ( AI ) -p=0.007 , with more favorable results observed in the AAG when compared to the CG . The AAG achieved the best results for BMD ; however , no inter or intragroup statistical differences were recorded for total femur -p=0.975 and lumbar L(2)-L(4)p=0.597 . For serum osteocalcin , intra and intergroup statistical differences of p=0.042 and p=0.027 were observed in the AAG , respectively . This demonstrates that an eight-month aquatic aerobic exercise program can improve functional autonomy and osteocalcin levels , although training did not improve lumbar and total femur BMD in the older women",
"[ Purpose ] The purpose of the present study was to examine the effects of an aqua aerobic therapy exercise for older adults on biomechanical and physiological factors affecting gait . [ Subjects ] A total of 15 subjects participated in this study and they were r and omly divided into the experimental and the control group . [ Methods ] Physiological variables , leg strength , power and flexibility , and biomechanical variables , both kinematic and kinetic , were measured before and after the aqua aerobic therapy exercise . Each subject was instructed to walk along an elevated walkway and during the trials a trapdoor opened at r and om to create a 10 cm falling perturbation . Full body motion and kinetics was gathered during the gait . [ Results ] There were significant reductions in body weight , and body fat mass , and stride time after the perturbation . Significant increases in leg strength corresponded to the maximum joint moment of the l and ing leg showing that the subjects ' ability for recovery of balance after the perturbation improved . [ Conclusion ] As the results showed significant improvements in gait pattern and recovery time after perturbed gait , we conclude that aqua aerobic therapy is an effective exercise method for training older adults to reduce their risk of falling",
"This study evaluated the effects of a water exercise training program that includes perturbation exercises ( WEP ) to improve the speed of voluntary stepping reaction in older adults . Speed of voluntary stepping considered as an important skill to prevent a fall when balance is lost . In a single-blinded r and omized controlled trial with a crossover design thirty-six independent old adults ( 64 - 88 years old ) were divided into two groups . Group A received WEP for the first 12 weeks , followed by no intervention for the second 12 weeks . Group B did not receive intervention for the first 12 weeks and received WEP for the second 12 weeks . Voluntary Step Execution Test and postural stability in upright st and ing ( eyes open and closed conditions ) were measured at baseline , 12 weeks , and 24 weeks . A significant interaction effect between group and time was found for the step execution , due to improvement in initiation phase and swing phase duration s in the WEP group . Also significant improvement in postural stability parameters in eyes open and closed conditions is noted . The present results indicate that the primary benefit of WEP that include perturbations to induce stepping , was a reduction in voluntary stepping times . The WEP generalized to a better control of balance in up-right st and ing",
"OBJECTIVE To analyze the effects of a water-based exercise program on peak torque ( PT ) and rate of torque development ( RTD ) during maximal voluntary ballistic isometric contractions of the lower limb muscles and the performance of a number of functional tests in the elderly . METHOD Thirty-seven elderly were r and omly assigned to water-based training ( 3 d/wk for 12 wk ) or a control group . Extensor and flexor PT and RTD of the ankle , knee , and hip joints and functional tests were evaluated before and after training . RESULTS PT increased after training for the hip flexors ( 18 % ) and extensors ( 40 % ) and the plantar-flexor ( 42 % ) muscles in the water-based group . RTD increased after training for the hip-extensor ( 10 % ) , knee-extensor ( 11 % ) , and ankle plantar-flexor ( 27 % ) muscles in the water-based group . Functional tests also improved after training in the water-based group ( p water-based program improved PT and RTD and functional performance in the elderly",
"UNLABELLED Aging of the worldwide population is a concern of most governmental entities , spanning practically all areas of prevention and rehabilitation . Aging leads to physiological alterations that result in adverse social and financial effects . There is a trend to emphasize prevention , which is less expensive and socially more desirable than therapeutic intervention . PURPOSE To assess the effect of a program of aquatic versus non-aquatic respiratory exercises on respiratory muscle strength in healthy aged persons . METHODS The respiratory muscle strength was measured in 81 subjects between 60 and 65 years , 59 of which completed the program . Subjects were r and omized into 3 groups . G(aquatic ) undertook a program of respiratory exercise in an aquatic environment . G(non-aquatic ) undertook the same program in a non-aquatic environment . G(control ) acted as the negative control . Programs were applied three times a week for 10 consecutive weeks . Subsequently , subjects were reevaluated , and results compared to each individual 's pre-treatment own result and between the groups . The data were statistically analyzed using the paired t test and the Sign test . Comparisons between the groups were performed through parametric and nonparametric variance . A comparison of G(aquatic ) and G(non-aquatic ) versus G(control ) was performed using the Dunnett test . RESULTS A significant improvement in the inspiratory muscle strength in the G(aquatic ) group compared to the G(control ) , group was found , suggesting beneficial effects mediated by the aquatic exercise . The expiratory muscles did not show significant alterations . CONCLUSION Aquatic respiratory exercise improves the inspiratory muscle strength of healthy aged persons . However , neither aquatic nor non-aquatic respiratory exercise influences the expiratory muscle strength",
"BACKGROUND Aging compromises the ability of the central nervous system to maintain body balance and reduces the capacity for adaptive reactions . To prevent falls , the reception conditions for sensory information need to be improved . OBJECTIVES To evaluate the impact of a structured aquatic and a non-aquatic exercise program for lower-limb muscle endurance on the static and dynamic balance of elderly people . METHODS This was a prospect i ve r and omized clinical study in which the variables were assessed before and after the training program . Thirty-six elderly people were evaluated using four tests : the Berg Balance Scale , Dynamic Gait Index , gait speed and t and em gait . The participants were r and omized into three groups : aquatic exercise group , non-aquatic exercise group and control group . The exercise groups underwent a program for lower-limb muscle endurance that consisted of 40-minute sessions twice a week for six weeks . The participants were reevaluated after six weeks . The data were analyzed statistically using the univariate ANOVA test for comparisons between the groups before and after the intervention . RESULTS The program for lower-limb muscle endurance significantly increased balance ( p improvement in static and dynamic balance among community-dwelling elderly people . It was also possible to infer that this improvement occurred regardless of the environment , i.e. aquatic or non-aquatic . Article registered in the Australian New Zeal and Clinical Trials Registry ( ANZCTR ) under the number ACTRN 12609000780257",
"Objective This study aims to investigate the effects of an aquatic exercise program ( HydrOS ) on neuromuscular function and falls among postmenopausal women . Methods One hundred eight postmenopausal women ( mean [ SD ] age , 58.8 [ 6.4 ] y ) were r and omly divided into the control group ( CG ; n = 44 ) and the aquatic exercise group ( AEG ; n = 64 ) . Both groups received elementary calcium 500 mg/day and cholecalciferol 1,000 IU/day . For 24 weeks , the AEG participated in the aquatic exercise program , whereas the CG remained sedentary . The following variables were measured before and after the program : number of falls and fallers ( 7 mo before and after the intervention ) ; flexibility , using Wells ’ Sit- and -Reach Test ( FLEX ) ; static balance , using the Unipedal Stance Test ( UST ) ; mobility , using the Timed-Up- and -Go test ( TUG ) ; h and grip strength of the dominant h and ( HGS ) ; and maximal isometric strength of back extensor muscles ( SBE ) , strength of hip flexor muscles ( SHF ) , and strength of knee extensor muscles ( SKE ) . The muscle strength tests were considered the primary outcome , whereas the other neuromuscular tests , together with falls , were considered secondary outcomes . Results were significant when P ⩽ 0.05 . Results Serum 25-hydroxyvitamin D significantly increased by 21 % in the CG and by 23 % in the AEG ( P after the program remained unchanged in the CG ; in the AEG , the mean number of falls decreased from 2.00 to 0.29 ( P 0.0001 ) , and the number of fallers decreased by 44 % ( P ) . All neuromuscular variables significantly improved in the AEG : FLEX ( 26.6 % ; P 0.001 ) , HGS ( 13.4 % ; P , SBE ( 26.2 % ; P 0.039 ) , and SKE ( 7.7 % ; P increasing serum 25-hydroxyvitamin D level attributable to supplementation . Conclusions The aquatic exercise program HydrOS is a safe and efficient way to improve physical function and to reduce falls among postmenopausal women",
"Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists",
"AIM The effectiveness of a water-based exercise ( WE ) program and a walking on l and ( WL ) program was evaluated in older women ( aged 62 - 65 years ) . METHODS Fifty healthy sedentary women were r and omly assigned to sedentary ( S ) , WE and WL groups . The two groups were exercised for 12 weeks at 70 % of the age-predicted maximum heart rate ( HR ) . The subjects were evaluated before and after the training period , and measurements of bodyweight , HR at rest , maximum aerobic power ( VO(2max ) mL/kg per min ) and neuromuscular performance ( upper and lower body strength ; agility ; upper and lower body flexibility ) were included . RESULTS After training , bodyweight was unchanged in both programs . The WE decreased the HR at rest by 10 % . Both WE and WL enhanced VO(2max ) by 42 % and 32 % , respectively . However , for the WE group the VO(2max ) values were significantly higher compared with the WL group ( P neuromuscular parameters improved after exercise , but only the WE group showed a significant improvement on the upper body strength and lower body flexibility . Besides , the upper and lower body strength and upper and lower body flexibility were significantly higher in the WE group compared with the WL group ( P WE and WL programs improved the cardiorespiratory and neuromuscular fitness of older women . Furthermore , when the effectiveness of the training programs were compared , it was verified that the WE program was more powerful in inducing changes in physical fitness versus the WL program",
"Objective The purpose of this study was to investigate the effects of water exercise at a day service facility and the effects of water exercise frequency on health-related quality of life ( HRQL ) . Methods Participants ( n = 30 ) were r and omly separated into three groups : two indicating exercise frequency , at once-weekly or twice-weekly , and a control group . One-hour exercise intervention sessions were carried out once or twice a week , accordingly , for 24 weeks . The water exercise session comprised a warm-up on l and , activities of daily living ( ADL ) exercises , stretching , strength training , and relaxation in water . HRQL was evaluated using the Medical Outcomes Survey Short-Form 36 ( SF-36 ) question naire , and ADL disability was assessed using the Functional Independence Measure . Results Significant differences were found between pre- and 6 months in both the once- and twice-weekly groups in HRQL ( p ADL disability shows significant correlation with HRQL . Conclusion Water exercise intervention at a day service facility improved participants ’ HRQL for 6 months by improving exercise habits and ADL disability . Furthermore , the HRQL change differed according to exercise frequency : twice-weekly exercise showed more rapid improvement than once-weekly",
" Deep water running with wet vest is a safe form of exercise for elderly with mobility limitations . However , it is not known to what extent their aerobic power may be improved . Therefore , the aim was to assess the effects of high intensity deep water interval training with vest in elderly women . Twenty-nine healthy women 69 ± 4 years old participated . They performed a grade d maximal exercise test on the cycle ergometer . They were r and omly assigned to a control or to a training group . A submaximal exercise test on the cycle ergometer was executed only by the training group . They trained in deep water running/walking wearing a vest two times a week for 8 weeks . The target heart rate was 75 % of maximal heart rate and the training consisted of several short working periods and resting intervals . After the intervention the heart rate at rest was 8 % lower for the training group ( P Their heart rate at submaximal exercise was 3 % less ( P their maximal oxygen uptake was raised by 10 % ( P and their maximal ventilation was increased 14 % ( P conclusion , high intensity deep water running with vest improves submaximal work capacity , maximal aerobic power , and maximal ventilation with the effects transferable to l and -based activities in elderly women",
"PURPOSE The purpose of this study was to identify the effects of water-based exercises on the physical functions and quality of life ( QOL ) in community-dwelling elderly people with history of falling . MATERIAL S AND METHODS Participants were r and omly assigned to the water-based exercise group ( n=34 ) or l and -based exercise groups ( n=32 ) . To identify the effects on physical functions , muscle strength , flexibility , and mobility were measured . QOL and fear of falling were evaluated using the Short Form 36-item question naire and the modified falls efficacy scale ( M-FES ) . The measurements were performed before and after the 10-week training period . RESULTS Within-group analysis indicated that hip abduction and adduction strength improved significantly in both groups ( p=0.005 ; p=0.007 ) . However , no statistically significant within-group differences were found in the back scratch test ( p=0.766 ) and chair sit- and -reach test ( p=0.870 ) . QOL was significantly different in both groups ( health transition : p=0.014 , physical functioning : p M-FES in both groups ( p=0.040 ) . CONCLUSIONS These results indicate that water-based exercises are beneficial to improve the QOL , as well as physical activities , of community-dwelling elderly compared with l and -based exercise . Water-based exercises would be useful to improve physical and psychological health in the elderly people with history of falling",
"OBJECTIVE To examine in previously sedentary older women the effects of exercise mode and a behavioural intervention on short and long-term retention and adherence . METHODS Healthy , sedentary women aged 50 - 70 years ( N=116 ) were r and omly assigned to a supervised 6-month swimming or walking program 3 sessions a week . They were further r and omised to usual care or a behavioural intervention . The same program was further continued unsupervised for 6 months . We assessed retention , adherence , stage of exercise behaviour and changes in fitness . RESULTS One hundred women ( 86 % ) completed 6 months and 86 ( 74 % ) continued for 12 months . Retention rates were similar for both exercise modes at 6 and 12 months . Adherence to swimming or walking was similar after 6 months ( 76.3 ( 95 % CI : 69.5 , 83.1)% vs. 74.3 ( 67.7 , 80.9)% ) and 12 months ( 65.8 ( 57.9 , 73.8)% vs. 62.2 ( 54.6 , 70.0)% ) . The behavioural intervention did not enhance retention or adherence . Fitness improved for both exercise modes after 6 months and was maintained at 12 months . CONCLUSIONS Either swimming or walking programs initiated with careful supervision over 6 months result ed in similar high retention and adherence rates by highly motivated older women over 12 months . Behavioural intervention in this setting did not improve these rates further",
"PURPOSE The purpose of this study was to determine the physiological responses of elderly women to a well-rounded exercise program performed in water ( WEX ) . METHODS The participants ( 60 - 75 yr of age ) were r and omly divided into a training ( TR ) group ( N = 15 ) and a control group ( N = 15 ) . The TR group participated in a 12-wk supervised WEX program , 70 min x day(-1 ) , 3 d x wk(-1 ) . The WEX consisted of 20 min of warm-up and stretching exercise , 10 min of resistance exercise , 30 min of endurance-type exercise ( walking and dancing ) , and 10 min of cool-down exercise . RESULTS The WEX led to an increase ( P peak VO2 ( 12 % ) and VO2 at lactate threshold ( 20 % ) . Muscular strength evaluated by a hydraulic resistance machine increased significantly at resistance dial setting 8 ( slow ) for knee extension ( 8 % ) , knee flexion ( 13 % ) , chest press ( 7 % ) and pull ( 11 % ) , shoulder press ( 4 % ) and pull ( 6 % ) , and back extension ( 6 % ) . Vertical jump ( 9 % ) , side-stepping agility ( 22 % ) , trunk extension ( 11 % ) , and FEV1.0 ( 7 % ) also increased significantly . There was a significant decrease in skin-fold thickness ( -8 % ) , low-density lipoprotein ( LDL ) cholesterol ( -17 % ) , and total cholesterol ( -11 % ) . There were no significant changes in these variables in the control group . CONCLUSION These results indicate that WEX elicits significant improvements in cardiorespiratory fitness , muscular strength , body fat , and total cholesterol in older adult women . Water-based exercise appears to be a very safe and beneficial mode of exercise that can be performed as part of a well-rounded exercise program",
"BACKGROUND The fear of falling may cause elderly people to limit their movement . As movement errors are known to facilitate the acquisition of motor skills , the elderly may inadvertently cause the loss of postural skills by constraining their movements , and hence avoid potential movement errors . It was hypothesized that by having elderly individuals exercise in a risk-free environment-water was utilized in this experiment-their postural capabilities would improve . METHODS Four groups of elderly subjects ( 80 + /- 5.8 years old ) were placed into four groups : Water Exercisers ; L and Exercisers ; Water Sitters ; and L and Sitters . Each group met twice per week for 45 minutes for 5 weeks of simple exercises or socializing in the design ated medium . The distance each individual could reach ( Functional Reach , FR ) was measured at the end of each week . RESULTS Initially , each group was at risk ( FR Exercisers ( WE ) increased their FR almost every week ; the L and Exercisers ( LE ) increased only during the first week ; and the Water Sitters ( WS ) and L and Sitters ( LS ) did not increase at all . The FRs after 5 weeks were 13.4 + /- 1.6 ( WE ) , 11.3 + /- 1.5 ( LE ) , 9.6 + /- 1.3 ( WS ) , and 9.3 + /- 0.71 ( LS ) inches for each group , respectively . CONCLUSIONS The data showed that the postural capabilities in these elderly people , as measured by the FR , were enhanced by the production of movement errors that was facilitated in a water environment ( in the case of the Water groups ) or the initiation of a novel exercise program ( L and Exercisers ) . Alternative explanations , and implication of these results , are discussed",
"The purpose of the present study was to determine the effectiveness of a 24-week aquatic training ( AT ) program , which included both aerobic and resistance components , on muscle strength ( isometric and dynamic ) , flexibility , and functional mobility in healthy women over 60 years of age . Twenty-two subjects were assigned r and omly to either an AT ( n = 12 ) or a control ( C , n = 10 ) group . Volunteers participated in a supervised shallow-water exercise program for 60 minutes a day , 3 days a week ; the exercise program consisted of a 10-minute warm-up and stretching , 25 minutes of endurance-type exercise ( dancing ) at 80 % of heart rate (HR)max , 20 minutes of upper- and lower-body resistance exercises with specialized water-resistance equipment , and a 5-minute cool down . Maximal isometric torque of knee extensors ( KEXT ) and knee flexors ( KFLEX ) were evaluated by a Cybex Norm dynamometer , grip strength ( HGR ) was evaluated using a Jamar hydraulic dynamometer , and dynamic strength was evaluated via the 3 repetition maximum ( 3RM ) test for chest press , knee extension , lat pull down , and leg press . Jumping performance was evaluated using the squat jump ( SJ ) , functional mobility with the timed up- and -go ( TUG ) test , and trunk flexion with the sit- and -reach test . Body composition was measured using the bioelectrical impedance method . The AT induced significant improvements in KEXT ( 10.5 % ) and KFLEX ( 13.4 % ) peak torque , HGR strength ( 13 % ) , 3RM ( 25.7–29.4 % ) , SJ ( 24.6 % ) , sit- and -reach ( 11.6 % ) , and TUG ( 19.8 % ) performance . The AT group demonstrated a significant increase in lean body mass ( 3.4 % ) . No significant changes in these variables were observed in the C group . The results indicate that AT , with both aerobic and resistance components , is an alternative training method for improving neuromuscular and functional fitness performance in healthy elderly women",
"Exercise in a water medium reduces weight-bearing stresses on the skeletal joints , which may be advantageous for older individuals needing rehabilitation . The purpose of this study was to determine the effects of nonswimming exercises on muscle endurance , % body fat , and aerobic work capacity of an older adult population . Twelve subjects were in an exercise group ( 10 females and two males ) , and eight were in a control group ( five females and three males ) . The mean ages of the groups were 65 ( + /- 5.29 ) years and 56 ( + /- 6.78 ) years , respectively . Before and after 12 weeks of training , subjects were measured three times weekly for resting heart rate , maximum heart rate , VO2 max , body composition , and work capacity in water . A general linear model ANCOVA was used with age as the covariate . The exercise group improved significantly ( p body composition after 12 weeks . However , the control group experienced no significant changes on any variable over this period . In the comparisons between groups , the exercise group significantly surpassed the control group on all variables except body composition , where neither group experienced change . Nonswimming exercises appear to be a viable and effective means to improve cardiorespiratory function and physical work capacity of the elderly",
"The purpose of this study was to determine the effectiveness of a generalized water-based exercise program ( WBE ) compared to a l and -based exercise program ( LBE ) on improving cardiorespiratory fitness , body composition , forward trunk flexion and strength measurements of elderly women aged 70 + /- 3.2 years ( mean + /- SD ) . Forty-one healthy , sedentary women were selected to participate in the study and were r and omly assigned to the LBE or WBE . The 2 groups exercised for 12 weeks , 3 times/week for 45 min . Fitness testing was done before , during and after training , and included measurements of peak aerobic power ( VO2 peak ) , forward trunk flexion , sum of skinfolds , grip strength , curl-ups and push-ups . Between the tests performed before and after training , there were significant improvements in VO2 peak in both groups ( p 0.05 ) . The LBE group also showed a significant improvement in the total number of curl-ups performed ( p trunk forward flexion , total ( right plus left ) grip strength , push-ups , waist to hip ratio , sum of skinfolds or body mass index between the tests performed before and after training over time within groups or between groups ( p > 0.05 ) . The results show that general exercise interventions result ed in improvements in cardiovascular fitness ( for both groups ) and abdominal endurance ( in the LBE only ) , but the two exercise programs used were not specific enough or long enough to cause improvements in muscular strength , flexibility or body composition . Furthermore , except for changes in abdominal endurance , the type of exercise venue ( l and vs. water ) did not have a significant effect on the results obtained",
"Different types of exercise are indicated for the elderly to prevent functional capacity limitations due to aging and reduce the risk of falls . This study aim ed to evaluate the effect of three different exercises ( mini-trampoline , MT ; aquatic gymnastics , AG and general floor gymnastics , GG ) on postural balance in elderly women . Seventy-four physically independent elderly women , mean age 69±4 years , were r and omly assigned to three intervention groups : ( 1 ) MT ( n=23 ) , ( 2 ) AG ( n=28 ) , and ( 3 ) GG ( n=23 ) . Each group performed physical training , including cardiorespiratory , muscular strength and endurance , flexibility and sensory-motor exercises for 12 weeks . To determine the effects on each intervention group , five postural balance tasks were performed on a force platform ( BIOMEC 400 ) : the two-legged st and with eyes open ( TLEO ) and two-legged st and with eyes closed ( TLEC ) ; the semi-t and em st and with eyes open ( STEO ) and semi-t and em st and with eyes closed ( STEC ) and the one-legged st and . Three trials were performed for each task ( with 30s of rest between them ) and the mean was used to compute balance parameters such as center of pressure ( COP ) sway movements . All modalities investigated such as the MT , AG and GG were significantly ( P improving the postural balance of elderly women after 12 weeks of training . These results provide further evidence concerning exercise and balance for promoting health in elderly women",
"Graef , FI , Pinto , RS , Alberton , CL , de Lima , WC , and Kruel , LFM . The effects of resistance training performed in water on muscle strength in the elderly . J Strength Cond Res 24(11 ) : 3150 - 3156 , 2010-The purpose of the present study was to compare the effects of a program of resistance training in water-based exercises ( RWE ) with those of a program without resistance control in water-based exercises ( WEs ) . Twenty-seven women ( aged 60 - 74 years ) were r and omly assigned to the RWE group ( n = 10 ) , WE group ( n = 10 ) , or nontraining control ( CON ) group ( n = 7 ) . The RWE and WE groups trained classes with aerobic exercises and localized muscular resistance exercises for 50 minutes , twice a week for 12 weeks . For the RWE group , the program included 4 mesocycles of 3 weeks-respectively , 4 sets of 15 repetitions , 4 sets of 12 repetitions , 5 sets of 10 repetitions , and 5 sets of 8 repetitions-of shoulder horizontal flexion exercise at maximum speed , with the use of resistive equipment . For the WE group , the training was not periodized , and the resistance in the localized muscular exercises was not controlled . One repetition maximum ( 1RM ) was measured on a pectoral fly machine at baseline and after the training period . The level of significance adopted was p ≤ 0.05 . The results showed that the only significant increase in 1RM ( 10.89 % , p that WEs with emphasis on resistance training in a periodized program can efficiently increase maximum strength in elderly women . Thus , it is suggested that the strategies used in WE programs be modified to offer suitable stimuli for the development of strength"
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BACKGROUND Studies have suggested that the fat mass and obesity-associated ( FTO ) genotype is associated with individual variability in weight loss in response to diet/lifestyle interventions , but results are inconsistent . OBJECTIVE We aim ed to provide a summary of the literature evaluating the relation between the FTO genotype and weight loss in response to diet/lifestyle interventions . DESIGN A search of English- language articles in the PubMed and Embase data bases ( through 30 April 2015 ) was performed . Eligible studies were diet/lifestyle weight-loss intervention studies conducted in adults that reported changes in body weight or body mass index ( BMI ) by the FTO variant rs9939609 ( or its proxy ) . Differences in weight loss between FTO genotypes across studies were pooled with the use of fixed-effect models . RESULTS A meta- analysis of 10 studies ( comprising 6951 participants ) that reported the results of additive genetic models showed that individuals with the FTO TA genotype and AA genotype ( those with the obesity-predisposing A allele ) had 0.18-kg ( 95 % CI : -0.09- , 0.45-kg;P= 0.19 ; NS ) and 0.44-kg ( 95 % CI : 0.09- , 0.79-kg;P= 0.015 ) greater weight loss , respectively , than those with the TT genotype . A meta- analysis of 14 studies ( comprising 7700 participants ) that reported the results of dominant genetic models indicated a 0.20-kg ( -0.43- , 0.04-kg ) greater weight loss in the TA/AA genotype than in the TT genotype ( P= 0.10 ) . In addition , differences in weight loss between the AA genotype and TT genotype were significant in studies with a diet intervention only , adjustment for baseline BMI or body weight , and several other subgroups . However , the relatively small number of studies limited these stratified analyses , and there was no statistically significant difference between subgroups . CONCLUSIONS This meta- analysis suggests that individuals carrying the homozygous FTO obesity-predisposing allele may lose more weight through diet/lifestyle interventions than noncarriers . Our data provide evidence for genetic variability in response to diet/lifestyle interventions on weight loss , although clinical applications of these findings need further investigations
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"Objectives We investigated cross-sectionally and longitudinally the relationship between FTO rs9939609 and obesity-related characteristics in the European children of the IDEFICS project and the interaction of this variant with a lifestyle intervention . Population and Methods A cohort of 16224 children ( 2–9 years ) was recruited into a population -based survey ( T0 ) from eight European countries . A second survey ( T1 ) reassessed the children two years later . A r and om sample of 4405 children was extracted for genetic studies . 3168 children were re-examined two years later . Half of them underwent a lifestyle intervention program . The FTO rs9939609 was genotyped . Weight , height , waist circumference , triceps and subscapular skinfolds were measured at T0 and T1 . Results At T0 , the risk A allele of rs9939609 was significantly associated with higher values of body mass index ( BMI ) , waist circumference and skinfolds ( age , sex , and country-adjusted p-values : all p increased risk of overweight/obesity . Over the two year follow-up , no interaction between genotype and intervention was observed . The A allele was associated to a significantly higher increase in all the anthropometric variables examined at T0 independently from the study group ( intervention versus control ) ( p-values : all p overweight/obesity occurred . A statistically significant higher incidence of overweight/obesity was associated to the A allele [ ORA = 1.95 , 95 % CI = ( 1.29 ; 2.97 ) ] . Conclusions We confirmed the association between the FTO rs9939609 and body mass and overweight/obesity risk in European children . The main finding of the study is that the A allele carriers present higher increase of body mass and central adiposity over time and higher risk of developing overweight/obesity during growth , independently from intervention measures",
"The common single-nucleotide polymorphism in the FTO ( fat mass and obesity associated ) gene is consistently associated with an increased risk of obesity . However , the knowledge of a potential modifying effect of the FTO gene on changes in body weight achieved by lifestyle intervention is limited . We examined whether the FTO gene variant ( rs9939609 , T/A ) is associated with body weight and BMI and long-term weight changes in the Finnish Diabetes Prevention Study ( DPS ) . Altogether , 522 ( aged 40 - 65 years ; BMI > or=25 kg/m(2 ) ) subjects with impaired glucose tolerance ( IGT ) were r and omized to control and lifestyle intervention groups . SNP rs9939609 was genotyped from 502 subjects . At baseline , those with the AA genotype had higher BMI than subjects with other genotypes ( P = 0.006 ) . The association was observed in women ( P = 0.016 ) but not in men . During the 4-year follow-up , the subjects with the AA genotype had consistently the highest BMI ( P = 0.009 ) in the entire study population . The magnitude of weight reduction was greater in the intervention group , but the risk allele did not modify weight change in either of the groups . Our results confirm the association between the common FTO variant and BMI in a cross-sectional setting and during the long-term lifestyle intervention . We did not observe association between FTO variant and the magnitude of weight reduction achieved by long-term lifestyle intervention . Based on the results from the DPS , it is unlikely that the common variant of the FTO gene affects the success of lifestyle modification on weight loss",
"BACKGROUND The possible advantage for weight loss of a diet that emphasizes protein , fat , or carbohydrates has not been established , and there are few studies that extend beyond 1 year . METHODS We r and omly assigned 811 overweight adults to one of four diets ; the targeted percentages of energy derived from fat , protein , and carbohydrates in the four diets were 20 , 15 , and 65 % ; 20 , 25 , and 55 % ; 40 , 15 , and 45 % ; and 40 , 25 , and 35 % . The diets consisted of similar foods and met guidelines for cardiovascular health . The participants were offered group and individual instructional sessions for 2 years . The primary outcome was the change in body weight after 2 years in two-by-two factorial comparisons of low fat versus high fat and average protein versus high protein and in the comparison of highest and lowest carbohydrate content . RESULTS At 6 months , participants assigned to each diet had lost an average of 6 kg , which represented 7 % of their initial weight ; they began to regain weight after 12 months . By 2 years , weight loss remained similar in those who were assigned to a diet with 15 % protein and those assigned to a diet with 25 % protein ( 3.0 and 3.6 kg , respectively ) ; in those assigned to a diet with 20 % fat and those assigned to a diet with 40 % fat ( 3.3 kg for both groups ) ; and in those assigned to a diet with 65 % carbohydrates and those assigned to a diet with 35 % carbohydrates ( 2.9 and 3.4 kg , respectively ) ( P>0.20 for all comparisons ) . Among the 80 % of participants who completed the trial , the average weight loss was 4 kg ; 14 to 15 % of the participants had a reduction of at least 10 % of their initial body weight . Satiety , hunger , satisfaction with the diet , and attendance at group sessions were similar for all diets ; attendance was strongly associated with weight loss ( 0.2 kg per session attended ) . The diets improved lipid-related risk factors and fasting insulin levels . CONCLUSIONS Reduced-calorie diets result in clinical ly meaningful weight loss regardless of which macronutrients they emphasize . ( Clinical Trials.gov number , NCT00072995 .",
"BACKGROUND Common polymorphisms of the fat mass and obesity associated gene ( FTO ) have been linked to obesity in some population s. One of these genetic variants ( rs9939609 ) has been related to an increased risk of obesity . OBJECTIVE Our aim was to evaluate weight loss and adipocytokine levels after two hypocaloric diets with different macronutrient distribution in obese subjects with RS9939609 gene variant . DESIGN 305 obese patients were enrolled in a prospect i ve way . In the basal visit , patients were r and omly allocated during 3 months to low carbohydrates and low fat . RESULTS After treatment with both diets and in both genotypes , weight , fat mass , waist circumference and systolic blood pressures decreased . With the diet type I and in TT genotype , insulin ( -6.6 ± 9.8 IU/L ) and homeostasis model assessment ( -2.9 ± 6.1 units ) decreased . With the diet type II and in both genotypes ( wild and mutant type ) , insulin ( -5.2 ± 6.1 vs. -3.8 ± 6.1 IU/L ; p homeostasis model assessment ( -2.4 ± 4.8 vs. -1.1 ± 3.8 kg ; p was detected in total cholesterol levels ( -11.5 ± 20.1 mg/dL ) , low density lipoprotein cholesterol levels ( -13.2 ± 20.9 mg/dL ) and c-reactive protein levels ( -1.3 ± 3.8 mg/dL ) secondary to weight loss after treatment with diet II . The decrease of leptin levels was higher in mutant type group than wild type group with low fat diet ( -10.3 ± 36.1 vs. -28.6 ± 53.7 ng/mL ; p CONCLUSION Metabolic improvement secondary to weight loss was better in A carriers with a low fat hypocaloric diet ",
"Recent evidence suggests that the fat mass and obesity-associated gene ( FTO ) genotype may interact with dietary intakes in relation to adiposity . We tested the effect of FTO variant on weight loss in response to 2-year diet interventions . FTO rs1558902 was genotyped in 742 obese adults who were r and omly assigned to one of four diets differing in the proportions of fat , protein , and carbohydrate . Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and computed tomography . We found significant modification effects for intervention varying in dietary protein on 2-year changes in fat-free mass , whole body total percentage of fat mass , total adipose tissue mass , visceral adipose tissue mass , and superficial adipose tissue mass ( for all interactions , P greater reduction in weight , body composition , and fat distribution in response to a high-protein diet , whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet . Likewise , significant interaction patterns also were observed at 6 months . Our data suggest that a high-protein diet may be beneficial for weight loss and improvement of body composition and fat distribution in individuals with the risk allele of the FTO variant rs1558902",
"BACKGROUND Common genetic variants in the insulin receptor substrate 1 ( IRS1 ) gene have been recently associated with insulin resistance and hyperinsulinemia . We examined whether the best-associated variant modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets in Preventing Overweight Using Novel Dietary Strategies ( POUNDS LOST ) trial . METHODS AND RESULTS We genotyped IRS1 rs2943641 in 738 overweight adults ( 61 % were women ) who were r and omly assigned to 1 of 4 diets varying in macronutrient contents for 2 years . We assessed the progress in fasting insulin , homeostasis model assessment of insulin resistance ( HOMA-IR ) and weight loss by genotypes . At 6 months , participants with the risk-conferring CC genotype had greater decreases in insulin ( P=0.009 ) , HOMA-IR ( P=0.015 ) , and weight loss ( P=0.018 ) than those without this genotype in the highest-carbohydrate diet group whereas an opposite genotype effect on changes in insulin and HOMA-IR ( P≤0.05 ) was observed in participants assigned to the lowest-carbohydrate diet group . No significant differences were observed across genotypes in the other 2 diet groups . The tests for genotype by intervention interactions were all significant ( P on changes in insulin and HOMA-IR remained significant in the highest-carbohydrate diet group ( P improvement of insulin and HOMA-IR ( P for genotype-time interaction ≤0.009 ) in participants with the CC genotype than those without this genotype across 2-year intervention . CONCLUSIONS Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet . CLINICAL TRIAL REGISTRATION http : www . clinical trials.gov . Unique identifier : NCT00072995",
"Background : Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity . We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss . Methods : Established obesity risk alleles available on the Illumina CARe iSelect ( IBC ) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD ( Action for Health in Diabetes ) , a r and omized trial to determine the effects of intensive lifestyle intervention ( ILI ) and diabetes support and education ( DSE ) on cardiovascular morbidity and mortality . Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and r and omized treatment arm in predicting weight change at year 1 , and weight regain at year 4 among individuals who lost 3 % or more of their baseline weight by year 1 . Results : No single-nucleotide polymorphisms ( SNPs ) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1 . However , fat mass and obesity associated gene ( FTO ) rs3751812 predicted weight regain within DSE ( 1.56 kg per risk allele , P=0.005 ) , but not ILI ( P=0.761 ) , result ing in SNP × treatment arm interaction ( P=0.009 ) . In a partial replication of prior research , the obesity risk ( G ) allele at BDNF rs6265 was associated with greater weight regain across treatment arms ( 0.773 kg per risk allele ) , although results were of borderline statistical significance ( P=0.051 ) . Conclusions : Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss",
"Little is known about whether cholesteryl ester transfer protein ( CETP ) genetic variation may modify the effect of weight-loss diets varying in fat content on changes in lipid levels . We analyzed the interaction between the CETP variant rs3764261 and dietary interventions on changes in lipid levels among 732 overweight/obese adults from a 2 year r and omized weight-loss trial [ Preventing Overweight Using Novel Dietary Strategies ( POUNDS LOST ) ] , and replicated the findings in 171 overweight/obese adults from an independent 2 year weight-loss trial [ Dietary Intervention R and omized Controlled Trial ( DIRECT ) ] . In the POUNDS LOST , participants with the CETP rs3764261 CC genotype on the high-fat diet had larger increases in HDL cholesterol ( P = 0.001 ) and decreases in triglycerides ( P = 0.007 ) than those on the low-fat diet at 6 months , while no significant difference between these two diets was observed among participants carrying other genotypes . The gene-diet interactions on changes in HDL-cholesterol and triglycerides were replicated in the DIRECT ( pooled P for interaction ≤ 0.01 ) . Similar results on trajectory of changes in HDL cholesterol and triglycerides over the 2 year intervention were observed in both trials . Our study provides replicable evidence that individuals with the CETP rs3764261 CC genotype might derive greater effects on raising HDL cholesterol and lowering triglycerides by choosing a low-carbohydrate/high-fat weight-loss diet instead of a low-fat diet",
"Introduction : The aim of this study was to analyze the effects of the rs9939609 ( T/A ) gene variant in fat mass and obesity-associated gene ( FTO ) on body weight changes after 3 years and its modification by a r and omized nutritional intervention with a Mediterranean-style diet in a population of subjects at high cardiovascular risk . Design : A sub study of PREDIMED , which is a r and omized trial aim ed at assessing the effect of the Mediterranean diet ( MD ) for primary cardiovascular disease prevention . There were three nutritional intervention groups : two of them with a Mediterranean-style diet and the third was a control group advised to follow a conventional low-fat diet . Subjects : A total of 776 high cardiovascular risk subjects aged 55–80 years . Measurements : Anthropometric measurements were recorded at baseline and at 3 years . The participants were genotyped by RT-PCR , followed by allelic discrimination . Results : Homozygous subjects had the highest baseline body weight . The dominant model showed that subjects carrying the A allele had the lowest body weight gain ( B=−0.685 ; P=0.022 ) after 3 years of nutritional intervention compared with nonmutated subjects ( TT genotype ) regardless of the nutritional intervention . Moreover , this effect was statistically significant in carriers of the A allele only among those allocated to the MD groups ( B=−0.830 ; P=0.018 ) , but it was not significant among those allocated to the control group ( P for interaction=0.649 ) . Conclusion : This study confirmed the association between body weight and the FTO rs9939609 polymorphism . Interestingly , our results showed that , although at baseline the A allele was associated with higher body weight , after 3 years of nutritional intervention with a Mediterranean-style-diet , A-allele carriers had lower body weight gain than wild type subjects . No interaction between nutritional intervention and the polymorphism was found",
"BACKGROUND A common obesity-risk variant rs9939609 in the fat mass- and obesity-associated ( FTO ) gene was recently shown to affect appetite , and the gene is sensitive to the regulation of amino acids . OBJECTIVE We examined the interaction between FTO genotype and protein intake on the long-term changes in appetite in a r and omized controlled trial . DESIGN We genotyped FTO rs9939609 in 737 overweight adults in the 2-y Preventing Overweight Using Novel Dietary Strategies trial and assessed 4 appetite-related traits including cravings , fullness , hunger , and prospect i ve consumption . RESULTS We showed that dietary protein significantly modified genetic effects on changes in food cravings and appetite scores at 6 mo after adjustment for age , sex , ethnicity , baseline body mass index , weight change , and baseline value for respective outcomes ( P-interaction = 0.027 and 0.048 , respectively ) . The A allele was associated with a greater decrease in food cravings and appetite scores in participants with high-protein-diet intake ( P = 0.027 and 0.047 , respectively ) but not in subjects in the low-protein-diet group ( P = 0.384 and 0.078 , respectively ) . The weight regain from 6 to 24 mo attenuated gene-protein interactions . Protein intakes did not modify FTO genotype effects on other appetite measures . CONCLUSION Our data suggest that individuals with the FTO rs9939609 A allele might obtain more benefits in a reduction of food cravings and appetite by choosing a hypocaloric and higher-protein weight-loss diet . This trial was registered at clinical trials.gov as NCT00072995",
"Background : The A risk allele of rs9939609 of the fat mass- and obesity-associated gene ( FTO ) increases body fat mass . Objective : To examine whether FTO rs9939609 affects obese individuals ' response to a high-fat , low-carbohydrate ( CHO ) ( HF ) or low-fat , high-CHO ( LF ) , hypo-energetic diet and whether the effect of the FTO variant depends on dietary fat and CHO content . Design : In a 10-week , European , multi-centre dietary intervention study 771 obese women and men were r and omized to either LF ( 20–25 % of energy ( % E ) from fat , 60–65%E from CHO ) or HF ( 40–45%E from fat , 40–45%E from CHO ) , hypo-energetic diet ( measured resting metabolic rate multiplied by 1.3–600 kcal day−1 ) . Body weight , fat mass ( FM ) , fat-free mass ( FFM ) , waist circumference ( WC ) , resting energy expenditure ( REE ) , fasting fat oxidation as % of REE ( FatOx ) , insulin release ( HOMA-β ) and a surrogate measure of insulin resistance ( HOMA-IR ) were measured at baseline and after the intervention . In all , 764 individuals were genotyped for FTO rs9939609 . Results : For A-allele carriers the drop-out rate was higher on HF than LF diet ( in AT , P=0.002 ; in AT/AA combined , P=0.003 ) . Among those individuals completing the intervention , we found no effect of FTO rs9939609 genotype on Δweight , ΔFM , ΔFFM , ΔWC or ΔFatOx . However , participants with TT had a smaller reduction in REE on LF than on HF diet ( 75 kcal/24 h ; interaction : P=0.0055 ) . These individuals also showed the greatest reduction in HOMA-β and HOMA-IR ( interaction : P=0.0083 and P=0.047 ) . Conclusion : The FTO rs9939609 may interact with the macronutrient composition in weight loss diets in various ways ; carriers of the A allele on LF diet appear to have a lower risk for drop out , and TT individuals have a smaller decrease in REE and greater decrease in HOMA-β and HOMA-IR on LF than on HF diet",
"OBJECTIVE We examined associations between the fat-mass and obesity-associated ( FTO ) gene ( rs9939609 ) and any weight change over a 5-year period following a 14-week lifestyle intervention among middle-aged Japanese women . MATERIAL S/ METHODS One hundred twenty-eight Japanese women ( BMI > 25 kg/m² ) participated in a 14-week weight loss intervention between 2004 and 2006 . Of the participants , 62 consented to the 5-year follow-up measurement session . Of these women , 47 women who achieved a weight loss of at least 10 % from their baseline values during the 14-week intervention were included in the analysis . Body weight , body fat , abdominal fat assessed by CT scans , and metabolic risk factors ( i.e. , blood pressure , lipids , and glucose ) were measured at baseline , post-intervention , and at the 5-year follow-up . RESULTS During the 5-year non-intervention period , increases in body weight , fat mass , total abdominal fat , and subcutaneous abdominal fat were significantly greater in subjects with the homozygous minor allele ( AA genotype , n=4 ; 8.5 % ) than in those with the homozygous major allele ( TT genotype , n=31 ; 66.0 % ) or heterozygous allele ( TA genotype , n=12 ; 25.5 % ) . In multiple regression analyses , the variation in rs9939609 was a significant and independent predictor ( P regaining weight during the 5-year follow-up . CONCLUSIONS Our data suggest that Japanese women with the risk allele ( AA ) of rs9939609 may have more difficulty preventing fat gain from reoccurring after weight loss intervention than women with the other genotypes",
"The mechanisms through which common polymorphisms in the fat mass and obesity-associated gene ( FTO ) drive the development of obesity in humans are poorly understood . Using cross-sectional data from 985 older people ( 50 % females ) who participated at age 70 years in the Prospect i ve Investigation of the Vasculature in Uppsala Seniors ( PIVUS ) , circulating levels of ghrelin and leptin were measured after an overnight fast . In addition , subjects were genotyped for FTO rs17817449 ( AA , n = 345 [ 35 % ] ; AC/CA , n = 481 [ 48.8 % ] ; CC , n = 159 [ 16.1 % ] ) . Linear regression analyses controlling for sex , self-reported physical activity level , fasting plasma glucose , and BMI were used . A positive relationship between the number of FTO C risk alleles and plasma ghrelin levels was found ( P = 0.005 ; relative plasma ghrelin difference between CC and AA carriers = ∼9 % ) . In contrast , serum levels of the satiety-enhancing hormone leptin were inversely linked to the number of FTO C risk alleles ( P = 0.001 ; relative serum leptin difference between CC and AA carriers = ∼11 % ) . These associations were also found when controlling for waist circumference . The present findings suggest that FTO may facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger-promoting hormone ghrelin",
"SCOPE Insulin resistance , a condition associated with type 2 diabetes mellitus , results from the interaction of environmental and genetic factors . The aim of this study was to explore the influence of the G972R polymorphism at the insulin receptor substrate 1 gene on insulin sensitivity in a healthy young population . Furthermore , we examined whether the presence of this single nucleotide polymorphism ( SNP ; GR or GG ) interacts with dietary fat to modulate insulin sensitivity . METHODS AND RESULTS Fifty-nine healthy volunteers consumed three diets during 4 wk each following a r and omized crossover design : a saturated fatty acid diet , a low-fat and high carbohydrate ( CHO ) diet or a MUFA diet . For each diet , we investigated peripheral insulin sensitivity with the insulin suppression test . Steady-state plasma glucose and plasma-free fatty acids concentrations were significantly lower in GR subjects after the intake of a CHO diet , than did homozygous GG subjects ( p Insulin sensitivity increased in GR subjects for the G972R polymorphism at the insulin receptor substrate 1 gene locus , after intake of a CHO diet . Increased knowledge of how these and other genes influence insulin sensitivity should increase the underst and ing of personalized nutrition",
"BACKGROUND The apolipoprotein A5 gene ( APOA5 ) is a major gene that regulates lipid metabolism and is modulated by dietary factors . A novel variant rs964184 in APOA5 was identified to be associated with lipids in genome-wide association studies . OBJECTIVE We examined whether this variant modified changes in lipid concentrations in response to a 2-y weight-loss diet intervention in a r and omized trial . DESIGN The current analyses were secondary analyses of a data set from the Pounds Lost Trial . We genotyped APOA5 rs964184 in 734 overweight or obese adults who were r and omly assigned to one of 4 diets that differed in percentages of energy derived from fat , protein , and carbohydrate for 2 y. We evaluated changes in fasting serum concentrations of total cholesterol ( TC ) , LDL cholesterol , HDL cholesterol , and triglyceride from baseline to 2 y of follow-up . RESULTS After a 2-y dietary intervention , we showed significant interactions between the APOA5 rs964184 polymorphism and dietary fat intake ( low compared with high ) in the determination of changes in TC , LDL cholesterol , and HDL cholesterol ( P-interaction = 0.007 , 0.017 , and 0.006 , respectively ) . In the low-fat intake group ( 20 % of energy derived from fat ) , carriers of the risk allele ( G allele ) exhibited greater reductions in TC and LDL cholesterol than did noncarriers ( P = 0.036 and 0.039 , respectively ) , whereas in the high-fat diet group ( 40 % of energy derived from fat ) , participants with the G allele had a greater increase in HDL cholesterol than did participants without this allele ( P = 0.038 ) . CONCLUSION Our data showed better improvement in lipid profiles from long-term low-fat diet intake in the APOA5 rs964184 risk allele"
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Infantile colic , the cause of 10–20 % of all early paediatrician visits , can lead to parental exhaustion and stress . A systematic review was conducted to examine whether dietary change provides an effective therapy for infantile colic . Six data bases were search ed from 1960 , and 24 studies selected for inclusion . In breastfed infants , evidence suggests that a hypoallergenic maternal diet may be beneficial for reducing symptoms of colic . In formula-fed infants , colic may improve after changing from a st and ard cow ’s milk formula to either a hydrolysed protein formula or a soy-based formula . Fibre-supplemented formulae had no effect . Removal of poorly digested carbohydrates from the infant ’s diet has promise , but additional clinical studies must be conducted before a recommendation can be made . Use of a universal definition to measure symptoms of infantile colic and consistent analysis of urine and faecal sample s would improve the evidence in this area
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"Background . There is controversy regarding whether hypersensitivity to food proteins contributes to colic among breastfed infants . Methods . A r and omized , controlled trial of a low-allergen maternal diet was conducted among exclusively breastfed infants presenting with colic . In the active arm , mothers excluded cow 's milk , eggs , peanuts , tree nuts , wheat , soy , and fish from their diet ; mothers in the control group continued to consume these foods . Outcomes were assessed after 7 days , as the change in cry/fuss duration over 48 hours , with vali date d charts . The primary end point was a reduction in cry/fuss duration of ≥25 % from baseline . Mothers also assessed the responses to diet with categorical and visual analog scales . Results . Of 107 infants , 90 completed the trial ( mean age : 5.7 weeks ; range : 2.9–8.6 weeks ; 54 male infants ) . Infants in both groups presented with significant distress ( geometric mean : low-allergen group : 690 minutes per 48 hours ; control group : 631 minutes per 48 hours ) . In follow-up assessment s on days 8 and 9 , there were significantly more responders in the low-allergen group ( 74 % vs 37 % ) , ie , an absolute risk reduction of 37 % ( 95 % confidence interval : 18–56 % ) . Cry/fuss duration per 48 hours was reduced by a substantially greater amount in the low-allergen group ; the adjusted geometric mean ratio was 0.79 ( 95 % confidence interval : 0.63–0.97 ) , ie , an average reduction of 21 % ( 95 % confidence interval : 3–37 % ) . Mothers ' subjective assessment s of the responses to diet indicated little difference between the groups . Conclusion . Exclusion of allergenic foods from the maternal diet was associated with a reduction in distressed behavior among breastfed infants with colic presenting in the first 6 weeks of life",
"Because infants with colic appear to have abdominal pain similar to that of adults with irritable bowel syndrome , who may benefit from the addition of fiber to their diet , we tested whether fiber added to infant formula would alleviate colic . Twenty-seven normal , term infants ( aged 2 to 8 weeks ; 14 girls ) with colic , defined as crying plus fussing for more than 3 hours a day for at least 3 days of a 6-day baseline period , were enrolled . Infants were r and omly assigned in 9-day periods to a sequence of placebo ( Isomil formula ) followed by fiber-supplemented formula ( Isomil plus soy polysaccharide ) ( n = 12 ) or the reverse ( n = 15 ) . Daily diaries of crying , fussing , sleeping , formula , intake , and stooling were kept . Twenty-two infants completed three lactulose breath hydrogen tests at the end of the baseline period and after each study period . The crossover trial was followed by 30 to 35 days of use of the study formula chosen by the parents as most beneficial but unknown to the investigators . Growth was monitored throughout . Serum cholesterol , calcium , phosphate , albumin , iron , and zinc concentrations were measured at the conclusion . There were no significant differences in average daily time spent by the infants in fussing and crying during ingestion of the fiber-supplemented formula . However , parents of 18 of 27 infants chose fiber-supplemented formula as most beneficial in ameliorating symptoms of colic . While the infants were consuming fiber-supplemented formula , stool frequency increased , and breath hydrogen excretion increased significantly , in response to lactulose . Growth and serum biochemical measurements were normal in all infants . Supplementation of infant formula with the level of soy polysaccharide used in this study may have reduced crying and fussing in some infants but did not affect colicky behavior in the majority of infants , who continued to cry and fuss excessively",
"AIM AND OBJECTIVE The aim of the study was to evaluate the effectiveness of massage , sucrose solution , herbal tea or hydrolysed formula , each used individually in the treatment of infantile colic . BACKGROUND The term colic describes a group of symptoms that occur frequently in infants , consisting of paroxysmal abdominal pain and severe crying . Infant colic is of importance for both parents and the community health services that provide families with care , and is therefore an important clinical problem that is amenable to nursing interventions . DESIGN This prospect i ve and r and omised-controlled study involved 175 infants in Turkey . METHODS Data were gathered by using Wessel criteria ; parents wrote a daily structured diary , recording the onset and duration of crying . Patients were assigned r and omly into four different intervention groups ( massage , sucrose solution , herbal tea and hydrolysed formula ) and control group . Duration of crying following each intervention was recorded in the diary by parents for a one week period . RESULTS There was a significant reduction in crying hours per day in all intervention groups . The difference between mean duration of total crying ( hours/day ) before and after the intervention infants in hydrolysed formula group was found higher than massage , sucrose and herbal tea group . The difference between mean duration of total crying(hours/day ) before and after the intervention infants in massage group was found lower than other intervention groups and all groups . CONCLUSION Our findings demonstrated that varied interventions such as administration of massage , sucrose solution , herbal tea and hydrolysed formula are effective in the treatment of colic . The difference between mean duration of total crying ( hours/day ) before and after the intervention in hydrolysed formula group was found higher than other intervention groups . Hydrolysed formula was the most effective in reducing the duration of crying ( hours/day ) when compared with the other intervention groups . Massage intervention yielded the least symptomatic improvement among all the interventions . RELEVANCE TO CLINICAL PRACTICE Colic treatment models used in this study can be used by nurses in neonatal and primary healthcare setting s as an aid to families for the treatment of infantile colic",
"We evaluated the effect of an herbal tea preparation on infantile colic in a prospect i ve double-blind study . The use of tea eliminated the colic in 19 ( 57 % ) of 33 infants , whereas placebo was helpful in only 9 ( 26 % ) of 35 ( p mean colic score was significantly improved in tea-treated infants . No significant differences were noted between groups regarding number of night wakings",
"The possible role of cows milk intolerance in the aetiology of infant colic was evaluated in 19 babies presenting to their health visitor or general practitioner in one town . Over a three week period a st and ard modified cows milk formula was compared with a soya milk formula on a double blind basis . The duration of colic symptoms was significantly reduced during the week on soya milk ( P less than 0.01 ) , with 11 out of 19 babies fulfilling the diagnostic criteria for cows milk intolerance . Four babies whose symptoms failed to improve either spontaneously or with soya milk were given a hydrolysed protein milk with a positive response in two , confirmed by challenge testing . Thus in 13 out of 19 babies ( 68 % ) the symptoms of infant colic resolved almost completely with dietary change",
"This study investigated the effect of changing the formulas of colicky infants and addressed the method ologic flaws of earlier studies . Attention was paid to issues of design ing a blind study , providing a washout period , and measuring and reproducing the effect . In this r and omized , double-blind trial , three changes of formula were made : for each of four 4-day periods , colicky infants alternately received a casein hydrolysate formula ( Nutramigen ) and a formula containing cow milk . Mothers recorded crying in diaries and indicated which crying episodes they considered to have been caused by colic . Nine infants were started on Nutramigen and eight on the cow milk formula . With the first formula change there was significantly less crying and colic in infants when they were fed Nutramigen than when they were fed cow milk ( p less than 0.01 ) ; with the second change there was less colic when infants were fed Nutramigen ( p less than 0.05 ) but not significantly less crying . By the third change there were no significant differences between formulas . Further analyses demonstrated that there were more clinical ly meaningful positive responses ( a change in crying by at least one third ) to Nutramigen than to cow milk ( p less than 0.05 ) . However , only one subject had a clinical ly meaningful response in colic to all three formula changes . These results demonstrate that in some instances , colic improves with elimination of cow milk formula . However , the effect diminishes with time , and only infrequently is the effect reproducible",
" This study examined 120 infants , aged 3–12 weeks , with severe colics and compared the results of a specific hypoallergenic diet ( group A ) with those of pharmacological treatment ( group B ) . Non‐breastfed group A infants received soy milk and if unresponsive , hydrolyzed milk formulas ; mothers of breast‐fed infants received a diet without cow 's milk , eggs or fish . Breast‐fed and non‐breast‐fed group B infants received dicyclomine hydrochloride 3 mg/kg/day . Results , based on quantitative measurements of crying . indicated that in breast‐fed infants there was no significant improvement between group A ( 62.5 % ) and group B ( 66.6 % ) infants . Among formula‐fed infants , comparison of positive results using soy milk ( 65.9 % ) with positive results using dicyclomine ( 53.3 % ) was not significant ; positive results using soy milk and hydrolyzed milk formulas in non‐responders to soy milk , provided an improvement in 95.4 % of cases . Pharmacological treatment provided an improvement in 53.3 % ) of cases . The diffcrence was significant ( p<0.01 )",
"Objectives : The aim of this study was to evaluate the efficacy on crying episodes owing to infantile colic of a new infant formula containing partially hydrolysed whey proteins , prebiotic oligosaccharides ( OS ) , with a high β-palmitic acid content . Design : Prospect i ve r and omized controlled study . Setting : Italy . Subjects : Two hundred and sixty-seven formula-fed infants , aged less than 4 months , with infantile colic , were r and omized to receive either the new infant formula ( study treatment ( ST ) ) or a st and ard formula and simethicone ( 6 mg/kg twice a day ) ( control treatment ( CT ) ) . A question naire was given to parents to evaluate for 14 days the daily number of colic episodes and crying time . Results : Out of the 199 infants who completed the study , 96 were treated with the new formula and 103 were not treated . Infants receiving the new formula had a significant decrease in colic episodes after 1 week ( 2.47±1.94 at day 7 vs 5.99±1.84 at the study entry ) compared to infants receiving the CT ( 3.72±1.98 at day 7 vs 5.41±1.88 at the study entry ) ( P the crying episodes were significantly different between the two groups of infants ( 1.76±1.60 in ST vs 3.32±2.06 in CT ) ( P partially hydrolysed formula supplemented with fructo- and galacto-OS induces a reduction of crying episodes in infants with colic after 7 and 14 days when compared with a st and ard formula and simethicone . Sponsorship : The study was supported by funds from Numico , Italy",
"This study found that two casein hydrolysate formulas varying in composition were equally effective in managing colicky symptoms associated with protein sensitivity . Both hydrolysate formulas were associated with a significant , comparable reduction in crying duration and intensity from baseline in 15 of 22 infants with complete data . Subsequent challenge data suggest that the population studied were infants experiencing colicky symptoms due to protein sensitivity . A greater proportion of infants showed a positive reaction ( ≥1.5h of crying/d ) to the protein challenges than the placebo challenge , and crying was rated as more intense during whey and milk protein challenges",
"OBJECTIVE To determine the effectiveness of whey hydrolysate formula in the treatment of infantile colic in a primary care setting in the Netherl and s. STUDY DESIGN R and omized , double-blind , parallel trial with a 1-week qualification period and a 1-week intervention period . Participants . Forty-three healthy , thriving , formula-fed infants , 3 hours per day on at least 3 days per week . Infants were r and omized to whey hydrolysate formula ( n = 23 ) or st and ard formula ( n = 20 ) . MAIN OUTCOME MEASURE Difference in duration of crying ( minutes per day ) between qualification week and intervention week . RESULTS Analysis according to the intention to treat principle showed a difference in the decrease of crying duration of 63 minutes per day [ 95 % confidence interval : 1 - 127 minutes per day ] in favor of the whey hydrolysate formula . Five infants did not complete the trial . The scope of the study was not sufficient to expect significant differences in the subgroup analyses . CONCLUSIONS An extensively hydrolyzed whey formula is effective in reducing the duration of crying in a primary care setting",
"Treating the infant colic syndrome by counseling the parents concerning more effective responses to the infant crying is compared to the elimination of soy or cow 's milk protein from the infant 's diet in a r and omized clinical trial . Because symptoms of vomiting and diarrhea are not part of the infant colic syndrome , infants with these gastrointestinal symptoms were excluded from the study . Dietary changes were accomplished by either feeding the infants a hydrolyzed casein formula or by requiring mothers to eliminate milk from their diets . In phase 1 of the study , the group receiving counseling ( n = 10 ) had a decrease in crying from 3.21 + /- 1.10 h/d to 1.08 + /- 0.70 h/d ( P = .001 ) . The crying in the group that received dietary changes ( n = 10 ) decreased from 3.19 + /- 0.69 h/d to 2.03 + /- 1.07 h/d ( P = .01 ) , a level still greater than twice normal . The decrease in those receiving counseling was faster and greater than that of those given dietary changes ( P less than .02 ) . In the second phase of the study , group 2 infants were reexposed to cow 's milk or soy protein and the parents received counseling . In this phase , counseling again decreased crying significantly from 2.09 + /- 1.07 h/d to 1.19 + /- 0.60 h/d ( P = .05 ) . No infant in the study who improved with changes in his or her diet had a significant increase in crying , with reexposure to soy or cow 's milk protein . ( ABSTRACT TRUNCATED AT 250 WORDS",
"There are several causes of infantile colic . The aim of this study was to evaluate , under controlled conditions , whether bovine whey proteins can elicit symptoms of infantile colic in colicky formula-fed infants . The mean age for entering the study was 6.4 weeks and the mean age for colic debut was 3.7 weeks . In 24 of 27 infants with severe colic , the symptoms disappeared when they were given a cow 's milk-free diet ( Nutramigen ) . These 24 infants were entered into a double-blind crossover study . The infants ( receiving cow 's milk-free diet ) were given the contents of identical capsules with each meal during day 6 . The same procedure was repeated on day 10 . The capsules contained either whey protein powder ( with Nutramigen added ) or human albumin powder ( with Nutramigen added ) . Eighteen infants receiving the whey protein-containing capsules reacted with colic , two infants receiving placebo reacted with colic ( P less than .001 ) , and four infants did not react at all . Crying hours per day for the 24 infants were 5.6 hours for formula-fed infants and 0.7 hour for cow 's milk-free diet-fed infants ( P less than .001 ) . Crying hours per day were 3.2 hours for the infants receiving whey protein capsules and 1.0 hour for those receiving placebo ( P less than .001 ) . In conclusion , bovine whey protein can elicit symptoms of infantile colic in colicky formula-fed infants",
"During early infancy , problems of crying , colic , spitting , and feeding difficulties often provoke anxiety and lack of self-confidence in parents . We studied prospect ively what proportion of mothers felt that their infants had problems of this type and determined risk factors for perceived problems identified in the early postnatal period . The mothers of 189 breast-fed and 184 formula-fed infants completed question naires post partum and responded to a follow-up interview at four months . Thirty-five percent of mothers in each group reported that their infants had moderate or severe problems of feeding or crying behavior . Risk factors for perceived problems were identified using stepwise logistic regression analyses . Inquiry about , and early attention to , risk factors may alleviate the parents ' concerns and possibly affect the development of these problems",
"This paper reports the results of placebo-controlled double-blind r and omized cross-over trial design ed to examine the effects of elimination of cow 's milk from maternal diet on rates of infantile colic . Subjects were 20 exclusively breast-fed infants , aged 3 - 18 weeks , with persistent colic . Each mother was given 600 ml drink to be drunk every day ; on 6 of the days the drink contained 300 ml of cow 's milk and 300 ml of soya milk ; on the remaining days it contained 600 ml of soya milk ; the 2 drinks were formulated to be undistinguishable ; the trial days were grouped into blocks of 2 days , r and omly assigned . Mothers were also instructed to record time and duration of any colic , and to record their own daily diet . Avoidance of cow 's milk produced no beneficial effects on the incidence of colic in the babies ; but when frequency of colic was related to days on which specific foods were eaten by the mothers the rates of colic were found to be significantly higher on days on which mothers reported eating chocolate or fruit . These results do not support the contention that elimination of cow 's milk from maternal diet may influence the likelihood of infantile colics ; the source of colic , however , can not be attributed to a single dietary component , but it may involve a combination of foodstuffs",
"OBJECTIVE To determine whether infantile colic ( IC ) is associated with malabsorption of carbohydrates present in fruit juices . METHODS In this double-blind study , parents of 30 healthy infants ( 5.1 + /- 0.7 months , 7.4 + /- 1.0 kg , 64 + /- 4 cm ) were administered a question naire to quantitatively assess IC . Thereafter , they were divided into 2 groups , 16 infants with and 14 without IC . Within each treatment group infants were fed 120 mL ( 16.3 + /- 2.0 mL/kg ) of either white grape ( sorbitol-free ; 1:1 fructose-to-glucose ratio ) or apple ( sorbitol 0.5 g/dL ; 2.6:1 fructose-to-glucose ratio ) juice . Physical activity ( PA ) , energy expenditure ( EE ) , crying , and sleeping times were measured for 0.5 and 3.0 hours before and after juice feeding , respectively , using the Enhanced Metabolic Testing Activity Chamber . Carbohydrate malabsorption was determined by breath hydrogen ( BH(2 ) ) gas analysis after juice feedings . Statistical differences between groups were determined by 2-way analysis of variance with the Tukey procedure . RESULTS Infants with IC fed apple juice exhibited carbohydrate malabsorption as shown by increased BH(2 ) excretion , whereas those without IC absorbed carbohydrates normally when fed this juice . Infants fed apple juice with carbohydrate malabsorption cried more and consequently slept less during the last 1.5 hours of the study . This was associated with increased PA and EE as compared with infants without IC fed apple juice . In contrast , infants fed white grape juice , regardless of IC , showed no increase in BH(2 ) excretion , PA , and EE . Furthermore , crying and sleeping times were unchanged in infants fed white grape juice regardless of the presence or absence of IC . CONCLUSIONS IC was associated with carbohydrate malabsorption from fruit juices containing sorbitol and a high fructose-to-glucose ratio",
"In a double blind crossover study 10 children with infantile colic were fed breast milk and cow 's milk formula , untreated and treated with lactase . Colic was present on 71 % of breast milk and 89 % of cow 's milk days . Daily duration and severity of colic did not differ for milk preparations",
"BACKGROUND Most infants consume fruit juices by 6 months of age . However , fruit juices containing sorbitol may be associated with carbohydrate malabsorption without clinical symptoms . We hypothesized that increased physical activity and metabolic rate may be associated with carbohydrate malabsorption . METHODS Physical activity and metabolic rate were determined in 14 healthy infants ( [ mean + /- SD ] age , 5.1 + /- 0.8 months ; weight , 7.8 + /- 1.1 kg ; length , 67 + /- 4.2 cm ; and body fat , 26 % + /- 5 % ) for 3 hours in a respiratory chamber . Seven were fed pear juice , and the other 7 were fed white grape juice ( 120 mL ) after a 2-hour fast . Pear juice contains sorbitol and a high fructose-glucose ratio , whereas white grape juice is sorbitol free and has a low fructose-glucose ratio . Carbohydrate absorption was determined by breath hydrogen gas analysis . The study was double-blinded . RESULTS When compared with the infants without carbohydrate malabsorption ( peak breath hydrogen level pear juice and 2 of the 7 infants fed white grape juice exhibited carbohydrate malabsorption ( peak breath hydrogen level > or = 20 ppm above baseline ; P physical activity ( P metabolic rate ( P pear juice exhibited increases in physical activity ( P physical activity and metabolic rate in infants . Most of the infants who had carbohydrate malabsorption consumed pear juice . Therefore , fruit juices containing sorbitol and high levels of fructose may not be optimal for young infants",
" Very fussy or extremely fussy infants were r and omized to receive : soy-based formula ( Soy : n = 82 ) or a partially hydrolyzed cow 's milk protein ( CMP ) , low-lactose formula ( PHF : n = 77 ) in a multicenter , double-blind , r and omized , parallel , prospect i ve 28-day feeding trial . Body weight and infant formula tolerance were reported . Adverse events were recorded throughout the study . A significant reduction in mean scores of fussiness , gas , spit-up , and crying compared with baseline measures was observed in infants who received either Soy or PHF within 1 day of formula intake ; improvement in symptoms was sustained by study end . Stool consistency remained constant through day 28 in the PHF group , whereas stools in the Soy group became more firm by day 2 and did not return to pre study consistency . PHF , with a protein profile patterned more closely on human breast milk , improved symptoms of formula intolerance as well as soy-based formula",
"BACKGROUND The effect of diet change in 38 bottle-fed and 77 breast-fed \" colicky \" infants , referred from community-based pediatric facilities was studied over a 1-week period in a double-blind ( within each feeding mode ) , r and omized , placebo-controlled trial . METHODS Bottle-fed infants were assigned to either casein hydrolysate or cow 's milk formula . All mothers of breast-fed infants were started on an artificial color-free , preservative-free , additive-free diet and also r and omized to an active low allergen diet ( milk- , egg- , wheat- , nut-free ) or a control diet . RESULTS The response to diet was assessed on day 1 and day 8 with the use of a previously vali date d infant distress chart on which parents recorded distress levels . If successful outcome was defined as a reduction in distress of 25 % or more , after adjusting for age and feeding mode , infants on active diet had a significantly higher rate of improvement than those on the control diet ( odds ratio , 2.32 ; 95 % confidence interval , 1.07 - 5.0 ; p = 0.03 ) . Analysis of the day 8 to day 1 distress ratio , again adjusted for age and feeding mode , showed that infants on the active diet had distress reduced by 39 % ( 95 % confidence interval , 26 - 50 ) compared with 16 % ( 95 % confidence interval , 0 - 30 ) for those on the control diet ( p = 0.012 ) . CONCLUSION The results suggest a period of dietary modification with a low allergen diet and appropriate nutritional support should be considered in healthy infants with colic",
"The role of cow 's milk in infantile colic in formula-fed infants was estimated in a double-blind study . Sixty colicky infants were given a cow 's milk-containing formula ( Enfamil ) and a cow 's milk-free formula based on soy ( ProSobee ) . Eleven infants ( 18 % ) were free of symptoms while receiving soy formula . Symptoms of 32 infants ( 53 % ) were unchanged or worse when they were fed cow 's milk formula and soy formula , but symptoms disappeared when they were fed a formula containing hydrolyzed casein ( Nutramigen ) . Symptoms of 17 infants ( 29 % ) could not be related to the diet ; these infants were permitted to continue on a cow 's milk-based formula . A challenge with cow 's milk-based formula after one month ( at approximately age 3 months ) produced symptoms of infantile colic in 22 infants ( 36 % ) . At age 6 months , a challenge with cow 's milk was positive in 11 infants ( 18 % ) with epidermal and gastrointestinal symptoms . Eight infants ( 13 % ) at 12 months of age and five infants ( 8 % ) at 16 months of age were still intolerant to cow 's milk . Cow 's milk seems to be a major cause of infantile colic in formula-fed infants . A dietary treatment is suggested for moderate or severe forms of the colic . Cow 's milk protein intolerance is common later in infancy in these infants"
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The purpose of this project was to summarise the available evidence on the effectiveness of exercise therapy for patients with disorders of the musculoskeletal , nervous , respiratory , and cardiovascular systems . Systematic review s were identified by means of a comprehensive search strategy in 11 bibliographic data bases ( 08/2002 ) , in combination with reference tracking . Review s that included ( i ) at least one r and omised controlled trial investigating the effectiveness of exercise therapy , ( ii ) clinical ly relevant outcome measures , and ( iii ) full text written in English , German or Dutch , were selected by two review ers . Thirteen independent and blinded review ers participated in the selection , quality assessment and data - extraction of the systematic review s. Conclusions about the effectiveness of exercise therapy were based on the results presented in reasonable or good quality systematic review s ( quality score > or = 60 out of 100 points ) . A total of 104 systematic review s were selected , 45 of which were of reasonable or good quality . Exercise therapy is effective for patients with knee osteoarthritis , sub-acute ( 6 to 12 weeks ) and chronic ( > or = 12 weeks ) low back pain , cystic fibrosis , chronic obstructive pulmonary disease , and intermittent claudication . Furthermore , there are indications that exercise therapy is effective for patients with ankylosing spondylitis , hip osteoarthritis , Parkinson 's disease , and for patients who have suffered a stroke . There is insufficient evidence to support or refute the effectiveness of exercise therapy for patients with neck pain , shoulder pain , repetitive strain injury , rheumatoid arthritis , asthma , and bronchiectasis . Exercise therapy is not effective for patients with acute low back pain . It is concluded that exercise therapy is effective for a wide range of chronic disorders
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"Percutaneous transluminal angioplasty ( PTA ) is a commonly performed procedure for the treatment of intermittent claudication despite the lack of controlled studies . The aim of this study was to compare PTA with supervised exercise therapy for patients with arterial occlusive disease judged suitable for PTA at angiography . Patients were assessed before treatment commenced and at three monthly intervals afterwards . Assessment included measurement of resting ankle brachial pressure indices ( ABPI ) , and claudicating and maximum walking distances on a treadmill up a 10 degrees incline . Twenty patients were r and omised to receive PTA and 16 exercise . The groups were similar in age , sex , smoking habits and arteriographic pattern of disease . In the PTA group two patients had angioplasties that were technically unsuccessful and two other patients subsequently required surgery . One patient in the exercise group subsequently had a PTA . After PTA , mean ABPI were significantly improved at 3 , 6 and 9 months ( P less than 0.01 ) without a corresponding significant increase in mean maximum walking distances . However in the exercise group despite no increase in mean ABPI , mean maximum walking distances increased progressively , with significant increases at 6 , 9 and 12 months ( P less than 0.01 )",
"The effectiveness of ongoing rehabilitation services for postacute stroke survivors is poorly documented . We design ed a r and omized control , single-blinded study to demonstrate the effectiveness of intensive outpatient therapy . The treatment intervention consisted of 1 hr each of physical and occupational therapy , four times per week , for 12 wk ; therapy focused on neuromuscular facilitation and functional tasks . All subjects were screened before the therapies and after 3 mo and 9 mo . Forty-nine stroke survivors , who were at least l yr ( mean , 2.9 yr ) poststroke , were r and omized with two treated patients to each control ( no treatment supplied ) . All patients had received inpatient rehabilitation at the time of their acute stroke , but no patient had any ongoing therapy within the last 6 mo . The outcome measures included the Functional Independence Measure ( FIM ) , Brunnstrom stages of motor recovery , timed mobility tasks , and the Jebson h and evaluation . We also evaluated the level of depression , self-esteem , and socialization . The treated patients demonstrated an improvement of 6.6 points over the 3 mo of therapy compared with only 1.5 points in the control group in the FIM motor score transformed using Rasch analysis . The change from time 0 to 3 mo was significant in the treated group but not in the controls . Treated patients maintained their gains at the 9-mo follow-up , and controls lost ground . The treated group improved in terms of socialization and self-esteem as evidence d by a lower Sickness Impact Profile , whereas the controls tended to get worse . There was a trend toward less depression , but this did not reach a P = 0.05 level of significance . This study demonstrates that significant functional gains can still be attained in the postacute stroke survivor , despite prior inpatient rehabilitation services",
"Of the 373 stroke patients 95 were admitted to the feasibility study of stroke rehabilitation . The patients were divided into two groups , an intensive and a normal treatment group . In this study , the functional recovery of stroke , measured by ADL and motor function was significantly better in the intensive treatment group . There was no difference in institutionalization or incidence of death between the groups . The gain of ADL and motor function was greatest during the first three months after stroke in the intensive treatment group . The conclusion is that intensified physiotherapy seems to improve the functional recovery of stroke patients",
"The medical treatment of idiopathic Parkinson 's disease has improved the quality of life and increased survival of patients with Parkinson 's disease . However , as the illness progresses , impairments in daily living activities occur . A clinical trial for a group rehabilitation program was initiated to maintain the functional status of these patients . The research protocol consisted of a pretreatment evaluation , r and om assignment to experimental or control groups , and posttreatment evaluations after therapy , at 6 months and at 1 year . The results showed that the subjects of the treated experimental group maintained their functional status after 1 year , demonstrated a significant decrease of bradykinesia , and perceived a significant improvement in their psychological well-being . This study confirms the value of an occupational therapy group approach and its benefits to the functional independence , to the improvement of physical and motor symptoms , and to the quality of life of persons with Parkinson 's disease",
" Of 1094 patients with a confirmed stroke admitted to Northwick Park , a district general hospital , 364 ( 33 % ) died while in hospital , 215 ( 20 % ) were fully recovered when discharged , and 329 ( 30 % ) were too frail or too ill from diseases other than stroke to be considered for active rehabilitation . Only 121 ( 11 % ) were suitable for intensive treatment . They and 12 patients referred direct to out patients were allocated at r and om to one of three different courses of rehabilitation . Intensive was compared with conventional rehabilitation and with a third regimen which included no routine rehabilitation , but under which patients were encouraged to continue with exercises taught while in hospital and were regularly seen at home by a health visitor . Progress at three months and 12 months was measured by an index of activities of daily living . Improvement was greatest in those receiving intensive treatment , intermediate in those receiving conventional treatment , and least in those receiving no routine treatment . Decreasing intensity of treatment was associated with a significant increase in the proportions of patients who deteriorated and in the extent to which they deteriorated . Probably only a few stroke patients , mostly men , are suitable for intensive outpatient rehabilitation , but for those patients the treatment is effective and realistic",
"Ninety-two chronic low back pain patients were r and omly allocated to two groups to evaluate the effectiveness of a back school compared with an exercise-only regimen according to specified outcome variables . The data from 78 patients with 7 years mean duration of symptoms was analyzed . Three assessment s were made : before treatment and 6 and 16 weeks after treatment . Changes in patients ' levels of pain , functional disability , and other related variables were compared in the two groups . Almost all variables showed an improvement at 6 weeks . At 16 weeks , functional disability and pain levels showed a significant difference . Back school patients continued to make an improvement . This method of managing low back pain makes maximal use of limited re sources and appears to be effective , especially in the longer term",
" Fifty-three patients with ankylosing spondylitis ( AS ) were r and omly allocated ; 26 experimental patients received physiotherapy and disease education , 27 control patients received neither . The primary treatment outcome was change in spinal mobility measured at 4 months by fingertip-to-floor distance . Experimental patients had more improvement in fingertip-to-floor distance ( p2 less than 0.004 ) and in function ( p2 less than 0.001 ) than control patients . Physiotherapy with disease education is effective in the treatment of patients with AS",
"In a r and omized , single-blind , crossover study , we evaluated physical disability in moderately advanced Parkinson 's disease ( PD ) patients after 4 weeks of normal physical activity and 4 weeks of an intensive physical rehabilitation program . We used a timed motor task and a st and ard assessment of PD severity ( the Unified Parkinson 's Disease Rating Scale [ UPDRS ] with subscales for mentation , activities of daily living [ ADL ] , and motor function ) completed by an investigator blinded to the physical rehabilitation status of the patient . Following physical rehabilitation , there was significant improvement in the UPDRS ADL and motor scores , but no change in mentation score . During the 6 months following physical rehabilitation , patients did not regularly exercise , and the UPDRS scores returned to baseline . We conclude that physical disability in moderately advanced PD objective ly improves with a regular physical rehabilitation program , but this improvement is not sustained when normal activity is resumed",
"OBJECTIVES To describe the impact of musculoskeletal pain ( MP ) ; to compare management of MP by the population and by primary care physicians ; and to identify misconceptions about treatment . METHODS 5803 people with MP and 1483 primary care physicians , r and omly selected , in eight European countries were interviewed by telephone . A structured question naire was used to ask about usual management of MP and perceived benefits and risks of treatment . Current health status ( SF-12 ) was also assessed . RESULTS From primary care physicians ' perceptions , MP appears to be well managed . All presenting patients are offered some form of treatment , 90 % or more doctors are trying to improve patients ' quality of life , and most are aware and concerned about the risks of treatment with NSAIDs . From a population perspective , up to 27 % of people with pain do not seek medical help and of those who do , several wait months/years before seeing a doctor . 55 % or fewer patients who have seen a doctor are currently receiving prescription treatment for their pain . Communication between doctors and patients is poor ; few patients are given information about their condition ; and many have misconceptions about treatment . CONCLUSIONS Management of MP is similar across eight European countries , but there is discordance between physician and patient perspectives of care . Some people with pain have never sought medical help despite being in constant/daily pain . Those who do seek help receive little written information or explanation and many have misperceptions about the benefits and risks of treatment that limit their ability to actively participate in decisions about their care",
"The efficacy of physical training alone or combined with antiplatelet thera py ( dipyridamole and aspirin ) was studied in 30 patients with stage II peripheral arterial occlusive disease ( PAOD ) . Patients were r and omly allocated to one of the following groups : Group A— dipyridamole 75 mg three times daily and aspirin 330 mg once daily : Group B— physical exercise ; Group C — physical exercise and dipyridamole 75 mg three time daily and aspirin 330 mg once daily . After six months ' treatment the pain-free walking time ( PFWT ) and the max imum walking time ( MWT ) improved significantly ( p PFWT lengthened by 35 % ( from 101.00 ± 34.56 to 137.32 ± 40.50 s ) and the MWT by 38 % ( from 150.34 ± 55.60 to 207.26 ± 60.67 s ) ; in group B the PFWT lengthened by 90 % ( from 90.65 ± 40.54 to 171.45 ± 55.60 s ) and the MWT by 86 % ( from 145.39 ± 60.50 to 270.63 ± 63.61 s ) . When physical exer cise was associated with drugs as in group C , the PFWT lengthened by 120 % ( from 89.51 ± 43.89 to 196.72 ±51.73 s ) and the MWT by 105 % ( from 160.43 ± 59.84 to 329.05 ± 63.96 s ) . No significant variations were observed at any stage of the study in the ankle/arm pressure ratio at rest and after st and ard treadmill exercise , in the plethysmographic rest and peak flows , or in the trans cutaneous oxygen pressure in basal conditions and in its half recovery time after an induced ischemia . The results confirm the benefits of regular exercise in stage II PAOD pa tients but suggest they may be enhanced by antiplatelet therapy ",
"UNLABELLED RESEARCH PROBLEM AND METHODS : There are currently 1.5 million stroke survivors in the United States . More than half of these individuals have significant residual physical disability and functional impairment . Survivors of stroke constitute the largest group of patients receiving rehabilitation services in this country . We examined existing clinical trials investigating the effectiveness of stroke rehabilitation programs to improve functional outcomes and discharge destination . One hundred twenty-four research reports were initially identified . From this sample , 36 trials meeting selected criteria were evaluated by the methods of meta- analysis . RESULTS A total of 3717 patients participated in the 36 clinical trials included in the meta- analysis . The results revealed a mean d-index of 0.40 + /- 0.33 . This effect size index was converted to a U3 value of 65.5 , indicating that the average patient receiving a program of focused stroke rehabilitation performed better than approximately 65.5 % of those patients in comparison groups ( 95 % confidence interval , 63.6 % to 67.3 % ) . The results also revealed a significant interaction between type of research design and method of recording the outcome of a clinical trial . Blind recording of the outcome measure appears to be an essential design characteristic in clinical trials that do not r and omize patients to conditions . CONCLUSIONS Programs of focused stroke rehabilitation may improve functional performance for some patients who have experienced a stroke . The improvement in performance appears related to early initiation of treatment , but not to the duration of intervention . Improvements are also associated with the patient 's age and the type of design . Research design should be considered an important moderator variable in planning and interpreting future clinical trials of treatment effectiveness in stroke rehabilitation",
"Summary Several new studies have indicated that an active approach to patients with chronic disabling low back pain ( LBP ) seems effective . Some of these studies emphasize the importance of dealing with the patient 's total situation in comprehensive multidisciplinary programs — the bio-psycho-social model . However , these programs are expensive . The aim of this study was to evaluate the rehabilitation outcome from three different active programs in terms of : ( 1 ) return-to-work rate , ( 2 ) days of sick leave , ( 3 ) health-care contacts , ( 4 ) pain and disability scores , and ( 5 ) staying physically active . The subjects included 132 patients r and omized to the study , of whom 123 started one of the treatment programs . They had all had at least 6 months of chronic LBP . The patients were r and omized into one of three programs : group 1 — a full-time , intensive 3-week multidisciplinary program , including active physical and ergonomic training and psychological pain management , followed by 1 day weekly for the subsequent 3 weeks ; group 2 — active physical training , twice a week for 6 weeks , for a total of 24h ; group 3 — psychological pain management combined with active physical training , twice a week for 6 weeks , also for a total of 24h . The results presented here are based on data collected 4 months following treatment , which shows an 86 % response rate . The initial examination and the follow-up evaluation were performed by a blinded observer . The results show that 4 months after treatment , the intensive multidisciplinary program is superior to the less intensive programs in terms of return-to-work rate , health-care contacts , pain and disability scores , and staying physically active . In conclusion , it seems that although the multidisciplinary program is initially expensive compared to the less intensive programs , the savings in sick pay , early retirement pensions , and health care contacts make it economically worthwhile . Long-term follow-up will show whether this effect continues",
"OBJECTIVE --To determine the quality of r and omised controlled trials of exercise therapy for back pain . DESIGN --Computer aided search of published papers and blinded assessment of the methods of studies . SUBJECTS--23 r and omised controlled trials , of which 16 studied exercise therapy given by physiotherapists to individual patients with back pain . Other conservative treatments could be included . MAIN OUTCOME MEASURES --Score for quality of methods ( based on four main categories : study population , interventions , measurement of effect , and data presentation and analysis ) and main conclusion of author(s ) with regard to exercise therapy . RESULTS --Only four studies scored more than 50 points ( maximum 100 ) , indicating that most were of poor quality . Six studies found that exercise was better than reference treatments and 10 reported it to be no better or worse than the reference treatment . Those reporting positive results tended to have higher methods scores ( 4/6 positive v 4/10 negative scored greater than or equal to 42 ) . CONCLUSIONS --No conclusion can be drawn about whether exercise therapy is better than other conservative treatments for back pain or whether a specific type of exercise is more effective . Further trials are needed in which greater attention is paid to methods of study",
"This study reports the initial evaluation of treatment efficiency in 75 patients with intermittent claudication who were r and omized to three treatment groups : 1 ) reconstructive surgery , 2 ) recon structive surgery with subsequent physical training , and 3 ) physical training alone . Before treatment , there were no statistically significant differences between the groups in age , sex , smoking habits , symptom duration of claudication , ankle-arm blood pressure quotient ( ankle-index ) , maximal plethysmographic calf blood flow , symptom-free and maximal walking distance , the history of other atherosclerotic manifestations or in the medical treatment . The walking performance was improved in all three groups at follow-up 13 ± 0.5 months after r and omization . Surgery was most effective , but the addition of training to surgery improved the symptom-free walking distance even further . In pooled observations of the three groups , age , symptom duration , and a history of myocardial ischemic disease correlated negatively with walking performance after treatment . In the operated group , the duration of claudication and a history of myocardial ischemic disease correlated negatively with the walking performance . This was not the case when patients were censored if limited by other symptoms than intermittent claudication after treatment . In the trained group , the duration of claudication correlated negatively to symptom-free and maximal walking distance . Ankle-index and maximal plethysmographic calf blood flow after treatment and the change of these variables with treatment correlated positively with both symptom-free and maximal walking distance when results were pooled for all patients . Although this mainly was a consequence of the improved blood flow after surgery , the change of maximal plethysmographic calf blood flow also correlated with symptom-free but not with maximal walking distance in the trained group . The results demonstrate that , compared with physical training alone , operation alone or in combination with subsequent training are superior treatment modalities in patients with intermittent claudication",
"OBJECTIVE To determine the effectiveness of exercise therapy in patients with osteoarthritis ( OA ) of the hip or knee . METHODS A r and omized single blind , clinical trial was conducted in a primary care setting . Patients with hip or knee OA by American College of Rheumatology criteria were selected . Two intervention groups were compared . Both groups received treatment from the patients ' general practitioner , including patient education and medication if necessary . The experimental group also received exercise therapy from a physiotherapist in primary care . The treatment period was 12 weeks . The main outcome measures were pain , medication use ( nonsteroidal antiinflammatory drugs , NSAID ) and observed disability . RESULTS A total of 201 patients were r and omized . Exercise therapy was associated with a reduction of pain in the past week ( difference in change -17.0 ; 95 % CI -23.6 , -10.4 ) and observed disability ( -0.19 ; 95 % CI -0.38 ; -0.01 ) . Effect sizes were medium ( 0.58 ) and small ( 0.28 ) , respectively . No effect of exercise therapy was found for the use of NSAID . Additional beneficial effects ( p = 0.05 ) were found for the use of paracetamol ( effect size 0.33 ) , global effect as perceived by the patient ( effect size 0.68 ) , and muscle strength of the hip ( effect size 0.34 ) . CONCLUSION After 12 weeks , exercise therapy is effective in reducing pain and disability . The size of the effects is medium and small , respectively"
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4117ceb8-06ff-11f0-808a-c43d1ab1c353
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The current systematic review and meta- analysis of r and omized controlled trials ( RCTs ) was conducted to evaluate the potential effect of melatonin supplementation on blood pressure in patients with metabolic disorders . The following data bases were search ed until June 2018 : PubMed , MEDLINE , EMBASE , Web of Science , and Cochrane Central Register of Controlled Trials . Two review ers independently assessed the eligibility of retrieved studies , extracted data from included trials , and evaluated the risk of bias of included studies . Statistical heterogeneity was tested using Cochran ’s Q test and I-square ( I2 ) statistic . Data were pooled using r and om-effect models and st and ardized mean difference ( SMD ) was considered as the effect size . Eight RCTs , out of 743 potential citations , were eligible to be included in the current meta- analysis . The pooled findings indicated a significant reduction in systolic ( SBP ) ( SMD = −0.87 ; 95 % CI , −1.36 , −0.38 ; P = 0.001 ; I2 : 84.3 ) and diastolic blood pressure ( DBP ) ( SMD = −0.85 ; 95 % CI , −1.20 , −0.51 ; P = 0.001 ; I2 : 68.7 ) following melatonin supplementation in individuals with metabolic disorders . In summary , the current meta- analysis demonstrated that melatonin supplementation significantly decreased SBP and DBP in patients with metabolic disorders . Additional prospect i ve studies are recommended using higher supplementation doses and longer intervention periods to confirm our findings
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"Abstract — Patients with essential hypertension have disturbed autonomic cardiovascular regulation and circadian pacemaker function . Recently , the biological clock was shown to be involved in autonomic cardiovascular regulation . Our objective was to determine whether enhancement of the functioning of the biological clock by repeated nighttime melatonin intake might reduce ambulatory blood pressure in patients with essential hypertension . We conducted a r and omized , double-blind , placebo-controlled , crossover trial in 16 men with untreated essential hypertension to investigate the influence of acute ( single ) and repeated ( daily for 3 weeks ) oral melatonin ( 2.5 mg ) intake 1 hour before sleep on 24-hour ambulatory blood pressure and actigraphic estimates of sleep quality . Repeated melatonin intake reduced systolic and diastolic blood pressure during sleep by 6 and 4 mm Hg , respectively . The treatment did not affect heart rate . The day – night amplitudes of the rhythms in systolic and diastolic blood pressures were increased by 15 % and 25 % , respectively . A single dose of melatonin had no effect on blood pressure . Repeated ( but not acute ) melatonin also improved sleep . Improvements in blood pressure and sleep were statistically unrelated . In patients with essential hypertension , repeated bedtime melatonin intake significantly reduced nocturnal blood pressure . Future studies in larger patient group should be performed to define the characteristics of the patients who would benefit most from melatonin intake . The present study suggests that support of circadian pacemaker function may provide a new strategy in the treatment of essential hypertension",
"Glycemic control and prevention of secondary complications are the most important goals of using pharmacologic treatment of diabetes mellitus ( DM ) . The inadequate responses to oral hypoglycemic agents may be attributed to inadequate postreceptor events even when insulin levels are quite sufficient , and associated with oxidative stress induced by long-term hyperglycemia . The administration of antioxidants such as melatonin and zinc may improve tissue responses to insulin and increase the efficacy of drugs , e.g. metformin , which act through this pathway . This project was design ed to evaluate the effects of melatonin and zinc on the lipid profile and renal function in type 2 DM patients poorly controlled with metformin . A placebo-controlled , double-blind clinical trial was performed in which 46 type 2 diabetic patients were selected and allocated into three groups . These groups were treated with single daily oral doses of both 10 mg of melatonin and 50 mg of zinc acetate alone : 10 mg of melatonin and 50 mg of zinc acetate in addition to the regularly used metformin or placebo , given at bedtime for 90 days . Fasting lipid profiles and microalbuminuria ( MAU ) were measured before initiating the treatments ( zero time ) and after 30 and 90 days of treatment . Daily administration of melatonin and zinc improved the impaired lipid profile and decreased the level of MAU ; the addition of this treatment regimen in combination with metformin improved the tissue responses to this oral hypoglycemic agent . In conclusion , the combination of melatonin and zinc acetate , when used alone or in combination with metformin , improves DM-related complications such as the impaired lipid profile and MAU in type 2 DM patients",
"OBJECTIVES The aim of this study was to assess the relations between the circadian variations of blood pressure ( BP ) and the pattern of ischemia and autonomic activity in normotensive and hypertensive patients with coronary artery disease ( CAD ) . PATIENTS AND METHODS On the basis of the results of ambulatory BP monitoring , 115 patients with stable CAD were divided into Group 1 ( with arterial hypertension ) and Group 2 ( normotensives ) . Groups were subdivided into dippers and non-dippers . Holter monitoring was performed to assess the occurrence and circadian pattern of ischemic episodes . Time domain and frequency domain HRV analyses were performed to evaluate the autonomic activity . RESULTS The total number of ischemic episodes was similar in dippers and non-dippers . Non-dippers had a greater number of silent episodes and a different circadian pattern of ischemia with more night episodes . Among the time-domain HRV parameters , only SDNN was similar in dippers and non-dippers . Non-dippers had lower pNN50 and rMSSD-the parameters expressing parasympathetic activity . Differences between diurnal and nocturnal results of spectral HRV analysis were observed in dipper patients only . They presented an elevation of HF power and a decline of LF power at night . All differences between dippers and non-dippers were of similar significance in both hypertensives and normotensives . CONCLUSIONS A lack of a nocturnal fall in BP is present in normotensive and hypertensive patients with CAD . Non-dippers with CAD had silent and nighttime ischemia more often . They also had an abnormal pattern of autonomic activity with higher sympathetic and lower parasympathetic modulation",
"PURPOSE Nocturnal hypertension is associated with a high risk of morbidity and mortality . A blunted nocturnal surge in melatonin excretion has been described in nondipping hypertensive patients . We therefore studied the potency of melatonin to reduce nighttime blood pressure ( BP ) in treated hypertensive patients with nocturnal hypertension . PATIENTS AND METHODS Thirty-eight treated hypertensive patients ( 22 males , mean age 64+/-11 years ) with confirmed nocturnal hypertension ( mean nighttime systolic BP > 125 mm Hg ) , according to repeated 24-hour ambulatory blood pressure monitoring ( ABPM ) , were r and omized in a double-blind fashion to receive either controlled release (CR)-melatonin 2 mg or placebo 2 hours before bedtime for 4 weeks . A 24-hour ABPM was then performed . RESULTS Melatonin treatment reduced nocturnal systolic BP significantly from 136+/-9 to 130+/-10 mm Hg ( P=.011 ) , and diastolic BP from 72+/-11 to 69+/-9 mm Hg ( P=.002 ) , whereas placebo had no effect on nocturnal BP . The reduction in nocturnal systolic BP was significantly greater with melatonin than with placebo ( P=.01 ) , and was most prominent between 2:00 AM and 5:00 AM ( P=.002 ) . CONCLUSIONS Evening CR-melatonin 2 mg treatment for 4 weeks significantly reduced nocturnal systolic BP in patients with nocturnal hypertension . Thus , an addition of melatonin 2 mg at night to stable antihypertensive treatment may improve nocturnal BP control in treated patients with nocturnal hypertension",
"AIMS As melatonin has been found to play a role in the mechanisms of cardiovascular regulation , we design ed the present study to evaluate whether the evening ingestion of the pineal hormone might interfere with the antihypertensive therapy in hypertensive patients well-controlled by nifedipine monotherapy . METHODS Forty-seven mild to moderate essential hypertensive out patients taking nifedipine GITS 30 or 60 mg monotherapy at 08.30 h for at least 3 months , were given placebo or melatonin 5 mg at 22.30 h for 4 weeks according to a double-blind cross-over study . At the end of each treatment period patients underwent a 24 h noninvasive ambulatory blood pressure monitoring ( ABPM ) during usual working days ; sleeping period was scheduled to last from 23.00 to 07.00 h. RESULTS The evening administration of melatonin induced an increase of blood pressure and heart rate throughout the 24 h period ( DeltaSBP = + 6.5 mmHg , P DBP as well as the HR increase were particularly evident during the morning and the afternoon hours . CONCLUSIONS We hypothesize that competition between melatonin and nifedipine , is able to impair the antihypertensive efficacy of the calcium channel blocker . This suggests caution in uncontrolled use of melatonin in hypertensive patients . As the pineal hormone might interfere with calcium channel blocker therapy , it can not be considered simply a dietary supplement",
"The aim of this study was to assess the effects of 5 mg melatonin before sleep in patients with coronary artery disease ( CAD ) and with an abnormal circadian pattern of blood pressure ( BP ) on changes in circadian BP profile and heart rate variability ( HRV ) . Sixty patients with CAD , nondippers aged 48–80 years ( male 75 % ) , were included . In addition to previous treatment , they were r and omly allocated to melatonin or placebo . After 90 days , a second 24-h BP monitoring was carried out . Each patient had two sessions ( before r and omization and at the end of study ) of 24-h ECG monitoring to assess the changes in HRV . Inclusion of melatonin led to BP pattern normalization in 35 % of patients in the melatonin group and in 15 % of controls ( P=0.609 ) . This effect was reached not only by a decrease in nighttime BP , but also by an increase in daytime BP ( significant in the melatonin group ) . A nonoptimal effect for BP profile was observed in 12.5 % of patients : extreme- or reverse dippers . In patients with conversion from nondippers to dippers ( responders ) , an increase in st and ard deviation of normal-to-normal intervals between initial and final HRV analyses was observed . Nonresponders represented an increase in the mean circadian heart rate . To avoid nonoptimal effects , the inclusion of melatonin in pharmacotherapy of patients with CAD should be based on monitoring of circadian BP profile , before and during treatment . As melatonin caused not only a nocturnal decrease in BP but also a daytime increase , it should not be recommended in patients with ‘ high normal ’ values of BP because of the danger of induction of arterial hypertension",
"BACKGROUND The Cochrane Collaboration is strongly encouraging the use of a newly developed tool , the Cochrane Collaboration Risk of Bias Tool ( CCRBT ) , for all review groups . However , the psychometric properties of this tool to date have yet to be described . Thus , the objective of this study was to add information about psychometric properties of the CCRBT including inter-rater reliability and concurrent validity , in comparison with the Effective Public Health Practice Project Quality Assessment Tool ( EPHPP ) . METHODS Both tools were used to assess the method ological quality of 20 r and omized controlled trials included in our systematic review of the effectiveness of knowledge translation interventions to improve the management of cancer pain . Each study assessment was completed independently by two review ers using each tool . We analysed the inter-rater reliability of each tool 's individual domains , as well as final grade assigned to each study . RESULTS The EPHPP had fair inter-rater agreement for individual domains and excellent agreement for the final grade . In contrast , the CCRBT had slight inter-rater agreement for individual domains and fair inter-rater agreement for final grade . Of interest , no agreement between the two tools was evident in their final grade assigned to each study . Although both tools were developed to assess ' quality of the evidence ' , they appear to measure different constructs . CONCLUSIONS Both tools performed quite differently when evaluating the risk of bias or method ological quality of studies in knowledge translation interventions for cancer pain . The newly introduced CCRBT assigned these studies a higher risk of bias . Its psychometric properties need to be more thoroughly vali date d , in a range of research fields , to underst and fully how to interpret results from its application",
"In this study it was investigated whether the oral administration of melatonin ( 1 mg ) in comparison to placebo was able to reduce blood pressure , vascular reactivity , and catecholamines in men , as previously reported in young women . The administration of melatonin significantly reduced blood pressure , the pulsatility index in the internal carotid artery , and catecholamines levels within 90 minutes . The effect of melatonin on the artery pulsatility index was related to baseline values , being greater in men with higher baseline values . The present data indicate that melatonin may blunt the activity of the cardiovascular system and may have both physiopathologic and clinical implication",
"AIMS The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation ( AF ) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF , among individuals with type 2 diabetes . METHODS AND RESULTS About 11 140 patients with type 2 diabetes ( 7.6 % of whom had AF at baseline ) were r and omized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . We compared total mortality and cardiovascular disease outcomes and effects of r and omized treatment for 4.3 years on such outcomes between patients with and without AF at baseline . After multiple adjustments , AF was associated with a 61 % ( 95 % confidence interval 31 - 96 , P of all-cause mortality and comparable higher risks of cardiovascular death , stroke , and heart failure ( all P perindopril and indapamide produced similar relative , but greater absolute , risk reductions for all-cause and cardiovascular mortalities in patients with AF , compared with those without AF . The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline . CONCLUSION Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes . This arrhythmia identifies individuals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment . Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors"
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QUESTION What are typical values of physical function for women diagnosed with breast cancer and how do these compare to normative data ? DESIGN Systematic review with meta- analysis . PARTICIPANTS Women diagnosed with breast cancer who were before , during or after treatment . OUTCOME MEASURES Physical function was divided into three categories : aerobic capacity , upper and lower extremity muscular fitness , and mobility . Measures of aerobic capacity included field tests ( 6-minute walk test , 12-minute walk tests , Rockport 1-mile test , and 2-km walk time ) and submaximal/maximal exercise tests on a treadmill or cycle ergometer . Measures of upper and lower extremity muscular fitness included grip strength , one repetition maximum ( bench , chest or leg press ) , muscle endurance tests , and chair st and s. The only measure of mobility was the Timed Up and Go test . RESULTS Of the 1978 studies identified , 85 were eligible for inclusion . Wide ranges of values were reported , reflecting the range of ages , disease severity , treatment type and time since treatment of participants . Aerobic fitness values were generally below average , although 6-minute walk time was closer to population norms . Upper and lower extremity strength was lower than population norms for women who were currently receiving cancer treatment . Lower extremity strength was above population norms for women who had completed treatment . CONCLUSION Aerobic capacity and upper extremity strength in women diagnosed with breast cancer are generally lower than population norms . Assessment of values for lower extremity strength is less conclusive . As more research is published , expected values for sub-groups by age , treatment , and co-morbidities should be developed . [ Neil-Sztramko SE , Kirkham AA , Hung SH , Niksirat N , Nishikawa K Campbell KL ( 2014 ) Aerobic capacity and upper limb strength are reduced in women diagnosed with breast cancer : a systematic review .Journal of Physiotherapy60 : 189 - 200 ]
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"This pilot study examined the efficacy of two home-based exercise programs on alleviating fatigue and improving functional capacity in breast cancer survivors . Participants were r and omly assigned into one of three groups : aerobic exercise ( AE ) , resistance exercise ( RE ) , or usual care control ( CON ) . After receiving individualized instruction and training , participants assigned to the AE and RE groups were asked to perform the prescribed exercise(s ) 3 times per week for 12 weeks at home . Both groups were instructed to keep their perceived exercise intensity in the \" fairly light \" to \" somewhat hard \" range using the Borg Perceived Exertion Scale . All participants completed the revised Piper Fatigue Scale ( PFS ) and the 6-minute walk test ( 6MWT ) at baseline and 12-week post-exercise program . Analysis of pre- and post-training data revealed a significant reduction in fatigue levels on the PFS among participants in the AE group ( Z=2.521 , one-tailed P=0.006 ) , and a significant improvement in the distance of the 6MWT for the RE group ( Z=2.366 , one-tailed P=0.009 ) at the end of 12-week study period . No significant changes in fatigue or functional status were observed in the CON group . Findings provide preliminary support for RE as a viable strategy for improving functional capacity in breast cancer survivors , while AE may be more effective in attenuating cancer-related fatigue . Incorporating RE training for future research may help advance the growing body of knowledge in symptom management for breast cancer survivors",
"The \" Timed Get-up- and -Go \" ( TGUG ) test measures the overall time to complete a series of functionally important tasks . In the \" Exp and ed Timed Get-up- and -Go \" ( ETGUG ) test , times for the component tasks are measured using a multimemory stopwatch . Results from the ETGUG test were compared to those from the TGUG test on three groups of subjects : nonimpaired young , nonimpaired elderly , and elderly subjects at risk of falling . Significant differences were found between the two control groups and the at-risk group for all components of the test . Walking speed was the only measurement found to be significantly different between the young and elderly controls . The ETGUG test is a sensitive and objective assessment of function that requires minimal equipment , training , or expense . It better isolates functional deficits , thereby aiding the clinician in devising prevention strategies and guiding both treatment and further testing",
"BACKGROUND AND PURPOSE The interpretation of patient scores on clinical tests of physical mobility is limited by a lack of data describing the range of performance among people without disabilities . The purpose of this study was to provide data for 4 common clinical tests in a sample of community-dwelling older adults . SUBJECTS Ninety-six community-dwelling elderly people ( 61 - 89 years of age ) with independent functioning performed 4 clinical tests . METHODS Data were collected on the Six-Minute Walk Test ( 6MW ) , Berg Balance Scale ( BBS ) , and Timed Up & Go Test ( TUG ) and during comfortable- and fast-speed walking ( CGS and FGS ) . Intraclass correlation coefficients ( ICCs ) were used to determine the test-retest reliability for the 6MW , TUG , CGS , and FGS measurements . Data were analyzed by gender and age ( 60 - 69 , 70 - 79 , and 80 - 89 years ) cohorts , similar to previous studies . Means , st and ard deviations , and 95 % confidence intervals for each measurement were calculated for each cohort . RESULTS The 6MW , TUG , CGS , and FGS measurements showed high test-retest reliability ( ICC [2,1]=.95-.97 ) . Mean test scores showed a trend of age-related declines for the 6MW , BBS , TUG , CGS , and FGS for both male and female subjects . DISCUSSION AND CONCLUSION Preliminary descriptive data suggest that physical therapists should use age-related data when interpreting patient data obtained for the 6MW , BBS , TUG , CGS and FGS . Further data on these clinical tests with larger sample sizes are needed to serve as a reference for patient comparisons",
"PURPOSE Breast cancer chemotherapy may cause unfavorable changes in physical functioning , body composition , psychosocial functioning , and quality of life ( QOL ) . We evaluated the relative merits of aerobic and resistance exercise in blunting these effects . PATIENTS AND METHODS We conducted a multicenter r and omized controlled trial in Canada between 2003 and 2005 that r and omly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy ( median , 17 weeks ; 95 % CI , 9 to 24 weeks ) . Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary end points were fatigue , psychosocial functioning , physical fitness , body composition , chemotherapy completion rate , and lymphedema . RESULTS The follow-up assessment rate for our primary end point was 92.1 % , and adherence to the supervised exercise was 70.2 % . Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem ( P = .015 ) , aerobic fitness ( P = .006 ) , and percent body fat ( adjusted P = .076 ) . Resistance exercise was superior to usual care for improving self-esteem ( P = .018 ) , muscular strength ( P lean body mass ( P = .015 ) , and chemotherapy completion rate ( P = .033 ) . Changes in cancer-specific QOL , fatigue , depression , and anxiety favored the exercise groups but did not reach statistical significance . Exercise did not cause lymphedema or adverse events . CONCLUSION Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy , but they did improve self-esteem , physical fitness , body composition , and chemotherapy completion rate without causing lymphedema or significant adverse events",
"Using a meta-analytic approach , we recently reported that the rate of decline in maximal oxygen uptake ( VO2 max ) with age in healthy women is greatest in the most physically active and smallest in the least active when expressed in milliliters per kilogram per minute per decade . We tested this hypothesis prospect ively under well-controlled laboratory conditions by study ing 156 healthy , nonobese women ( age 20 - 75 yr ) : 84 endurance-trained runners ( ET ) and 72 sedentary subjects ( S ) . ET were matched across the age range for age-adjusted 10-km running performance . Body mass was positively related with age in S but not in ET . Fat-free mass was not different with age in ET or S. Maximal respiratory exchange ratio and rating of perceived exertion were similar across age in ET and S , suggesting equivalent voluntary maximal efforts . There was a significant but modest decline in running mileage , frequency , and speed with advancing age in ET . VO2 max ( ml . kg-1 . min-1 ) was inversely related to age ( P absolute rate of decline in VO2 max was greater in ET ( -5.7 ml . kg-1 . min-1 . decade-1 ) compared with S ( -3.2 ml . kg-1 . min-1 . decade-1 ; P relative ( % ) rate of decline was similar ( -9.7 vs -9 . 1%/decade ; not significant ) . The greater absolute rate of decline in VO2 max in ET compared with S was not associated with a greater rate of decline in maximal heart rate ( -5.6 vs. -6.2 beats . min-1 . decade-1 ) , nor was it related to training factors . The present cross-sectional findings provide additional evidence that the absolute , but not the relative , rate of decline in maximal aerobic capacity with age may be greater in highly physically active women compared with their sedentary healthy peers . This difference does not appear to be related to age-associated changes in maximal heart rate , body composition , or training factors",
"The purpose of the present paper was to evaluate the effects of an 8-week multimodal program focused on core stability exercises and recovery massage with DVD support for a 6-month period in physical and psychological outcomes in breast cancer survivors . A r and omized controlled clinical trial was performed . Seventy-eight ( n = 78 ) breast cancer survivors were assigned to experimental ( core stability exercises plus massage-myofascial release ) and control ( usual health care ) groups . The intervention period was 8 weeks . Mood state , fatigue , trunk curl endurance , and leg strength were determined at baseline , after the last treatment session , and at 6 months of followup . Immediately after treatment and at 6 months , fatigue , mood state , trunk curl endurance , and leg strength exhibited greater improvement within the experimental group compared to placebo group . This paper showed that a multimodal program focused on core stability exercises and massage reduced fatigue , tension , depression , and improved vigor and muscle strength after intervention and 6 months after discharge",
"OBJECTIVES To determine normal values for four commonly used clinical functional balance tests from community-dwelling women aged 20 to 80 and to identify any significant decline due to aging . DESIGN A cross-sectional study was undertaken to provide normative values for four clinical balance tests across 6 decade cohorts . SETTING The Betty Byrne-Henderson Center for Women and Aging , Royal Womens ' Hospital , Brisbane , Australia . PARTICIPANTS Four hundred fifty-six community-dwelling , independently ambulant women with no obvious neurological or musculoskeletal-related disability , aged 20 to 80 , were r and omly recruited from a large metropolitan region . MEASUREMENTS The clinical balance measures /tests were the Timed Up and Go test , step test , Functional Reach test , and lateral reach test . Multivariate analysis was used to test the effect for age , height , and activity level . RESULTS Normal data were produced for each test across each decade cohort . Gradual decline in balance performance was confirmed , with significant effect for age demonstrated . CONCLUSION New normative data across the adult age decades are available for these clinical tests . Use of clinical balance tests could complement other balance tests and be used to screen women aged 40 to 60 whose performance is outside the normal values for age and to decrease later falls risk",
"Background —Peak oxygen uptake ( peak & OV0312;o2 ) is a strong predictor of mortality and is commonly used in the evaluation of patients for cardiac transplantation . β-Blockers reduce mortality in patients with heart failure , without influencing peak & OV0312;o2 , raising the possibility that peak & OV0312;o2 is no longer suitable as an indicator of prognosis in these patients . Methods and Results —We analyzed prospect ively gathered data on 2105 patients referred for cardiopulmonary testing for all-cause mortality and for occurrence of death or transplantation . Patients receiving β-blockers were younger , more likely to have coronary disease , and had a greater mean ejection fraction but had a similar peak & OV0312;o2 . There were 555 deaths ( 26 % ) and 194 ( 9 % ) transplants during a median follow-up of 3.5 years . Peak & OV0312;o2 was a predictor of mortality irrespective of β-blocker use ; a decrease of 1 mL · kg−1 · min−1 result ed in an adjusted hazard ratio ( HR ) of 1.13 ( 95 % CI 1.09 to 1.17 , P patients not receiving β-blockers and 1.27 ( 95 % CI 1.18 to 1.36 , P patients receiving β-blockers . Similar findings were noted when considering death or transplantation as an end point . β-Blocker use was associated with better outcomes until peak & OV0312;o2 values became very low ( ≈10 mL · kg−1 · min−1 ) , at which level survival rates were equally poor . Conclusion —Peak & OV0312;o2 is a determinant of survival in patients in heart failure even in the setting of β-blockade . Because of improved survival in patients treated with β-blockers , the cut point value of 14 mg · kg−1 · min−1 for referral for cardiac transplantation in these patients requires reevaluation , and a lower cut point may be more appropriate",
"PURPOSE Physical activity may protect against breast cancer . Few prospect i ve studies have evaluated breast cancer mortality in relation to cardiorespiratory fitness ( CRF ) , an objective marker of physiologic response to physical activity habits . METHODS We examined the association between CRF and risk of death from breast cancer in the Aerobics Center Longitudinal Study . Women ( N = 14,811 ) , aged 20 to 83 yr with no prior breast cancer history , received a preventive medical examination at the Cooper Clinic in Dallas , Texas , between 1970 and 2001 . Mortality surveillance was completed through December 31 , 2003 . CRF was quantified as maximal treadmill exercise test duration and was categorized for analysis as low ( lowest 20 % of exercise duration ) , moderate ( middle 40 % ) , and high ( upper 40 % ) . At baseline , all participants were able to complete the exercise test to at least 85 % of their age-predicted maximal heart rate . RESULTS A total of 68 breast cancer deaths occurred during follow-up ( mean = 16 yr ) . Age-adjusted breast cancer mortality rates per 10,000 woman-years were 4.4 , 3.2 , and 1.8 for low , moderate , and high CRF groups , respectively ( trend P = 0.008 ) . After further controlling for body mass index , smoking , drinking , chronic conditions , abnormal exercise ECG responses , family history of breast cancer , oral contraceptive use , and estrogen use , hazard ratios ( 95 % CI ) for breast cancer mortality across incremental CRF categories were 1.00 ( referent ) , 0.67 ( 0.35 - 1.26 ) , and 0.45 ( 0.22 - 0.95 ) ( trend P = 0.04 ) . CONCLUSIONS These results indicate that CRF is associated with a reduced risk of dying from breast cancer in women",
"Purpose . To determine which mode of exercise is preferred by breast cancer survivors and to evaluate this response between grade d exercise testing on a treadmill and on a cycle ergometer . Methods . Twelve breast cancer survivors completed 2 maximal aerobic stress tests on separate days . The women completed a ramp protocol on an electronically braked cycle ergometer and an incremental step protocol on a treadmill to volitional fatigue . Test order was r and omized . Expired gases were collected for the determination of peak aerobic capacity ( Vo2peak ) . Results . Exercise mode had a significant effect on the grade d exercise response in breast cancer survivors , P = .003 . Treadmill Vo2peak was significantly greater than bike Vo2peak ( 28.7 ± 4.7 vs 23.9 ± 4.7 mL/min/kg , respectively , P = .003 ) and VEmax was equivalent between exercise modes ( P = .731 ) . Maximal heart rate was significantly higher by 11 bpm during the treadmill protocol ( P = .004 ) , and Ve/VCo2 exhibited possible mode dependency ( P = .018 ) . Conclusion . This patient population felt more comfortable and produced significantly greater Vo2peak values using the treadmill protocol . These results discuss the potential implication s concerning the design and interpretation of exercise interventions for breast cancer survivors",
"Background Many patients suffer from severe shoulder complaints after breast cancer surgery and axillary lymph node dissection . Physiotherapy has been clinical ly observed to improve treatment of these patients . However , it is not a st and ard treatment regime . The purpose of this study is to investigate the efficacy of physiotherapy treatment of shoulder function , pain and quality of life in patients who have undergone breast cancer surgery and axillary lymph node dissection . Methods Thirty patients following breast cancer surgery and axillary lymph node dissection were included in a r and omised controlled study . Assessment s were made at baseline and after three and six months . The treatment group received st and ardised physiotherapy treatment of advice and exercises for the arm and shoulder for three months ; the control group received a leaflet containing advice and exercises . If necessary soft tissue massage to the surgical scar was applied . Primary outcome variables were amount of pain in the shoulder/arm recorded on the Visual Analogue Scale , and shoulder mobility ( flexion , abduction ) measured using a digital inclinometer under st and ardized conditions . Secondary outcome measures were shoulder disabilities during daily activities , edema , grip strength of both h and s and quality of life . The research er was blinded to treatment allocation . Results All thirty patients completed the trial . After three and six months the treatment group showed a significant improvement in shoulder mobility and had significantly less pain than the control group . Quality of life improved significantly , however , h and grip strength and arm volume did not alter significantly . Conclusion Physiotherapy reduces pain and improves shoulder function and quality of life following axillary dissection after breast cancer . Trial registration IS RCT"
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BACKGROUND Meta-analyses and a recent guideline acknowledge that conservative management of uncomplicated appendicitis with antibiotics can be successful for patients who wish to avoid surgery . However , guidance as to specific management does not exist . METHODS PUBMED and EMBASE search of trials describing methods of conservative treatment was conducted according to Preferred Reporting Items for Systematic review s and Meta-Analyses guidelines . RESULTS Thirty-four studies involving 2,944 antibiotic-treated participants were identified . The greatest experience with conservative treatment is in persons 5 to 50 years of age . In most trials , imaging was used to confirm localized appendicitis without evidence of abscess , phlegmon , or tumor . Antibiotics regimens were generally consistent with intra-abdominal infection treatment guidelines and used for a total of 7 to 10 days . Approaches ranged from 3-day hospitalization on parenteral agents to same-day hospital or ED discharge of stable patients with outpatient oral antibiotics . Minimum time allowed before response was evaluated varied from 8 to 72 hours . Although pain was a common criterion for nonresponse and appendectomy , analgesic regimens were poorly described . Trials differed in use of other response indicators , that is , white blood cell count , C-reactive protein , and reimaging . Diet ranged from restriction for 48 hours to as tolerated . Initial response rates were generally greater than 90 % and most participants improved by 24 to 48 hours , with no related severe sepsis or deaths . In most studies , appendectomy was recommended for recurrence ; however , in several , patients had antibiotic retreatment with success . CONCLUSION While further investigation of conservative treatment is ongoing , patients considering this approach should be advised and managed according to study methods and related guidelines to promote informed shared decision-making and optimize their chance of similar outcomes as described in published trials . Future studies that address biases associated with enrollment and response evaluation , employ best- practice pain control and antibiotic selection , better define cancer risk , and explore longer time thresholds for response , minimized diet restriction and hospital stays , and antibiotic re-treatment will further our underst and ing of the potential effectiveness of conservative management . LEVEL OF EVIDENCE Systematic review , level II
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"METHODS We r and omly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever , leukocytosis , and ileus , with a maximum of 10 days of therapy ( control group ) , or to receive a fixed course of antibiotics ( experimental group ) for 4±1 calendar days . The primary outcome was a composite of surgical-site infection , recurrent intraabdominal infection , or death within 30 days after the index source -control procedure , according to treatment group . Secondary outcomes included the duration of therapy and rates of subsequent infections",
"Purpose Appendectomy versus conservative antibiotic treatment ( CAT ) for children with acute uncomplicated appendicitis ( AUA ) remains unresolved , with concerns regarding the practicality of CAT . We analyzed our center ’s experience with CAT for AUA , using a protocol with strict inclusion , exclusion and treatment criteria . Methods Non-r and omized , prospect i ve cohort study included all children admitted betwee 2014 and 2016 , with clinical and laboratory tests suspicious for AUA . Data collected included clinical signs and symptoms ; laboratory , ultrasound and pathology results . Follow-up was conducted through clinic visits , telephone conversations and national registry analysis . Results Included in CAT : 362 children , 19 underwent appendectomy within 1–2 days . Overall , 75 were readmitted for recurrent acute appendicitis during 22 months ( 6–43 ) follow-up . Thirty were treated successfully with antibiotics a second time . The remaining 45 had appendectomy . Overall , 86.8 % underwent CAT with no surgery . Histology of all recurrent AUA revealed no perforations . Conclusion We confirm the feasibility of conservative management of AUA in children . A rigorous diagnostic plan with strict inclusion and exclusion criteria will lead to high success rate of CAT with a strong safety profile . CAT does not compete with surgery or render appendectomy unnecessary . It is a safe alternative to surgery in selected cases",
"IMPORTANCE Current evidence suggests that nonoperative management of uncomplicated appendicitis is safe , but overall effectiveness is determined by combining medical outcomes with the patient 's and family 's perspective , goals , and expectations . OBJECTIVE To determine the effectiveness of patient choice in nonoperative vs surgical management of uncomplicated acute appendicitis in children . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve patient choice cohort study in patients aged 7 to 17 years with acute uncomplicated appendicitis presenting at a single pediatric tertiary acute care hospital from October 1 , 2012 , through March 6 , 2013 . Participating patients and families gave informed consent and chose between nonoperative management and urgent appendectomy . INTERVENTIONS Urgent appendectomy or nonoperative management entailing at least 24 hours of inpatient observation while receiving intravenous antibiotics and , on demonstrating improvement of symptoms , completion of 10 days of treatment with oral antibiotics . MAIN OUTCOMES AND MEASURES The primary outcome was the 1-year success rate of nonoperative management . Successful nonoperative management was defined as not undergoing an appendectomy . Secondary outcomes included comparisons of the rates of complicated appendicitis , disability days , and health care costs between nonoperative management and surgery . RESULTS A total of 102 patients were enrolled ; 65 patients /families chose appendectomy ( median age , 12 years ; interquartile range [ IQR ] , 9 - 13 years ; 45 male [ 69.2 % ] ) and 37 patients /families chose nonoperative management ( median age , 11 years ; IQR , 10 - 14 years ; 24 male [ 64.9 % ] ) . Baseline characteristics were similar between the groups . The success rate of nonoperative management was 89.2 % ( 95 % CI , 74.6%-97.0 % ) at 30 days ( 33 of 37 children ) and 75.7 % ( 95 % CI , 58.9%-88.2 % ) at 1 year ( 28 of 37 children ) . The incidence of complicated appendicitis was 2.7 % in the nonoperative group ( 1 of 37 children ) and 12.3 % in the surgery group ( 8 of 65 children ) ( P = .15 ) . After 1 year , children managed nonoperatively compared with the surgery group had fewer disability days ( median [ IQR ] , 8 [ 5 - 18 ] vs 21 [ 15 - 25 ] days , respectively ; P lower appendicitis-related health care costs ( median [ IQR ] , $ 4219 [ $ 2514-$7795 ] vs $ 5029 [ $ 4596-$5482 ] , respectively ; P = .01 ) . CONCLUSIONS AND RELEVANCE When chosen by the family , nonoperative management is an effective treatment strategy for children with uncomplicated acute appendicitis , incurring less morbidity and lower costs than surgery . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01718275",
"PURPOSE Urgent appendectomy has long been the st and ard of care for acute appendicitis . Six r and omized trials have demonstrated that antibiotics can safely treat appendicitis , but approximately 1 in 4 of these patients eventually requires appendectomy . Overall treatment success may be limited by complex disease including perforation . Patients ׳ success on antibiotic therapy may depend on preoperative identification of complex disease on imaging . However , the effectiveness of computed tomography ( CT ) in differentiating complex disease including perforated from nonperforated appendicitis remains to be determined . The purpose of this study was to assess the preoperative diagnostic accuracy of CT in determining appendiceal perforation in patients operated for acute appendicitis . METHODS We performed a retrospective review of pathology and radiology reports from consecutive patients who presented to the emergency department with suspicion for acute appendicitis between January 2012 and May 2015 . CT scans were re- review ed by abdominal imaging fellowship-trained radiologists using st and ardized criteria , and the radiologists were blinded to pathology and surgical findings . Radiologists specifically noted presence or absence of periappendiceal gas , abscess , appendicolith , fat str and ing , and bowel wall thickening . The overall radiologic impression as well as these specific imaging findings was compared to results of pathology and operative reports . Pathology reports were considered the st and ard for diagnostic accuracy . RESULTS Eighty-nine patients ( 65 % male , average age of 34 years ) presenting with right lower quadrant pain underwent CT imaging and prompt appendectomy . Final pathology reported perforation in 48 % ( n = 43 ) of cases . Radiologic diagnosis of perforation was reported in 9 % ( n = 8) , correctly identifying perforation in 37.5 % ( n = 3 ) , and incorrectly reporting perforation in 62.5 % of nonperforated cases per pathology . Radiology missed 93 % ( n = 40 ) of perforations postoperatively diagnosed by pathology . There was no secondary finding ( fat str and ing , diameter > 13 mm , abscess , cecal wall thickening , periappendiceal gas , simple fluid collection , appendicolith , and phlegmon ) with a clinical ly reliable sensitivity or specificity to predict perforated appendicitis . Surgeon׳s report of perforation was consistent with the pathology report of perforation in only 28 % of cases . CONCLUSIONS The usefulness of a CT for determining perforation in acute appendicitis is limited , and methods to improve precision in identifying patients with complicated appendicitis should be explored as this may help for improving risk prediction for failure of treatment with antibiotic therapy and help guide patients and providers in shared decision-making for treatment options",
"Background Antibiotic treatment of acute appendicitis has gained interest and inquiries . Reports have demonstrated both safety and high resolution of symptoms and inflammation following antibiotic treatment of appendicitis , but information on long-term results is required . Our present aim was therefore to evaluate long-term recurrence rate of initial antibiotics-alone treatment for suspected acute appendicitis . Methods Patients with favourable response to antibiotics in earlier r and omized ( RCT , n = 97 ) and population -based ( PBT , n = 342 ) studies as well as subsequently treated non-r and omized ( Non-R , n = 271 ) patients are evaluated for long-term risk to relapse dem and ing surgical appendectomy ; altogether 710 patients . Results Clinical characteristics among r and omized and non-r and omized patients were similar without any statistical difference according to abdominal symptoms and degree of systemic inflammation ( CRP , WCC ) when antibiotic treatment started . Females and males showed the same results . The median follow-up time was 2162 days ( 5.92 years ) , and the range across highest and lowest follow-up was 3495 days ( range 2–3497 ) for the entire group , without significant differences among subgroups ( RCT , PBT , Non-R ) . The cumulative probability for relapse of appendicitis dem and ing appendectomy was : 0.09 , 0.12 , 0.12 and 0.13 at 1- , 2- , 3- and 5-year follow-up , with a probability of 0.86 ± 0.013 without appendectomy after 8 years . This may imply an overall benefit of 60–70 % by antibiotics during expected 10-year follow-up accounting for initial treatment failures at 10–23 % in our published reports . Conclusion Antibiotic treatment is safe and effective as a first-line therapy in unselected adults with acute appendicitis with a risk around 15 % for long-term relapse following favourable initial treatment response",
"Background Appendectomy has been the treatment for acute appendicitis for over 120 years . Antibiotic treatment has occasionally been used in small uncontrolled studies , instead of operation , but this alternative has never before been tried in a multicenter r and omized trial . Patients and Methods Male patients , 18–50 years of age , admitted to six different hospitals in Sweden between 1996 and 1999 were enrolled in the study . No women were enrolled by decision of the local ethics committee . If appendectomy was planned , patients were asked to participate , and those who agreed were r and omized either to surgery or to antibiotic therapy . Patients r and omized to surgery were operated on with open surgery or laparoscopically . Those r and omized to antibiotic therapy were treated intravenously for 2 days , followed by oral treatment for 10 days . If symptoms did not resolve within 24 hours , an appendectomy was performed . Participants were monitored at the end of 1 week , 6 weeks , and 1 year . Results During the study period 252 men participated , 124 in the surgery group and 128 in the antibiotic group . The frequency of appendicitis was 97 % in the surgery group and 5 % had a perforated appendix . The complication rate was 14 % in the surgery group . In the antibiotic group 86 % improved without surgery ; 18 patients were operated on within 24 hours , and the diagnosis of acute appendicitis was confirmed in all but one patient , and he was suffering from terminal ileitis . There were seven patients ( 5 % ) with a perforated appendix in this group . The rate of recurrence of symptoms of appendicitis among the 111 patients treated with antibiotics was 14 % during the 1-year follow-up . Conclusions Acute nonperforated appendicitis can be treated successfully with antibiotics . However , there is a risk of recurrence in cases of acute appendicitis , and this risk should be compared with the risk of complications after appendectomy",
"Although antibiotic therapy seemed to be a safe treatment option for acute appendicitis , indications of this treatment have not been fully evaluated . We hypothesized that clinical and radiologic mild appendicitis may be a c and i date for short-term antibiotic therapy . The purpose of present study was to examine the efficacy and the recurrence rate of short-term antibiotic therapy for consecutive patients with mild appendicitis . A prospect i ve observational study was conducted over 3 years . The mild appendicitis was defined as the intermediate Alvarado score ( 4 - 8 ) and dilated appendix from 6 mm to 10 mm in radiologic study . All patients received initial antibiotics administration with clinical observation during 48 hours . The failure to respond to therapy and the incidence of recurrence were assessed . There were 107 enrolled patients with the mean Alvarado score of 6 ± 1 and the mean appendiceal diameter of 7.4 ± 1 mm . Of these , 97 ( 91 % ) exhibited improved symptoms and were discharged . The remaining 10 patients underwent surgery because of clinical aggravation , and pathology revealed true appendicitis in six of them . Of the 97 patients in whom the initial treatment was successful , five patients ( 5 % ) exhibited recurrent symptoms during a median follow-up period of 18 months . Of these five patients , three were treated with surgery ( all true appendicitis ) , and the remaining two were once again treated with antibiotics . Patients with suspected appendicitis , those in whom mild appendicitis was diagnosed after clinical and radiologic evaluations , were found to benefit from short-term antibiotic therapy",
"BACKGROUND Carefully selected children with early appendicitis may be managed nonoperatively . However , it is unknown whether nonoperative management ( NOM ) is applicable to all patients with uncomplicated appendicitis . The purpose of this study was to evaluate the outcomes of NOM of uncomplicated appendicitis with exp and ed inclusion criteria . METHODS A prospect i ve , nonr and omized patient-preference study comparing NOM versus laparoscopic appendectomy ( LA ) was performed in children with radiographic/ clinical evidence of uncomplicated appendicitis . RESULTS Demographics , laboratory values , and clinical presentation were similar between the NOM ( n=51 ) and LA ( n=32 ) groups . Initial failure rate was 31 % . The outcomes were similar between groups , except that NOM had fewer days of pain medication . Patients who failed NOM had a longer duration of symptoms prior to admission . Patients with appendicolith had a failure rate of 50 % compared to 24 % without appendicolith . The recurrence rate was 26 % . Overall , 51 % avoided appendectomy . Costs were similar between NOM and LA . CONCLUSIONS When exp and ing the inclusion criteria for children with presumed uncomplicated appendicitis , NOM was associated with high failure and recurrence rates . These high rates may be because of the inclusion of patients with complicated appendicitis and patients with an appendicolith . Even in this setting of less-restrictive exclusion criteria , NOM remained cost neutral . LEVEL OF EVIDENCE LEVEL II ( Treatment Study : Prospect i ve Comparative Study )",
"Background Although the st and ard treatment of acute appendicitis ( AA ) consists of an early appendectomy , there has recently been both an interest and an increase in the use of antibiotic therapy as the primary treatment for uncomplicated AA . However , the use of antibiotic therapy in the treatment of uncomplicated AA is still controversial . Methods / design The APPAC trial is a r and omized prospect i ve controlled , open label , non-inferiority multicenter trial design ed to compare antibiotic therapy ( ertapenem ) with emergency appendectomy in the treatment of uncomplicated AA . The primary endpoint of the study is the success of the r and omized treatment . In the antibiotic treatment arm successful treatment is defined as being discharged from the hospital without the need for surgical intervention and no recurrent appendicitis during a minimum follow-up of one-year ( treatment efficacy ) . Treatment efficacy in the operative treatment arm is defined as successful appendectomy evaluated to be 100 % . Secondary endpoints are post-intervention complications , overall morbidity and mortality , the length of hospital stay and sick leave , treatment costs and pain scores ( VAS , visual analoque scale ) . A maximum of 610 adult patients ( aged 18–60 years ) with a CT scan confirmed uncomplicated AA will be enrolled from six hospitals and r and omized by a closed envelope method in a 1:1 ratio either to undergo emergency appendectomy or to receive ertapenem ( 1 g per day ) for three days continued by oral levofloxacin ( 500 mg per day ) plus metronidazole ( 1.5 g per day ) for seven days . Follow-up by a telephone interview will be at 1 week , 2 months and 1 , 3 , 5 and 10 years ; the primary and secondary endpoints of the trial will be evaluated at each time point . Discussion The APPAC trial aims to provide level I evidence to support the hypothesis that approximately 75–85 % of patients with uncomplicated AA can be treated with effective antibiotic therapy avoiding unnecessary appendectomies and the related operative morbidity , also result ing in major cost savings . Trial registration Clinical",
"IMPORTANCE An increasing amount of evidence supports the use of antibiotics instead of surgery for treating patients with uncomplicated acute appendicitis . OBJECTIVE To compare antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis confirmed by computed tomography ( CT ) . DESIGN , SETTING , AND PARTICIPANTS The Appendicitis Acuta ( APPAC ) multicenter , open-label , noninferiority r and omized clinical trial was conducted from November 2009 until June 2012 in Finl and . The trial enrolled 530 patients aged 18 to 60 years with uncomplicated acute appendicitis confirmed by a CT scan . Patients were r and omly assigned to early appendectomy or antibiotic treatment with a 1-year follow-up period . INTERVENTIONS Patients r and omized to antibiotic therapy received intravenous ertapenem ( 1 g/d ) for 3 days followed by 7 days of oral levofloxacin ( 500 mg once daily ) and metronidazole ( 500 mg 3 times per day ) . Patients r and omized to the surgical treatment group were assigned to undergo st and ard open appendectomy . MAIN OUTCOMES AND MEASURES The primary end point for the surgical intervention was the successful completion of an appendectomy . The primary end point for antibiotic-treated patients was discharge from the hospital without the need for surgery and no recurrent appendicitis during a 1-year follow-up period . RESULTS There were 273 patients in the surgical group and 257 in the antibiotic group . Of 273 patients in the surgical group , all but 1 underwent successful appendectomy , result ing in a success rate of 99.6 % ( 95 % CI , 98.0 % to 100.0 % ) . In the antibiotic group , 70 patients ( 27.3 % ; 95 % CI , 22.0 % to 33.2 % ) underwent appendectomy within 1 year of initial presentation for appendicitis . Of the 256 patients available for follow-up in the antibiotic group , 186 ( 72.7 % ; 95 % CI , 66.8 % to 78.0 % ) did not require surgery . The intention-to-treat analysis yielded a difference in treatment efficacy between groups of -27.0 % ( 95 % CI , -31.6 % to ∞ ) ( P = .89 ) . Given the prespecified noninferiority margin of 24 % , we were unable to demonstrate noninferiority of antibiotic treatment relative to surgery . Of the 70 patients r and omized to antibiotic treatment who subsequently underwent appendectomy , 58 ( 82.9 % ; 95 % CI , 72.0 % to 90.8 % ) had uncomplicated appendicitis , 7 ( 10.0 % ; 95 % CI , 4.1 % to 19.5 % ) had complicated acute appendicitis , and 5 ( 7.1 % ; 95 % CI , 2.4 % to 15.9 % ) did not have appendicitis but received appendectomy for suspected recurrence . There were no intra-abdominal abscesses or other major complications associated with delayed appendectomy in patients r and omized to antibiotic treatment . CONCLUSIONS AND RELEVANCE Among patients with CT-proven , uncomplicated appendicitis , antibiotic treatment did not meet the prespecified criterion for noninferiority compared with appendectomy . Most patients r and omized to antibiotic treatment for uncomplicated appendicitis did not require appendectomy during the 1-year follow-up period , and those who required appendectomy did not experience significant complications . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01022567",
"Objectives The appendix may modulate colon microbiota and bowel inflammation . We investigated whether appendectomy alters colorectal cancer risk . Methods We identified a cohort of 75979 patients who underwent appendectomy between 1997 and 1999 based on the insurance cl aims of Taiwan . A comparison cohort of 303640 persons without appendectomy was selected r and omly , frequency matched by age , sex , comorbidity and entry year was also selected . We monitored subsequent colorectal cancer development in both cohorts . Results The overall colorectal cancer incidence was 14 % higher in the appendectomy patients than in the comparison cohort ( p . The incidence of colorectal cancer was much higher in 1.5 - 3.5 years post appendectomy follow-up than for the comparisons ( HR of 2.13 ) . Patients who received an incidental appendectomy had an HR of 2.90 when compared to the comparisons . Conclusions Results of our study suggest that appendectomy in patients with appendicitis is likely associated with the development of colorectal cancer in the post-surgery period",
"OBJECTIVE The aim of this study was to evaluate the feasibility and safety of nonoperative treatment of acute nonperforated appendicitis with antibiotics in children . METHODS A pilot r and omized controlled trial was performed comparing nonoperative treatment with antibiotics versus surgery for acute appendicitis in children . Patients with imaging-confirmed acute nonperforated appendicitis who would normally have had emergency appendectomy were r and omized either to treatment with antibiotics or to surgery . Follow-up was for 1 year . RESULTS Fifty patients were enrolled ; 26 were r and omized to surgery and 24 to nonoperative treatment with antibiotics . All children in the surgery group had histopathologically confirmed acute appendicitis , and there were no significant complications in this group . Two of 24 patients in the nonoperative treatment group had appendectomy within the time of primary antibiotic treatment and 1 patient after 9 months for recurrent acute appendicitis . Another 6 patients have had an appendectomy due to recurrent abdominal pain ( n = 5 ) or parental wish ( n = 1 ) during the follow-up period ; none of these 6 patients had evidence of appendicitis on histopathological examination . CONCLUSIONS Twenty-two of 24 patients ( 92 % ) treated with antibiotics had initial resolution of symptoms . Of these 22 , only 1 patient ( 5 % ) had recurrence of acute appendicitis during follow-up . Overall , 62 % of patients have not had an appendectomy during the follow-up period . This pilot trial suggests that nonoperative treatment of acute appendicitis in children is feasible and safe and that further investigation of nonoperative treatment is warranted",
"Abstract Aim The main goal of our study was to assess a 7 days long course of antibiotics for acute uncomplicated appendicitis . Material s and Methods From March 2014 to November 2015 , all patients diagnosed with acute appendicitis have been considered to be treated by only antibiotics . Inclusion criteria included clinical ( tenderness ) , biological ( C‐reactive protein [ CRP ] 6 mm ) . All patients were treated with intravenous amoxicillin and clavulanic acid ( 100 mg/kg/day ) for 2 days ( six doses ) . At the end of the treatment , clinical and para clinical examinations included blood sample s at day 7 and ultrasound ( US ) scan at 3 months . Results A total of 166 patients were treated and followed up prospect ively during the study period . Mean age at diagnosis was 10.8 ± 0.6 years . All children , but four were discharged with a clinical improvement after 48 hours and six intravenous antibiotics injection according to our protocol . Four children required surgery during the initial hospitalization period . Initial ultrasound scan showed a mean diameter of 7.85 ± 1.6 mm , with inflamed fat in 124 patients ( 74.7 % ) . At Day 7 , the diameter was 5.2 ± 1.6 mm ( p Conclusion Non‐operative treatment ( NOT ) is a safe alternative for the management of uncomplicated acute appendicitis in children . Further study should be conducted to determine relapse risk factors",
"Introduction : The management approach for acute appendicitis has been challenged in recent years , with numerous r and omized controlled trials demonstrating that antibiotics/conservative management is an efficacious treatment , with lower complication rates . Methods : A national survey of all consultant general surgeons evaluating their practice s was performed . Reasons for changed practice s , choice of antibiotics and follow-up investigations were evaluated . In addition , the role of interval appendicectomy and conservative management in the pediatric population was also assessed . Results : The response rate for this survey was 74.7 % ( n = 74/99 ) . Over one-fifth ( n = 17 , 22.9 % ) routinely treat acute appendicitis conservatively , while another 14.8 % ( n = 11 ) consider this approach in selected cases . Main reasons for modified practice s included the presence of inflammatory phlegmon ( 75 % ) , delayed presentation ( 64 % ) , and recent evidence -based medicine developments ( 46 % ) . Co-amoxiclav/clavulanic acid was the most popular antibiotic for conservative management ( 53 % ) . Alternatively , combinations of antibiotics were also utilized . One-third felt interval appendicectomy was warranted , while one-fifth supported conservative management in the paediatric setting . The overwhelming majority ( > 95 % ) advocate follow-up colonoscopy ± computed tomography in any patient aged > 40 years managed conservatively . Conclusion : Considerable variation in management of uncomplicated appendicitis remains in Irel and despite growing evidence suggesting that the non-operative approach is safe . Reasons for adopting a conservative management practice have been identified and reflect the exp and ing literature on this subject",
"Study objective R and omized trials suggest that nonoperative treatment of uncomplicated appendicitis with antibiotics‐first is safe . No trial has evaluated outpatient treatment and no US r and omized trial has been conducted , to our knowledge . This pilot study assessed feasibility of a multicenter US study comparing antibiotics‐first , including outpatient management , with appendectomy . Methods Patients aged 5 years or older with uncomplicated appendicitis at 1 US hospital were r and omized to appendectomy or intravenous ertapenem greater than or equal to 48 hours and oral cefdinir and metronidazole . Stable antibiotics‐first‐treated participants older than 13 years could be discharged after greater than or equal to 6‐hour emergency department ( ED ) observation with next‐day follow‐up . Outcomes included 1‐month major complication rate ( primary ) and hospital duration , pain , disability , quality of life , and hospital charges , and antibiotics‐first appendectomy rate . Results Of 48 eligible patients , 30 ( 62.5 % ) consented , of whom 16 ( 53.3 % ) were r and omized to antibiotics‐first and 14 ( 46.7 % ) to appendectomy . Median age was 33 years ( range 9 to 73 years ) , median WBC count was 15,000/&mgr;L ( range 6,200 to 23,100/&mgr;L ) , and median computed tomography appendiceal diameter was 10 mm ( range 7 to 18 mm ) . Of 15 antibiotic‐treated adults , 14 ( 93.3 % ) were discharged from the ED and all had symptom resolution . At 1 month , major complications occurred in 2 appendectomy participants ( 14.3 % ; 95 % confidence interval [ CI ] 1.8 % to 42.8 % ) and 1 antibiotics‐first participant ( 6.3 % ; 95 % CI 0.2 % to 30.2 % ) . Antibiotics‐first participants had less total hospital time than appendectomy participants , 16.2 versus 42.1 hours , respectively . Antibiotics‐first‐treated participants had less pain and disability . During median 12‐month follow‐up , 2 of 15 antibiotics‐first‐treated participants ( 13.3 % ; 95 % CI 3.7 % to 37.9 % ) developed appendicitis and 1 was treated successfully with antibiotics ; 1 had appendectomy . No more major complications occurred in either group . Conclusion A multicenter US trial comparing antibiotics‐first to appendectomy , including outpatient management , is feasible to evaluate efficacy and safety",
"PURPOSE The purpose of this study was to determine if early , acute appendicitis in children can be safely and effectively managed with antibiotics alone . METHODS A retrospective review was performed of children ( non-operatively ( NOM ) for early , acute appendicitis since May 2012 . These were compared to patients treated with appendectomy between January 2011 and October 2011 ( OM ) . Inclusion criteria included : ( a ) symptoms . RESULTS Twelve patients ( 66 % female , mean age 12.2,SD=4.2 yrs ) were treated non-operatively , while 12 ( 50 % female , mean age 12.5,SD=3.2 yrs ) were treated operatively . Two NOM children ( 16.7 % ) required initial appendectomy . One patient developed recurrent appendicitis requiring appendectomy 7 months post-discharge . Four other NOM patients returned with symptoms but did not require admission or surgery . Two OM patients ( 8.3 % ) had hospital visits and admissions related to surgical site infections . Mean length of stay ( LOS ) for the first visit was 1.5 days ( SD=1.0d ) ( NOM ) vs. 1.3 days ( SD=0.5d ) ( OM ) ( p=0.61 ) . Including first and subsequent admissions , mean LOS was 1.8 days ( SD=1.1d ) ( NOM ) vs. 1.7 days ( SD=1.5d ) ( OM ) ( p=0.97 ) . CONCLUSION Early acute appendicitis in appropriately selected children can be successfully treated non-operatively . R and omized trials with longer follow-up are required",
"Uncomplicated appendicitis may resolve spontaneously or require treatment with antibiotics or appendicectomy . The aim of this r and omized trial was to compare the outcome of a non‐antibiotic management strategy with that of antibiotic therapy in uncomplicated appendicitis",
"BACKGROUND The purpose of this study was to investigate the feasibility of nonoperative management of acute appendicitis in children with an appendicolith identified on preoperative imaging . STUDY DESIGN We performed a prospect i ve nonr and omized trial of nonoperative management of uncomplicated acute appendicitis with an appendicolith in children aged 7 to 17years . The primary outcome was the failure rate of nonoperative management , defined as having undergone an appendectomy . Early termination was set to occur if the lower limit of the 95 % confidence interval of the failure rate was greater than 20 % at 30days or 30 % at 1year . RESULTS Recruitment for this study was halted after enrollment of 14 patients ( N=5 nonoperative ; N=9 surgery ) . The failure rate of nonoperative management was 60 % ( 3/5 ) at a median follow-up of 4.7months ( IQR 1.0 - 7.6 ) with a 95 % CI of 23%-88 % . None of the three patients that failed nonoperative management had complicated appendicitis at the time of appendectomy , while six out of nine patients who chose surgery had complicated appendicitis ( 0/3 vs. 6/9 , p=0.18 ) . The trial was stopped for concerns over patient safety . CONCLUSIONS Nonoperative management of acute appendicitis with an appendicolith in children result ed in an unacceptably high failure rate",
"OBJECTIVE The aim of the present study is to determine the feasibility and safety of antibiotics for uncomplicated simple appendicitis in pregnancy . METHOD We conducted a 6-year prospect i ve observational study on 20 pregnant women in whom uncomplicated simple appendicitis ( appendiceal diameter ≤11 mm and with no signs of appendicoliths , perforation , or abscess ) was radiologically verified and managed with a 4-day course of antibiotics . Treatment failure rate , defined as the need for an appendectomy during hospitalization and recurrence in the follow-up period ( median 25 months ) , and maternal or fetal complications during the pregnancy were evaluated . RESULTS Mean age of patients was 33.4 years , and gestational age was 17.8 weeks . Three patients failed to respond to antibiotic therapy during hospitalization and underwent subsequent appendectomy ( 2 suppurative and 1 perforated appendicitis ) . There was 1 wound infection postoperatively . During follow-up , 2 patients during their ongoing pregnancy experienced recurrence at 3 and 6 months post-treatment , and a new course of antibiotics was determined . Patients also experienced recurrence at 8 and 10 months post-treatment and underwent appendectomy . Treatment failure occurred in 5 patients ( 25 % ) with no fetal complications during the pregnancy . CONCLUSIONS Antibiotic therapy for uncomplicated appendicitis in pregnancy may be a feasible treatment option without severe maternal and fetal complications ",
"BACKGROUND Because of concerns about masking important physical findings , there is controversy surrounding whether it is safe to provide analgesia to patients with undifferentiated abdominal pain . The purpose of this study was to address the effects of analgesia on the physical examination and diagnostic accuracy for patients with abdominal pain . STUDY DESIGN The study was a prospect i ve , double-blind clinical trial in which adult Emergency Department ( ED ) patients with undifferentiated abdominal pain were r and omized to receive placebo ( control group , n = 36 ) or morphine sulphate ( MS group , n = 38 ) . Diagnostic and physical examination assessment s were recorded before and after a 60-minute period during which study medication was titrated . Diagnostic accuracy and physical examination changes were compared between groups using univariate statistical analyses . RESULTS There were no differences between control and MS groups with respect to changes in physical or diagnostic accuracy . The overall likelihood of change in severity of tenderness was similar in MS ( 37.7 % ) as compared with control ( 35.3 % ) patients ( risk ratio [ RR ] 1.07 , 95 % confidence interval [ CI ] 0.64 - 1.78 ) . MS patients were no more likely than controls to have a change in pain location ( 34.0 % versus 41.2 % , RR 0.82 , 95 % CI 0.50 - 1.36 ) . Diagnostic accuracy did not differ between MS and control groups ( 64.2 % versus 66.7 % , RR 0.96 , 95 % CI 0.73 - 1.27 ) . There were no differences between groups with respect to likelihood of any change occurring in the diagnostic list ( 37.7 % versus 31.4 % , RR 1.20 , 95 % CI 0.71 - 2.05 ) . Correlation with clinical course and final diagnosis revealed no instance of masking of physical examination findings . CONCLUSIONS Results of this study support a practice of early provision of analgesia to patients with undifferentiated abdominal pain",
"BACKGROUND One of the major challenges faced by the treatment planning teams is how to manage postoperative pain . Previous studies agreed upon the effects of preoperative administration of nonsteroidal anti-inflammatory drugs on postoperative pain , but all have focused on patients with surgical noninflammatory diseases ( ie , inguinal hernia or breast biopsy ) . The aim of this study was to evaluate the effects of rectal indomethacin on reducing postoperative pain in patients with acute appendicitis . METHODS It is a simple r and omized , clinical trial including 200 patients with acute appendicitis who were divided into two groups ( A1 and A2 ) . The case group ( A1 ) received 100 mg rectal indomethacin during 2 hours before the operation . Pain intensity was assessed in all patients using a visual analog scale ( VAS ) . Similarly , total dosage of meperidine analgesic medication and postoperative time to use of rescue analgesia were evaluated . RESULTS Patients who received preoperative rectal indomethacin ( A1 ) showed a significant reduction in the VAS score . Also , a reduction in total dose of meperidine and longer time to use of rescue analgesic medication were observed in A1 group . CONCLUSION Preoperative administration of rectal indomethacin in acute appendicitis reduces postoperative pain",
"BACKGROUND In this prospect i ve study , operative and nonoperative management of acute appendicitis were evaluated regarding their safety and cost effectiveness . METHODS Two hundred ninety patients presenting to our Emergency Department between March 2005 and March 2006 with acute appendicitis were included in this prospect i ve study . Nonoperative medical therapy was performed in 107 patients ( Group 1 ) , and 183 patients were treated surgically ( Group 2 ) . Routine follow-up controls were done on the 10th day , at the 3rd and 6th months and at the first year after discharge in Group 1 . Both groups were compared regarding age , gender , mean hospital stay , modified Alvarado score , morbidity , mortality , and cost effectiveness . RESULTS The male/female ratio of Groups 1 and 2 were 65/42 ( mean age : 30.98+/-1.30 ) and 125/58 ( mean age : 26.25+/-0.79 ) , respectively . In Group 1 , 19 patients were operated . Operation indications were resistance to therapy , patient 's request , and operation in another hospital . Although the mean hospital stay of Group 1 was statistically significantly longer than Group 2 , the mean cost of the therapy was $ 559 in Group 2 and $ 433 in Group 1 . Morbidity rates were similar , with no mortality in either group . CONCLUSION With its high success rate and cost effectiveness , medical treatment seems to be a good alternative to the gold st and ard therapy of surgery in management of acute appendicitis",
"PURPOSE To evaluate whether antibiotics without surgery is sufficient treatment for children with clinical ly and ultrasonographically suspected acute appendicitis ( AA ) . METHOD Children with clinical , laboratory and radiological findings suspicious for AA were evaluated prospect ively . Patients with mild clinical signs , without peritonitis were considered for IV followed by oral antibiotics without surgery . RESULTS From 1 November 2013 through 30 June 2014 , 45 children were diagnosed with early , acute appendicitis . Ages ranged from 4 to 15 years ( mean 9.3 ) and 32 ( 75 % ) were boys . All had routine , clinical laboratory and ultrasound workup . Forty-two improved with antibiotic treatment and were discharged home within 3 - 5 days , without surgery . Three of them were operated on within 24 hours , another two underwent appendectomy for recurrent appendicitis : one at 2 weeks and the other 2 months after discharge . There was no more recurrent appendicitis in 6 - 14-month follow-up . CONCLUSION Our series of patients with AA treated with antibiotics only are a product of the observation that some children improve with antibiotics alone at a stage in which surgery is still debatable . These results ( 89 % success rate ) support the conservative approach in cases of early appendicitis , without increased morbidity in failed cases",
"BACKGROUND Initial antibiotic treatment for acute appendicitis has been shown to be safe in adults ; so far , not much is known about the safety and efficacy of this treatment in children . The aims of this study were to investigate the feasibility of a r and omized controlled trial ( RCT ) evaluating initial antibiotic treatment for acute appendectomy in children with acute simple appendicitis and to evaluate the safety of this approach . METHODS In a multicenter , prospect i ve cohort study patients aged 7 - 17 years with a radiologically confirmed simple appendicitis were eligible . Intravenous antibiotics ( amoxicillin/clavulanic acid 250/25 mg/kg 4 times daily ; maximum 6,000/600 mg/d and gentamicin 7 mg/kg once daily ) were administered for 48 - 72 hours . Clinical reevaluation every 6 hours , daily blood sample s , and ultrasound follow-up after 48 hours was performed . In case of improvement after 48 hours , oral antibiotics were given for a total of 7 days . At any time , in case of clinical deterioration or non-improvement after 72 hours , an appendectomy could be performed . Follow-up continued until 8 weeks after discharge . Adverse events were defined as major complications of antibiotic treatment , such as allergic reactions , perforated appendicitis , and recurrent appendicitis . RESULTS Of 44 eligible patients , 25 participated ( inclusion rate , 57 % ; 95 % CI , 42%-70 % ) . Delayed appendectomy was performed in 2 , and the other 23 were without symptoms at the 8 weeks follow-up . Minor complications occurred in three patients . None of the patients suffered from an adverse event or a recurrent appendicitis . CONCLUSION Our study shows that an RCT comparing initial antibiotic treatment strategy with urgent appendectomy is feasible in children ; the intervention seems to be safe",
"Importance Short-term results support antibiotics as an alternative to surgery for treating uncomplicated acute appendicitis , but long-term outcomes are not known . Objective To determine the late recurrence rate of appendicitis after antibiotic therapy for the treatment of uncomplicated acute appendicitis . Design , Setting , and Participants Five-year observational follow-up of patients in the Appendicitis Acuta ( APPAC ) multicenter r and omized clinical trial comparing appendectomy with antibiotic therapy , in which 530 patients aged 18 to 60 years with computed tomography – confirmed uncomplicated acute appendicitis were r and omized to undergo an appendectomy ( n = 273 ) or receive antibiotic therapy ( n = 257 ) . The initial trial was conducted from November 2009 to June 2012 in Finl and ; last follow-up was September 6 , 2017 . This current analysis focused on assessing the 5-year outcomes for the group of patients treated with antibiotics alone . Interventions Open appendectomy vs antibiotic therapy with intravenous ertapenem for 3 days followed by 7 days of oral levofloxacin and metronidazole . Main Outcomes and Measures In this analysis , prespecified secondary end points reported at 5-year follow-up included late ( after 1 year ) appendicitis recurrence after antibiotic treatment , complications , length of hospital stay , and sick leave . Results Of the 530 patients ( 201 women ; 329 men ) enrolled in the trial , 273 patients ( median age , 35 years [ IQR , 27 - 46 ] ) were r and omized to undergo appendectomy , and 257 ( median age , 33 years , [ IQR , 26 - 47 ] ) were r and omized to receive antibiotic therapy . In addition to 70 patients who initially received antibiotics but underwent appendectomy within the first year ( 27.3 % [ 95 % CI , 22.0%-33.2 % ] ; 70/256 ) , 30 additional antibiotic-treated patients ( 16.1 % [ 95 % CI , 11.2%-22.2 % ] ; 30/186 ) underwent appendectomy between 1 and 5 years . The cumulative incidence of appendicitis recurrence was 34.0 % ( 95 % CI , 28.2%-40.1 % ; 87/256 ) at 2 years , 35.2 % ( 95 % CI , 29.3%-41.4 % ; 90/256 ) at 3 years , 37.1 % ( 95 % CI , 31.2%-43.3 % ; 95/256 ) at 4 years , and 39.1 % ( 95 % CI , 33.1%-45.3 % ; 100/256 ) at 5 years . Of the 85 patients in the antibiotic group who subsequently underwent appendectomy for recurrent appendicitis , 76 had uncomplicated appendicitis , 2 had complicated appendicitis , and 7 did not have appendicitis . At 5 years , the overall complication rate ( surgical site infections , incisional hernias , abdominal pain , and obstructive symptoms ) was 24.4 % ( 95 % CI , 19.2%-30.3 % ) ( n = 60/246 ) in the appendectomy group and 6.5 % ( 95 % CI , 3.8%-10.4 % ) ( n = 16/246 ) in antibiotic group ( P length of hospital stay , but there was a significant difference in sick leave ( 11 days more for the appendectomy group ) . Conclusions and Relevance Among patients who were initially treated with antibiotics for uncomplicated acute appendicitis , the likelihood of late recurrence within 5 years was 39.1 % . This long-term follow-up supports the feasibility of antibiotic treatment alone as an alternative to surgery for uncomplicated acute appendicitis . Trial Registration Clinical Trials.gov Identifier :",
"PURPOSE Although many patients receive antibiotic therapy for uncomplicated appendicitis , the relatively high treatment failure and recurrence rates are problematic . We assumed that patients with appendicitis and appendiceal diameters ≤ 10 mm , have better outcomes . The purpose of this prospect i ve non-r and omized study was to assess the outcomes of antibiotic therapy in patients with uncomplicated appendicitis and appendiceal diameters ≤ 10 mm . METHODS Over 2 years , we enrolled 119 patients who initially received antibiotic therapy . The failure of antibiotic therapy was defined as the need for appendectomy and true appendicitis . Peritonitis was defined as either complicated appendicitis or intra-abdominal abscess postoperatively . We evaluated the rates of treatment failure , peritonitis , and recurrence . RESULTS Nine patients ( 7.6 % ) failed to respond to initial antibiotic therapy , and 6 had true appendicitis after subsequent surgery . Two patients had complicated appendicitis ( peritonitis ) , but no patient displayed intra-abdominal abscess postoperatively . During a median follow-up period months of 14 months , 14 patients ( 12.7 % ) experienced recurrence . CONCLUSIONS Antibiotic therapy without surgery may be a safe treatment for uncomplicated appendicitis in select patients with appendiceal diameters ≤ 10 mm"
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IMPORTANCE Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms , but their efficacy for specific indications is not clear . OBJECTIVE To conduct a systematic review of the benefits and adverse events ( AEs ) of cannabinoids . DATA SOURCES Twenty-eight data bases from inception to April 2015 . STUDY SELECTION R and omized clinical trials of cannabinoids for the following indications : nausea and vomiting due to chemotherapy , appetite stimulation in HIV/AIDS , chronic pain , spasticity due to multiple sclerosis or paraplegia , depression , anxiety disorder , sleep disorder , psychosis , glaucoma , or Tourette syndrome . DATA EXTRACTION AND SYNTHESIS Study quality was assessed using the Cochrane risk of bias tool . All review stages were conducted independently by 2 review ers . Where possible , data were pooled using r and om-effects meta- analysis . MAIN OUTCOMES AND MEASURES Patient-relevant/disease-specific outcomes , activities of daily living , quality of life , global impression of change , and AEs . RESULTS A total of 79 trials ( 6462 participants ) were included ; 4 were judged at low risk of bias . Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials . Compared with placebo , cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response ( 47 % vs 20 % ; odds ratio [ OR ] , 3.82 [ 95 % CI , 1.55 - 9.42 ] ; 3 trials ) , reduction in pain ( 37 % vs 31 % ; OR , 1.41 [ 95 % CI , 0.99 - 2.00 ] ; 8 trials ) , a greater average reduction in numerical rating scale pain assessment ( on a 0 - 10-point scale ; weighted mean difference [ WMD ] , -0.46 [ 95 % CI , -0.80 to -0.11 ] ; 6 trials ) , and average reduction in the Ashworth spasticity scale ( WMD , -0.36 [ 95 % CI , -0.69 to -0.05 ] ; 7 trials ) . There was an increased risk of short-term AEs with cannabinoids , including serious AEs . Common AEs included dizziness , dry mouth , nausea , fatigue , somnolence , euphoria , vomiting , disorientation , drowsiness , confusion , loss of balance , and hallucination . CONCLUSIONS AND RELEVANCE There was moderate- quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity . There was low- quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy , weight gain in HIV infection , sleep disorders , and Tourette syndrome . Cannabinoids were associated with an increased risk of short-term AEs
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"Objective : To test whether cannabinoids reduce urge incontinence episodes without affecting voiding in patients with multiple sclerosis . This was part of the multicentre trial of the Cannabinoids in Multiple Sclerosis ( CAMS ) study . Subjects and methods : The CAMS study r and omised 630 patients to receive oral administration of cannabis extract , Δ9-tetrahydrocannabinol ( THC ) or matched placebo . For this sub study subjects completed incontinence diaries . Results : All three groups showed a significant reduction , p in adjusted episode rate ( i.e. correcting for baseline imbalance ) from baseline to the end of treatment : cannabis extract , 38 % ; THC , 33 % ; and placebo , 18 % . Both active treatments showed significant effects over placebo ( cannabis extract , p=0.005 ; THC , p=0.039 ) . Conclusion : The findings are suggestive of a clinical effect of cannabis on incontinence episodes in patients with MS . This is in contrast to the negative finding of the CAMS study , where no difference was seen in the primary outcome of spasticity ",
"Summary A prospect i ve r and omized double-blind trial comparing the butyrophenone analogue domperidone ( D ) and the synthetic cannabinoid nabilone ( N ) in the treatment of cytotoxic-induced emesis was conducted in 38 patients receiving highly emetogenic chemotherapy regimens ( 70 % containing cisplatin ) . Patients received 20 mg D or 1 mg N the night before chemotherapy and 8-hourly on each chemotherapy day for two consecutive cycles of treatment . Three of 19 patients r and omized to N completed only one cycle because of disease progression ( 2 ) or subjectively adverse effects ( 1 ) . Four of 19 patients completed only one cycle of D because of lack of efficacy ( 3 ) or chemotherapy toxicity ( 1 ) . In all , 32 cycles of N and 33 cycles of D were evaluable for efficacy . The mean number of vomiting episodes in cycle 1 was 4.76 for N and 12.95 for D ( P0.10 ) , and for cycles 1 and 2 combined , 4.53 for N and 10.81 for D ( P Nausea and food intake scores did not differ significantly , although there was a trend towards less nausea and an increased food intake with N. Subjectively adverse effects were more frequent with N and included drowsiness , dizziness , dry mouth , and postural hypotension . N is superior to D for the control of cytotoxic-induced emesis",
"A preliminary trial of oral delta-9-tetrahydrocannabinol ( THC ) demonstrated an analgesic effect of the drug in patients experiencing cancer pain . Placebo and 5 , 10 , 15 , and 20 mg THC were administered double blind to ten patients . Pain relief significantly superior to placebo was demonstrated at high dose levels ( 15 and 20 mg ) . At these levels , substantial sedation and mental clouding were reported",
"UNLABELLED We assessed the efficacy of dronabinol ( Marinol capsules ; Solvay Pharmaceuticals , Brussels , Belgium ) , a synthetic Delta(9)-THC ( tetrahydrocannabinol ) , in 30 patients taking opioids for chronic pain to determine its potential analgesic effects as an adjuvant treatment . Phase I of this 2-phase study was a r and omized , single-dose , double-blinded , placebo-controlled , crossover trial in which subjects were r and omly administered either 10 mg or 20 mg of dronabinol or identical placebo capsules over the course of three , 8-hour visits . Baseline self-report measures , hourly ratings of pain intensity , pain relief , pain bothersomeness , treatment satisfaction , mood , side effects , and blood serum levels were obtained . Phase II was an extended open-label titrated trial of dronabinol as add-on medication to patients on stable doses of opioids . Results of the Phase I study showed that patients who received dronabinol experienced decreased pain intensity and increased satisfaction compared with placebo . No differences in benefit were found between the 20 mg and 10 mg doses . In the Phase II trial , titrated dronabinol contributed to significant relief of pain , reduced pain bothersomeness , and increased satisfaction compared with baseline . The incidence of side effects was dose-related . Overall , the use of dronabinol was found to result in additional analgesia among patients taking opioids for chronic noncancer pain . PERSPECTIVE This study examines the effect of adding a cannabinoid to the regimen of patients with chronic pain who report significant pain despite taking stable doses of opioids . The results of our preliminary study suggest that dronabinol , a synthetic THC , may have an additive effect on pain relief",
"Abstract Objective To evaluate the effect of the oral synthetic δ-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis . Design R and omised double blind placebo controlled crossovertrial . Setting Outpatient clinic , University Hospital of Aarhus , Denmark . Participants 24 patients aged between 23 and 55 years with multiple sclerosis and central pain . Intervention Orally administered dronabinol at a maximum doseof 10 mg daily or corresponding placebo for three weeks ( 15 - 21days ) , separated by a three week washout period . Main outcome measure Median spontaneous pain intensity ( numericalrating scale ) in the last week of treatment . Results Median spontaneous pain intensity was significantlylower during dronabinol treatment than during placebo treatment(4.0 ( 25th to 75th centiles 2.3 to 6.0 ) v 5.0 ( 4.0 to 6.4),P = 0.02 ) , and median pain relief score ( numerical rating scale)was higher ( 3.0 ( 0 to 6.7 ) v > 0 ( 0 to 2.3 ) , P = 0.035 ) . Thenumber needed to treat for 50 % pain relief was 3.5 ( 95 % confidenceinterval 1.9 to 24.8 ) . On the SF-36 quality of life scale , thetwo items bodily pain and mental health indicated benefits fromactive treatment compared with placebo . The number of patients with adverse events was higher during active treatment , especiallyin the first week of treatment . The functional ability of themultiple sclerosis patients did not change . Conclusions Dronabinol has a modest but clinical ly relevantanalgesic effect on central pain in patients with multiple sclerosis . Adverse events , including dizziness , were more frequent withdronabinol than with placebo during the first week of treatment",
"This study compared the efficacy of a tetrahydrocannabinol : cannabidiol ( THC : CBD ) extract , a nonopioid analgesic endocannabinoid system modulator , and a THC extract , with placebo , in relieving pain in patients with advanced cancer . In total , 177 patients with cancer pain , who experienced inadequate analgesia despite chronic opioid dosing , entered a two-week , multicenter , double-blind , r and omized , placebo-controlled , parallel-group trial . Patients were r and omized to THC : CBD extract ( n = 60 ) , THC extract ( n = 58 ) , or placebo ( n = 59 ) . The primary analysis of change from baseline in mean pain Numerical Rating Scale ( NRS ) score was statistically significantly in favor of THC : CBD compared with placebo ( improvement of -1.37 vs. -0.69 ) , whereas the THC group showed a nonsignificant change ( -1.01 vs. -0.69 ) . Twice as many patients taking THC : CBD showed a reduction of more than 30 % from baseline pain NRS score when compared with placebo ( 23 [ 43 % ] vs. 12 [ 21 % ] ) . The associated odds ratio was statistically significant , whereas the number of THC group responders was similar to placebo ( 12 [ 23 % ] vs. 12 [ 21 % ] ) and did not reach statistical significance . There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups . No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment . However , the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Question naire showed a worsening in nausea and vomiting with THC : CBD compared with placebo ( P = 0.02 ) , whereas THC had no difference ( P = 1.0 ) . Most drug-related adverse events were mild/moderate in severity . This study shows that THC : CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids",
"A prospect i ve r and omised double blind crossover trial was conducted comparing the new synthetic cannabinoid nabilone with oral domperidone in a group of children receiving repeated identical courses of emetogenic chemotherapy for a variety of malignant diseases . Eighteen of 23 consecutive eligible children , aged 10 months to 17 years , completed the trial . When taking nabilone they experienced significantly fewer vomiting episodes and less nausea , and two thirds expressed a preference for the drug . The most common side effects of treatment with nabilone were somnolence and dizziness , with one patient being disturbed by hallucinations . The results indicate that nabilone is an effective antiemetic for children having chemotherapy , even for young children . It seems to be superior in this respect to domperidone , and although it has a higher incidence of side effects , these are mostly acceptable to patients . It can be recommended as an alternative to conventional antiemetic treatment throughout childhood",
"The objective was to determine whether a cannabis-based medicinal extract ( CBME ) benefits a range of symptoms due to multiple sclerosis ( MS ) . A parallel group , double-blind , r and omized , placebo-controlled study was undertaken in three centres , recruiting 160 out patients with MS experiencing significant problems from at least one of the following : spasticity , spasms , bladder problems , tremor or pain . The interventions were oromucosal sprays of matched placebo , or whole plant CBME containing equal amounts of delta-9- tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) at a dose of 2.5- 120 mg of each daily , in divided doses . The primary outcome measure was a Visual Analogue Scale ( VAS ) score for each patient ’s most troublesome symptom . Additional measures included VAS scores of other symptoms , and measures of disability , cognition , mood , sleep and fatigue . Following CBME the primary symptom score reduced from mean ( SE ) 74.36 ( 11.1 ) to 48.89 ( 22.0 ) following CBME and from 74.31 ( 12.5 ) to 54.79 ( 26.3 ) following placebo [ ns ] . Spasticity VAS scores were significantly reduced by CBME ( Sativex ) in comparison with placebo ( P- 0.001 ) . There were no significant adverse effects on cognition or mood and intoxication was generally mild",
"Objective : To test the effectiveness and long term safety of cannabinoids in multiple sclerosis ( MS ) , in a follow up to the main Cannabinoids in Multiple Sclerosis ( CAMS ) study . Methods : In total , 630 patients with stable MS with muscle spasticity from 33 UK centres were r and omised to receive oral Δ9-tetrahydrocannabinol ( Δ9-THC ) , cannabis extract , or placebo in the main 15 week CAMS study . The primary outcome was change in the Ashworth spasticity scale . Secondary outcomes were the Rivermead Mobility Index , timed 10 metre walk , UK Neurological Disability Score , postal Barthel Index , General Health Question naire-30 , and a series of nine category rating scales . Following the main study , patients were invited to continue medication , double blinded , for up to12 months in the follow up study reported here . Results : Intention to treat analysis of data from the 80 % of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months ( Δ9-THC mean reduction 1·82 ( n = 154 , 95 % confidence interval ( CI ) 0.53 to 3.12 ) , cannabis extract 0.10 ( n = 172 , 95 % CI −0.99 to 1.19 ) , placebo −0.23 ( n = 176 , 95 % CI −1.41 to 0.94 ) ; p = 0.04 unadjusted for ambulatory status and centre , p = 0.01 adjusted ) . There was suggestive evidence for treatment effects of Δ9-THC on some aspects of disability . There were no major safety concerns . Overall , patients felt that these drugs were helpful in treating their disease . Conclusions : These data provide limited evidence for a longer term treatment effect of cannabinoids . A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS",
"Cannabidiol is a component of marijuana that does not activate cannabinoid receptors , but moderately inhibits the degradation of the endocannabinoid an and amide . We previously reported that an elevation of an and amide levels in cerebrospinal fluid inversely correlated to psychotic symptoms . Furthermore , enhanced an and amide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition . In our translational approach , we performed a double-blind , r and omized clinical trial of cannabidiol vs amisulpride , a potent antipsychotic , in acute schizophrenia to evaluate the clinical relevance of our initial findings . Either treatment was safe and led to significant clinical improvement , but cannabidiol displayed a markedly superior side-effect profile . Moreover , cannabidiol treatment was accompanied by a significant increase in serum an and amide levels , which was significantly associated with clinical improvement . The results suggest that inhibition of an and amide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia",
"Background : Central pain in multiple sclerosis ( MS ) is common and often refractory to treatment . Methods : We conducted a single-center , 5-week ( 1-week run-in , 4-week treatment ) , r and omized , double-blind , placebo-controlled , parallel-group trial in 66 patients with MS and central pain states ( 59 dysesthetic , seven painful spasms ) of a whole-plant cannabis-based medicine ( CBM ) , containing delta-9-tetrahydrocannabinol : cannabidiol ( THC : CBD ) delivered via an oromucosal spray , as adjunctive analgesic treatment . Each spray delivered 2.7 mg of THC and 2.5 of CBD , and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours . Results : Sixty-four patients ( 97 % ) completed the trial , 34 received CBM . In week 4 , the mean number of daily sprays taken of CBM ( n = 32 ) was 9.6 ( range 2 to 25 , SD = 6.0 ) and of placebo ( n = 31 ) was 19.1 ( range 1 to 47 , SD = 12.9 ) . Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale . CBM was superior to placebo in reducing the mean intensity of pain ( CBM mean change −2.7 , 95 % CI : −3.4 to −2.0 , placebo –1.4 95 % CI : −2.0 to −0.8 , comparison between groups , p = 0.005 ) and sleep disturbance ( CBM mean change –2.5 , 95 % CI : −3.4 to −1.7 , placebo –0.8 , 95 % CI : −1.5 to −0.1 , comparison between groups , p = 0.003 ) . CBM was generally well tolerated , although more patients on CBM than placebo reported dizziness , dry mouth , and somnolence . Cognitive side effects were limited to long-term memory storage . Conclusions : Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated",
"Previous studies have suggested that marijuana ( cannabis sativa ) and delta-9-tetrahydrocannabinol ( delta9-THC ) , the major psychoactive ingredient of marijuana , are effective in the therapy of tics and associated behavioral disorders in Tourette Syndrome ( TS ) . Because there is also evidence that cannabis sativa may cause cognitive impairment in healthy users , we performed a r and omized double-blind placebo-controlled crossover trial for delta9-THC in 12 adult TS patients to investigate whether treatment of TS with a single dose of delta9-THC at 5.0 to 10.0 mg causes significant side effects on neuropsychological performance . Using a variety of neuropsychological tests , we found no significant differences after treatment with delta9-THC compared to placebo treatment in verbal and visual memory , reaction time , intelligence , sustained attention , divided attention , vigilance , or mood . Only when using the Symptom Checklist 90-R ( SCL-90-R ) did our data provide evidence for a deterioration of obsessive-compulsive behavior ( OCB ) and a trend towards an increase in phobic anxiety . However , these results should be interpreted with caution as SCL-90-R has known limitations on measuring OCB . We suggest that the increase in phobic anxiety is mainly due to the fact that a single-dose treatment rules out the possibility of administering the dosage slowly . In contrast to results obtained from healthy marijuana users , a single-dose treatment with delta9-THC in patients suffering from TS does not cause cognitive impairment . We therefore suggest that further investigations should concentrate on the effects of a longer-term therapy of TS with delta9-THC",
"Objective : Cannabis may alleviate some symptoms associated with multiple sclerosis ( MS ) . This study investigated the effect of an orally administered st and ardized Cannabis sativa plant extract in MS patients with poorly controlled spasticity . Methods : During their inpatient rehabilitation programme , 57 patients were enrolled in a prospect i ve , r and omized , double-blind , placebo-controlled crossover study of cannabis-extract capsules st and ardized to 2.5 mg tetrahydrocannabinol ( THC ) and 0.9 mg cannabidiol ( CBD ) each . Patients in group A started with a drug escalation phase from 15 to maximally 30 mg THC by 5 mg per day if well tolerated , being on active medication for 14 days before starting placebo . Patients in group B started with placebo for seven days , crossed to the active period ( 14 days ) and closed with a three-day placebo period ( active drug dose escalation and placebo sham escalation as in group A ) . Measures used included daily self-report of spasm frequency and symptoms , Ashworth Scale , Rivermead Mobility Index , 10-m timed walk , nine-hole peg test , paced auditory serial addition test ( PASAT ) , and the digit span test . Results : In the 50 patients included into the intention-to-treat analysis set , there were no statistically significant differences associated with active treatment compared to placebo , but trends in favour of active treatment were seen for spasm frequency , mobility and getting to sleep . In the 37 patients ( per- protocol set ) who received at least 90 % of their prescribed dose , improvements in spasm frequency ( P- 0.013 ) and mobility after excluding a patient who fell and stopped walking were seen ( P- 0.01 ) . Minor adverse events were slightly more frequent and severe during active treatment , and toxicity symptoms , which were generally mild , were more pronounced in the active phase . Conclusion : A st and ardized Cannabis sativa plant extract might lower spasm frequency and increase mobility with tolerable side effects in MS patients with persistent spasticity not responding to other drugs",
"Objective : To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model . Methods : Prospect i ve r and omized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy . Patients were r and omly assigned to smoke either cannabis ( 3.56 % tetrahydrocannabinol ) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days . Primary outcome measures included ratings of chronic pain and the percentage achieving > 30 % reduction in pain intensity . Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model . Results : Fifty patients completed the entire trial . Smoked cannabis reduced daily pain by 34 % ( median reduction ; IQR = −71 , −16 ) vs 17 % ( IQR = −29 , 8) with placebo ( p = 0.03 ) . Greater than 30 % reduction in pain was reported by 52 % in the cannabis group and by 24 % in the placebo group ( p = 0.04 ) . The first cannabis cigarette reduced chronic pain by a median of 72 % vs 15 % with placebo ( p 0.001 ) . Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli ( p ≤ 0.05 ) but appeared to have little effect on the painfulness of noxious heat stimulation . No serious adverse events were reported . Conclusion : Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy . The findings are comparable to oral drugs used for chronic neuropathic pain",
"Background : Spasticity is a common and poorly controlled symptom of multiple sclerosis . Our objective was to determine the short-term effect of smoked cannabis on this symptom . Methods : We conducted a placebo-controlled , crossover trial involving adult patients with multiple sclerosis and spasticity . We recruited participants from a regional clinic or by referral from specialists . We r and omly assigned participants to either the intervention ( smoked cannabis , once daily for three days ) or control ( identical placebo cigarettes , once daily for three days ) . Each participant was assessed daily before and after treatment . After a washout interval of 11 days , participants crossed over to the opposite group . Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale . Our secondary outcomes included patients ’ perception of pain ( as measured using a visual analogue scale ) , a timed walk and changes in cognitive function ( as measured by patient performance on the Paced Auditory Serial Addition Test ) , in addition to ratings of fatigue . Results : Thirty-seven participants were r and omized at the start of the study , 30 of whom completed the trial . Treatment with smoked cannabis result ed in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo ( p reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo ( p = 0.008 ) . Scores for the timed walk did not differ significantly between treatment and placebo ( p = 0.2 ) . Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo ( p = 0.003 ) . No serious adverse events occurred during the trial . Interpretation : Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity . Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact",
"Purpose The purpose of this study was to assess the effect on intraocular pressure ( IOP ) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol ( Δ-9-THC ) and cannabidiol ( CBD ) . Patients and Methods A r and omized , double-masked , placebo-controlled , 4 way crossover study was conducted at a single center , using cannabis-based medicinal extract of Δ-9-THC and CBD . Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg Δ-9-THC , 20 mg CBD , 40 mg CBD , or placebo . Main outcome measure was IOP . Secondary outcomes included visual acuity , vital signs , and psychotropic effects . Results Two hours after sublingual administration of 5 mg Δ-9-THC , the IOP was significantly lower than after placebo ( 23.5 mm Hg vs. 27.3 mm Hg , P=0.026 ) . The IOP returned to baseline level after the 4-hour IOP measurement . CBD administration did not reduce the IOP at any time . However , the higher dose of CBD ( 40 mg ) produced a transient elevation of IOP at 4 hours after administration , from 23.2 to 25.9 mm Hg ( P=0.028 ) . Vital signs and visual acuity were not significantly changed . One patient experienced a transient and mild paniclike reaction after Δ-9-THC administration . Conclusions A single 5 mg sublingual dose of Δ-9-THC reduced the IOP temporarily and was well tolerated by most patients . Sublingual administration of 20 mg CBD did not reduce IOP , whereas 40 mg CBD produced a transient increase IOP rise ",
"ABSTRACT Objective : To compare the efficacy and tolerability of dronabinol , ondansetron , or the combination for delayed chemotherapy-induced nausea and vomiting ( CINV ) in a 5-day , double-blind , placebo-controlled study . Research design and methods : Patients receiving moderately to highly emetogenic chemotherapy received dexamethasone ( 20 mg PO ) , ondansetron ( 16 mg IV ) and either placebo or dronabinol ( 2.5 mg ) prechemotherapy on day 1 . Patients r and omized to active treatment ( dronabinol and /or ondansetron ) also received dronabinol ( 2.5 mg ) after chemotherapy on day 1 . On day 2 , fixed doses of placebo , dronabinol ( 10 mg ) , ondansetron ( 16 mg ) , or combination therapy were administered . On days 3–5 , patients received placebo , flexible doses of dronabinol ( 10–20 mg ) , ondansetron ( 8–16 mg ) , or dronabinol and ondansetron ( 10–20 mg dronabinol , 8–16 mg ondansetron ) . Main outcome measures : Total response ( TR = nausea intensity on visual analog scale , no vomiting/retching , no rescue antiemetic ) , nausea ( occurrence and intensity ) and vomiting/retching episodes . Results : Sixty-four patients were r and omized ; 61 analyzed for efficacy . TR was similar with dronabinol ( 54 % ) , ondansetron ( 58 % ) , and combination therapy ( 47 % ) versus placebo ( 20 % ) . Nausea absence was significantly greater in active treatment groups ( dronabinol , 71 % ; ondansetron , 64 % ; combination therapy , 53 % ) versus placebo ( 15 % ; p all ) . Nausea intensity and vomiting/retching were lowest in patients treated with dronabinol . Active treatments were well tolerated . The low number of patients due to slow enrollment limits the interpretation of these data . Conclusions : Dronabinol or ondansetron was similarly effective for the treatment of CINV . Combination therapy with dronabinol and ondansetron was not more effective than either agent alone . Active treatments were well tolerated ",
"Background : Chronic neuropathic pain affects 1%–2 % of the adult population and is often refractory to st and ard pharmacologic treatment . Patients with chronic pain have reported using smoked cannabis to relieve pain , improve sleep and improve mood . Methods : Adults with post-traumatic or postsurgical neuropathic pain were r and omly assigned to receive cannabis at four potencies ( 0 % , 2.5 % , 6 % and 9.4 % tetrahydrocannabinol ) over four 14-day periods in a crossover trial . Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle , followed by a nine-day washout period . Daily average pain intensity was measured using an 11-point numeric rating scale . We recorded effects on mood , sleep and quality of life , as well as adverse events . Results : We recruited 23 participants ( mean age 45.4 [ st and ard deviation 12.3 ] years , 12 women [ 52 % ] ) , of whom 21 completed the trial . The average daily pain intensity , measured on the 11-point numeric rating scale , was lower on the prespecified primary contrast of 9.4 % v. 0 % tetrahydrocannabinol ( 5.4 v. 6.1 , respectively ; difference = 0.7 , 95 % confidence interval [ CI ] 0.02–1.4 ) . Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief . Participants receiving 9.4 % tetrahydrocannabinol reported improved ability to fall asleep ( easier , p = 0.001 ; faster , p drowsy , p = 0.003 ) and improved quality of sleep ( less wakefulness , p = 0.01 ) relative to 0 % tetrahydrocannabinol . We found no differences in mood or quality of life . The most common drug-related adverse events during the period when participants received 9.4 % tetrahydrocannabinol were headache , dry eyes , burning sensation in areas of neuropathic pain , dizziness , numbness and cough . Conclusion : A single inhalation of 25 mg of 9.4 % tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain , improved sleep and was well tolerated . Further long-term safety and efficacy studies are indicated . ( International St and ard R and omised Controlled Trial Register no. IS RCT N68314063",
"Objective Multiple sclerosis ( MS ) is associated with chronic symptoms , including muscle stiffness , spasms , pain and insomnia . Here we report the results of the Multiple Sclerosis and Extract of Cannabis ( MUSEC ) study that aim ed to substantiate the patient based findings of previous studies . Patients and methods Patients with stable MS at 22 UK centres were r and omised to oral cannabis extract ( CE ) ( N=144 ) or placebo ( N=135 ) , stratified by centre , walking ability and use of antispastic medication . This double blind , placebo controlled , phase III study had a screening period , a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase . The primary outcome measure was a category rating scale ( CRS ) measuring patient reported change in muscle stiffness from baseline . Further CRSs assessed body pain , spasms and sleep quality . Three vali date d MS specific patient reported outcome measures assessed aspects of spasticity , physical and psychological impact , and walking ability . Results The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo ( 29.4 % vs 15.7 % ; OR 2.26 ; 95 % CI 1.24 to 4.13 ; p=0.004 , one sided ) . Similar results were found after 4 weeks and 8 weeks , and also for all further CRSs . Results from the MS scales supported these findings . Conclusion The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of muscle stiffness in MS . This was supported by results for secondary efficacy variables . Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids . No new safety concerns were observed . Trial registration number NCT00552604",
"BACKGROUND : Sleep disorders affect many patients with chronic pain conditions . Cannabis has been reported by several patient population s to help sleep . We evaluated the safety and efficacy of nabilone , a synthetic cannabinoid , on sleep disturbance in fibromyalgia ( FM ) , a disease characterized by widespread chronic pain and insomnia . METHODS : We conducted a r and omized , double-blind , active-control , equivalency crossover trial to compare nabilone ( 0.5–1.0 mg before bedtime ) to amitriptyline ( 10–20 mg before bedtime ) in patients with FM with chronic insomnia . Subjects received each drug for 2 wk with a 2-wk washout period . The primary outcome was sleep quality , measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Question naire . Secondary outcomes included pain , mood , quality of life , and adverse events ( AEs ) . RESULTS : Thirty-one subjects were enrolled and 29 completed the trial ( 26 women , mean age 49.5 yr ) . Although sleep was improved by both amitriptyline and nabilone , nabilone was superior to amitriptyline ( Insomnia Severity Index difference = 3.2 ; 95 % confidence interval = 1.2–5.3 ) . Nabilone was marginally better on the restfulness ( Leeds Sleep Evaluation Question naire difference = 0.5 [ 0.0–1.0 ] ) but not on wakefulness ( difference = 0.3 [ −0.2 to 0.8 ] ) . No effects on pain , mood , or quality of life were observed . AEs were mostly mild to moderate and were more frequent with nabilone . The most common AEs for nabilone were dizziness , nausea , and dry mouth . CONCLUSIONS : Nabilone is effective in improving sleep in patients with FM and is well tolerated . Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline . Longer trials are needed to determine the duration of effect and to characterize long-term safety",
"BACKGROUND Multiple sclerosis is associated with muscle stiffness , spasms , pain , and tremor . Much anecdotal evidence suggests that cannabinoids could help these symptoms . Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis . METHODS We did a r and omised , placebo-controlled trial , to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity . 630 participants were treated at 33 UK centres with oral cannabis extract ( n=211 ) , Delta9-tetrahydrocannabinol ( Delta9-THC ; n=206 ) , or placebo ( n=213 ) . Trial duration was 15 weeks . Our primary outcome measure was change in overall spasticity scores , using the Ashworth scale . Analysis was by intention to treat . FINDINGS 611 of 630 patients were followed up for the primary endpoint . We noted no treatment effect of cannabinoids on the primary outcome ( p=0.40 ) . The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 ( 95 % CI -1.04 to 1.67 ) , and for those taking Delta9-THC versus placebo it was 0.94 ( -0.44 to 2.31 ) . There was evidence of a treatment effect on patient-reported spasticity and pain ( p=0.003 ) , with improvement in spasticity reported in 61 % ( n=121 , 95 % CI 54.6 - 68.2 ) , 60 % ( n=108 , 52.5 - 66.8 ) , and 46 % ( n=91 , 39.0 - 52.9 ) of participants on cannabis extract , Delta9-THC , and placebo , respectively . INTERPRETATION Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale . However , though there was a degree of unmasking among the patients in the active treatment groups , objective improvement in mobility and patients ' opinion of an improvement in pain suggest cannabinoids might be clinical ly useful",
"& NA ; The objective was to investigate the effectiveness of cannabis‐based medicines for treatment of chronic pain associated with brachial plexus root avulsion . This condition is an excellent human model of central neuropathic pain as it represents an unusually homogenous group in terms of anatomical location of injury , pain descriptions and patient demographics . Forty‐eight patients with at least one avulsed root and baseline pain score of four or more on an 11‐point ordinate scale participated in a r and omised , double‐blind , placebo‐controlled , three period crossover study . All patients had intractable symptoms regardless of current analgesic therapy . Patients entered a baseline period of 2 weeks , followed by three , 2‐week treatment periods during each of which they received one of three oromucosal spray preparations . These were placebo and two whole plant extracts of Cannabis sativa L. : GW‐1000‐02 ( Sativex ® ) , containing Δ9tetrahydrocannabinol (THC):cannabidiol ( CBD ) in an approximate 1:1 ratio and GW‐2000‐02 , containing primarily THC . The primary outcome measure was the mean pain severity score during the last 7 days of treatment . Secondary outcome measures included pain related quality of life assessment s. The primary outcome measure failed to fall by the two points defined in our hypothesis . However , both this measure and measures of sleep showed statistically significant improvements . The study medications were generally well tolerated with the majority of adverse events , including intoxication type reactions , being mild to moderate in severity and resolving spontaneously . Studies of longer duration in neuropathic pain are required to confirm a clinical ly relevant , improvement in the treatment of this condition",
" Twenty cancer patients who received chemotherapy were entered into a double-blind crossover design antiemetic study comparing 1 mg levonantradol , an investigational synthetic cannabinoid , to 10 mg prochlorperazine . Sixteen patients completed the crossover . For each antiemetic course , four doses of each study medication were given intramuscularly 2 hours before chemotherapy and then 2 , 6 , and 10 hours after chemotherapy administration . There were no statistical differences in patients ' responses to levonantradol and prochlorperazine . The frequency of side effects was greater with levonantradol than with prochlorperazine . The most common side effect of levonantradol were somnolence , dry mouth , dizziness , tachycardia , postural hypotension , and blurred vision , while those for prochlorperazine were somnolence , dry mouth , and tachycardia",
"This study was performed on a representative sample of the Danish population in order to investigate the connection to the use of psychoactive drugs and quality of life ( QOL ) by way of a question naire-based survey . The question naire was mailed in February 1993 to 2,460 persons aged between 18 and 88 , r and omly selected from the CPR ( Danish Central Register ) , and 7,222 persons from the Copenhagen Perinatal Birth Cohort 1959—61.A total of 1,501 persons between the ages 18 and 88 years and 4,626 persons between the ages 31 and 33 years returned the question naire ( response rates of 61.0 % and 64.1 % , respectively ) . Variables investigated in this study were ten different psychotropic drugs and quality of life . Our study showed that over half the Danish population had used illegal psychotropic drugs . The most commonly used was cannabis ( marijuana ) though experience of this drug appeared not to co-vary with QOL to any significant extent . Cocaine , amphetamine , and psilocybin had been used by 1.2 to 3.3 % of the population and this varied with QOL to a clear albeit small extent . LSD has been used by 1.2 % of the population and the users had a QOL score 10 % lower than those who had never used psychotropic drugs . The group with the lowest quality of life was found to be persons who had used heroin , morphine , methadone , and a mixture of alcohol and tranquilizers ( 10—20 % below the group with the highest quality of life )",
"Nabilone , a synthetic cannabinoid , and Prochlorperazine were compared in a double-blind crossover study of 34 patients with lung cancer undergoing a 3-day schedule of chemotherapy with Cyclophosphamide , Adriamycin and Etoposide . Symptom scores were significantly better for patients on nabilone for nausea , retching and vomiting ( P less than 0.05 ) . Fewer subjects vomited with nabilone ( P = 0.05 ) and the number of vomiting episodes was lower ( P less than 0.05 ) ; no patients on nabilone required additional parenteral anti-emetic . More patients preferred nabilone for anti-emetic control ( P less than 0.005 ) . Adverse effects common with nabilone were drowsiness ( 57 % ) , postural dizziness ( 35 % ) and lightheadedness ( 18 % ) . Euphoria was seen in 14 % and a \" high \" in 7 % . Erect systolic blood pressure was lower in nabilone patients on Day 1 ( P = 0.05 ) but postural hypotension was a major problem in only 7 % . Nabilone is an effective oral anti-emetic drug for moderately toxic chemotherapy , but the range and unpredictability of its side-effects warrant caution in its use",
"In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias",
"OBJECTIVES To assess the efficacy of a cannabis-based medicine ( CBM ) in the treatment of pain due to rheumatoid arthritis ( RA ) . METHODS We compared a CBM ( Sativex ) with placebo in a r and omized , double-blind , parallel group study in 58 patients over 5 weeks of treatment . The CBM was administered by oromucosal spray in the evening and assessment s were made the following morning . Efficacy outcomes assessed were pain on movement , pain at rest , morning stiffness and sleep quality measured by a numerical rating scale , the Short-Form McGill Pain Question naire ( SF-MPQ ) and the DAS28 measure of disease activity . RESULTS Seventy-five patients were screened and 58 met the eligibility criteria . Thirty-one were r and omized to the CBM and 27 to placebo . Mean ( S.D. ) daily dose achieved in the final treatment week was 5.4 ( 0.84 ) actuations for the CBM and 5.3 ( 1.18 ) for placebo . In comparison with placebo , the CBM produced statistically significant improvements in pain on movement , pain at rest , quality of sleep , DAS28 and the SF-MPQ pain at present component . There was no effect on morning stiffness but baseline scores were low . The large majority of adverse effects were mild or moderate , and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group . CONCLUSIONS In the first ever controlled trial of a CBM in RA , a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment . Whilst the differences are small and variable across the population , they represent benefits of clinical relevance and show the need for more detailed investigation in this indication",
"BACKGROUND Peripheral neuropathic pain ( PNP ) associated with allodynia poses a significant clinical challenge . The efficacy of Δ(9 ) -tetrahydrocannabinol/cannabidiol ( THC/CBD ) oromucosal spray , a novel cannabinoid formulation , was investigated in this 15-week r and omized , double-blind , placebo-controlled parallel group study . METHODS In total , 303 patients with PNP associated with allodynia were screened ; 128 were r and omized to THC/CBD spray and 118 to placebo , in addition to their current analgesic therapy . The co- primary efficacy endpoints were the 30 % responder rate in PNP 0 - 10 numerical rating scale ( NRS ) score and the mean change from baseline to the end of treatment in this score . Various key secondary measures of pain and functioning were also investigated . RESULTS At the 30 % responder level , there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis ( intention-to-treat ) data set [ p = 0.034 ; 95 % confidence interval ( CI ) : 1.05 - 3.70 ] . There was also a reduction in mean PNP 0 - 10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group , but which failed to reach statistical significance . Secondary measures of sleep quality 0 - 10 NRS score ( p = 0.0072 ) and Subject Global Impression of Change ( SGIC ) ( p = 0.023 ) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment . CONCLUSIONS These findings demonstrate that , in a meaningful proportion of otherwise treatment-resistant patients , clinical ly important improvements in pain , sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray . THC/CBD spray was well tolerated and no new safety concerns were identified",
"Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more",
"UNLABELLED A r and omized , double-blinded , placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis . In a crossover design , each participant was exposed to 4 single dosing sessions of placebo or to low ( 1 % tetrahydrocannabinol [ THC ] ) , medium ( 4 % THC ) , or high ( 7 % THC ) doses of cannabis . Baseline spontaneous pain , evoked pain , and cognitive testing were performed . Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective \" highness \" score was measured at 5 , 15 , 30 , 45 , and 60 minutes and then every 30 minutes for an additional 3 hours . Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours . The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models . There was a significant difference in spontaneous pain scores between doses ( P foam brush and von Frey evoked pain ( both P neuropsychological tests ( Paced Auditory Serial Addition Test , Trail Making Test Part B. PERSPECTIVE This small , short-term , placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain . This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain",
"Background : Many cannabinoid medications are approved in North America or in phase III trials , such as dronabinol , nabilone , or nabiximols . Little is known about their subjective psychoactive effects when used for pain management . We hypothesized that when used for pain , dronabinol has psychoactive effects in a dose-response relationship , whose peak effects are comparable with smoking marijuana . Methods : This was a r and omized controlled trial of single dose placebo , 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana . Participants completed the Addiction Research Center Inventory ( ARCI ) hourly for 8 hours during 3 monitored sessions . Comparison sample was the ARCI ratings in participants with no pain ( N=20 ) , monitored every 30 minutes after smoking a 1.99 % THC ( low ) and a 3.51 % ( high strength ) marijuana cigarette . Results : The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo ( P Average daily morphine use , total pain relief ( TOTPAR ) , age , sex , and baseline pain level were not significant covariates . ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes ( P=0.80 , 10 mg = low strength , 20 mg = high strength ) . Conclusions : In pain patients , oral dronabinol has similar psychoactive effects to smoking marijuana . This risk must be considered in any decision to prescribe cannabinoid medications for pain",
"Despite management with opioids and other pain modifying therapies , neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals . Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception . We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV . This was a phase II , double-blind , placebo-controlled , crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy ( DSPN ) . Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes ; they continued on their pre study analgesic regimens throughout the trial . Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting . Treatments were placebo and active cannabis ranging in potency between 1 and 8 % Δ-9-tetrahydrocannabinol , four times daily for 5 consecutive days during each of 2 treatment weeks , separated by a 2-week washout . The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale ( DDS ) from a pretreatment baseline to the end of each treatment week . Secondary measures included assessment s of mood and daily functioning . Of 127 volunteers screened , 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments . Among the completers , pain relief was greater with cannabis than placebo ( median difference in DDS pain intensity change , 3.3 points , effect size=0.60 ; p=0.016 ) . The proportions of subjects achieving at least 30 % pain relief with cannabis versus placebo were 0.46 ( 95%CI 0.28 , 0.65 ) and 0.18 ( 0.03 , 0.32 ) . Mood and daily functioning improved to a similar extent during both treatment periods . Although most side effects were mild and self-limited , two subjects experienced treatment-limiting toxicities . Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN",
"Pre clinical findings on ajulemic acid ( AJA ) showed analgesic and anti-allodynic effects without psychoactive properties making it an appealing substance for the treatment of pain . A recently published r and omized double-blind crossover clinical trial described the pain-reducing effects and side effect profile of AJA on 21 patients with chronic neuropathic pain . In this report from this same sample the effects of AJA on the mechanical hypersensitivity , on pain , and on psychological and physical performance were further characterized . During a 5-week study period , patients were divided into two 7-day treatment groups receiving either AJA or placebo capsules first , respectively . All patients received 40 and 80 mg of AJA or placebo daily in each treatment period . Pain measurements included the determination of mechanical hypersensitivity using the von Frey hair method as well as the visual analog scale ( VAS ) , for which the number needed to treat ( NNT ) was calculated . The side effect profile of the compound was evaluated using psychotropic and physical measurements as well as obtaining reports on possible subjective side effects . The results showed no significant reduction in mechanical hypersensitivity ( p=0.052 ) , although a tendency towards pain reduction could be seen . The VAS score showed significant pain reduction ( p=0.021 ) and NNT values for 30 % pain relief were 2.14 for the first treatment group and 5.29 for the second treatment group . No significant findings were observed regarding psychotropic or physical measurements . Reported subjective side effects were mainly dry mouth , tiredness and dizziness and did not increase with dose elevation . Overall , these study findings indicate that AJA shows pain-reducing effects on patients with chronic neuropathic pain without clinical ly relevant psychotropic or physical side effects",
"Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain . Design R and omised , double blind , crossover trial of 14 weeks ’ duration comparing dihydrocodeine and nabilone . Setting Outpatient units of three hospitals in the United Kingdom . Participants 96 patients with chronic neuropathic pain , aged 23 - 84 years . Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain , as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period . Secondary outcomes were changes in mood , quality of life , sleep , and psychometric function . Side effects were measured by a question naire . Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks . Treatment periods were separated by a 2 week washout period . Results Mean baseline visual analogue score was 69.6 mm ( range 29.4 - 95.2 ) on a 0 - 100 mm scale . 73 patients were included in the available case analysis and 64 patients in the per protocol analysis . The mean score was 6.0 mm longer for nabilone than for dihydrocodeine ( 95 % confidence interval 1.4 to 10.5 ) in the available case analysis and 5.6 mm ( 10.3 to 0.8 ) in the per protocol analysis . Side effects were more frequent with nabilone . Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects , although no major adverse events occurred for either drug . Trial registration Current Controlled Trials IS RCT N15330757",
"UNLABELLED Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge . Nabiximols ( Nabiximols is the U.S. Adopted Name [ USAN ] for Sativex [ GW Pharma Ltd , Wiltshire , U.K. ] , which does not yet have an INN ) , a novel cannabinoid formulation , is undergoing investigation as add-on therapy for this population . In a r and omized , double-blind , placebo-controlled , grade d-dose study , patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose ( 1 - 4 sprays/day ) , medium dose ( 6 - 10 sprays/day ) , or high dose ( 11 - 16 sprays/day ) . Average pain , worst pain and sleep disruption were measured daily during 5 weeks of treatment ; other question naires measured quality of life and mood . A total of 360 patients were r and omized ; 263 completed . There were no baseline differences across groups . The 30 % responder rate primary analysis was not significant for nabiximols versus placebo ( overall P = .59 ) . A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall ( P = .035 ) , and specifically in the low-dose ( P = .008 ) and medium-dose ( P = .039 ) groups . In the low-dose group , results were similar for mean average pain ( P = .006 ) , mean worst pain ( P = .011 ) , and mean sleep disruption ( P = .003 ) . Other question naires showed no significant group differences . Adverse events were dose-related and only the high-dose group compared unfavorably with placebo . This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials . PERSPECTIVE Nabiximols , a novel cannabinoid formulation , may be a useful add-on analgesic for patients with opioid-refractory cancer pain . A r and omized , double-blind , placebo-controlled , grade d-dose study demonstrated efficacy and safety at low and medium doses",
"Generalized Social Anxiety Disorder ( SAD ) is one of the most common anxiety conditions with impairment in social life . Cannabidiol ( CBD ) , one major non-psychotomimetic compound of the cannabis sativa plant , has shown anxiolytic effects both in humans and in animals . This preliminary study aim ed to compare the effects of a simulation public speaking test ( SPST ) on healthy control ( HC ) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo . A total of 24 never-treated patients with SAD were allocated to receive either CBD ( 600 mg ; n=12 ) or placebo ( placebo ; n=12 ) in a double-blind r and omized design 1 h and a half before the test . The same number of HC ( n=12 ) performed the SPST without receiving any medication . Each volunteer participated in only one experimental session in a double-blind procedure . Subjective ratings on the Visual Analogue Mood Scale ( VAMS ) and Negative Self-Statement scale ( SSPS-N ) and physiological measures ( blood pressure , heart rate , and skin conductance ) were measured at six different time points during the SPST . The results were su bmi tted to a repeated- measures analysis of variance . Pretreatment with CBD significantly reduced anxiety , cognitive impairment and discomfort in their speech performance , and significantly decreased alert in their anticipatory speech . The placebo group presented higher anxiety , cognitive impairment , discomfort , and alert levels when compared with the control group as assessed with the VAMS . The SSPS-N scores evidence d significant increases during the testing of placebo group that was almost abolished in the CBD group . No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment , discomfort , and alert factors of VAMS . The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD , result ing in a similar response as the HC",
"Abstract Cannabinoids are known to have analgesic properties . We evaluated the effect of oro‐mucosal sativex , ( THC : CBD ) , an endocannabinoid system modulator , on pain and allodynia , in 125 patients with neuropathic pain of peripheral origin in a five‐week , r and omised , double‐blind , placebo‐controlled , parallel design trial . Patients remained on their existing stable analgesia . A self‐titrating regimen was used to optimise drug administration . Sixty‐three patients were r and omised to receive sativex and 62 placebo . The mean reduction in pain intensity scores ( primary outcome measure ) was greater in patients receiving sativex than placebo ( mean adjusted scores −1.48 points vs. −0.52 points on a 0–10 Numerical Rating Scale ( p = 0.004 ; 95 % CI : −1.59 , −0.32 ) . Improvements in Neuropathic Pain Scale composite score ( p = 0.007 ) , sleep NRS ( p = 0.001 ) , dynamic allodynia ( p = 0.042 ) , punctate allodynia ( p = 0.021 ) , Pain Disability Index ( p = 0.003 ) and Patient ’s Global Impression of Change ( p vs. placebo . Sedative and gastrointestinal side effects were reported more commonly by patients on active medication . Of all participants , 18 % on sativex and 3 % on placebo withdrew during the study . An open‐label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks",
"CONTEXT 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid ( CT-3 ) , a potent analog of THC-11-oic acid , produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids . Therefore , CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain . OBJECTIVE To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans . DESIGN AND SETTING R and omized , placebo-controlled , double-blind crossover trial conducted in Germany from May-September 2002 . PARTICIPANTS Twenty-one patients ( 8 women and 13 men ) aged 29 to 65 years ( mean , 51 years ) who had a clinical presentation and examination consistent with chronic neuropathic pain ( for at least 6 months ) with hyperalgesia ( n = 21 ) and allodynia ( n = 7 ) . INTERVENTIONS Patients were r and omized to two 7-day treatment orders in a crossover design . Two daily doses of CT-3 ( four 10-mg capsules per day ) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days . After a washout and baseline period of 1 week each , patients crossed over to the second 7-day treatment period . MAIN OUTCOME MEASURES Visual analog scale ( VAS ) and verbal rating scale scores for pain ; vital sign , hematologic and blood chemistry , and electrocardiogram measurements ; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale ; and adverse effects . RESULTS The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence ( mean [ SD ] , -11.54 [ 14.16 ] vs 9.86 [ 21.43 ] ; P = .02 ) . Eight hours after intake of the drug , the pain scale differences between groups were less marked . No dose response was observed . Adverse effects , mainly transient dry mouth and tiredness , were reported significantly more often during CT-3 treatment ( mean [ SD ] difference , -0.67 [ 0.50 ] for CT-3-placebo sequence vs 0.10 [ 0.74 ] for placebo-CT-3 sequence ; P = .02 ) . There were no significant differences with respect to vital signs , blood tests , electrocardiogram , Trail-Making Test , and Addiction Research Center Inventory-Marijuana scale . No carryover or period effects were observed except on the Trail-Making Test . CONCLUSIONS In this preliminary study , CT-3 was effective in reducing chronic neuropathic pain compared with placebo . No major adverse effects were observed",
"The antiemetic effect of oral nabilone , a synthetic cannabinoid , given at a dose of 2 mg every 12 hours was compared to oral slow-release capsules of prochlorperazine given at a dose of 10 mg every 12 hours by a double-blind crossover method in 37 patients receiving cancer chemotherapy . Patients received one of the following as the primary emetic stimulus : high-dose cis-dichlorodiammineplatinum(II ) ( DDP ) , low-dose DDP , mechlorethamine , streptozotocin , actinomycin D , or DTIC . Although results varied according to strength of emetic stimulus received , both nabilone and prochlorperazine appeared to produce antiemetic effects . Eighteen of the 37 patients achieved a complete or partial elimination of symptoms : seven with nabilone alone , three with prochlorperazine alone , and eight with each drug . Nabilone appeared to be the more effective antiemetic for patients who received chemotherapy agents other than high dose DDP ; it was equivalent to prochlorperazine for those who did receive high-dose DDP . Side effects from prochlorperazine were limited to mild drowsiness occurring among 35 % of the patients . The side effects from nabilone were drowsiness and dizziness which occurred frequently and were dose-limiting in 25 % of patients",
"Previous studies provide evidence that marijuana ( Cannabis sativa ) and delta-9-tetrahydrocannabinol ( Δ9-THC ) , the major psychoactive ingredient of marijuana , respectively , are effective in the treatment of tics and behavioral problems in Tourette syndrome ( TS ) . It , therefore , has been speculated that the central cannabinoid receptor system might be involved in TS pathology . However , in healthy marijuana users there is an ongoing debate as to whether the use of cannabis causes acute and /or long-term cognitive deficits . In this r and omized double-blind placebo-controlled study , we investigated the effect of a treatment with up to 10 mg Δ9-THC over a 6-week period on neuropsychological performance in 24 patients suffering from TS . During medication and immediately as well as 5–6 weeks after withdrawal of Δ9-THC treatment , no detrimental effect was seen on learning curve , interference , recall and recognition of word lists , immediate visual memory span , and divided attention . Measuring immediate verbal memory span , we even found a trend towards a significant improvement during and after treatment . Results from this study corroborate previous data suggesting that in patients suffering from TS , treatment with Δ9-THC causes neither acute nor long-term cognitive deficits . Larger and longer- duration controlled studies are recommended to provide more information on the adverse effect profile of THC in patients suffering from TS",
"Summary Twenty nonseminomatous testicular cancer patients not pretreated with emetogenic chemotherapy were included in a crossover study of antiemetic therapy . Patients were r and omly assigned to receive either nabilone ( 2 × 2 mg/day ) or alizapride ( 3 × 150 mg/day ) prior to beginning lowdose cisplatin chemotherapy . Patients on nabilone had significantly fewer episodes of emesis than those on alizapride ( medians , 1.1 vs 2.9;p giving complete relief from nausea ( medians , 65 % vs 30%;p in shortening the duration of nausea ( medians , 1.3 h vs 5.1 h;p caused more adverse effects . It is concluded that nabilone has greater antiemetic activity than alizapride in young patients receiving low-dose cisplatin chemotherapy . Nabilone dosage should be reduced to decrease the incidence and degree of adverse reactions while leaving the definite antiemetic activity unchanged",
"Delta‐9‐tetrahydrocannabinol ( THC ) and prochlorperazine ( Compazine ) were found to be equally efficacious in reducing nausea and vomiting associated with cancer chemotherapy across a wide range of chemotherapeutic regimens and tumor types . Both drugs were administered orally one hour before chemotherapy , then every four hours for a total of four doses . Compazine was administered in a fixed dose of 10 mg ; THC was administered by body surface area ( BSA ) : BSA 1.8 m2 = 12.5 mg . Two hundred and fourteen subjects ( 75 % of whom had previously received Compazine with varying results ) were evaluated employing a double‐blind , crossover design . Additional parameters evaluated were study drug effects on appetite , food intake , mood , activity , relaxation , interaction , and concentration . There were significant drug effects with THC : less ability to concentrate ( P less social interaction ( P less activity ( P in the level of food intake or appetite . Patients of all ages did equally well on both drugs . Neither past marijuana use nor past Compazine use were related to study drug efficacy . Those patients who correctly identified their THC cycle did better on THC versus those who could not correctly identify which antiemetic they had received ( P drug‐related effects associated with THC , but these did not reduce the patients ' preference for the drug , and were associated with nausea reduction ( P < 0.05 )",
"AN ANTI-EMETIC DRUG , NABILONE , a synthetic cannabinoid , has been compared with prochlorperazine in 24 lung cancer patients receiving cancer chemotherapy . Each of the drugs studied was given orally every 12 hours , starting the night before chemotherapy , during one of two consecutive identical chemotherapy cycles in accordance with a double-blind crossover r and om order assignment . Single doses were 2 mg of nabilone , or 15 mg of prochlorperazine . The chemotherapeutic regimens given included the following drugs in various combinations : Cis-platinum , vincristine , cyelophosphamide , adriamycin , vinde-sine , and etoposide ( VP16 ) . Nabilone was significantly superior to prochlorperazine in the reduction of vomiting episodes . Side effects , mainly vertigo , were evident in nearly half of the patients after nabilone , and three patients were withdrawn from the study due to decreased coordination and hallucinations after nabilone . Side effects from prochlorperazine were limited to mild drowsiness in one patient . Two-thirds of the patients preferred nabilone to prochlorperazine . We conclude that nabilone is a moderately effective anti-emetic drug , but that the unpredictability of its side effects call for careful patient information , especially with elderly out patients . We recommend that at least after the first dose of nabilone , the patient should be kept under close observation during 4 hours",
"Abstract Central neuropathic pain ( CNP ) occurs in many multiple sclerosis ( MS ) patients . The provision of adequate pain relief to these patients can very difficult . Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol ( CBD ) oromucosal spray ( USAN name , nabiximols ; Sativex , GW Pharmaceuticals , Salisbury , Wiltshire , UK ) , to alleviate CNP . Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment , in a double-blind manner , for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain . This parallel-group phase of the study was then followed by an 18-week r and omized-withdrawal study ( 14-week open-label treatment period plus a double-blind 4-week r and omized-withdrawal phase ) to investigate time to treatment failure and show maintenance of efficacy . A total of 339 patients were r and omized to phase A ( 167 received THC/CBD spray and 172 received placebo ) . Of those who completed phase A , 58 entered the r and omized-withdrawal phase . The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met , with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo ( p = 0.234 ) . However , an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point ( p = 0.046 ) . During the r and omized-withdrawal phase , the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray , with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group ( p = 0.04 ) . The mean change from baseline in Pain Numerical Rating Scale ( NRS ) ( p = 0.028 ) and sleep quality NRS ( p = 0.015 ) scores , both secondary endpoints in phase B , were also statistically significant compared to placebo , with estimated treatment differences of −0.79 and 0.99 points , respectively , in favor of THC/CBD spray treatment . The results of the current investigation were equivocal , with conflicting findings in the two phases of the study . While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period , the primary endpoint was not met due to a similarly large number of placebo responders . In contrast , there was a marked effect in phase B of the study , with an increased time to treatment failure in the THC/CBD spray group compared to placebo . These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these patients",
"Eighty evaluable patients receiving chemotherapy were entered on a r and om prospect i ve double-blind study to evaluate the effectiveness of nabilone , a synthetic cannabinoid , compared to prochlorperazine . Most of these patients received cisplatin , a drug that universally produces severe nausea and vomiting , as part of a combination chemotherapy regimen . The patients served as their own controls , receiving either nabilone or prochlorperazine during two consecutive treatment courses with the identical chemotherapy . Side effects consisting of hypotension and lethargy were more pronounced with nabilone . Toxicity , in general , did not preclude antiemetic treatment and in no way interfered with chemotherapy . Sixty patients ( 75 per cent ) reported nabilone to be more effective than prochlorperazine for relief of nausea and vomiting . Of these 60 patients , 46 required further chemotherapy and continued taking nabilone as the antiemetic of choice",
"Two double-blind , crossover trials comparing the antiemetic effectiveness of nabilone , a new synthetic cannabinoid , with that of prochlorperazine were conducted in patients with severe nausea and vomiting associated with anticancer chemotherapy . Of 113 patients evaluated , 90 ( 80 per cent ) responded to nabilone therapy , whereas only 36 ( 32 per cent ) responded to prochlorperazine ( P less than 0.001 ) . Complete relief of symptoms was infrequent , occurring only in nine patients ( 8 per cent ) given nabilone . When both drugs were compared , both nausea ( P less than 0.01 ) and vomiting episodes ( P less than 0.001 ) were significantly lower in patients given nabilone . Moreover , patients clearly favored nabilone for continued use ( P less than 0.001 ) . Predominant side effects noted by patients were similar for both agents and included somnolence , dry mouth and dizziness but were about twice as frequent and more often severe in patients receiving nabilone . In addition , four patients ( 3 per cent ) taking nabilone had side effects ( hallucinations in three , hypotension in one ) that required medical attention . Euphoria associated with nabilone was infrequent ( 16 per cent ) and mild",
"Summary Oral delta-9-tetrahydrocannabinol ( THC ) , 15 mg/m2 , was compared to prochlorperazine ( PCZ ) , 10 mg . for the control of cancer chemotherapy-related emesis . Thirty-six patients whose vomiting was refractory to st and ard antiemetic therapy were entered in this r and omized comparative cross-over study . THC decreased nausea and vomiting in 23 of 36 ( 64 % ) patients compared to 1 of 36 receiving PCZ . THC efficacy was not dependent on the class of antineoplastic-agent inducing the emetic symptoms , age of patients or type of sensorial change experienced . Using the 15 mg/m2 dose , all patients experienced transient sensorial changes , characterized as a pleasant “ high ” in 19 or a variable state of dysphoria in 17 cases . This study confirms the usefulness of THC in patients whose chemotherapy-induced nausea and vomiting is refractory to other st and ard antiemetics . While excellent antiemetic control was achieved at the dosage 15 mg/m2 , dysphoria was encountered at this dose level and we recommend that an initial dose of 5 mg/m2 which , if necessary , can be carefully increased to achieve maximum antiemetic benefit ",
"BACKGROUND Preliminary studies suggested that delta-9-tetrahydrocannabinol ( THC ) , the major psychoactive ingredient of Cannabis sativa L. , might be effective in the treatment of Tourette syndrome ( TS ) . This study was performed to investigate for the first time under controlled conditions , over a longer-term treatment period , whether THC is effective and safe in reducing tics in TS . METHOD In this r and omized , double-blind , placebo-controlled study , 24 patients with TS , according to DSM-III-R criteria , were treated over a 6-week period with up to 10 mg/day of THC . Tics were rated at 6 visits ( visit 1 , baseline ; visits 2 - 4 , during treatment period ; visits 5 - 6 , after withdrawal of medication ) using the Tourette Syndrome Clinical Global Impressions scale ( TS-CGI ) , the Shapiro Tourette-Syndrome Severity Scale ( STSSS ) , the Yale Global Tic Severity Scale ( YGTSS ) , the self-rated Tourette Syndrome Symptom List ( TSSL ) , and a videotape-based rating scale . RESULTS Seven patients dropped out of the study or had to be excluded , but only 1 due to side effects . Using the TS-CGI , STSSS , YGTSS , and video rating scale , we found a significant difference ( p TSSL at 10 treatment days ( between days 16 and 41 ) there was a significant difference ( p serious adverse effects occurred . CONCLUSION Our results provide more evidence that THC is effective and safe in the treatment of tics . It , therefore , can be hypothesized that the central cannabinoid receptor system might play a role in TS pathology",
"Delta-9-tetrahydrocannabinol ( THC ) is an effective antiemetic as compared with placebos in patients receiving chemotherapy for cancer . In this study we compared THC with prochlorperazine ( compazine ) in a r and omized , double-blind , crossover trial with patients who had failed to benefit from st and ard antiemetic therapy . Regardless of the emetic activity of the chemotherapeutic agents , there were more complete responses to THC courses ( in 36 of 79 courses ) than to prochlorperazine ( in 16 of 78 courses ) . Of 25 patients who were treated with both drugs and who expressed a preference , 20 preferred THC ( P = 0.005 ) . Among patients under 20 years of age there was a higher proportion of complete responses to THC courses ( 15 of 20 ) than among older patients ( 21 of 59 courses ; P = 0.004 ) . Increased food intake occurred more frequently with THC ( P = 0.008 ) and was associated with the presence of a \" high . \" Of 36 THC courses result ing in complete antiemetic responses , 32 were associated with a high . We conclude that THC is an effective antiemetic in many patients who receive chemotherapy for cancer and for whom other antiemetics are ineffective . ( N Engl J Med 302:135 - -138 , 1980 )",
"Symptoms relating to spasticity are common in multiple sclerosis ( MS ) and can be difficult to treat . We have investigated the efficacy , safety and tolerability of a st and ardized oromucosal whole plant cannabis-based medicine ( CBM ) containing delta-9 tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) , upon spasticity in MS . A total of 189 subjects with definite MS and spasticity were r and omized to receive daily doses of active preparation ( n = 124 ) or placebo ( n = 65 ) in a double blind study over 6 weeks . The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity . Secondary endpoints included a measure of spasticity ( Ashworth Score ) and a subjective measure of spasm . The primary efficacy analysis on the intention to treat ( ITT ) population ( n = 184 ) showed the active preparation to be significantly superior ( P = 0.048 ) . Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance . The responder analysis favoured active preparation , 40 % of subjects achieved > 30 % benefit ( P = 0.014 ) . Eight withdrawals were attributed to adverse events ( AEs ) ; six were on active preparation and two on placebo . We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS",
"Anecdotal reports in Tourette 's syndrome ( TS ) have suggested that marijuana ( cannabis sativa ) and delta-9-tetrahydrocannabinol ( Delta(9)-THC ) , the major psychoactive ingredient of marijuana , reduce tics and associated behavioral disorders . We performed a r and omized double-blind placebo-controlled crossover single-dose trial of Delta(9)-THC ( 5.0 , 7.5 or 10.0 mg ) in 12 adult TS patients . Tic severity was assessed using a self-rating scale ( Tourette 's syndrome Symptom List , TSSL ) and examiner ratings ( Shapiro Tourette 's syndrome Severity Scale , Yale Global Tic Severity Scale , Tourette 's syndrome Global Scale ) . Using the TSSL , patients also rated the severity of associated behavioral disorders . Clinical changes were correlated to maximum plasma levels of THC and its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol ( 11-OH-THC ) and 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid ( THC-COOH ) . Using the TSSL , there was a significant improvement of tics ( p=0.015 ) and obsessive-compulsive behavior ( OCB ) ( p = 0.041 ) after treatment with Delta(9)-THC compared to placebo . Examiner ratings demonstrated a significant difference for the subscore \" complex motor tics \" ( p = 0.015 ) and a trend towards a significant improvement for the subscores \" motor tics \" ( p = 0.065 ) , \" simple motor tics \" ( p = 0.093 ) , and \" vocal tics \" ( p = 0.093 ) . No serious adverse reactions occurred . Five patients experienced mild , transient side effects . There was a significant correlation between tic improvement and maximum 11-OH-THC plasma concentration . Results obtained from this pilot study suggest that a single-dose treatment with Delta(9)-THC is effective and safe in treating tics and OCB in TS . It can be speculated that clinical effects may be caused by 11-OH-THC . A more long-term study is required to confirm these results",
"UNLABELLED A r and omized , double-blind , placebo-controlled trial was conducted to determine the benefit of nabilone in pain management and quality of life improvement in 40 patients with fibromyalgia . After a baseline assessment , subjects were titrated up on nabilone , from 0.5 mg PO at bedtime to 1 mg BID over 4 weeks or received a corresponding placebo . At the 2- and 4-week visits , the primary outcome measure , visual analog scale ( VAS ) for pain , and the secondary outcome measures , number of tender points , the average tender point pain threshold , and the Fibromyalgia Impact Question naire ( FIQ ) , were evaluated . After a 4-week washout period , subjects returned for re assessment of the outcome measures . There were no significant differences in population demographics between groups at baseline . There were significant decreases in the VAS ( -2.04 , P FIQ ( -12.07 , P anxiety ( -1.67 , P side effects per person at 2 and 4 weeks ( 1.58 , P beneficial , well-tolerated treatment option for fibromyalgia patients , with significant benefits in pain relief and functional improvement . PERSPECTIVE To our knowledge , this is the first r and omized , controlled trial to assess the benefit of nabilone , a synthetic cannabinoid , on pain reduction and quality of life improvement in patients with fibromyalgia . As nabilone improved symptoms and was well-tolerated , it may be a useful adjunct for pain management in fibromyalgia",
"The antiemetic activity and side-effects of delta-9-tetrahydrocannabinol ( THC ) were evaluated in 116 patients ( median age 61 years ) receiving combined 5-fluorouracil and semustine ( methyl CCNU ) therapy for gastrointestinal carcinoma . In a double-blind study , patients were r and omized to receive THC , 15 mg orally three times a day , prochlorperazine , 10 mg orally three times a day , or placebo . The THC had superior antiemetic activity in comparison to placebo , but it showed no advantage over prochlorperazine . Central nervous system side-effects , however , were significantly more frequent and more severe with THC . With the dosage and schedule we used , and in our patient population of largely elderly adults , THC therapy result ed in an overall more unpleasant treatment experience than that noted with prochlorperazine or placebo . Although THC may have a role in preventing nausea and vomiting associated with cancer chemotherapy , this role must be more clearly defined before THC can be recommended for general use",
"Summary In a r and omized crossover study 57 cancer patients receiving chemotherapy with high emetic potential were treated with low-dose levonantradol or st and ard-dose metoclopramide and crossed over to the other antiemetic drug in the next identical chemotherapy cycle . In the 45 patients evaluable for treatment response the antiemetic efficacy of levonantradol was significantly better : 62 % had less nausea and 58 % less vomiting , as against 11 % and 16 % , respectively , with metoclopramide . Patient preference for antiemetic treatment was levonantradol in 49 % and metoclopramide in 22 % of cases . Levonantradol treatment was accompanied by a relatively high incidence of side-effects ( 71 % ) compared with metoclopramide ( 29 % ) . The antiemetic efficacy of each single drug was incomplete in most cases of this trial , and antiemetic combination therapy is recommended for further trials",
" Fifty-five patients harboring a variety of neoplasms and previously found to have severe nausea or emesis from antitumor drugs were given antiemetic prophylaxis in a double-blind , r and omized , crossover fashion . Tetrahydrocannabinol ( THC ) , prochlorperazine , and placebo were compared . Nausea was absent in 40 of 55 patients receiving THC , eight of 55 patients receiving prochlorperazine , and five of 55 in the placebo group . The antiemetic effect of THC appeared to be more efficacious for cyclophosphamide , fluorouracil , and doxorubicin hydrochloride , and less so for mechlorethamine hydrochloride and the nitrosureas . Tetrahydrocannabinol appears to offer significant control of nausea in most patients and exceeding by far that provided by prochlorperazine",
" Summary Twenty-seven patients who were refractory to previously used common antiemetic treatment while on chemotherapy have been entered in a crossover , double-blind , r and omized study aim ed to compare efficacy and toxicity of 2 mg b.i.d . oral nabilone and 10 mg b.i.d . oral prochlorperazine . Eighteen patients are presently evaluable for efficacy . Severity of nausea was less during the nabilone period of administration . The number of vomiting ejections and dry retching episodes was significantly less ( P P P cis -plantinum- ( 50 mg/m 2 ) and adriamycin-pluscyclophosphamide-induced vomiting",
"BACKGROUND Neuropathic pain ( NPP ) is a chronic syndrome suffered by patients with multiple sclerosis ( MS ) , for which there is no cure . Underlying cellular mechanisms involved in its pathogenesis are multifaceted , presenting significant challenges in its management . METHODS A r and omized , double-blind , placebo-controlled study involving 15 relapsing-remitting MS patients with MS-induced NPP was conducted to evaluate nabilone combined with gabapentin ( GBP ) . Eligible patients stabilized on GBP ( ≥1,800 mg/day ) with inadequate pain relief were recruited . Nabilone or placebo was titrated over 4 weeks ( 0.5 mg/week increase ) followed by 5-week maintenance of 1 mg oral nabilone ( placebo ) twice daily . Primary outcomes included two daily patient-reported measures using a 100-mm visual analog scale ( VAS ) , pain intensity ( VASpain ) , and impact of pain on daily activities ( VASimpact ) . Hierarchical regression modeling was conducted on each outcome to determine if within-person pain trajectory differed across study groups , during 63-day follow-up . RESULTS After adjustment for key patient-level covariates ( e.g. , age , sex , Exp and ed Disability Status Scale , duration of MS , baseline pain ) , a significant group × time(2 ) interaction term was reported for both the VASpain ( P and VASimpact score ( P dizziness/drowsiness most frequently reported . CONCLUSION Nabilone as an adjunctive to GBP is an effective , well-tolerated combination for MS-induced NPP . The results of this study identify a novel therapeutic combination for use in this population of patients predisposed to tolerability issues that may otherwise prevent effective pain management",
"OBJECTIVE : To examine the effect of dronabinol ( delta-9-tetrahydrocannabinol ) on appetite and nutritional status in patients with symptomatic HIV infection and weight loss . DESIGN : Double-blind , r and omized , placebo-controlled , crossover trial with two five-week treatment periods separated by a two-week washout period . Patients received dronabinol 5 mg twice daily before meals or placebo . SETTING : A university-based HIV/AIDS clinic and a large infectious disease private practice largely devoted to care of patients with HIV . PARTICIPANTS : Twelve HIV-infected patients who had had at least a 2.25-kg weight loss participated in the study . Five patients completed the protocol , and seven withdrew ( two because of drug intolerance , two because of disease progression , two because of noncompliance , and one because of experimental antiretroviral therapy ) . MAIN OUTCOME MEASURES : Main outcome measures included caloric intake , weight , percent body fat , serum prealbumin , and symptom distress . RESULTS : During dronabinol treatment , subjects experienced increased percent body fat ( one percent , p=0.04 ) ; decreased symptom distress ( p=0.04 ) ; and trends toward weight gain ( 0.5 kg , p=0.13 ) , increased prealbumin ( 29.0 mg/L , p=0.11 ) , and improved appetite score ( p=0.14 ) . CONCLUSIONS : In a selected group of HIV-infected patients with weight loss , short-term treatment with dronabinol may result in improvement in nutritional status and symptom distress",
"UNLABELLED The Food and Drug Administration ( FDA ) , Substance Abuse and Mental Health Services Administration ( SAMHSA ) , and the National Institute for Drug Abuse ( NIDA ) report that no sound scientific studies support the medicinal use of cannabis . Despite this lack of scientific validation , many patients routinely use \" medical marijuana , \" and in many cases this use is for pain related to nerve injury . We conducted a double-blinded , placebo-controlled , crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain . Thirty-eight patients with central and peripheral neuropathic pain underwent a st and ardized procedure for smoking either high-dose ( 7 % ) , low-dose ( 3.5 % ) , or placebo cannabis . In addition to the primary outcome of pain intensity , secondary outcome measures included evoked pain using heat-pain threshold , sensitivity to light touch , psychoactive side effects , and neuropsychological performance . A mixed linear model demonstrated an analgesic response to smoking cannabis . No effect on evoked pain was seen . Psychoactive effects were minimal and well-tolerated , with some acute cognitive effects , particularly with memory , at higher doses . PERSPECTIVE This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain , and may be an alternative for patients who do not respond to , or can not tolerate , other drugs . However , the use of marijuana as medicine may be limited by its method of administration ( smoking ) and modest acute cognitive effects , particularly at higher doses",
"Abstract Background : Muscle spasticity is common in multiple sclerosis ( MS ) , occurring in more than 60 % of patients . Objective : To compare Sativex with placebo in relieving symptoms of spasticity due to MS . Methods : A 15-week , multicenter , double-blind , r and omized , placebo-controlled , parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy . Results : The primary endpoint was a spasticity 0–10 numeric rating scale ( NRS ) . Intention-to-treat ( ITT ) analysis showed a non-significant improvement in NRS score , in favor of Sativex . The per protocol ( PP ) population ( 79 % of subjects ) change in NRS score and responder analyses ( ≥30 % improvement from baseline ) were both significantly superior for Sativex , compared with placebo : −1·3 versus −0·8 points ( change from baseline , p=0·035 ) ; and 36 % versus 24 % ( responders , p=0·040 ) . These were supported by the time to response ( ITT : p=0·068 ; PP : p=0·025 ) analyses , carer global impression of change assessment ( p=0·013 ) and timed 10-meter walk ( p=0·042 ) . Among the subjects who achieved a ≥30 % response in spasticity with Sativex , 98 , 94 and 73 % reported improvements of 10 , 20 and 30 % , respectively , at least once during the first 4 weeks of treatment . Sativex was generally well tolerated , with most adverse events reported being mild-to-moderate in severity . Discussion and conclusions : The 0–10 NRS and responder PP analyses demonstrated that Sativex treatment result ed in a significant reduction in treatment-resistant spasticity , in subjects with advanced MS and severe spasticity . The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status",
"The effects of dronabinol on appetite and weight were evaluated in 139 patients with AIDS-related anorexia and > or = 2.3 kg weight loss in a multi-institutional study . Patients were r and omized to receive 2.5 mg dronabinol twice daily or placebo . Patients rated appetite , mood , and nausea by using a 100-mm visual analogue scale 3 days weekly . Efficacy was evaluable in 88 patients . Dronabinol was associated with increased appetite above baseline ( 38 % vs 8 % for placebo , P = 0.015 ) , improvement in mood ( 10 % vs -2 % , P = 0.06 ) , and decreased nausea ( 20 % vs 7 % ; P = 0.05 ) . Weight was stable in dronabinol patients , while placebo recipients had a mean loss of 0.4 kg ( P = 0.14 ) . Of the dronabinol patients , 22 % gained > or = 2 kg , compared with 10.5 % of placebo recipients ( P = 0.11 ) . Side effects were mostly mild to moderate in severity ( euphoria , dizziness , thinking abnormalities ) ; there was no difference in discontinued therapy between dronabinol ( 8.3 % ) and placebo ( 4.5 % ) recipients . Dronabinol was found to be safe and effective for anorexia associated with weight loss in patients with AIDS",
"CONTEXT Neuropathic pain caused by chemotherapy limits dosing and duration of potentially life-saving anti-cancer treatment and impairs quality of life . Chemotherapeutic neuropathy responds poorly to conventional treatments , and there is an urgent medical need for new treatments . Recent pre clinical studies demonstrate that cannabinoid agonists suppress established chemotherapy-evoked neuropathy . OBJECTIVES This was a pilot trial to begin to investigate a currently available cannabinoid agent , nabiximols ( oral mucosal spray containing cannabinoids ) , in the treatment of chemotherapy-induced neuropathic pain . METHODS A r and omized , placebo-controlled crossover pilot study was done in 16 patients with established chemotherapy-induced neuropathic pain . A 0 - 10 point numeric rating scale for pain intensity ( NRS-PI ) was used as the primary outcome measure . RESULTS When examining the whole group , there was no statistically significant difference between the treatment and the placebo groups on the NRS-PI . A responder analysis demonstrated that there were five participants who reported a two-point or greater reduction in pain that trended toward statistical significance and the number needed to treat was five . CONCLUSION Chemotherapy-induced neuropathic pain is particularly resistant to currently available treatments . This pilot trial found a number needed to treat of five and an average decrease of 2.6 on an 11-point NRS-PI in five \" responders \" ( as compared with a decrease of 0.6 with placebo ) and supports that it is worthwhile to study nabiximols in a full r and omized , placebo-controlled trial of chemotherapy-induced neuropathic pain",
"Summary A prospect i ve , r and omized , double-blind , crossover study of nabilone versus placebo was undertaken in three university cancer centers to determine the antiemetic efficacy and toxicity of nabilone in patients experiencing nausea and vomiting due to cancer chemotherapy . Identical study drug ( 2 mg of nabilone or placebo ) was given the evening before and the morning of chemotherapy and for at least 24 h afterwards on a b.i.d . schedule . Careful assessment of nausea , vomiting and finally patient preference for study drug was carried out on each of two identical courses of combination chemotherapy . Fifty-four patients were entered . Of the 24 patients fully evaluable for efficacy , nabilone significantly reduced the mean number of vomiting episodes ( 7 vs. 19 , P P P = 0.001 ) . Side effects were common with nabilone but acceptable and in 49 patients who were evaluable for toxicity consisted primarily of dizziness ( 65 % ) , drowsiness ( 51 % ) , dry mouth ( 31 % ) , sleep disturbance ( 14 % ) , ataxia ( 8 % ) , nausea ( 8 % ) and euphoria ( 6 % ) . Nabilone is an effective antiemetic agent for chemotherapy-induced nausea and vomiting",
"In a r and omized , double-blind , crossover trial , nabilone was compared to prochlorperazine for control of cancer chemotherapy-induced emesis in 30 children 3.5 to 17.8 years of age . All subjects received two consecutive identical cycles of chemotherapy with the trial antiemetics given in accordance to a body weight-based dosage schedule beginning eight to 12 hours before treatment . The overall rate of improvement of retching and emesis was 70 % during the nabilone and 30 % during the prochlorperazine treatment cycles ( P = .003 , chi 2 test ) . On completion of the trial , 66 % of the children stated that they preferred nabilone , 17 % preferred prochlorperazine , and 17 % had no preference ( P = .015 , chi 2 test ) . Major side effects ( dizziness , drowsiness , and mood alteration ) were more common ( 11 % v 3 % ) during the nabilone treatment cycles . CNS side effects appeared to be dose related and were most likely to occur when the nabilone dosage exceeded 60 micrograms/kg/d , but individual tolerance to nabilone varied considerably . Lower dosages of nabilone were associated with equivalent efficacy and no major side effects . Nabilone appears to be a safe , effective , and well-tolerated antiemetic drug for children receiving cancer chemotherapy . Although major side effects may occur at higher dosages , nabilone is preferable to prochlorperazine because of improved efficacy",
"A r and omized , double-blind controlled trial of nabilone versus chlorpromazine was performed in 20 patients with advanced gynaecological cancer who received chemotherapy including cis-platinum . Each patient served as his own control . Nabilone was administered at a dose of 3 mg given orally three times a day , starting the day before cis-platinum and ending the day after . Chlorpromazine was administered at a dose of 12.5 mg given IM , 15 minutes before the start of cis-platinum . Nabilone , in comparison with chlorpromazine did not significantly reduce the number of vomiting . Ten patients preferred nabilone , 5 preferred chlorpromazine and 3 were undecided . Predominant side effects noted by patients were similar for both agents and included somnolence , dry mouth and orthostatic hypotension . No other intervention besides reassurance of the patient was necessary to treat these adverse reactions",
"One hundred and eight patients selected to receive combinations of highly emetic cytotoxic chemotherapy for malignant disease were included in a study of anti-emetic therapy . The patients were r and omly allocated to receive levonantradol ( 0.5 , 0.75 or 1 mg ) or chlorpromazine ( 25 mg ) prior to receiving their first course of cytotoxic therapy . The appropriate anti-emetic was administered 2 hr prior to the start of chemotherapy , 2 hr after chemotherapy and subsequently at 4-hourly intervals for a further 8 hr . The extent of anorexia , nausea and vomiting along with other side-effects were assessed at regular intervals by physicians and nursing staff during the 24 hr following chemotherapy . In addition , a self- assessment question naire was completed by the patients . Levonantradol ( 0.5 mg ) was superior to chlorpromazine ( 25 mg ) as an anti-emetic . Both were reasonably well tolerated , although at this dose of levonantradol 22 % of patients experienced dysphoric reactions . At higher doses of levonantradol the proportion of patients experiencing these reactions rose to 50 % , but without a concomitant increase in antiemetic activity . Neither drug achieved satisfactory control of vomiting in patients receiving combinations containing cis-platinum . We conclude that levonantradol ( 0.5 mg ) is a more effective anti-emetic than chlorpromazine ( 25 mg ) in patients receiving cytotoxic chemotherapy . However , its use can not be recommended due to its high incidence of unacceptable central nervous system side-effects",
"Cannabinoids reduce allodynia/hyperalgesia in animal pain models , but few clinical studies evaluated the analgesic action in humans . We aim ed to evaluate the effect of delta-9-tetrahydrocannabinol ( dronabinol ) on central pain in MS patients . Twenty-four MS patients participated in a double-blind placebo-controlled crossover trial . Dronabinol reduced the spontaneous pain intensity significantly compared with placebo ( 4.0 ( 2.3 - 6.0 ) vs. 5.0 ( 4.0 - 6.4 ) , median ( 25th-75th percentiles ) , p = 0.02 ) . Though dronabinol 's analgesic effect is modest , its use should be evaluated considering the general difficulty in treating central pain",
"Fifty-five patients harboring a variety of neoplasms and previously found to have severe nausea or emesis from antitumor drugs were given antiemetic prophylaxis in a double-blind , r and omized crossover fashion . delta 9-Tetrahydrocannabinol ( THC ) , prochlorperazine , and placebo were compared . Nausea was absent in 40 of 55 patients receiving THC , in 8 of 55 patients receiving prochlorperazine , and in 5 of 55 in the placebo group . THC appeared to be more efficacious in controlling the emesis associated with cyclophosphamide , 5-fluorouracil , and doxorubicin and less so for nitrogen mustard and the nitrosourea . THC appears to offer significant control of nausea in most patients and exceeds by far that provided by prochlorperazine ( P less than 0.005 )",
"Dronabinol ( Marinol , Roxane Laboratories , Columbus , OH ) and prochlorperazine were tested alone and in combination in a r and omized , double-blind , parallel group , multicenter study . Patients were r and omized to receive either 1 ) dronabinol 10 mg every 6 hr plus placebo ; 2 ) placebo plus prochlorperazine 10 mg every 6 hr ; or 3 ) dronabinol and prochlorperazine , each 10 mg every 6 hr . Antiemetic treatment was begun 24 hr prior to and continued for 24 hr after the last dose of chemotherapy ; all was given orally . Only 29 % of patients in group 3 versus 47 % in group 1 and 60 % in group 2 experienced nausea after chemotherapy . In addition , the median duration per episode and severity of nausea were significantly less with combination therapy . Vomiting occurred after chemotherapy in 41 % , 55 % , and 35 % of patients in groups 1 , 2 , and 3 , respectively . The median duration per episode of vomiting was 1 min in group 3 versus two in group 1 and four in group 2 . Side effects , primarily CNS , were more common in group 1 than in group 2 ; addition of prochlorperazine to dronabinol appeared to decrease the frequency of dysphoric effects seen with the latter agent . The combination was significantly more effective than was either single agent in controlling chemotherapy-induced nausea and vomiting",
"AIMS Despite progress in anti-emetic treatment , many patients still suffer from chemotherapy-induced nausea and vomiting ( CINV ) . This is a pilot , r and omized , double-blind , placebo-controlled phase II clinical trial design ed to evaluate the tolerability , preliminary efficacy , and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine ( CBM ) containing delta-9-tetrahydrocannabinol and cannabidiol , taken in conjunction with st and ard therapies in the control of CINV . METHODS Patients suffering from CINV despite prophylaxis with st and ard anti-emetic treatment were r and omized to CBM or placebo , during the 120 h post-chemotherapy period , added to st and ard anti-emetic treatment . Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events ( AEs ) . The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response . RESULTS Seven patients were r and omized to CBM and nine to placebo . Only one patient in the CBM arm was withdrawn due to AEs . A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [ 5/7 ( 71.4 % ) with CMB vs. 2/9 ( 22.2 % ) with placebo , the difference being 49.2 % ( 95 % CI 1 % , 75 % ) ] , due to the delayed period . The incidence of AEs was higher in the CBM group ( 86 % vs. 67 % ) . No serious AEs were reported . The mean daily dose was 4.8 sprays in both groups . CONCLUSION Compared with placebo , CBM added to st and ard antiemetic therapy was well tolerated and provided better protection against delayed CINV . These results should be confirmed in a phase III clinical trial"
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4117cfa8-06ff-11f0-808a-c43d1ab1c353
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Evidence on the association between physical activity ( PA ) and adiposity in young children is inconclusive . A systematic review and meta-analyses were conducted to examine associations between accelerometer-derived PA and varying adiposity outcomes in preschool children . Search es were conducted in Embase , MEDLINE and Web of Science to identify studies on the association between total PA , sedentary behaviour or different PA intensities and adiposity in children aged 2 to 7 years . Separate r and om effects meta-analyses were performed for varying PA intensities and adiposity outcomes . Fifty-six articles were included in the review and 48 in the meta-analyses . There was substantial evidence of an inverse association between moderate-to-vigorous- or vigorous PA and body fat percentage ( stdβ [ SE ] = -0.162[0.041 ] ; 5 studies ) , weight status ( r = -0.120 , P studies ) , fat mass ( stdβ [ SE ] = -0.103[0.051 ] ; 5 studies ) , fat mass index ( stdβ [ SE ] = -0.121[0.036 ] ; 2 studies ) and skinfold thickness ( stdβ [ SE ] = -0.145[0.036 ] ; 4 studies ) . However , total PA , sedentary behaviour , and different PA intensities were not associated with body mass index ( BMI ) or waist circumference . Adiposity levels were lower among preschool children engaged in more ( moderate-to- ) vigorous PA compared with their peers , but no associations between PA and BMI or waist circumference were found
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"Background Identifying ways to promote physical activity and decrease sedentary time during childhood is a key public health issue . Research on the putative influences on preschool children ’s physical activity ( PA ) and sedentary behavior ( SB ) is limited and has yielded inconsistent results . Our aim was to identify correlates of PA and SB in preschool children . Methods Cross-sectional data were drawn from the Swiss Preschoolers ’ Health Study ( SPLASHY ) , a Swiss population -based cohort study . Of 476 two to six year old children , 394 ( 54 % boys ) had valid PA data assessed by accelerometry . Information on exposure data was directly measured or extracted from parental question naires . Multilevel linear regression modeling was used to separately assess associations between 35 potential correlates and total PA ( TPA ) , moderate-to-vigorous PA ( MVPA ) and SB . Results In total , 12 correlates from different domains were identified . TPA and MVPA were greater in boys than girls , increased with age and were positively associated with gross motor skills . Children from single parent families had a higher level of TPA and spent less time sedentary than those living with two parents . Time spent outdoors was positively associated with TPA and negatively with SB . The child ’s activity temperament was related all three outcomes , whereas parental sports club membership , living area per person and neighborhood safety were associated with SB only . Fixed and r and om factors in the final models accounted for 28 % , 32 % and 22 % of the total variance in TPA , MVPA and SB , respectively . Variance decomposition revealed that age , sex and activity temperament were the most influential correlates of both , TPA and MVPA , whereas the child ’s activity temperament , time outdoors and neighborhood safety were identified as the most important correlates of SB . Conclusions A multidimensional set of correlates of young children ’s activity behavior has been identified . Personal factors had the greatest influence on PA , whereas environmental-level factors had the greatest influence on SB . Moreover , we identified a number of previously unreported , potentially modifiable correlates of young children ’s PA and SB . These factors could serve to define target groups or become valuable targets for change in future interventions .Trial registration Current Controlled Trials IS RCT N41045021 ( date of registration : 21.03.14 )",
"Background : Recent studies have cl aim ed a positive effect of physical activity and body composition on vagal tone . In pediatric population s , there is a pronounced decrease in heart rate with age . While this decrease is often interpreted as an age-related increase in vagal tone , there is some evidence that it may be related to a decrease in intrinsic heart rate . This factor has not been taken into account in most previous studies . The aim of the present study was to assess the association between physical activity and /or body composition and heart rate variability ( HRV ) independently of the decline in heart rate in young children . Methods : Anthropometric measurements were taken in 309 children aged 2–6 years . Ambulatory electrocardiograms were collected over 14–18 h comprising a full night and accelerometry over 7 days . HRV was determined of three different night segments : ( 1 ) over 5 min during deep sleep identified automatically based on HRV characteristics ; ( 2 ) during a 20 min segment starting 15 min after sleep onset ; ( 3 ) over a 4-h segment between midnight and 4 a.m. Linear models were computed for HRV parameters with anthropometric and physical activity variables adjusted for heart rate and other confounding variables ( e.g. , age for physical activity models ) . Results : We found a decline in heart rate with increasing physical activity and decreasing skinfold thickness . HRV parameters decreased with increasing age , height , and weight in HR-adjusted regression models . These relationships were only found in segments of deep sleep detected automatically based on HRV or manually 15 min after sleep onset , but not in the 4-h segment with r and om sleep phases . Conclusions : Contrary to most previous studies , we found no increase of st and ard HRV parameters with age , however , when adjusted for heart rate , there was a significant decrease of HRV parameters with increasing age . Without knowing intrinsic heart rate correct interpretation of HRV in growing children is impossible",
"Objective : This study assesses differences in adiposity , aerobic fitness , and lifestyle characteristics in preschoolers according to their weight status and sports club ( SC ) participation . Method : As part of the Ballabeina study , 600 r and omly selected preschoolers ( mean age 5.1 ± 0.6 years ; 50.2 % girls ) were analyzed . Body composition was measured by bioelectrical impedance , aerobic fitness by the 20-meter shuttle run test , and physical activity by accelerometers . Eating habits , media use , and SC participation were assessed by question naires . Results : Overweight children ( Swiss national percentiles ) and children not participating in SC had both lower aerobic fitness and higher % body fat compared to their respective counterparts ( all p ≤ 0.028 ) . In addition , children not participating in SC were less physically active , had more media use , and ate less healthy compared to children participating in SC ( all p ≤ 0.023 ) . Controlling for parental sociocultural determinants attenuated differences in % body fat , in physical activity , and in eating habits . Conclusion : Aerobic fitness differs both according to weight status and SC participation in preschoolers . Furthermore , in view of the many differences in lifestyle behaviors , SC participation at this age could represent a more discriminatory indicator of healthy lifestyle characteristics than weight status",
"PURPOSE To determine if weight status modifies the relationship between motor skill ( MS ) performance and physical activity ( PA ) in preschoolers . METHODS Preschoolers ( N = 227 , age 3 - 5 y ) were recruited from 22 preschools . Preschoolers ' MS ( locomotor , object control , and total MS ) were assessed with the Children 's Activity and Movement in Preschool Study MS protocol . PA was measured by accelerometry . Mixed linear models were used to examine the relationship of MS performance and body mass index ( BMI ) z score to PA . Models were adjusted for age , race , sex , and parent education , with preschool as a r and om effect . RESULTS There was a significant correlation between MS performance and PA ( r = .14-.17 , P BMI z score and object control , and between BMI z score and total MS score on PA ( P = .03 ) . Preschoolers with higher BMI z scores and high object control scores engaged in significantly ( P = .03 ) more PA than preschoolers with lower BMI z scores and high object control scores ( PA = 15.04 min/h and 13.54 min/h , respectively ) . Similarly , preschoolers with higher BMI z scores and high total MS scores spent significantly ( P = .01 ) more time in PA compared with those with lower BMI z scores and high total MS scores ( PA = 15.65 min/h and 13.91 min/h , respectively ) . CONCLUSION Preschool children 's MS performance is positively correlated with PA , and BMI z score modified the relationship between MS performance and PA",
"OBJECTIVE To examine , using an Ecological Systems Theoretical framework , relationships between weight status and child , parent and community characteristics and risk factors among preschool children . METHODS Cross-sectional data was collected from 140 children and their parents from 11 r and omly selected preschools . Outcome variables included : motor development ; perceived competence ; objective ly measured physical activity ; time spent in active and quiet play ; location and number of televisions ; parental rules around physical activity and time spent watching television ; availability of sport and physical activity programs ; and parks and open spaces and access to footpaths . RESULTS Overweight children spent more time in quiet play and watching television and less time in active play and physical activity . Perceived competence and motor development were similar for both overweight and non-overweight children . Associations between weight status and several parent and community characteristics were not evident , except for access to footpaths . Overweight children had greater access to footpaths compared with non-overweight children ( p=0.046 ) . CONCLUSION The results reported here showed little difference between overweight and non-overweight children in relation to a variety of child , parent and community variables . However , for some characteristics , differences in older children have been reported . Longitudinal studies are required to confirm when these characteristics begin to differ , what effects these differences have on behaviour and weight-status , and therefore when targeted treatment should be provided during a child 's development",
"OBJECTIVE Preventing weight gain in adults and excessive weight gain in children is a high priority . We evaluated the ability of a family-based program aim ed at increasing steps and cereal consumption ( for breakfast and snacks ) to reduce weight gain in children and adults . RESEARCH METHODS AND PROCEDURES Families ( n = 105 ) with at least one 8- to 12-year-old child who was at-risk-for-overweight or overweight ( design ated as the target child ) were recruited for the study . Eighty-two families were r and omly assigned to receive the family-based intervention and 23 families to the control condition . The 13-week intervention consisted of specific increases in daily steps ( an additional 2000 steps/d ) and consumption of 2 servings/d of ready-to-eat cereal . RESULTS The intervention was successful in increasing walking ( steps ) and cereal consumption . The intervention had positive , significant effects on percentage BMI -for-age and percentage body fat for target children and weight , BMI , and percentage body fat for parents . On further analysis , the positive effects of the intervention were seen largely in target girls and moms , rather than in target boys and dads . DISCUSSION This family-based weight gain prevention program based on small changes holds promise for reducing excessive weight gain in families and especially in growing overweight children",
"OBJECTIVE The impact of physical activity patterns and sleep duration on growth and body composition of preschool-aged children remains unresolved . Aims were ( 1 ) to delineate cross-sectional associations among physical activity components , sleep , total energy expenditure ( TEE ) , and body size and composition ; and ( 2 ) to determine whether physical activity components , sleep , and TEE predict 1-year changes in body size and composition in healthy preschool-aged children . METHODS Anthropometry , body composition , accelerometry , and TEE by doubly labeled water were measured at baseline ; anthropometry and body composition were repeated 1 year later ( n = 111 ) . RESULTS Cross-sectionally , positive associations between sedentary activity and weight and fat-free mass ( FFM ) ( P = 0.009 - 0.047 ) , and a negative association between moderate-vigorous physical activity ( MVPA ) and percent fat mass ( FM ) ( P = 0.015 ) were observed . TEE and activity energy expenditure ( AEE ) were positively associated with weight , body mass index ( BMI ) , FFM , and FM ( P = 0.0001 - 0.046 ) . Prospect ively , TEE , AEE , physical activity level , and MVPA , but not sedentary activity , were positively associated with changes in BMI ( P = 0.0001 - 0.051 ) and FFM ( P = 0.0001 - 0.037 ) , but not percent FM . Sleep duration inversely predicted changes in FM ( P = 0.005 ) and percent FM ( P = 0.006 ) . CONCLUSIONS Prospect ively , MVPA , TEE , AEE , and physical activity level promote normal growth and accretion of FFM , whereas sleep duration inversely predicts changes in adiposity in preschool-aged children",
"PURPOSE Studies estimating the contribution of physical activity ( PA ) to the development of body mass index ( BMI ) in critical periods of childhood are warranted . Therefore , we have prospect ively investigated this relationship in boys and girls of the KOALA Birth Cohort study , the Netherl and s , in the period around adiposity rebound ( i.e. , 4 - 9 yr old ) . METHODS PA was assessed in 470 children ( 231 boys , 239 girls ) using accelerometers at the ages of 5 and 7 yr , and height and weight were measured at 5 , 7 , and 9 yr . BMI z-scores were calculated to st and ardize for age and sex . Leaner and heavier children were classified according to the 25th and 75th percentile of our study sample . To examine longitudinal relationships between PA and BMI z-scores , generalized estimating equation analyses were performed and stratified for sex and baseline weight status ( leaner , normal weight , and heavier children ) . RESULTS In heavier children , an increment of 6.5 min of moderate to vigorous PA ( MVPA ) was related to a subsequent decrease of 0.03 BMI z-scores both in boys ( 95 % confidence interval = -0.07 to -0.001 ) and girls ( 95 % confidence interval = -0.05 to -0.002 ) . Light PA was also associated with a decrease of BMI in heavier boys but not girls . In normal weight children , MVPA was associated with decrease of BMI in boys but not girls . CONCLUSION Increments of MVPA were associated with decreases in BMI z-score in heavier children , both boys and girls . Promoting MVPA should remain a major prevention vehicle for improving body composition in 4- to 9-yr-old children"
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4117cfe4-06ff-11f0-808a-c43d1ab1c353
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Background Recent systematic review s have identified that current patient-reported outcome instruments have content limitations when used to measure change following bariatric surgery . The aim of this study was to measure change after bariatric surgery using the BODY-Q , a PRO instrument design ed for weight loss and body contouring . Methods The BODY-Q is composed of 18 independently functioning scales and an obesity-specific symptom checklist that measure appearance , health-related quality of life ( HR-QOL ) and experience of health-care . The sample for this study included patients who were exploring or seeking bariatric surgery in Hamilton ( Canada ) at the time of the BODY-Q field-test study and who agreed to further contact from the research team . These patients were invited to complete 12 BODY-Q scales and the symptom checklist between 7 June 2016 and 29 November 2016 . Data were collected online ( REDCap ) and via postal surveys . Clinical change was measured using paired t-tests with effect sizes and st and ardized response means . Results The survey was completed by 58 of 89 ( 65 % ) pre-bariatric participants from the original BODY-Q field-test sample . The non- participants did not differ from participants in terms of age , gender , ethnicity , BMI or initial BODY-Q scale scores . Participants who had undergone bariatric surgery had a mean BMI of 49 ( SD = 7 ) at time 1 and 35 ( SD = 7 ) at time 2 . Time since bariatric surgery was on average 2 years ( SD = 0.5 ) ( range 0.4 to 3 years ) . Percentage total weight loss ranged from 12 to 51 ( mean 31 , SD = 9 ) . The difference in the proportion of patients to report an obesity-specific symptom on the BODY-Q checklist was significantly lower at follow-up for 5 of 10 symptoms . Participants improved on BODY-Q scales measuring appearance ( of abdomen , back , body , buttocks , hips/outer thighs , inner thigh ) , body image and physical function ( p social function ( p = 0.002 on paired t-test ) . These changes were associated with moderate to large effect sizes ( 0.60 to 2.29 ) and st and ardized response means ( 0.47 to 1.35 ) . Conclusions The BODY-Q provides a set of independently functioning scales that measure issues important to patients who undergo weight loss . BODY-Q scales were responsive to measuring clinical change associated with weight loss 2 years after bariatric surgery
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"OBJECTIVE Obesity research ers have a growing interest in measuring the impact of weight and weight reduction on quality of life . The Impact of Weight on Quality of Life question naire ( IWQOL ) was the first self-report instrument specifically developed to assess the effect of obesity on quality of life . Although the IWQOL has demonstrated excellent psychometric properties , its length ( 74 items ) makes it somewhat cumbersome as an outcome measure in clinical research . This report describes the development of a 31-item version of the IWQOL ( IWQOL-Lite ) . RESEARCH METHODS AND PROCEDURES IWQOLs from 996 obese patients and controls were used to develop the IWQOL-Lite . Psychometric properties of the IWQOL-Lite were examined in a separate cross-validation sample of 991 patients and controls . RESULTS Confirmatory factor analysis provided strong support for the adequacy of the scale structure . The five identified scales of the IWQOL-Lite ( Physical Function , Self-Esteem , Sexual Life , Public Distress , and Work ) and the total IWQOL-Lite score demonstrated excellent psychometric properties . The reliability of the IWQOL-Lite scales ranged from 0.90 to 0.94 and was 0.96 for the total score . Correlations between the IWQOL-Lite and collateral measures supported the construct validity of the IWQOL-Lite . Changes in IWQOL-Lite scales over time correlated significantly with changes in weight , supporting its sensitivity to change . Significant differences in IWQOL-Lite scale and total scores were found among groups differing in body mass index , supporting the utility of the IWQOL-Lite across the body mass index spectrum . DISCUSSION The IWQOL-Lite appears to be a psychometrically sound and clinical ly sensitive brief measure of quality of life in obese persons",
"This study represents a long-term effort to find optimal techniques for evaluating outcome in patients who have undergone total joint arthroplasty . Sensitivity of five health status question naires was studied in a longitudinal evaluation of orthopedic surgery . The question naires ( Arthritis Impact Measurement Scales [ AIMS ] , Functional Status Index [ FSI ] , Health Assessment Question naire [ HAQ ] , Index of Well Being [ IWB ] , and Sickness Impact Profile [ SIP ] ) were administered to 38 patients with end-stage arthritis at three points in time : two weeks before hip or knee arthroplasty , and at three-month and 12- to 15-month follow-up . Response values ( i.e. , changes within patients ) were calculated on four scales : global health , pain , mobility , and social function . By the three-month follow-up , most instruments detected large mean responses in global health , pain scores , and mobility . Smaller changes on these scales were found between three and 12 to 15 months . Social function showed small to modest gains at successive follow-ups . St and ardized response means were calculated to assess sensitivity to detect change . Confidence intervals for these indices were constructed using a jackknife procedure , and significance tests were performed by pairing selected indices . Finally , the study projected sample sizes required to assess a new therapy , using each response . These statistical tools facilitated comparisons among instruments and may prove useful in other setting",
"Health status measures are being used with increasing frequency in clinical research . Up to now the emphasis has been on the reliability and validity of these measures . Less attention has been given to the sensitivity of these measures for detecting clinical change . As health status measures are applied more frequently in the clinical setting , we need a useful way to estimate and communicate whether particular changes in health status are clinical ly relevant . This report considers effect sizes as a useful way to interpret changes in health status . Effect sizes are defined as the mean change found in a variable divided by the st and ard deviation of that variable . Effect sizes are used to translate “ the before and after changes ” in a “ one group ” situation into a st and ard unit of measurement that will provide a clearer underst and ing of health status results . The utility of effect sizes is demonstrated from four different perspectives using three health status data sets derived from arthritis population s administered the Arthritis Impact Measurement Scales ( AIMS ) . The first perspective shows how general and instrument-specific benchmarks can be developed and how they can be used to translate the meaning of clinical change . The second perspective shows how effect sizes can be used to compare traditional clinical measures with health status measures in a st and ard clinical drug trial . The third application demonstrates the use of effect sizes when comparing two drugs tested in separate drug trials and shows how they can facilitate this type of comparison . Finally , our health status results show how effect sizes can supplement st and ard statistical testing to give a more complete and clinical ly relevant picture of health status change . We conclude that effect sizes are an important tool that will facilitate the use and interpretation of health status measures in clinical research in arthritis and other chronic diseases"
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4117d020-06ff-11f0-808a-c43d1ab1c353
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Background : Study ing the impact of genetic testing interventions on lifestyle behaviour change has been a priority area of research in recent years . Substantial heterogeneity exists in the results and conclusions of this literature , which has yet to be explained using vali date d behaviour change theory and an assessment of the quality of genetic interventions . The theory of planned behaviour ( TPB ) helps to explain key contributors to behaviour change . It has been hypothesized that personalization could be added to this theory to help predict changes in health behaviours . Purpose : This systematic review provides a detailed , comprehensive identification , assessment , and summary of primary research articles pertaining to lifestyle behaviour change ( nutrition , physical activity , sleep , and smoking ) result ing from genetic testing interventions . The present review further aims to provide in-depth analyses of studies conducted to date within the context of the TPB and the quality of genetic interventions provided to participants while aim ing to determine whether or not genetic testing facilitates changes in lifestyle habits . This review is timely in light of a recently published “ call-to-action ” paper , highlighting the need to incorporate the TPB into personalized healthcare behaviour change research . Methods : Three bibliographic data bases , one key website , and article reference lists were search ed for relevant primary research articles . The PRISMA Flow Diagram and PRISMA Checklist were used to guide the search strategy and manuscript preparation . Out of 32,783 titles retrieved , 26 studies met the inclusion criteria . Three quality assessment s were conducted and included : ( 1 ) risk of bias , ( 2 ) quality of genetic interventions , and ( 3 ) consideration of theoretical underpinnings – primarily the TPB . Results : Risk of bias in studies was overall rated to be “ fair . ” Consideration of the TPB was “ poor , ” with no study making reference to this vali date d theory . While some studies ( n = 11 ; 42 % ) made reference to other behaviour change theories , these theories were generally mentioned briefly , and were not thoroughly incorporated into the study design or analyses . The genetic interventions provided to participants were overall of “ poor ” quality . However , a separate analysis of studies using controlled intervention research methods demonstrated the use of higher- quality genetic interventions ( overall rated to be “ fair ” ) . The provision of actionable recommendations informed by genetic testing was more likely to facilitate behaviour change than the provision of genetic information without actionable lifestyle recommendations . Several studies of good quality demonstrated changes in lifestyle habits arising from the provision of genetic interventions . The most promising lifestyle changes were changes in nutrition . Conclusions : It is possible to facilitate behaviour change using genetic testing as the catalyst . Future research should ensure that high- quality genetic interventions are provided to participants , and should consider vali date d theories such as the TPB in their study design and analyses . Further recommendations for future research are provided
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"Background There is evidence that physical activity ( PA ) can attenuate the influence of the fat mass- and obesity-associated ( FTO ) genotype on the risk to develop obesity . However , whether providing personalized information on FTO genotype leads to changes in PA is unknown . Objective The purpose of this study was to determine if disclosing FTO risk had an impact on change in PA following a 6-month intervention . Methods The single nucleotide polymorphism ( SNP ) rs9939609 in the FTO gene was genotyped in 1279 participants of the Food4Me study , a four-arm , Web-based r and omized controlled trial ( RCT ) in 7 European countries on the effects of personalized advice on nutrition and PA . PA was measured objective ly using a TracmorD accelerometer and was self-reported using the Baecke question naire at baseline and 6 months . Differences in baseline PA variables between risk ( AA and AT genotypes ) and nonrisk ( TT genotype ) carriers were tested using multiple linear regression . Impact of FTO risk disclosure on PA change at 6 months was assessed among participants with inadequate PA , by including an interaction term in the model : disclosure ( yes/no ) × FTO risk ( yes/no ) . Results At baseline , data on PA were available for 874 and 405 participants with the risk and nonrisk FTO genotypes , respectively . There were no significant differences in objective ly measured or self-reported baseline PA between risk and nonrisk carriers . A total of 807 ( 72.05 % ) of the participants out of 1120 in the personalized groups were encouraged to increase PA at baseline . Knowledge of FTO risk had no impact on PA in either risk or nonrisk carriers after the 6-month intervention . Attrition was higher in nonrisk participants for whom genotype was disclosed ( P=.01 ) compared with their at-risk counterparts . Conclusions No association between baseline PA and FTO risk genotype was observed . There was no added benefit of disclosing FTO risk on changes in PA in this personalized intervention . Further RCT studies are warranted to confirm whether disclosure of nonrisk genetic test results has adverse effects on engagement in behavior change . Trial Registration Clinical Trials.gov NCT01530139 ; http:// clinical trials.gov/show/NCT01530139 ( Archived by WebCite at : http://www.webcitation.org/6XII1QwHz",
"Background : As genetic testing for health risk becomes increasingly available , it becomes important to study the prospect i ve impact of testing on modifiable health behavior . Purpose : This study examines the impact of genetic testing for alpha-1 antitrypsin ( AAT ) deficiency , a condition that usually results in emphysema in individuals exposed to cigarette smoke . We evaluated whether AAT testing , performed in the home and with minimal contact ( reading material s including advice on cessation ) , results in quit attempts and abstinence . Methods : Identified smokers ( N=199 ) from a larger study of genetic testing were surveyed 3 months following receipt of their AAT genotype . The primary endpoint was the incidence of quit attempts . Results : Smokers who tested severely AAT deficient were significantly more likely to report a 24-hr quit attempt ( 59 % ) than were those who tested normal ( 26 % ) . Carriers had a 34 % quit attempt rate . Severely AAT deficient smokers were more likely than both carriers and normals to seek information on treatment , use pharmacotherapy for smoking cessation , and report greater reductions in their smoking . There were no group differences in 3-month abstinence rates . Conclusions : Knowledge of severe AAT deficiency , but not carrier status , may motivate smokers toward cessation . The AAT testing experience may have consequences for outcomes of other genetic conditions with modifiable health behaviors",
"Background The high prevalence of physical inactivity worldwide calls for innovative and more effective ways to promote physical activity ( PA ) . There are limited objective data on the effectiveness of Web-based personalized feedback on increasing PA in adults . Objective It is hypothesized that providing personalized advice based on PA measured objective ly alongside diet , phenotype , or genotype information would lead to larger and more sustained changes in PA , compared with nonpersonalized advice . Methods A total of 1607 adults in seven European countries were r and omized to either a control group ( nonpersonalized advice , Level 0 , L0 ) or to one of three personalized groups receiving personalized advice via the Internet based on current PA plus diet ( Level 1 , L1 ) , PA plus diet and phenotype ( Level 2 , L2 ) , or PA plus diet , phenotype , and genotype ( Level 3 , L3 ) . PA was measured for 6 months using triaxial accelerometers , and self-reported using the Baecke question naire . Outcomes were objective and self-reported PA after 3 and 6 months . Results While 1270 participants ( 85.81 % of 1480 actual starters ) completed the 6-month trial , 1233 ( 83.31 % ) self-reported PA at both baseline and month 6 , but only 730 ( 49.32 % ) had sufficient objective PA data at both time points . For the total cohort after 6 months , a greater improvement in self-reported total PA ( P=.02 ) and PA during leisure ( nonsport ) ( P=.03 ) was observed in personalized groups compared with the control group . For individuals advised to increase PA , we also observed greater improvements in those two self-reported indices ( P=.006 and P=.008 , respectively ) with increased personalization of the advice ( L2 and L3 vs L1 ) . However , there were no significant differences in accelerometer results between personalized and control groups , and no significant effect of adding phenotypic or genotypic information to the tailored feedback at month 3 or 6 . After 6 months , there were small but significant improvements in the objective ly measured physical activity level ( P moderate PA ( P sedentary time ( P objective PA . We found no evidence that personalized advice is more effective than conventional “ one size fits all ” guidelines to promote changes in PA in our Web-based intervention when PA was measured objective ly . Based on self-reports , PA increased to a greater extent with more personalized advice . Thus , it is crucial to measure PA objective ly in any PA intervention study . Trial Registration Clinical Trials.gov NCT01530139 ; http:// clinical trials.gov/show/NCT01530139 ( Archived by WebCite at : http://www.webcitation.org/6XII1QwHz",
"Background There are few empirical data to inform the debate surrounding the use and regulation of direct-to-consumer ( DTC ) genome-wide disease risk tests . This study aim ed to determine the long term psychological , behavioural , and clinical impacts of genomic risk testing for common disease . Methods The Scripps Genomic Health Initiative is a prospect i ve longitudinal cohort study of adults who purchased the Navigenics Health Compass , a commercially available genomic test . Web based assessment s were administered at baseline , short ( 3 months ) , and long term ( 1 year ) follow-up . Results 2240 participants completed either or both follow-ups and a subset of 1325 completed long term follow-up . There were no significant differences from baseline in anxiety ( p=0.50 ) , fat intake ( p=0.34 ) , or exercise ( p=0.39 ) at long term follow-up , and 96.8 % of the sample had no test related distress . Longitudinal linear mixed model analyses were consistent with results of cross-sectional analyses . Screening test completion was associated with sharing genomic test results with a physician ( 36.0 % shared ; p perceived utility of the test ( 61.5 % high perceived utility ; p=0.002 ) , but was not associated with the genomic risk estimate values themselves . Conclusions Over a third of DTC genomic test recipients shared their results with their own physician during an approximate 1 year follow-up period , and this sharing was associated with higher screening test completion . Genomic testing was not associated with long term psychological risks , and most participants reportedly perceived the test to be of high personal utility",
"PURPOSE Markers of genetic susceptibility to tobacco-related cancers could personalize harms of smoking and motivate cessation . Our objective was to assess whether a multicomponent intervention that included feedback about genetic susceptibility to lung cancer increased risk perceptions and rates of smoking cessation compared with a st and ard cessation intervention . EXPERIMENTAL DESIGN Our design was a two-arm trial with eligible smokers r and omized in a 1:2 ratio to Enhanced Usual Care or Biomarker Feedback ( BF ) . Surveys were conducted at baseline , 6 , and 12 months later . The setting was an inner city community health clinic . African-American patients who were current smokers ( n = 557 ) were identified by chart abstract ion and provider referral . All smokers received a self-help manual and , if appropriate , nicotine patches . Smokers in the BF arm also were offered a blood test for genotyping the GST(3 ) gene ( GSTM1 ) , sent a test result booklet , and called up to four times by a health educator . Prevalent abstinence was assessed by self-report of having smoked no cigarettes in the prior 7 days at the 6- and 12-month follow-ups and sustained abstinence , i.e. , not smoking at either follow-up or in-between . RESULTS Smoking cessation was greater for the BF arm than the Enhanced Usual Care arm ( 19 % versus 10 % , respectively ; P short-term cessation rates compared with st and ard intervention , genetic feedback of susceptibility may not benefit smokers with high baseline risk perceptions",
"Nutrigenetics research is anticipated to lay the foundation for personalized dietary recommendations ; however , it remains unclear if providing individuals with their personal genetic information changes dietary behaviors . Our objective was to evaluate if providing information for a common variant in the fatty acid desaturase 1 ( FADS1 ) gene changed omega-3 fatty acid ( FA ) intake and blood levels in young female adults ( 18–25 years ) . Participants were r and omized into Genetic ( intervention ) and Non-Genetic ( control ) groups , with measurements taken at Baseline and Final ( 12 weeks ) . Dietary intake of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) was assessed using an omega-3 food frequency question naire . Red blood cell ( RBC ) FA content was quantified by gas chromatography . Implication s of participation in a nutrigenetics study and awareness of omega-3 FAs were assessed with online question naires . Upon completion of the study , EPA and DHA intake increased significantly ( p = 1.0 × 10−4 ) in all participants . This change was reflected by small increases in RBC % EPA . Participants in the Genetic group showed increased awareness of omega-3 terminology by the end of the study , reported that the dietary recommendations were more useful , and rated cost as a barrier to omega-3 consumption less often than those in the Non-Genetic group . Providing participants FADS1 genetic information did not appear to influence omega-3 intake during the 12 weeks , but did change perceptions and behaviors related to omega-3 FAs in this timeframe",
"Background Proponents of consumer genetic tests cl aim that the information can positively impact health behaviors and aid in chronic disease prevention . However , the effects of disclosing genetic information on dietary intake behavior are not clear . Methods A double-blinded , parallel group , 2∶1 online r and omized controlled trial was conducted to determine the short- and long-term effects of disclosing nutrition-related genetic information for personalized nutrition on dietary intakes of caffeine , vitamin C , added sugars , and sodium . Participants were healthy men and women aged 20–35 years ( n = 138 ) . The intervention group ( n = 92 ) received personalized DNA-based dietary advice for 12-months and the control group ( n = 46 ) received general dietary recommendations with no genetic information for 12-months . Food frequency question naires were collected at baseline and 3- and 12-months after the intervention to assess dietary intakes . General linear models were used to compare changes in intakes between those receiving general dietary advice and those receiving DNA-based dietary advice . Results Compared to the control group , no significant changes to dietary intakes of the nutrients were observed at 3-months . At 12-months , participants in the intervention group who possessed a risk version of the ACE gene , and were advised to limit their sodium intake , significantly reduced their sodium intake ( mg/day ) compared to the control group ( −287.3±114.1 vs. 129.8±118.2 , p = 0.008 ) . Those who had the non-risk version of ACE did not significantly change their sodium intake compared to the control group ( 12-months : −244.2±150.2 , p = 0.11 ) . Among those with the risk version of the ACE gene , the proportion who met the targeted recommendation of 1500 mg/day increased from 19 % at baseline to 34 % after 12 months ( p = 0.06 ) . Conclusions These findings demonstrate that disclosing genetic information for personalized nutrition results in greater changes in intake for some dietary components compared to general population -based dietary advice . Trial Registration Clinical Trials.gov",
"Objective To test the hypothesis that adding obesity gene feedback ( FTO ) to simple weight control advice at a life stage with raised risk of weight gain ( university ) increases readiness to control weight . Methods Individually r and omized controlled trial comparing the effect of : ( i ) simple weight control advice plus FTO feedback ( FA ) and ( ii ) simple weight control advice only ( AO ) on readiness to engage with weight control . Differences in stage of change by genotype and differential weight control behaviors were secondary outcomes . Results Of 1,016 participants r and omized , only 279 completed follow-up , yielding 90 % power to detect a small effect for readiness to control weight . As predicted , FA participants were more likely to be in the contemplation stage than AO participants ( P = 0.023 ) . Participants receiving higher-risk genetic results were at a higher stage of change than controls ( P = 0.003 ) , with a trend toward a higher stage of change than those getting lower-risk results ( P = 0.051 ) . Lower-risk results did not decrease weight control intentions compared with controls ( P = 0.55 ) . There were no group differences in adherence to recommended weight control behaviors ( P = 0.87 ) . Conclusions Adding FTO feedback to weight control advice enhanced readiness to control weight , without evidence for genetic determinism , but had no more effect on behavior than weight control advice alone",
"Direct-to-consumer genetic testing has generated speculation about how customers will interpret results and how these interpretations will influence healthcare use and behavior ; however , few empirical data on these topics exist . We conducted an online survey of DTC customers of 23 and Me , deCODEme , and Navigenics to begin to address these questions . R and om sample s of U.S. DTC customers were invited to participate . Survey topics included demographics , perceptions of two sample DTC results , and health behaviors following DTC testing . Of 3,167 DTC customers invited , 33 % ( n = 1,048 ) completed the survey . Forty-three percent of respondents had sought additional information about a health condition tested ; 28 % had discussed their results with a healthcare professional ; and 9 % had followed up with additional lab tests . Sixteen percent of respondents had changed a medication or supplement regimen , and one-third said they were being more careful about their diet . Many of these health-related behaviors were significantly associated with responses to a question that asked how participants would perceive their colon cancer risk ( as low , moderate , or high ) if they received a test result showing an 11 % lifetime risk , as compared to 5 % risk in the general population . Respondents who would consider themselves to be at high risk for colon cancer were significantly more likely to have sought information about a disease ( p = 0.03 ) , discussed results with a physician ( p = 0.05 ) , changed their diet ( p = 0.02 ) , and started exercising more ( p = 0.01 ) . Participants ’ personal health context s — including personal and family history of disease and quality of self-perceived health — were also associated with health-related behaviors after testing . Subjective interpretations of genetic risk data and personal context appear to be related to health behaviors among DTC customers . Sharing DTC test results with healthcare professionals may add perceived utility to the tests",
"BACKGROUND Genetic susceptibility testing for Alzheimer disease ( AD ) with APOE genotype disclosure is not recommended for clinical use but is available through direct-to-consumer ( DTC ) genetic testing companies . Little is known about whether APOE genotype disclosure would actually prompt changes in nutrition behaviors among at-risk individuals . OBJECTIVE We studied the effect of APOE genotype disclosure for AD risk assessment on dietary supplement use in adults with a family history of AD . DESIGN As part of a secondary analysis of data from the second Risk Evaluation and Education for Alzheimer 's Disease Study , we examined the effect of genotype disclosure on health-behavior changes among 272 unaffected first-degree relatives of persons with AD . RESULTS Overall , 16 % of all participants reported a change in dietary supplement use after AD risk assessment . Participants who learned that they had at least one copy of the risk-increasing epsilon4 allele ( epsilon4 + ) had 4.75 times the odds of reporting a change in dietary supplement use than did their counterparts who had an absence of the risk-increasing epsilon4 allele ( epsilon4- ) ( 95 % CI : 2.23 , 10.10 ; P overall diet , exercise , or medications . CONCLUSIONS In this sample of first-degree relatives receiving genetic susceptibility testing for AD , an APOE epsilon4 + genotype status was positively associated with dietary supplement use after risk disclosure . Such changes occurred despite the absence of evidence that supplement use reduces the risk of AD . Given the expansion of DTC genetic tests , this study highlights the need for future studies in disease risk communication",
"Background and Objectives Although more and more genetic information is available , it is unclear whether this information is helpful for patients . Therefore , we assessed the positive and negative effects of informing obese people about the genetic etiology of being overweight . Design , Participants Two hundred ninety-four obese people were r and omized to 2 interventions ( a 1-session consultation for obese people on how to manage obesity either including genetic information or not ) ; their results were compared to a control group ( 116 ) . Subjects were assessed before and after consultation and 6 months later . Measurements Weight , scales on feeling guilty for being overweight , self-control , negative mood ( primary endpoint ) , body acceptance , restraint eating . Results Both types of consultations were considered helpful by the participants , and had comparable effects on body weight . The consultation with genetic information was rated superior in terms of leading to new insights ( advantage for consultation with genetic information , even 6 months later ; p = 0.046 ) . No negative effects ( e.g. , loss of self-efficacy/self-control , increase of body weight ; all p > 0.20 for interaction consultation × time ) were observed for informing obese people about the genetic etiology of being overweight . The consultation result ed in long-term improvement of negative mood if it included genetic information in the case of participants with a family history of obesity and if it included no genetic information in the case of obese people without a family history of obesity ( p = 0.03 for interaction of group , intervention , and time ) . Conclusions Consultations in obesity can be helpful in general . These consultations should include genetic information if people have a family history of obesity",
"This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia ( FH ) by finding a genetic mutation reduces patients ' perceptions of control over the disease and adherence to risk‐reducing behaviors . Three hundred forty‐one families , comprising 341 hypercholesterolemia prob and s and 128 adult relatives , were r and omized to one of two groups : ( a ) routine clinical diagnosis ; ( b ) routine clinical diagnosis plus genetic testing ( mutation search ing in prob and s and direct gene testing in relatives ) . The main outcome measures were perceptions of control over hypercholesterolemia , adherence to cholesterol‐lowering medication , diet , physical activity , and smoking . There was no support for the main hypothesis : finding a mutation had no impact on perceived control or adherence to risk‐reducing behavior ( all P‐values > 0.10 ) . While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack , participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level ( P = 0.02 at 6 months ) and showed a trend in believing more strongly in the efficacy of cholesterol‐lowering medication ( P = 0.06 at 6 months ) . In conclusion , finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk‐reducing behaviors . The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition , but does affect their perceptions of how control is most effectively achieved . Further work is needed to determine whether similar results will be obtained in population s with little previous awareness of their risks . © 2004 Wiley‐Liss ,",
"Objective We examined the clinical utility of supplementing type 2 diabetes mellitus ( DM ) risk counseling with DM genetic test results and counseling . Research Design and Methods In this r and omized controlled trial , non-diabetic overweight/obese veteran out patients aged 21 to 65 years received DM risk estimates for lifetime risk , family history , and fasting plasma glucose , followed by either genetic test results ( CR+G ; N = 303 ) or control eye disease counseling ( CR+EYE ; N = 298 ) . All participants received brief lifestyle counseling encouraging weight loss to reduce the risk of DM . Results The mean age was 54 years , 53 % of participants were black , and 80 % were men . There was no difference between arms in weight ( estimated mean difference between CR+G vs. CR+EYE at 3 months = 0.2 kg , 95 % CI : −0.3 to 0.7 ; at 6 months = 0.4 kg , 95 % CI : −0.3 to 1.1 ) , insulin resistance , perceived risk , or physical activity at 3 or 6 months . Calorie and fat intake were lower in the CR+G arm at 3 months ( p ’s ≤ 0.05 ) but not at 6 months ( p ’s > 0.20 ) . Conclusions Providing patients with genetic test results was not more effective in changing patient behavior to reduce the risk of DM compared to conventional risk counseling . Trial registration : Clinical Trials.gov NCT01060540 http:// clinical",
"OBJECTIVES It is well-known that smoking causes many diseases including cancers . Informing smokers of their genotypes associated with the vulnerability to the harms of smoking may be effective measures for smoking cessation . The present study examined the effects of genotype notification of an oncogene ( L-myc ) genotype to smokers on their behavior to quit smoking . METHODS Subjects were 562 employees of a bank who answered to be a smoker for a question naire used at annual health checkup at workplace from July to December 2002 . Those enrolled on August , October , and December were allocated into the genotype notification group ( intervention group ) , and the rest into the controls . Among 286 smokers allocated into the intervention group , 257 participants ( 89.9 % ) agreed to genotype testing . One year after the enrollment , a follow-up question naire survey was conducted for all smokers including controls . RESULTS Those who stated to have quitted smoking were 22 ( 8.0 % ) among the 276 controls and 15 ( 5.8 % ) among the 257 genotype notified participants , providing that the odds ratio ( OR ) of cessation for the intervention was 0.64 ( 95 % confidence interval , 0.32 - 1.28 ) . No psychological problems associated with genotype notification were observed . CONCLUSION The present study did not show positive effects of genotype notification on smoking cessation rate . To elevate the cessation rate , methods to explain and notify genotypes should be improved",
"ABSTRACT The present study prospect ively examined change in diet and physical activity behaviors in 115 women undergoing BRCA1/2 gene testing ( 46 mutation positive , 46 uninformative and 23 definitive negative ) . Participants completed measures of diet and physical activity at three time points : prior to genetic testing and 1- and 6-months after receipt of genetic test results . Repeated measures analyses examined between- and within-group differences among participants who received BRCA1/2 positive , uninformative , or definitive negative results . There were no within-group differences across time points or between-group differences at any time point for diet or physical activity . Most participants , overall and within each group , did not meet recommended guidelines for fruit and vegetable and dietary fat consumption . These findings suggest that women do not make spontaneous changes in diet and physical activity following the genetic testing and counseling process . A brief intervention may be necessary for patients who are interested in making changes in modifiable risk factors to complement more definitive risk-reduction strategies",
"Risk information for Alzheimer disease ( AD ) may be communicated through susceptibility gene disclosure , even though this is not currently in clinical use . The REVEAL Study is the first r and omized clinical trial of risk assessment for AD with apolipoprotein E ( APOE ) genotype and numerical risk estimate disclosure . We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors . One hundred sixty-two participants were r and omized to either intervention ( APOE disclosure ) or control ( no genotype disclosure ) groups . Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD . The intervention group received their APOE genotype . Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation . Participants who learned they were ϵ4 positive were significantly more likely than ϵ4 negative participants to report AD-specific health behavior change 1 year after disclosure ( adjusted odds ratio : 2.73 ; 95 % confidence interval : 1.14 , 6.54 ; P=0.02 ) . Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change . Despite lack of preventive measures for AD , knowledge of APOE genotype , numerical lifetime risk , or both , influences health behavior",
"BACKGROUND To evaluate whether feedback of genetic information regarding an L-myc polymorphism , identified as impacting on tobacco-related cancer risk , has an influence on smoking cessation , an intervention study was conducted . METHODS We recruited smokers from first-visit out patients at Aichi Cancer Center Hospital . Six hundred and seventeen participated and were allocated into two groups : the biomarker feedback group ( BF ) and the follow-up smoking status group ( FS ) . The subjects were asked for their smoking status at enrolment and at 3- and 9-month follow-ups . BF subjects were notified about their L-myc genotype . RESULTS The smoking cessation rate at 9-month follow-up was essentially the same for both BF and FS cases , at 18.8 % and 17.0 % , respectively ( P = 0.798 ) . However , a difference in the rate was evident with non-cancer subjects ( 12.7 % and 8.4 % , respectively , P = 0.237 ) , especially in females ( 15.0 % and 4.2 % , respectively , P = 0.024 ) . The non-cancer subjects informed of their genotype were more likely to quit smoking than the FS patients ; particularly in those having a risky genotype , this was significant ( odds ratio : 2.87 , P = 0.003 ) . Again it was most prominent in females . CONCLUSION Feedback regarding an L-myc polymorphism did not impact on smoking cessation overall but appeared to benefit smokers without cancer . In addition , gender could affect the response to the feedback",
"Objective To test the hypothesis that communicating risk of developing Crohn ’s disease based on genotype and that stopping smoking can reduce this risk , motivates behaviour change among smokers at familial risk . Design Parallel group , cluster r and omised controlled trial . Setting Families with Crohn ’s disease in the United Kingdom . Participants 497 smokers ( mean age 42.6 ( SD 14.4 ) years ) who were first degree relatives of prob and s with Crohn ’s disease , with outcomes assessed on 209/251 ( based on DNA analysis ) and 217/246 ( st and ard risk assessment ) . Intervention Communication of risk assessment for Crohn ’s disease by postal booklet based on family history of the disease and smoking status alone , or with additional DNA analysis for the NOD2 genotype . Participants were then telephoned by a National Health Service Stop Smoking counsellor to review the booklet and deliver brief st and ard smoking cessation intervention . Calls were tape recorded and a r and om sub sample selected to assess fidelity to the clinical protocol . Main outcome measure The primary outcome was smoking cessation for 24 hours or longer , assessed at six months . Results The proportion of participants stopping smoking for 24 hours or longer did not differ between arms : 35 % ( 73/209 ) in the DNA arm versus 36 % ( 78/217 ) in the non-DNA arm ( difference −1 % , 95 % confidence interval −10 % to 8 % , P=0.83 ) . The proportion making a quit attempt within the DNA arm did not differ between those who were told they had mutations putting them at increased risk ( 36 % ) , those told they had none ( 35 % ) , and those in the non-DNA arm ( 36 % ) . Conclusion Among relatives of patients with Crohn ’s disease , feedback of DNA based risk assessment s does not motivate behaviour change to reduce risk any more or less than st and ard risk assessment . These findings accord with those across a range of population s and behaviours . They do not support the promulgation of commercial DNA based tests nor the search for gene variants that confer increased risk of common complex diseases on the basis that they effectively motivate health related behaviour change . Trial registration Current Controlled Trials IS RCT N21633644",
"BACKGROUND Type 2 diabetes affects approximately 8 percent of adults in the United States . Some risk factors -- elevated plasma glucose concentrations in the fasting state and after an oral glucose load , overweight , and a sedentary lifestyle -- are potentially reversible . We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes . METHODS We r and omly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo , metformin ( 850 mg twice daily ) , or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week . The mean age of the participants was 51 years , and the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 34.0 ; 68 percent were women , and 45 percent were members of minority groups . RESULTS The average follow-up was 2.8 years . The incidence of diabetes was 11.0 , 7.8 , and 4.8 cases per 100 person-years in the placebo , metformin , and lifestyle groups , respectively . The lifestyle intervention reduced the incidence by 58 percent ( 95 percent confidence interval , 48 to 66 percent ) and metformin by 31 percent ( 95 percent confidence interval , 17 to 43 percent ) , as compared with placebo ; the lifestyle intervention was significantly more effective than metformin . To prevent one case of diabetes during a period of three years , 6.9 persons would have to participate in the lifestyle-intervention program , and 13.9 would have to receive metformin . CONCLUSIONS Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk . The lifestyle intervention was more effective than metformin",
"The behavioural and psychological impact of genetic testing for lung cancer susceptibility was examined among smokers ( N = 61 ) who were r and omly allocated to a GSTM1 genetic testing group ( with GSTM1-missing or GSTM1-present result ) or no-test control group . The GSTM1-missing ( higher risk ) group reported greater motivation to quit smoking , and both genetic testing groups reported lower depression than the control group at one-week follow-up ( p < .05 for all ) . Differences were not significant at two months follow-up . This study indicates the feasibility of much-needed research into the risks and benefits for individuals of emerging lifestyle-related genetic susceptibility tests",
"This study evaluated the long-term impact of genetic susceptibility biomarker feedback on smoking behavior change and symptoms of depression in 426 male and female smokers . Smokers were r and omized to one of three smoking-cessation interventions : minimal contact quit-smoking counseling ( QSC ) , QSC + exposure biomarker feedback ( EBF ) , and QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer ( SBF ) . The logistic regression model for quit attempt revealed a significant main effect for treatment such that participants in the SBF group were more than two times more likely to make a quit attempt than participants in the QSC group . There was not a significant difference between EBF and QSC participants . The results also revealed a significant effect for baseline stage of change . Those smokers in the preparation stage at baseline were more than three times more likely to make a quit attempt over the 12 months following treatment . The models for 30-day cessation and follow-up smoking rate revealed no significant main or interacting effects for treatment . A repeated measures analysis of variance revealed a significant main effect for time , indicating that an initial increase in depression in the genetic susceptibility group was not maintained over time . Genetic susceptibility feedback has the intended effects on motivation to quit , but it may need to be delivered within a more intensive smoking-cessation treatment for the heightened motivation to translate into smoking cessation",
"The seven articles in this issue , and the accompanying meta- analysis in Health Psychology Review [ McEachan , R.R.C. , Conner , M. , Taylor , N. , & Lawton , R.J. ( 2011 ) . Prospect i ve prediction of health-related behaviors with the theory of planned behavior : A meta- analysis . Health Psychology Review , 5 , 97–144 ] , illustrate the wide application of the theory of planned behaviour [ Ajzen , I. ( 1991 ) . The theory of planned behavior . Organizational Behavior and Human Decision Processes , 50 , 179–211 ] in the health domain . In this editorial , Ajzen reflects on some of the issues raised by the different authors . Among the topics addressed are the nature of intentions and the limits of predictive validity ; rationality , affect and emotions ; past behaviour and habit ; the prototype/willingness model ; and the role of such background factors as the big five personality traits and social comparison tendency"
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BACKGROUND Poor adherence to anti-diabetic medications contributes to suboptimal glycaemic control in patients with type 2 diabetes ( T2D ) . A range of interventions have been developed to promote anti-diabetic medication adherence . However , there has been very little focus on the characteristics of these interventions and how effectively they address factors that predict non-adherence . In this systematic review we assessed the characteristics of interventions that aim ed to promote adherence to anti-diabetic medications . METHOD Using appropriate search terms in Medline , Embase , CINAHL , International Pharmaceutical Abstract s ( IPA ) , PUBmed , and PsychINFO ( years 2000 - 2013 ) , we identified 52 studies which met the inclusion criteria . RESULTS Forty-nine studies consisted of patient-level interventions , two provider-level interventions , and one consisted of both . Interventions were classified as educational ( n = 7 ) , behavioural ( n = 3 ) , affective , economic ( n = 3 ) or multifaceted ( a combination of the above ; n = 40 ) . One study consisted of two interventions . The review found that multifaceted interventions , addressing several non-adherence factors , were comparatively more effective in improving medication adherence and glycaemic target in patients with T2D than single strategies . However , interventions with similar components and those addressing similar non-adherence factors demonstrated mixed results , making it difficult to conclude on effective intervention strategies to promote adherence . Educational strategies have remained the most popular intervention strategy , followed by behavioural , with affective components becoming more common in recent years . Most of the interventions addressed patient-related ( n = 35 ) , condition-related ( n = 31 ) , and therapy-related ( n = 20 ) factors as defined by the World Health Organization , while fewer addressed health care system ( n = 5 ) and socio-economic-related factors ( n = 13 ) . CONCLUSION There is a noticeable shift in the literature from using single to multifaceted intervention strategies addressing a range of factors impacting adherence to medications . However , research limitations , such as limited use of st and ardized methods and tools to measure adherence , lack of individually tailored adherence promoting strategies and variability in the interventions developed , reduce the ability to generalize the findings of the studies review ed . Furthermore , this review highlights the need to develop multifaceted interventions which can be tailored to the individual patient 's needs over the duration of their diabetes management
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"Abbreviations ACCORD Action to Control Cardiovascular Risk in Diabetes ADVANCE Action in Diabetes and Vascular Disease : Preterax and Diamicron Modified-Release Controlled Evaluation AGI α-Glucosidase inhibitor CAD Coronary artery disease CKD Chronic kidney disease CVD Cardiovascular disease DPP-4 Dipeptidyl peptidase IV GIP Glucose-dependent insulinotropic peptide GLP-1 Glucagon-like peptide 1 NPH Neutral protamine Hagedorn TZD Thiazolidinedione UKPDS UK Prospect i ve Diabetes Study VADT Veterans Affairs Diabetes",
"Purpose The purpose of this study was to examine whether integrating depression treatment into care for type 2 diabetes mellitus among older African Americans improved medication adherence , glycemic control , and depression outcomes . Methods Older African Americans prescribed pharmacotherapy for type 2 diabetes mellitus and depression from physicians at a large primary care practice in west Philadelphia were r and omly assigned to an integrated care intervention or usual care . Adherence was assessed at baseline , 2 , 4 , and 6 weeks using the Medication Event Monitoring System to assess adherence . Outcomes assessed at baseline and 12 weeks included st and ard laboratory tests to measure glycemic control and the Center for Epidemiologic Studies Depression Scale ( CES-D ) to assess depression . Results In all , 58 participants aged 50 to 80 years participated . The proportion of participants who had 80 % or greater adherence to an oral hypoglycemic ( intervention 62.1 % vs usual care 24.1 % ) and an antidepressant ( intervention 62.1 % vs usual care 10.3 % ) was greater in the intervention group in comparison with the usual care group at 6 weeks . Participants in the integrated care intervention had lower levels of glycosylated hemoglobin ( intervention 6.7 % vs usual care 7.9 % ) and fewer depressive symptoms ( CES-D mean scores : intervention 9.6 vs usual care 16.6 ) compared with participants in the usual care group at 12 weeks . Conclusion A pilot r and omized controlled trial integrating type 2 diabetes mellitus treatment and depression was successful in improving outcomes among older African Americans . Integrated interventions may be more feasible and effective in real-world practice s with competing dem and s for limited re sources",
"Purpose The purpose of this study was to evaluate the effectiveness of integrative health ( IH ) coaching on psychosocial factors , behavior change , and glycemic control in patients with type 2 diabetes . Methods Fifty-six patients with type 2 diabetes were r and omized to either 6 months of IH coaching or usual care ( control group ) . Coaching was conducted by telephone for fourteen 30-minute sessions . Patients were guided in creating an individualized vision of health , and goals were self-chosen to align with personal values . The coaching agenda , discussion topics , and goals were those of the patient , not the provider . Preintervention and postintervention assessment s measured medication adherence , exercise frequency , patient engagement , psychosocial variables , and A1C . Results Perceived barriers to medication adherence decreased , while patient activation , perceived social support , and benefit finding all increased in the IH coaching group compared with those in the control group . Improvements in the coaching group alone were also observed for self-reported adherence , exercise frequency , stress , and perceived health status . Coaching participants with elevated baseline A1C ( ≥7 % ) significantly reduced their A1C . Conclusions A coaching intervention focused on patients ’ values and sense of purpose may provide added benefit to traditional diabetes education programs . Fundamentals of IH coaching may be applied by diabetes educators to improve patient self-efficacy , accountability , and clinical outcomes",
"Purpose The purpose of this pilot study was to evaluate a culturally tailored intervention for rural African Americans . Social Cognitive Theory provided the framework for the study . Methods Twenty-two participants were recruited and r and omly assigned to either Group or Individual diabetes self-management ( DSME ) . Group DSME included story-telling , h and s-on activities , and problem-solving exercises . Individual DSME sessions focused on goal - setting and problem-solving strategies . Sessions were offered in an accessible community center over a 10-week period . Results Outcomes included glycosylated hemoglobin ( A1C ) , self-care actions , self-efficacy level , goal attainment , and satisfaction with DSME . Participants in both Group and Individual DSME improved slightly over the 3-month period in self-care activities , A1C level , and goal attainment . Although differences were not statistically significant , trends indicate improved scores on dietary actions , foot care , goal attainment , and empowerment for those experiencing Group DSME . Conclusions The culturally tailored approach was well received by all participants . Improvements among those receiving Individual DSME may indicate that brief sessions using a culturally tailored approach could enhance self-care and glycemic control . Additional testing among more participants over a longer time period is recommended",
"PURPOSE This study was conducted to determine whether objective clinical , patient performance , quality -of-life , and subjective outcomes are significantly different among African American men with type 2 diabetes who received follow-up at either monthly or 3-month intervals after participating in a structured diabetes self-management education program . METHODS Prior to the diabetes self-management education program , 30 African American men with type 2 diabetes were r and omly assigned to 2 groups to receive telephone follow-up at either monthly or 3-month intervals over a 6-month period . Information obtained at follow-up contact included HbA1c level , perception of general health , and present diabetes knowledge . In addition , daily foot care , dietary , exercise , and medication compliance measures were assessed postprogram . RESULTS There were no significant differences between the participants who received follow-up at monthly and 3-month intervals on any measures of the selected clinical , patient performance , quality -of-life , and subjective outcomes . CONCLUSIONS This cross-sectional study showed that telephone follow-up at 3 month intervals following a structured program of diabetes self-management education may be just as effective in contributing to favorable diabetes health outcomes as monthly follow-up",
"AIM To compare the effectiveness of two methods of follow-up : short message service and telephone follow-up on type 2 diabetes adherence for three months . BACKGROUND Using telemedicine approaches may preserve appropriate blood glucose levels and may improve adherence to diabetes control recommendations in diabetic patients . DESIGN A quasi-experimental , two-group , pretest and post-test design was used in this study to evaluate the effectiveness of nurse 's follow-up via cellular phones and telephones . METHODS The sample consisted of 77 patients with type 2 diabetes that r and omly were assigned to two groups : telephone follow-up ( n = 39 ) and short message service ( n = 38 ) . Telephone interventions were applied by a research er for three months ; twice a week for the first month and every week for the second and third month . For three successive months , the short message service group that received messages about adherence to therapeutic regimen was examined . The data gathering instrument included data sheets - to record glycosylated haemoglobin - and the question naire related to adherence therapeutic regimen . Data gathering was carried out at the beginning of the study and after three and six months . The data were analysed using descriptive and inferential statistic methods with SPSS version 11.5 . RESULTS Results showed that both interventions had significant mean changes in glycosylated haemoglobin . For the telephone group ( p short message service group ( p diet adherence ( p = 0.000 ) , physical exercise ( p = 0.000 ) and medication taking ( p = 0.000 ) adherence in either groups . CONCLUSION Intervention using short message services of cellular phones and nurse-led-telephone follow-up improved HbA1c levels and adherence to diabetes therapeutic regimen for three months in type 2 diabetic patients . RELEVANCE TO CLINICAL PRACTICE Both of follow-up intervention uses in this study can decrease HbA1c levels and escalate adherence to diabetes control recommendations in people with type 2 diabetes for three months",
"Background Failure to take medication reduces the effectiveness of treatment leading to increased morbidity and mortality . We evaluated the efficacy of a consultation-based intervention to support objective ly-assessed adherence to oral glucose lowering medication ( OGLM ) compared to usual care among people with type 2 diabetes . Methods This was a parallel group r and omised trial in adult patients with type 2 diabetes and HbA1c≥7.5 % ( 58 mmol/mol ) , prescribed at least one OGLM . Participants were allocated to a clinic nurse delivered , innovative consultation-based intervention to strengthen patient motivation to take OGLM regularly and support medicine taking through action-plans , or to usual care . The primary outcome was the percentage of days on which the prescribed dose of medication was taken , measured objective ly over 12 weeks with an electronic medication-monitoring device ( TrackCap , Aardex , Switzerl and ) . The primary analysis was intention-to-treat . Results 211 patients were r and omised between July 1 , 2006 and November 30 , 2008 in 13 British general practice s ( primary care clinics ) . Primary outcome data were available for 194 participants ( 91.9 % ) . Mean ( sd ) percentage of adherent days was 77.4 % ( 26.3 ) in the intervention group and 69.0 % ( 30.8 ) in st and ard care ( mean difference between groups 8.4 % , 95 % confidence interval 0.2 % to 16.7 % , p = 0.044 ) . There was no significant adverse impact on functional status or treatment satisfaction . Conclusions This well-specified , theory based intervention delivered in a single session of 30 min in primary care increased objective ly measured medication adherence , with no adverse effect on treatment satisfaction . These findings justify a definitive trial of this approach to improving medication adherence over a longer period of time , with clinical and cost-effectiveness outcomes to inform clinical practice .Trial registration Current Controlled Trials IS RCT",
"OBJECTIVE This study examined the impact of a 6-month , empowerment-based diabetes self-management support ( DSMS ) intervention on clinical outcomes , self-care behaviors , and quality of life ( QOL ) compared to a 6-month control period . METHODS This control-intervention cohort study recruited 77 African-American adults with type 2 diabetes . Baseline , 6-month , and 12-month assessment s measured A1C , weight , body mass index ( BMI ) , blood pressure , lipids , self-care behaviors , and QOL . During the control period , participants received weekly educational newsletters . During the intervention period , participants attended weekly DSMS groups as frequently as they needed . Sessions were guided by participants ' self-management questions and concerns , and also emphasized experiential learning , coping , problem-solving , and goal - setting . RESULTS The control period found significant improvements for diastolic BP ( p serum cholesterol ( p following a healthy diet ( p monitoring blood glucose ( p A1C ( p weight ( p BMI ( p LDL ( p A1C ( p empowerment-based , DSMS intervention is promising for improving and /or maintaining diabetes-related health , particularly A1C . PRACTICAL IMPLICATION S Incorporating empowerment principles in DSMS interventions may be useful for supporting patients ' self-management efforts in \" real-world \" setting",
"Objective To test the effectiveness of peer support for patients with type 2 diabetes . Design Cluster r and omised controlled . Setting 20 general practice s in the east of the Republic of Irel and . Participants 395 patients ( 192 in intervention group , 203 in control group ) and 29 peer supporters with type 2 diabetes . Intervention All practice s introduced a st and ardised diabetes care system . The peer support intervention ran over a two year period and contained four elements : the recruitment and training of peer supporters , nine group meetings led by peer supporters in participant ’s own general practice , and a retention plan for the peer supporters . Main outcome measures HbA1c ; cholesterol concentration ; systolic blood pressure ; and wellbeing score . Results There was no difference between intervention and control patients at baseline . All practice s and 85 % ( 337 ) of patients were followed up . At two year follow-up , there were no significant differences in HbA1c ( mean difference −0.08 % , 95 % confidence interval −0.35 % to 0.18 % ) , systolic blood pressure ( −3.9 mm Hg , −8.9 to 1.1 mm Hg ) , total cholesterol concentration ( −0.03 mmol/L , −0.28 to 0.22 mmol/L ) , or wellbeing scores ( −0.7 , −2.3 to 0.8 ) . While there was a trend towards decreases in the proportion of patients with poorly controlled risk factors at follow-up , particularly for systolic blood pressure ( 52 % ( 87/166 ) > 130 mm Hg in intervention v 61 % ( 103/169 ) > 130 mm Hg in control ) , these changes were not significant . The process evaluation indicated that the intervention was generally delivered as intended , though 18 % ( 35 ) of patients in the intervention group never attended any group meetings . Conclusions A group based peer support intervention is feasible in general practice setting s , but the intervention was not effective when targeted at all patients with type 2 diabetes . While there was a trend towards improvements of clinical outcomes , the results do not support the widespread adoption of peer support . Trial registration Current Controlled Trials IS RCT N42541690",
"OBJECTIVE To compare the effectiveness of a telephonic and a print intervention over 1 year to improve diabetes control in low-income urban adults . RESEARCH DESIGN AND METHODS A r and omized trial in Spanish and English comparing a telephonic intervention implemented by health educators with a print intervention . Participants ( N = 526 ) had an A1C ≥7.5 % and were prescribed one or more oral agents . All were members of a union/employer jointly sponsored health benefit plan . Health coverage included medications . Primary outcomes were A1C and pharmacy cl aims data ; secondary outcomes included self-report of two medication adherence measures and other self-care behaviors . RESULTS Participants were 62 % black and 23 % Hispanic ; 77 % were foreign born , and 42 % had annual family incomes . Baseline median A1C was 8.6 % ( interquartile range 8.0–10.0 ) . Insulin was also prescribed for 24 % of participants . The telephone group had mean ± SE decline in A1C of 0.23 ± 0.11 % over 1 year compared with a rise of 0.13 ± 0.13 % for the print group ( P = 0.04 ) . After adjusting for baseline A1C , sex , age , and insulin use , the difference in A1C was 0.40 % ( 95 % CI 0.10–0.70 , P = 0.009 ) . Change in medication adherence measured by cl aims data , but not by self-report measures , was significantly associated with change in A1C ( P = 0.01 ) . Improvement in medication adherence was associated ( P = 0.005 ) with the telephonic intervention , but only among those not taking insulin . No diabetes self-care activities were significantly correlated with the change in A1C . CONCLUSIONS A 1-year tailored telephonic intervention implemented by health educators was successful in significantly , albeit modestly , improving diabetes control compared with a print intervention in a low-income , insured , minority population",
"The increasing prevalence of diabetes and obesity , growing health disparities , and shortage of bilingual and culturally trained health care professionals underscore the role of trained community health workers ( CHWs ) to provide economically sustainable and culturally relevant services . This prospect i ve r and omized design evaluated the relative effectiveness of a CHW intervention among Hispanic persons with newly diagnosed type 2 diabetes , as compared with usual clinic practice in three inner-city health centers . In sum , 189 Hispanic patients newly diagnosed with type 2 diabetes were r and omly assigned to one of three 6-month diabetes management approaches — CHW , case management , and st and ard provider care— and assessed for diabetes-related health measures and clinical indicators at baseline and postintervention . Participants in the CHW group achieved greater improvements than did the controls in program measures : health status , emergency department utilization , dietary habits , physical activity , and medication adherence . They also had 2.9 times greater odds of decreasing body mass index",
"BACKGROUND Patient involvement in the choice of antihyperglycemic agents could improve adherence and optimize glycemic control in patients with type 2 diabetes mellitus . METHODS We conducted a pilot , cluster r and omized trial of Diabetes Medication Choice , a decision aid that describes 5 antihyperglycemic drugs , their treatment burden ( adverse effects , administration , and self-monitoring dem and s ) , and impact on hemoglobin A(1c ) ( HbA(1c ) ) levels . Twenty-one clinicians were r and omized to use the decision aid during the clinical encounter and 19 to dispense usual care and an educational pamphlet . We used surveys and video analysis to assess postvisit decisional outcomes , and medical and pharmacy records to assess 6-month medication adherence and HbA(1c ) levels . RESULTS Compared with usual care patients ( n = 37 ) , patients receiving the decision aid ( n = 48 ) found the tool more helpful ( clustered-adjusted mean difference [ AMD ] in a 7-point scale , 0.38 ; 95 % confidence interval [ CI ] , 0.04 - 0.72 ) ; had improved knowledge ( AMD , 1.10 of 10 questions ; 95 % CI , 0.11 - 2.09 ) ; and had more involvement in making decisions about diabetes medications ( AMD , 21.8 of 100 ; 95 % CI , 13.0 - 30.5 ) . At 6-month follow-up , both groups had nearly perfect medication use ( median , 100 % of days covered ) , with better adherence ( AMD , 9 % more days covered ; 95 % CI , 4%-14 % ) and persistence ( AMD , 12 more days covered ; 95 % CI , 3 - 21 days ) in the usual care group , and no significant impact on HbA(1c ) levels ( AMD , 0.01 ; 95 % CI , -0.49 to 0.50 ) . CONCLUSION An innovative decision aid effectively involved patients with type 2 diabetes mellitus in decisions about their medications but did not improve adherence or HbA(1c ) levels . Trial Registration clinical trials.gov Identifier : NCT00388050",
"OBJECTIVES To investigate the acceptability and feasibility of using short message services ( SMS ) via cell phones to ensure adherence to management prescriptions by diabetic patients . METHODS Type 2 diabetic patients with 5 or more years of diabetes and having HbA1c between 7.0 % to 10 % were r and omized to the control arm ( n = 105 ) to receive st and ard care and to the intervention arm ( SMS , n = 110 ) . Messages in English on principles of diabetes management were sent once in 3 days , the contents and frequencies varied as per the patients ' preferences . The study duration was 1 year . All participants were advised to report for quarterly clinic visits . A comparative assessment of the clinical , biochemical and anthropometric outcomes was made among the groups at the annual visit . RESULTS Annual review was possible in 71 % of intervention group and 63 % of control group . SMS was acceptable to the patients and the median number requested was 2 per week . HbA1c and plasma lipids improved significantly in the SMS group . CONCLUSIONS The pilot study showed that frequent communication via SMS was acceptable to diabetic patients and it helped to improve the health outcomes",
"OBJECTIVE The aim of this study was to examine patient-reported outcomes in a controlled trial of a multifaceted provider-level intervention to improve quality of care for rural patients with type 2 diabetes . RESEARCH DESIGN AND METHODS We conducted a before/after intervention study with concurrent controls in two rural regions in Alberta , Canada . The intervention consisted of six monthly visits by a multidisciplinary health care team and was primarily directed at primary care providers . Clinical and patient-reported outcomes were assessed after 6 months . Patient-reported outcomes included changes in health-related quality of life ( Health Utilities Index Mark 3 [ HUI3 ] ) , satisfaction with care , lifestyle ( Diabetes Lifestyle Form ) , and adherence to self-care activities . Analysis of covariance was used to assess differences over time between the control and intervention regions . RESULTS A total of 200 intervention and 172 control subjects were included in this analysis . After adjusting for important clinical and demographic differences , a statistically significant and clinical ly important improvement in the overall HUI3 score was seen at the 6-month follow-up in the intervention region ( 0.06 [ 95 % CI 0.02 - 0.10 ] ) compared with the control region ( 0.01 [ -0.04 to 0.04 ] ) ( P = 0.03 for the difference between groups ) . Satisfaction with general medical care ( P diabetes care ( P Self-efficacy , attitudes , and beliefs about diabetes control all increased in the intervention region when compared with the control region , but adherence to self-care activities did not . CONCLUSIONS A provider-level intervention directed at improving quality of clinical care for patients with type 2 diabetes also had a favorable impact on overall health-related quality of life , satisfaction with care , and other humanistic outcomes",
"Introduction This study evaluated the impact of a waiting room-administered , low-literacy , computer multimedia diabetes education program on patient self-management and provider intensification of therapy . Methods In this r and omized , controlled trial , 129 participants either viewed a computer multimedia education program ( intervention group ) or read an educational brochure ( control group ) while in the waiting room . Participants were uninsured , primarily ethnic minority adults with type 2 diabetes receiving care from a county clinic in Chicago , Illinois . Wilcoxon test , t-test , and linear mixed model analyses evaluated changes in diabetes knowledge , self-efficacy , behaviors , medications prescribed , hemoglobin A1c ( HbA1c ) , and blood pressure levels over 3 months . Results During the study period , there was an increase in the number of oral diabetes medications prescribed over three months to multimedia users compared with those in the control group ( P=0.017 ) . HbA1c declined by 1.5 in the multimedia group versus 0.8 in the control group ( P=0.06 ) . There were no differences between groups in changes in blood pressure levels , self-efficacy , and most diabetes-related behaviors . Self-reported exercise increased in the control group compared with the multimedia group ( 0.9 days/week vs. 0.1 days/week , P=0.016 ) . Conclusion Multimedia users received a greater intensification of diabetes therapy , but demonstrated no difference in self-management in comparison with those receiving educational brochures . The availability of a computer multimedia program in the waiting room appears to be a novel and acceptable approach in providing diabetes education for underserved population",
"PURPOSE Chilean patients with type 2 diabetes mellitus ( T2DM ) have a low rate of blood sugar control . We studied the effectiveness of a culturally sensitive family oriented intervention design ed to improve metabolic control in primary care patients with uncontrolled T2DM . METHODS Patients with T2DM from three primary care clinics in Santiago , Chile were r and omly selected for inclusion if they had a recent HbA1c ≥7 % , were between 18 and 70 years old and lived with a family member . Patients from one clinic received the family oriented intervention ; patients from the other two ( control ) clinics received st and ard care . The intervention involved family members in care and included family counselling during clinic visits , family meetings and home visits . The primary outcome was HbA1c , measured at 6 and 12 months . RESULTS A total of 243 patients were enrolled and 209 ( 86 % ) completed the study . The intervention was fully administered to only 34 % of patients in the intervention clinic . The reduction in the HbA1c from baseline to 12 months was not significantly different between clinics . During the second 6-month period , when the intervention was more intensive , the patients in the intervention clinic significantly improved their HbA1c ( P CONCLUSIONS A family intervention for the control of T2DM was associated with a significant reduction in HbA1c when the intervention was provided . Incomplete implementation , low statistical power and potential confounding variables between groups could be some of the main factors that explain the lack of difference between clinics in the 12-month period",
"Objective To evaluate the efficiency of pharmaceutical care on the control of clinical parameters , such as fasting glycaemia and glycosylated haemoglobin in patients with Type 2 Diabetes mellitus . Setting This study was conducted at the Training and Community Health Centre of the College of Medicine of Ribeirao Preto , University of Sao Paulo , Brazil . Methods A prospect i ve and experimental study was conducted with 71 participants divided in two groups : ( i ) pharmaceutical care group ( n=40 ) , and ( ii ) the control group ( n=31 ) . The distribution of patients within these groups was made casually , and the patients were monitored for 12 months . Main outcome measure : Values for fasting glycaemia and glycosylated haemoglobin were collected . Results Mean values of fasting glycaemia in the pharmaceutical care group were significantly reduced whilst a small reduction was detected in the control group at the same time . A significant reduction in the levels of glycosylated haemoglobin was detected in patients in the pharmaceutical care group , and an average increase was observed in the control group . Furthermore , the follow-up of the intervention group by a pharmacist contributed to the resolution of 62.7 % of 142 drug therapy problems identified . Conclusion In Brazil , the information provided by a pharmacist to patients with Type 2 Diabetes mellitus increases compliance to treatment , solving or reducing the Drug Therapy Problem and , consequently , improving glycaemic control",
"OBJECTIVE : To improve medication adherence by reducing self-reported adherence barriers , and to identify medication discrepancies by comparing physician-prescribed and patient-reported medical regimens . DESIGN : Prospect i ve , r and omized , controlled trial . SETTING AND PARTICIPANTS : A single academically affiliated community health center . Eligible patients had type 2 diabetes , had undergone laboratory testing in the year preceding the study , and had visited the clinic in the 6 months preceding the study . INTERVENTION : A pharmacist administered detailed question naires , provided tailored education regarding medication use and help with appointment referrals , and created a summary of adherence barriers and medication discrepancies that was entered into the medical record and electronically forwarded to the primary care provider . MEASUREMENTS : Changes in self-reported adherence rates and barriers were compared 3 months after the initial interview . Intervention patients with medication discrepancies at baseline were assessed for resolution of discrepancies at 3 months . RESULTS : Rates of self-reported medication adherence were very high and did not improve further at 3 months ( 6.9 of 7 d , with all medicines taken as prescribed ; p = 0.3 ) . Medical regimen discrepancies were identified in 44 % of intervention patients , involving 45 doses of medicines . At 3-month follow-up , 60 % of discrepancies were resolved by corrections in the medical record , while only 7 % reflected corrections by patients . CONCLUSIONS : In this community cohort , patients reported few adherence barriers and very high medication adherence rates . Our patient-tailored intervention did not further reduce these barriers or improve self-reported adherence . The high prevalence of medication discrepancies appeared to mostly reflect inaccuracies in the medical record rather than patient errors",
"Electronic caps , pill caps that record the date and time of pill bottle opening provide an objective measure of adherence to prescribed medication . A promising intervention to improve adherence , cue-dose training , involves review ing patients ' pill cap-generated reports concerning their medication-taking and offering individualized recommendations for remembering to take medications at specific times of day . In this preliminary study , 79 patients prescribed the antihyperglycemic medication metformin had adherence assessed during a 4-week baseline period . Adherence , defined as proportion of prescribed doses taken within a predetermined 4-h window , was measured using electronic MEMS caps . Those who had less than 80 % baseline adherence ( n = 33 ) were r and omly assigned to either receive 4 months of cue-dose training ( n = 16 ) or to a control group ( n = 17 ) . Cue-dose training was associated with significantly better adherence to metformin ( mean improvement of 15 % ) . The effects of cue-dose training on adherence to other antihyperglycemic medication did not reach statistical significance . Glycosylated hemoglobin ( a measure of blood sugar control ) did not differ between groups . Data from nine patients who review ed pill cap-generated data with their primary care providers suggested that both patients and providers found the discussion moderately helpful and not at all uncomfortable ",
"This study examines the effectiveness of a brief self-management intervention to support patients recently diagnosed with type-2 diabetes to achieve sustained improvements in their self-care behaviours . Based on proactive coping , the intervention emphasizes the crucial role of anticipation and planning in maintaining self-care behaviours . In a r and omised controlled trial among recent screen-detected patients , participants who received the intervention were compared with usual-care controls , examining changes in proximal outcomes ( intentions , self-efficacy and proactive coping ) , self-care behaviour ( diet , physical activity and medication ) and weight over time ( 0 , 3 and 12 months ) . Subsequently , the contribution of proactive coping in predicting maintenance of behavioural change was analysed using stepwise hierarchical regression analyses , controlling for baseline self-care behaviour , patient characteristics , and intentions and self-efficacy as measured after the course . The intervention was effective in improving proximal outcomes and behaviour with regard to diet and physical activity , result ing in significant weight loss at 12 months . Furthermore , proactive coping was a better predictor of long-term self-management than either intentions or self-efficacy . Proactive coping thus offers new insights into behavioural maintenance theory and can be used to develop effective self-management interventions ",
"Background : Although adherence to long‐term drug therapy is an important issue , the means to facilitate its assessment and improvement in clinical practice remain a challenge . Objective : To evaluate the impact of prescription refill feedback and adherence education provided to primary care physicians . Methods : We provided 83 resident and attending physicians at a university‐based general internal medicine practice with refill adherence reports on each of 340 diabetic patients . An educational session on adherence assessment and improvement techniques was held , and all physicians received a written outline on this topic . Physician attitude toward the intervention and 6‐month change in refill adherence ( doses filled/doses prescribed ) of their patient panels were assessed . A nonr and omized comparison group of patients receiving hypertension medications for whom the physicians did not receive feedback was also evaluated . Results : The overall improvement in mean refill adherence was not significant ( 83.9 % vs 86.0 % , P = 0.18 ) . The educational session was attended by 53 % of the physicians . The patient refill adherence of physicians attending the educational session improved by 5.0 % ( P no adherence change among patients for whom physicians did not receive refill feedback data , regardless of educational session attendance . Conclusions : Patients of physicians that received refill feedback and attended an educational session improved their refill adherence . After replication of these results in a r and omized trial , broad implementation of this approach could have substantial impact from a public health perspective , given the ubiquity of prescription cl aims data",
"Abstract Objective : To evaluate the feasibility and impact of a structured approach for community pharmacist input as a member of the multidisciplinary team caring for patients with type-2 diabetes and health professional providing advice on medication . Methods : Prospect i ve pretest-posttest single group study . Sixty-two patients on oral hypoglycaemic therapy , identified as regular customers of four Scottish ( UK ) community pharmacies , were recruited . Each patient underwent an initial assessment : review of medical general practice notes/community pharmacy PMR ( Patient medication record ) system and structured interview . St and ardised documentation was completed , a pharmaceutical care plan ( PCP ) prepared , peer- review ed and then discussed face-to-face with patients ' GPs ( general practitioners ) . A second ( final ) assessment was conducted 24 to 28 weeks from the initial interview . Main outcome measures : Pharmaceutical care issues ( PCIs ) throughout study period ; change in parameters from initial to final assessment : patient knowledge of oral hypoglycaemic and anti-hypertensive therapy ; HbA1c ; blood pressure ; total cholesterol ; medication compliance . Results : A total of 178 PCIs were identified ( mean [ range ] 2.9 [ 1–5 ] per patient ) and categorised : drug therapy problems ( n=76 ) ; monitoring ( n=21 ) ; and patient knowledge ( n=81 ) . Drug therapy problems discussed with the GPs were agreed for 74 ( 97 % ) and resolved for 55 ( 72 % ) at final assessment . Biological outcome measures were assessed for 59 patients ( 3 drop-outs ) . A reduction ( P HbA1c , blood pressure and total cholesterol was observed over the study period . Patients knowledge was poor for oral hypoglycaemic therapy but improved ( initial-51 % , final-72 % , P diabetes patients in an European country . The results have shown the pharmacist to be effective and well accepted by GPs and patients",
"BACKGROUND : There is limited information from r and omized controlled studies about the influence of pharmacist interventions on diabetes control . OBJECTIVE : To evaluate the effect of a pharmacist intervention on improving diabetes control ; secondary endpoints were medication appropriateness and self-reported adherence . METHODS : A r and omized , controlled , multi-clinic trial was conducted in the University of Washington Medicine Neighborhood Clinics . Seventy-seven subjects , ⩾18 years old with a hemoglobin ( Hb ) A1c ⩾9 % at baseline and taking at least one oral diabetes medication , were r and omized to receive a pharmacist intervention ( n = 43 ) or usual care ( n = 34 ) for 6 months followed by a 6-month usual-care observation period for both groups . Subjects met with a clinical pharmacist to establish and initiate a diabetes care plan followed by weekly visits or telephone calls to facilitate diabetes management and adherence . HbA1c , medication appropriateness , and self-reported adherence were assessed at baseline , 6 months , and 12 months . RESULTS : The mean HbA1c did not differ between groups over the 12-month period ( p = 0.61 ) . A reduction in HbA1c was noted for both groups over time compared with baseline ( p = 0.001 ) ; however , control subjects relied more heavily on provider visits . Medication appropriateness was not improved for diabetes medications ( p = 0.65 ) . Self-reported adherence was not significantly improved by the intervention . CONCLUSIONS : This pharmacist intervention did not significantly improve diabetes control , but did allow for similar HbA1c control with fewer physician visits . Medication appropriateness and self-reported adherence compared with usual care in individuals with poorly controlled diabetes were not changed",
"Brief , cost-effective interventions to promote diabetes self-management are needed . This study evaluated the effects of a brief , regular , proactive , telephone “ coaching ” intervention delivered by paraprofessionals on diabetes adherence , glycemic control , diabetes-related medical symptoms , and depressive symptoms . Therapeutic mechanisms underlying the intervention ’s effect on the primary outcomes were also examined . Adults diagnosed with type 2 diabetes ( N = 62 ) were r and omly assigned to receive the “ coaching ” intervention and treatment as usual , or only treatment as usual . The intervention increased frequency of exercise and feet inspection , improved diet , reduced diabetes medical symptoms , and lowered depressive symptoms . Self-efficacy , reinforcement , and awareness of self-care goals mediated the treatment effect on depression , exercise , and feet inspection , respectively . A brief telephone intervention delivered by paraprofessionals had positive effects on type 2 diabetes patients",
"Inadequate knowledge of the influence of lifestyle on clinical outcomes contributes to the difficulties many African Americans experience with type 2 diabetes mellitus ( T2DM ) . This pilot study examined a 12-week church-based culturally targeted diabetes self-management education ( DSME ) intervention for middle-aged and older African Americans with T2DM . Quantitative data were collected at baseline and at 12 weeks and included question naires and anthropometric measures . There were significant increases in medication adherence ( p = .006 ) , healthy eating ( p = .009 ) , and foot care adherence ( p = .003 ) . The intervention had a clinical ly significant effect on systolic blood pressure , blood lipids , physical activity , and waist circumference . Church-based culturally targeted DSME interventions may result in improved outcomes for African-American adults with T2DM . The authors discuss the value of community-based interventions that target behavioural changes in population s of chronically ill patients , particularly those who historically have been disenfranchised and /or underserved",
"RATIONALE , AIMS AND OBJECTIVES Utilizing information technology , such as Internet and cellphones , holds great promise in enhancing diabetic care . Yet few studies have examined the impact of cellphone technology on type 2 diabetics ' self-care . The primary aim of the study is to examine the feasibility of utilizing this technology to assist with diabetes self-care in a clinic population as well as its impact on clinical outcomes . METHODS Thirty patients with a diagnosis of type 2 diabetes at two Community Health Centers were r and omized to intervention or control . Intervention patients participated in a brief intervention and received tailored daily messages via cellphone prompting them to enhance their diabetic self-care behaviour . Patients at the control site continued with their st and ard diabetes self-management . RESULTS A mean improvement in HbA1c levels was apparent ( -0.1 , SD = 0.3 % ; P = 0.1534 ) in the intervention group , compared with a mean deterioration in the control ( 0.3 , SD = 1.0 % ; P = 0.3813 ) , yet without statistical significance . Self-efficacy scores improved significantly in the intervention group ( -0.5 , SD = 0.6 ; P = 0.0080 ) compared with no improvement in the control ( 0.0 , SD = 1.0 ; P = 0.9060 ) . Participants encountered numerous technological barriers when attempting to adhere to the intervention protocol . CONCLUSION The results indicate the intervention had a positive impact on some clinical outcome and self-efficacy . Although the technology appears feasible in a clinical setting technology must be made more user-friendly before a larger phase II trial is conducted",
"WHAT IS KNOWN AND OBJECTIVE There is little evidence from well- design ed r and omized controlled trials of the impact of community pharmacist intervention on the clinical management of patients with type 2 diabetes . It is also not known how sustainable any observed effects on glycaemic control are , over time . This study was initiated to address both these issues . METHODS A 6-month , r and omized , controlled parallel-group trial in 66 community pharmacies was conducted in Belgium . Patients were r and omly assigned to receive usual pharmacist care ( n = 135 ) or a predefined pharmacist intervention ( n = 153 ) . The intervention mainly focused on correct medication use , medication adherence and healthy lifestyle promotion . Primary outcome was glycaemic control , as measured by fasting plasma glucose and HbA1c . Sustainability of changes in glycaemic control was assessed by additional glucose measurements 18 months after the end of the study . RESULTS AND DISCUSSION The intervention significantly reduced HbA1c ( between-group difference : 0·5 % , P = 0.009 ) . The largest impact on HbA1c was observed when pharmacotherapy changes ( i.e. , type and /or dose of hypoglycaemic agents ) initiated by the physician were sustained with pharmaceutical care : HbA1c was reduced by 1·05 % in the intervention group , whose medication was changed , compared with a reduction of 0·02 % in the therapy-modification only , group . It was also found that the diabetes education program result ed in improved self-management and better knowledge of diabetes . Eighteen months after the end of the formal study period , the mean HbA1c of the intervention group did not differ significantly from the control group ( 7·4 % vs. 7·2 % ) . WHAT IS NEW AND CONCLUSION This study provides new evidence , from a r and omized controlled trial , of the beneficial effect of community pharmacist intervention in the clinical management of type 2 diabetic patients . However , questions remain about the sustainability of the observed improvements",
"BACKGROUND Increased emphasis is being placed on the critical need to control hypertension ( HTN ) in patients with diabetes . OBJECTIVE The objective of this study was to evaluate the efficacy of a nurse-managed home telehealth intervention to improve outcomes in veterans with comorbid diabetes and HTN . DESIGN A single-center , r and omized , controlled clinical trial design comparing two remote monitoring intensity levels and usual care in patients with type 2 diabetes and HTN being treated in primary care was used . MEASUREMENTS Primary outcomes were hemoglobin A1c and systolic blood pressure ( SBP ) ; secondary outcome was adherence . RESULTS Intervention subjects experienced decreased A1c during the 6-month intervention period compared with the control group , but 6 months after the intervention was withdrawn , the intervention groups were comparable with the control group . For SBP , the high-intensity subjects had a significant decrease in SBP compared with the other groups at 6 months and this pattern was maintained at 12 months . Adherence improved over time for all groups , but there were no differences among the three groups . LIMITATIONS Subjects had relatively good baseline control for A1c and SBP ; minorities and women were underrepresented . CONCLUSIONS Home telehealth provides an innovative and pragmatic approach to enhance earlier detection of key clinical symptoms requiring intervention . Transmission of education and advice to the patient on an ongoing basis with close surveillance by nurses can improve clinical outcomes in patients with comorbid chronic illness",
"Objectives : To evaluate the reach and effectiveness of a diabetes self-management DVD compared to classroom-based instruction . Methods : A hybrid preference/r and omized design was used with participants assigned to Choice v. R and omized and DVD v. Class conditions . One hundred and eighty-nine adults with type 2 diabetes participated . Key outcomes included self-management behaviours , process measures including DVD implementation and hypothesized mediators and clinical risk factors . Results : In the Choice condition , four times as many participants chose the mailed DVD as selected Class-based instruction ( 38.8 v. 9.4 % , p DVD produced results generally not significantly different than classroom-based instruction , but a combined Class plus DVD condition did not improve outcomes beyond those produced by the classes alone . Discussion : The DVD appears to have merit as an efficient and appealing alternative to brief classroom-based diabetes education , and the hybrid design is recommended to provide estimates of programme reach",
"BACKGROUND Poor adherence to oral antidiabetics has a negative influence on glycaemic control in type 2 diabetes patients . Real Time Medication Monitoring ( RTMM ) combines real time monitoring of patients ' medication use with SMS reminders sent only if patients forget their medication , aim ing to improve adherence . This study aim ed to investigate the effect of these SMS reminders on adherence to oral antidiabetics in patients using RTMM and investigate patients ' experiences with RTMM . METHODS Data were collected in a RCT involving 104 type 2 diabetes patients with suboptimal adherence to oral antidiabetics . Fifty-six patients were r and omised to receive SMS reminders if they forgot their medication , 48 patients received no reminders . Primary outcome measure was adherence to oral antidiabetics registered with RTMM , measured as : ( 1 ) days without dosing ; ( 2 ) missed doses ; ( 3 ) doses taken within predefined st and ardized time windows . Patients ' experiences were assessed with written question naires . RESULTS Over the six-month study period , patients receiving SMS reminders took significantly more doses within predefined time windows than patients receiving no reminders : 50 % vs. 39 % within a 1-h window ( p=0.003 ) up to 81 % vs. 70 % within a 4-h window ( p=0.007 ) . Reminded patients tended to miss doses less frequently than patients not reminded ( 15 % vs. 19 % , p=0.065 ) . Days without dosing were not significantly different between the groups . The majority of patients reported positive experiences with RTMM and SMS reminders . CONCLUSION RTMM with SMS reminders improves adherence of type 2 diabetes patients , especially the precision with which patients follow their prescribed regimen , and is well accepted by patients . TRIAL REGISTRATION Netherl and s Trial Register NTR1882",
"OBJECTIVE To evaluate the impact of a community pharmacy-based medication adherence detection and intervention protocol on medication adherence for patients with diabetes . DESIGN R and omized controlled trial . SETTING Four community chain pharmacies in the Seattle , WA , area from April 2008 to October 2009 . PATIENTS Patients with diabetes ( n = 265 ) who were taking oral diabetes medications and late for refills by 6 days or more . INTERVENTION Telephone-initiated adherence support by pharmacists following computer-generated missed refill alerts . Patients were r and omized at the pharmacy level with pharmacists blinded to r and omization . MAIN OUTCOMES MEASURES Changes in medication adherence ( i.e. , days late at first refill , percent with a refill gap of 6 days or more at first refill , medication possession ratio [ MPR ] at 6 and 12 months ) measured during three time periods . RESULTS Baseline MPR ( previous 12 months ) of oral diabetes medications for study versus control participants was relatively high and similar ( 0.86 and 0.84 , respectively ) . At 12 months , MPR was significantly improved for the study group ( P = 0.004 ) compared with the control group ( difference between groups , P = 0.01 ) . The intervention showed greater effect for patients with baseline MPR less than 80 % ( difference between groups , P = 0.02 ) . The likelihood of MPR above 80 % at the 12-month follow-up for any patient significantly favored the intervention group ( odds ratio 4.77 [ 95 % CI 2.00 - 11.40 ] ) . CONCLUSION A brief missed refill intervention program involving urban community chain pharmacies was effective in achieving improved diabetes medication adherence , particularly among individuals with baseline MPR of 0.80 or less",
"R and omised controlled trials are widely accepted as the most reliable method of determining effectiveness , but most trials have evaluated the effects of a single intervention such as a drug . Recognition is increasing that other , non-pharmacological interventions should also be rigorously evaluated.1 - 3 This paper examines the design and execution of research required to address the additional problems result ing from evaluation of complex interventions —that is , those “ made up of various interconnecting parts.”4 The issues dealt with are discussed in a longer Medical Research Council paper ( www.mrc.ac.uk/complex_packages.html ) . We focus on r and omised trials but believe that this approach could be adapted to other design s when they are more appropriate . # # # # Summary points Complex interventions are those that include several components The evaluation of complex interventions is difficult because of problems of developing , identifying , documenting , and reproducing the intervention A phased approach to the development and evaluation of complex interventions is proposed to help research ers define clearly where they are in the research process Evaluation of complex interventions requires use of qualitative and quantitative evidence There are specific difficulties in defining , developing , documenting , and reproducing complex interventions that are subject to more variation than a drug . A typical example would be the design of a trial to evaluate the benefits of specialist stroke units . Such a trial would have to consider the expertise of various health professionals as well as investigations , drugs , treatment guidelines , and arrangements for discharge and follow up . Stroke units may also vary in terms of organisation , management , and skill mix . The active components of the stroke unit may be difficult to specify , making it difficult to replicate the intervention . The box gives other examples of complex interventions . # # # # Examples of complex interventions Service delivery and organisation : Stroke units Hospital at home Interventions directed at health professionals ' behaviour : Strategies for implementing guidelines Computerised decision support Community interventions : Community",
"BACKGROUND Less than 63 % of individuals with diabetes meet professional guidelines target of hemoglobin A1c A1c of a cell phone-based diabetes management software system used with web-based data analytics and therapy optimization tools . Secondary aims examined health care provider ( HCP ) adherence to prescribing guidelines and assessed HCPs ' adoption of the technology . METHODS Thirty patients with type 2 diabetes were recruited from three community physician practice s for a 3-month study and evenly r and omized . The intervention group received cell phone-based software design ed by endocrinologists and CDEs ( WellDoc Communications , Inc. , Baltimore , MD ) . The software provided real-time feedback on patients ' blood glucose levels , displayed patients ' medication regimens , incorporated hypo- and hyperglycemia treatment algorithms , and requested additional data needed to evaluate diabetes management . Patient data captured and transferred to secure servers were analyzed by proprietary statistical algorithms . The system sent computer-generated logbooks ( with suggested treatment plans ) to intervention patients ' HCPs . RESULTS The average decrease in A1c for intervention patients was 2.03 % , compared to 0.68 % ( P medications titrated or changed by their HCP compared to controls ( 23 % , P = 0.002 ) . Intervention patients ' HCPs reported the system facilitated treatment decisions , provided organized data , and reduced logbook review time . CONCLUSIONS Adults with type 2 diabetes using WellDoc 's software achieved statistically significant improvements in A1c . HCP and patient satisfaction with the system was clinical ly and statistically significant",
"BACKGROUND Type 2 diabetes mellitus is increasing in incidence and research has shown that normalization of blood glucose levels can moderate the risk of microvascular and neurological complications . AIM The purpose of this study was to investigate the effect of nurse telephone calls on glycosylated haemoglobin ( HbA1c ) levels and adherence to diabetes control recommendations . METHODS A r and omized design with control and experimental groups being assessed pre- and post intervention was used to assess the effectiveness of nurse telephone calls . Twenty patients were r and omly assigned to an intervention group and 16 to a control group . The goal of the intervention was to keep blood glucose concentrations close to the normal range ( HbA1c continued education and reinforcement of diet , exercise , medication adjustment recommendations , as well as frequent self-monitoring of blood glucose levels . Telephone intervention was performed twice per week for the first month and then weekly for the second and third month . Participants were requested to write self-management logs including blood glucose levels , diet and an exercise diary . A dietitian analysed the diet diaries and participants were informed about their results by telephone or mail . All medication adjustments were communicated to participants ' doctors . The HbA1c and diabetes adherence were measured before and after the intervention . RESULTS Patients in the intervention group had a mean decrease of 1.2 % in HbA1c levels and those in the control group had a mean increase of 0.6 % in HbA1c levels . The intervention group had greater diet and blood glucose testing adherence than the control group . CONCLUSION These findings indicate that a nurse telephone intervention can improve HbA1c , and diet and blood glucose testing adherence",
"PURPOSE Depression commonly accompanies diabetes , result ing in reduced adherence to medications and increased risk for morbidity and mortality . The objective of this study was to examine whether a simple , brief integrated approach to depression and type 2 diabetes mellitus ( type 2 diabetes ) treatment improved adherence to oral hypoglycemic agents and antidepressant medications , glycemic control , and depression among primary care patients . METHODS We undertook a r and omized controlled trial conducted from April 2010 through April 2011 of 180 patients prescribed pharmacotherapy for type 2 diabetes and depression in primary care . Patients were r and omly assigned to an integrated care intervention or usual care . Integrated care managers collaborated with physicians to offer education and guideline -based treatment recommendations and to monitor adherence and clinical status . Adherence was assessed using the Medication Event Monitoring System ( MEMS ) . We used glycated hemoglobin ( HbA1c ) assays to measure glycemic control and the 9-item Patient Health Question naire ( PHQ-9 ) to assess depression . RESULTS Intervention and usual care groups did not differ statistically on baseline measures . Patients who received the intervention were more likely to achieve HbA1c levels of less than 7 % ( intervention 60.9 % vs usual care 35.7 % ; P remission of depression ( PHQ-9 score of less than 5 : intervention 58.7 % vs usual care 30.7 % ; P primary care . An integrated approach to depression and type 2 diabetes treatment may facilitate its deployment in real-world practice s with competing dem and s for limited re sources"
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Background Post-orthodontic white-spot lesions ( WSL ) in esthetically relevant incisor and canine areas impair dentofacial esthetics , and preventive dentistry treatment is definitely required in case of enamel cavitations . The incidence of lingual post-orthodontic WSL and cavitation following lingual MB treatment has been reported to be distinctively decreased compared to labial MB treatment . Moreover , lingual WSL do not impair dentofacial esthetics . It was the objective of this study to calculate consequential costs of preventive dental care necessary to recover labial or lingual post-orthodontic cavitations as well as esthetically relevant WSL following either labial or lingual MB interventions . Methods MB treatments ( labial / lingual ) were simulated in 1,000,000 patients between the ages of 12 - 18Y , with a median residual life time expectancy of 58Y based on local mortality tables . Range of MB Tx duration was 9–45 mo . Frequencies of post-orthodontic ( labial / lingual ) enamel damages were derived from large-scale WSL incidence studies . Anterior composite survival rates were based on a systematic review on the subject . Within the context of the German dental fee system ( GOZ 2.3 and 3.5 fee increments ) , simulation of costs for enamel damage treatment and re-treatment ( maximum : 5x ) were based on single-surface composite restorations for lingual or labial cavitations and labial WSL treatment ; and lingual WSL fluoridation . Results Overall mean total costs for Tx and re-Tx of both WSLs and cavitations may sum up to 1718.91 Eur in the high-cost ( GOZ 3.5 ) scenario for conventional MB cases , versus 19.94 Eur for lingually treated cases , given that renewal of simulated single-surface restorations takes place at 15-year intervals . When focussing on patients diagnosed with least of one WSL , and /or cavitation , these mean costs increase up to 2332.35 Eur for conventionally treated MB patients , or 65.03 Eur for lingual MB patients . Conclusion Costs for repeated treatment of post-orthodontic enamel damages produced by conventional vestibular fixed appliances may easily exceed the initially higher costs associated with lingual orthodontic treatment . Judged economically in the long term , lingual MB Tx may be considered as a more cost-effective solution for a correction of malocclusion
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"Summary Background : Using lingual enamel surfaces for bracket placement not only has esthetic advantages , but may also be suitable in terms of reducing frequencies of enamel decalcifications . Objective : To test the None-hypothesis that there is no significant difference in enamel decalcification or cavitation incidence adjacent to and beneath bracket bases between two lingual multi-bracket ( MB ) appliances that are different in terms of design , material composition , and manufacturing technology ( group A : WIN , DW-LingualSystems ; group B : Incognito , 3M-Unitek ) , taking into account patient- and treatment-related variables on white spot lesion ( WSL ) formation . Methods : St and ardized , digital , top-view photographs of 630 consecutive subjects ( 16214 teeth ; n Incognito = 237/6076 teeth ; n WIN = 393/10138 teeth ; mean age : 17.47±7.8 ; m/f 43.2/56.8 % ) with completed lingual MB treatment of the upper and lower permanent teeth 1–7 were screened for decalcification or cavitation adjacent to and beneath the bracket bases before and after treatment , scored from 0 to 7 . Non-parametric ANOVA was used for main effects ‘ appliance type ’ , ‘ gender ’ , ‘ treatment complexity ’ , ‘ grouped age ’ ( ≤16/>16 years ) , and ‘ treatment duration ’ as covariable , at an α-level of 5 % . Results : About 2.57 % [ 5.94 % ] of all teeth in group A [ B ] developed decalcifications . Subject-related incidence was 9.59 % [ 16.17 % ] for upper incisors in group A [ B ] , and 12.98 % [ 25.74 % ] for all teeth 16–46 . There were significant effects by gender , age , and treatment duration . Conclusion : The None-hypothesis was rejected : sub-bracket lesions were significantly less frequent in group A , while frequencies of WSL adjacent to brackets were not significantly affected by appliance type . In view of the overall low incidences of lingual post-orthodontic white-spot lesions , the use of lingual appliances is advocated as a valid strategy for a reduction of enamel decalcifications during orthodontic treatment",
"Background White spot lesions ( WSLs ) are a frequent side-effect of multibracket appliance treatment . The effect of local fluoridation on post-orthodontic WSL is however inconclusive . Objective Assessment of WSL changes in response to weekly 1.25 per cent fluoride gel application after multibracket appliance treatment . Trial design R and omized , single-centre , double-blind , parallel-group , placebo-controlled study . Participants Patients with not less than 1 WSL ( modified score 1 or 2 ) on not less than 1 upper front teeth after debonding . Interventions Professional fluoride/placebo gel application during weeks 1 - 2 ; self-administered home application ( weeks 3 - 24 ) . Outcomes Photographic WSL assessment ( dimension and luminance ) of the upper front teeth ( T0-T5 ) . R and omization R and om assignment to test ( n = 23 ) or placebo group ( n = 23 ) using a sequentially numbered list ( r and om allocation sequence generated for 50 subjects in 25 blocks of 2 subjects each ) . Recruitment The clinical study duration lasted from March 2011 to September 2013 . Blinding Unblinding was performed after complete data evaluation . Numbers analysed Intent-to-treat analysis set comprising 39 participants ( test : n = 21 , placebo : n = 18 ) . Outcome Dimensional WSL quantification showed limited reliability . Luminance improvement ( % ) of WSL , however , was seen after 6 months ( test/placebo : tooth 12 , 24.8/18.0 ; tooth 11 , 38.4/35.4 ; tooth 21 , 39.6/38.3 ; and tooth 22 , 15.2/25.0 ) . No statistically significant group difference existed . Data suggest that WSLs are difficult to measure with respect to reliability and repeatability and methods for monitoring WSLs in clinical trials require improvement/validation . Harms Similar adverse events occurred in both groups ; none was classified as possibly related to the study product . Limitations The number of dropouts was higher than expected and the socio-economic status was not assessed . Furthermore , the unknown level of compliance during the home application phase must be considered as limitation . Conclusion Based on the results of this study , no difference could be detected with respect to the development of WSL under post-orthodontic high-dose fluoride treatment . Registration The study was registered with Clinical Trials.gov ( Identifier : NCT01329731 ) . Protocol The protocol was n't published before trial commencement",
"Orthodontic treatment with fixed appliances is considered a risk factor for the development of white spot caries lesions ( WSL ) . Traditionally , brackets are bonded to the buccal surfaces . Lingual brackets are developing rapidly and have become more readily available . Buccal surfaces are considered to be more caries prone than lingual surfaces . Furthermore , lingual brackets are shaped to fit the morphology of the teeth and seal almost the entire surface . In the present study we tested the hypothesis that lingual brackets result in a lower caries incidence than buccal brackets . We tested this hypothesis using a split-mouth design where subjects were allocated r and omly to a group receiving either buccal or lingual brackets on the maxillary teeth and the alternative bracket type in the m and ible . The results indicate that buccal surfaces are more prone to WSL development , especially when WSL existed before treatment . The number of WSL that developed or progressed on buccal surfaces was 4.8 times higher than the number of WSL that developed or progressed on lingual surfaces . When measured using quantitative light-induced fluorescence ( QLF ) , the increase in integrated fluorescence loss was 10.6 times higher buccally than lingually . We conclude that lingual brackets make a difference when caries lesion incidence is concerned",
"Introduction The occurrence of side-effects of fixed orthodontic therapy , such as white-spot lesions and root resorption , are known to be significantly more frequent with increasing duration of treatment . Multi-bracket treatment should be as short as possible , in order to minimize the risks of collateral damage to teeth . The aim of this non-r and omized clinical trial was to compare treatment duration with each of two types of customized lingual orthodontic appliances ( Incognito , 3 M-Unitek ; WIN , DW LingualSystems ) , taking into account treatment complexity . The None-hypothesis was that there would be no significant difference in active orthodontic treatment duration between them . Methods Of 402 potentially eligible participants , a population sample of n = 376 subjects ( nIncognito = 220 ; nWIN = 156 ; m/f 172/204 ; mean age ± SD 17.3 ± 7.7Y ) treated in one orthodontic center ( Bad Essen , Germany ) with completely customized lingual appliances in upper and lower permanent dental arches was recruited with the inclusion criterion of initiated and completed lingual multi-bracket treatment within the assessment period of April 1st 2010 – Nov 30 , 2013 , and the exclusion criterion of less than 24 bracketed teeth . We used four-factorial ANOVA to assess the impact of the following factors : initial degree of severity of malocclusion ( mild to moderate , S1 ; severe , S2 ) , appliance type ( Incognito ; WIN ) , sex , and age group ( 16 Y ) on the duration of lingual multi-bracket treatment . Results Overall , mean treatment duration was 21.7 ( SD 7.2 ) months , which was significantly shorter for WIN for both sub-groups of treatment complexity ( S1 : 17.96 mo ; S2 : 20.49 mo ) compared to Incognito ( S1 : 22.7 mo ; S2 : 29.79 mo ) . ANOVA revealed a significant influence of the main effects ‘ appliance type ’ , and ‘ severity ’ , independent of each other . Therefore , the None-hypothesis was rejected . Conclusion In terms of treatment duration , the WIN appliance performed significantly better than the Incognito appliance . Consequently , subjects treated with the WIN appliance are expected to be exposed to lower risks of the typical side-effects associated with longer multi-bracket treatment duration s , such as root resorption and enamel decalcification",
"INTRODUCTION Dental caries , specifically decalcified white-spot lesions ( WSL ) , is a well-known side-effect of orthodontic treatment . The incidence of labial incipient caries lesions and its relationship with various patient and treatment variables was investigated in patients treated with comprehensive orthodontics . METHODS R and omly selected orthodontic patient records ( n = 350 ) were examined to determine incipient caries lesion development . Labial surfaces on pretreatment and posttreatment photographs were scored with a st and ardized scoring system . Independent variables were collected by chart abstract ion . RESULTS The incidence of patients who developed at least 1 new WSL during treatment was 72.9 % , and this incidence was 2.3 % for cavitated lesions . Treatment duration was significantly associated with new WSL development ( P = 0.03 ) . Development of WSL and cavitated lesions increased ( both , P WSL development , but initial oral-hygiene score was moderately associated ( P in patients treated with comprehensive orthodontics was significantly high , and the preventive therapy provided appeared to be ineffective . This widespread problem is alarming and warrants significant attention from both patients and providers that should result in greatly increased emphasis on effective caries prevention",
"SUMMARY BACKGROUND / OBJECTIVES White spot lesions ( WSLs ) are unwelcome side effects of fixed appliances that compromise the treatment outcome . Recently , infiltration of WSLs has been introduced as a viable treatment alternative . The objective was to evaluate the colour improvement of WSLs and their stability against discolouration following infiltration , fluoride , or micro-abrasion treatments in vitro . MATERIAL S/ METHODS Artificial WSLs were created in bovine enamel ( N = 96 ) using acidic buffer solution ( pH 5 , 10 days ) and were r and omly allocated to four groups . Specimens were treated with infiltration ( Icon , DMG ) , fluoride ( Elmex Caries Protection , GABA ) , and micro-abrasion ( Opalustre , Ultradent ) or remained untreated ( control ) . Groups were discoloured for 24 hours in tea or tea + citric acid . Colour components and visible colour change ( L * , a * , b * , ΔE ) were measured spectrophotometrically on following time points : baseline , after WSL formation , after treatment , and during discolouration ( 8 , 16 , and 24 hours ) . Data were analysed using Kruskal-Wallis and Mann-Whitney tests . RESULTS WSL formation increased ( L * ) in all groups . Only infiltration reduced this effect to baseline . Highest ΔE improvement was obtained by infiltration and micro-abrasion followed by fluoride . This improvement was stable only for infiltration during discolouration . L * , a * , and b * changed significantly during discolouration in all groups except infiltration . Within the same treatment group , discolouration solutions did not differ significantly . LIMITATIONS In vitro testing can not replicate the actual mode of colour improvement or stability but can be used for ranking material s and techniques . CONCLUSIONS / IMPLICATION S Infiltration and micro-abrasion treatments were capable of diminishing the whitish appearance of WSLs . Only infiltrated WSLs were stable following discolouration challenge",
"INTRODUCTION A new , highly filled primer is currently marketed as a fluoride delivery system effective in reducing white spot lesions in orthodontic patients . However , no studies in the literature support this cl aim . The purpose of this in-vivo study was to investigate the retention and the efficacy of this primer in reducing the formation of white spot lesions . METHODS In each patient for whom premolar extraction s were planned ( n = 22 ) , 1 premolar was r and omly chosen as the experimental tooth for the application of the fluoride delivery system ( Opal Seal ; Ultradent Products , South Jordan , Utah ) , and the contralateral tooth was assigned as the control to receive the st and ard treatment ( Transbond XT ; 3 M Unitek , Monrovia , Calif ) . After the bonding procedures , separators were placed around the premolar brackets to encourage plaque retention over 8 weeks . After the extraction s , the tooth surfaces were evaluated visually and with microhardness techniques for demineralization . Primer retention was also investigated . RESULTS There were no statistically significant differences in the numbers of white spot lesions between the 2 groups . The primer retention was calculated as 50 % . CONCLUSIONS The results indicated no significant difference between the efficacies of the fluoride-releasing primer and the control primer in reducing demineralization over the duration of the study",
"INTRODUCTION White spot lesions that form during orthodontic treatment are a problem for patients and clinicians . Lesion infiltration with low-viscosity light-cured resin has been proposed as a treatment to inhibit further demineralization . The purpose of this study was to assess the durability of assimilation of white spot lesions and sound adjacent enamel achieved over 6 months with resin infiltration . METHODS Twenty-one consecutive subjects with 231 noncavitated , unrestored white spot lesions after multibracket treatment were recruited at the Department of Orthodontics , University of Göttingen ( Germany ) , for lesion infiltration . A simple r and omized , split-mouth , controlled design was used to allocate subjects to the treatment and control groups . In the treatment group , white spot lesion infiltration of the anterior teeth was performed with low-viscosity light-cured resin after enamel conditioning with a 15 % HCl gel . Color and lightness of the white spot lesions and the sound adjacent enamel were assessed with a spectrophotometer before infiltration and after 1 day , 1 week , 4 weeks , 3 months , and 6 months , using the system of the Commission Internationale de l'Eclairage . Multifactorial analysis of variance with repeated measures and pair-wise comparisons were used to analyze the effects of infiltration and time elapsed on the color differences at an α level of 5 % and a power of 80 % . RESULTS Analysis of 20 subjects and 39 quadrants in each group ( 108 teeth in the control group ; 111 teeth in the treatment group ) showed that both parameters of treatment and time duration had globally a highly significant influence on the color difference values . Assimilation of white spot lesion color to the surrounding enamel after infiltration was stable with no significant changes over 6 months ; the mean color difference of white spot lesions vs sound adjacent enamel ( ΔE baseline vs 6 months ) was 2.55 ( 95 % confidence interval [ CI ] , 1.431 - 3.678 ) . The untreated control teeth showed no significant changes over 6 months compared with the baseline : mean ( ΔE ) , 0.29 ( 95 % CI , -0.335 - 0.928 ) . No important adverse events or side effects were observed . CONCLUSIONS Resin infiltration improves the esthetic appearance of demineralized teeth . The results showed sufficient durability over 6 months",
"White spot or areas of decalcification are carious lesions of varying extent . The incidence and severity of white spots after a full term of orthodontic treatment were studied among patients in the separate private practice s of two of the authors . To establish a base line of comparison , the presence of white spots in a r and om sample of untreated persons was observed . The incidence of white spots among patients treated by a multibonded technique was recorded at the time of debonding . In addition , white spots were sought in the before- and after-treatment Kodachrome slides of persons whose maxillary incisors had been h and ed . It was found that individual teeth , b and ed or bonded , exhibited significantly more white spot formation than was found in the control group . For the teeth studied , there was no difference in white spot formation in those that were b and ed or bonded . The labiogingival area of the maxillary lateral incisors had the highest incidence of white spots . When studied by segments , the highest incidence occurred among the maxillary incisors ; the lowest was in the maxillary posterior segment . No white spots were found on the lingual surfaces of m and ibular canines and incisors after prolonged use of a canine-to-canine bonded retainer . These findings suggest a relationship between resistance to white spot formation and the rate of salivary flow . Despite the lack of any preventive fluoride program among the study groups , 50 % of the patients demonstrated resistance to white spot formation . The obvious degree of latrogenic damage during orthodontic treatment suggests the need for preventive programs using fluoride . Further clinical research is needed"
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4117d0de-06ff-11f0-808a-c43d1ab1c353
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BACKGROUND The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established . However , the extent to which these effects differ by baseline blood pressure , presence of comorbidities , or drug class is less clear . We therefore performed a systematic review and meta- analysis to clarify these differences . METHOD For this systematic review and meta- analysis , we search ed MEDLINE for large-scale blood pressure lowering trials , published between Jan 1 , 1966 , and July 7 , 2015 , and we search ed the medical literature to identify trials up to Nov 9 , 2015 . All r and omised controlled trials of blood pressure lowering treatment were eligible for inclusion if they included a minimum of 1000 patient-years of follow-up in each study arm . No trials were excluded because of presence of baseline comorbidities , and trials of antihypertensive drugs for indications other than hypertension were eligible . We extracted summary -level data about study characteristics and the outcomes of major cardiovascular disease events , coronary heart disease , stroke , heart failure , renal failure , and all-cause mortality . We used inverse variance weighted fixed-effects meta-analyses to pool the estimates . RESULTS We identified 123 studies with 613,815 participants for the tabular meta- analysis . Meta-regression analyses showed relative risk reductions proportional to the magnitude of the blood pressure reductions achieved . Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events ( relative risk [ RR ] 0·80 , 95 % CI 0·77 - 0·83 ) , coronary heart disease ( 0·83 , 0·78 - 0·88 ) , stroke ( 0·73 , 0·68 - 0·77 ) , and heart failure ( 0·72 , 0·67 - 0·78 ) , which , in the population s studied , led to a significant 13 % reduction in all-cause mortality ( 0·87 , 0·84 - 0·91 ) . However , the effect on renal failure was not significant ( 0·95 , 0·84 - 1·07 ) . Similar proportional risk reductions ( per 10 mm Hg lower systolic blood pressure ) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure ( all ptrend>0·05 ) . There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history , except for diabetes and chronic kidney disease , for which smaller , but significant , risk reductions were detected . β blockers were inferior to other drugs for the prevention of major cardiovascular disease events , stroke , and renal failure . Calcium channel blockers were superior to other drugs for the prevention of stroke . For the prevention of heart failure , calcium channel blockers were inferior and diuretics were superior to other drug classes . Risk of bias was judged to be low for 113 trials and unclear for 10 trials . Heterogeneity for outcomes was low to moderate ; the I(2 ) statistic for heterogeneity for major cardiovascular disease events was 41 % , for coronary heart disease 25 % , for stroke 26 % , for heart failure 37 % , for renal failure 28 % , and for all-cause mortality 35 % . INTERPRETATION Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities . Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease , coronary heart disease , stroke , diabetes , heart failure , and chronic kidney disease . FUNDING National Institute for Health Research and Oxford Martin School
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"AIM Reduction of elevated blood pressure ( BP ) has been an important treatment goal in elderly hypertensive patients . However , it has been reported that an excessive reduction of systolic BP to less than 120mmHg might be harmful in such patients . We investigated whether this was the case in a study which assessed long-term antihypertensive efficacy , tolerability and impact on cardiovascular/cerebrovascular ( CV ) morbidity/mortality in a large cohort of Japanese patients . METHODS This study was performed at general practitioners ' offices nationwide with a target sample size of 1500 patients . Hypertensive patients aged 60years or more who achieved successful BP control with c and esartan monotherapy , and who tolerated the treatment for at least 8weeks , were enrolled into the study and followed for 3years . RESULTS BP was maintained below the target level of 140/90mmHg over the 3-year period . The incidence of CV events during the study period was 20.4/1000person-years . Investigation of the relationship between BP and the incidence of CV events revealed that patients with higher BP generally had a higher incidence of events . However , very elderly patients ( ≥75years ) with a systolic BP ( SBP ) of less than 120mmHg also had a higher incidence of CV events compared with those with an SBP of 120 - 139mmHg . CONCLUSION This study demonstrated that treatment with c and esartan maintained long-term control of BP in elderly hypertensive patients without serious adverse events . CV events demonstrated a J-curve relationship with SBP in patients aged 75years or older , which suggests that excessive BP reductions might be harmful for very elderly patients",
"Summary Background The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared . In this study , we aim ed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease . Methods We used linked electronic health records from 1997 to 2010 in the CALIBER ( CArdiovascular research using LInked Bespoke studies and Electronic health Records ) programme to assemble a cohort of 1·25 million patients , 30 years of age or older and initially free from cardiovascular disease , a fifth of whom received blood pressure-lowering treatments . We studied the heterogeneity in the age-specific associations of clinical ly measured blood pressure with 12 acute and chronic cardiovascular diseases , and estimated the lifetime risks ( up to 95 years of age ) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30 , 60 , and 80 years . This study is registered at Clinical Trials.gov , number NCT01164371 . Findings During 5·2 years median follow-up , we recorded 83 098 initial cardiovascular disease presentations . In each age group , the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90–114 mm Hg and diastolic blood pressure of 60–74 mm Hg , with no evidence of a J-shaped increased risk at lower blood pressures . The effect of high blood pressure varied by cardiovascular disease endpoint , from strongly positive to no effect . Associations with high systolic blood pressure were strongest for intracerebral haemorrhage ( hazard ratio 1·44 [ 95 % CI 1·32–1·58 ] ) , subarachnoid haemorrhage ( 1·43 [ 1·25–1·63 ] ) , and stable angina ( 1·41 [ 1·36–1·46 ] ) , and weakest for abdominal aortic aneurysm ( 1·08 [ 1·00–1·17 ] ) . Compared with diastolic blood pressure , raised systolic blood pressure had a greater effect on angina , myocardial infa rct ion , and peripheral arterial disease , whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure . Pulse pressure associations were inverse for abdominal aortic aneurysm ( HR per 10 mm Hg 0·91 [ 95 % CI 0·86–0·98 ] ) and strongest for peripheral arterial disease ( 1·23 [ 1·20–1·27 ] ) . People with hypertension ( blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs ) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3 % ( 95 % CI 62·9–63·8 ) compared with 46·1 % ( 45·5–46·8 ) for those with normal blood pressure , and developed cardiovascular disease 5·0 years earlier ( 95 % CI 4·8–5·2 ) . Stable and unstable angina accounted for most ( 43 % ) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years , whereas heart failure and stable angina accounted for the largest proportion ( 19 % each ) of years of life lost from index age 80 years . Interpretation The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range , and that diastolic and systolic associations are concordant , are not supported by the findings of this high-resolution study . Despite modern treatments , the lifetime burden of hypertension is substantial . These findings emphasise the need for new blood pressure-lowering strategies , and will help to inform the design of r and omised trials to assess them . Funding Medical Research Council , National Institute for Health Research , and Wellcome Trust",
"Hypertension guidelines recommend blood pressure self-measurement at home ( HBP ) , but no previous trial has assessed cardiovascular outcomes in hypertensive patients treated according to HBP . The multicenter Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure ( HOMED-BP ; 2001–2010 ) trial involved 3518 patients ( 50 % women ; mean age 59.6 years ) with an untreated systolic/diastolic HBP of 135–179/85–119 mm Hg . In a 2 × 3 design , patients were r and omized to usual control ( 125–134/80–84 mm Hg ( UC ) ) vs. tight control ( ( TC ) ) of HBP and to initiation of drug treatment with angiotensin converting enzyme inhibitors , angiotensin receptor blockers or calcium channel blockers . During follow-up , a computer algorithm automatically generated treatment recommendations based on HBP . At the last follow-up ( median 5.3 years ) , TC patients used more antihypertensive drugs than UC patients ( 1.82 vs. 1.74 defined daily doses , P=0.045 ) and had a greater HBP reduction ( 21.3/13.1 mm Hg vs. 22.7/13.9 mm Hg , P=0.018/0.020 ) , but they less frequently achieved the lower HBP targets ( 37.4 vs. 63.5 % , P , cardiovascular death plus stroke and myocardial infa rct ion , occurred in 25 UC and 26 TC patients ( hazard ratio , 1.02 ; 95 % confidence interval , 0.59–1.77 ; P=0.94 ) . Rates were similar ( P⩾0.13 ) in the three drug groups . In all patients combined , the risk of the primary end point independently increased by 41 % ( 6–89 % ; P=0.019 ) and 47 % ( 15–87 % ; P=0.0020 ) for a 1-s.d . increase in baseline ( 12.5 mm Hg ) and follow-up ( 13.2 mm Hg ) systolic HBP . The 5-year risk was minimal ( ⩽1 % ) if on-treatment systolic HBP was 131.6 mm Hg or less . HOMED-BP proved the feasibility of adjusting antihypertensive drug treatment based on HBP and suggests that a systolic HBP level of 130 mm Hg should be an achievable and safe target",
"BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain . METHODS We r and omly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk , but without diabetes , to a systolic blood-pressure target of less than 120 mm Hg ( intensive treatment ) or a target of less than 140 mm Hg ( st and ard treatment ) . The primary composite outcome was myocardial infa rct ion , other acute coronary syndromes , stroke , heart failure , or death from cardiovascular causes . RESULTS At 1 year , the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the st and ard-treatment group . The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the st and ard-treatment group ( 1.65 % per year vs. 2.19 % per year ; hazard ratio with intensive treatment , 0.75 ; 95 % confidence interval [ CI ] , 0.64 to 0.89 ; P All-cause mortality was also significantly lower in the intensive-treatment group ( hazard ratio , 0.73 ; 95 % CI , 0.60 to 0.90 ; P=0.003 ) . Rates of serious adverse events of hypotension , syncope , electrolyte abnormalities , and acute kidney injury or failure , but not of injurious falls , were higher in the intensive-treatment group than in the st and ard-treatment group . CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , result ed in lower rates of fatal and nonfatal major cardiovascular events and death from any cause , although significantly higher rates of some adverse events were observed in the intensive-treatment group . ( Funded by the National Institutes of Health ; Clinical Trials.gov number , NCT01206062 . )",
"BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or placebo . The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes",
"BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors have been used for more than a decade to treat high blood pressure , despite the lack of data from r and omised intervention trials to show that such treatment affects cardiovascular morbidity and mortality . The Captopril Prevention Project ( CAPPP ) is a r and omised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension . METHODS CAPPP was a prospect i ve , r and omised , open trial with blinded endpoint evaluation . 10,985 patients were enrolled at 536 health centres in Sweden and Finl and . Patients aged 25 - 66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were r and omly assigned captopril or conventional antihypertensive treatment ( diuretics , beta-blockers ) . Analysis was by intention-to-treat . The primary endpoint was a composite of fatal and non-fatal myocardial infa rct ion , stroke , and other cardiovascular deaths . FINDINGS Of 5492 patients assigned captopril and 5493 assigned conventional therapy , 14 and 13 , respectively , were lost to follow-up . Primary endpoint events occurred in 363 patients in the captopril group ( 11.1 per 1000 patient-years ) and 335 in the conventional-treatment group ( 10.2 per 1000 patient-years ; relative risk 1.05 [ 95 % CI 0.90 - 1.22 ] , p=0 - 52 ) . Cardiovascular mortality was lower with captopril than with conventional treatment ( 76 vs 95 events ; relative risk 0.77 [ 0.57 - 1 - 04 ] , p=0.092 ) , the rate of fatal and non-fatal myocardial infa rct ion was similar ( 162 vs 161 ) , but fatal and non-fatal stroke was more common with captopril ( 189 vs 148 ; 1.25 [ 1 - 01 - 1 - 55 ] . p=0.044 ) . INTERPRETATION Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality . The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients r and omised to conventional therapy",
"BACKGROUND Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear . It has been suggested that antihypertensive therapy may reduce the risk of stroke , despite possibly increasing the risk of death . METHODS We r and omly assigned 3845 patients from Europe , China , Australasia , and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide ( sustained release , 1.5 mg ) or matching placebo . The angiotensin-converting-enzyme inhibitor perindopril ( 2 or 4 mg ) , or matching placebo , was added if necessary to achieve the target blood pressure of 150/80 mm Hg . The primary end point was fatal or nonfatal stroke . RESULTS The active-treatment group ( 1933 patients ) and the placebo group ( 1912 patients ) were well matched ( mean age , 83.6 years ; mean blood pressure while sitting , 173.0/90.8 mm Hg ) ; 11.8 % had a history of cardiovascular disease . Median follow-up was 1.8 years . At 2 years , the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group . In an intention-to-treat analysis , active treatment was associated with a 30 % reduction in the rate of fatal or nonfatal stroke ( 95 % confidence interval [ CI ] , -1 to 51 ; P=0.06 ) , a 39 % reduction in the rate of death from stroke ( 95 % CI , 1 to 62 ; P=0.05 ) , a 21 % reduction in the rate of death from any cause ( 95 % CI , 4 to 35 ; P=0.02 ) , a 23 % reduction in the rate of death from cardiovascular causes ( 95 % CI , -1 to 40 ; P=0.06 ) , and a 64 % reduction in the rate of heart failure ( 95 % CI , 42 to 78 ; P serious adverse events were reported in the active-treatment group ( 358 , vs. 448 in the placebo group ; P=0.001 ) . CONCLUSIONS The results provide evidence that antihypertensive treatment with indapamide ( sustained release ) , with or without perindopril , in persons 80 years of age or older is beneficial . ( Clinical Trials.gov number , NCT00122811 [ Clinical Trials.gov ] . )",
"CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline",
"BACKGROUND This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease , cardiovascular disease , or both . METHODS In a double-blind fashion , we r and omly assigned 8561 patients to aliskiren ( 300 mg daily ) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker . The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation ; nonfatal myocardial infa rct ion ; nonfatal stroke ; unplanned hospitalization for heart failure ; end-stage renal disease , death attributable to kidney failure , or the need for renal-replacement therapy with no dialysis or transplantation available or initiated ; or doubling of the baseline serum creatinine level . RESULTS The trial was stopped prematurely after the second interim efficacy analysis . After a median follow-up of 32.9 months , the primary end point had occurred in 783 patients ( 18.3 % ) assigned to aliskiren as compared with 732 ( 17.1 % ) assigned to placebo ( hazard ratio , 1.08 ; 95 % confidence interval [ CI ] , 0.98 to 1.20 ; P=0.12 ) . Effects on secondary renal end points were similar . Systolic and diastolic blood pressures were lower with aliskiren ( between-group differences , 1.3 and 0.6 mm Hg , respectively ) and the mean reduction in the urinary albumin-to-creatinine ratio was greater ( between-group difference , 14 percentage points ; 95 % CI , 11 to 17 ) . The proportion of patients with hyperkalemia ( serum potassium level , ≥6 mmol per liter ) was significantly higher in the aliskiren group than in the placebo group ( 11.2 % vs. 7.2 % ) , as was the proportion with reported hypotension ( 12.1 % vs. 8.3 % ) ( P addition of aliskiren to st and ard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful . ( Funded by Novartis ; ALTITUDE Clinical Trials.gov number , NCT00549757 . )",
"Abstract Objective : To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes . Design : R and omised controlled trial comparing tight control of blood pressure aim ing at a blood pressure of angiotensin converting enzyme inhibitor captopril or a β blocker atenolol as main treatment ) with less tight control aim ing at a blood pressure of 20 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Subjects : 1148 hypertensive patients with type 2 diabetes ( mean age 56 , mean blood pressure at entry 160/94 mm Hg ) ; 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , deaths related to diabetes , and all cause mortality . Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography . Results : Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control ( 144/82 mm Hg ) compared with the group assigned to less tight control ( 154/87 mm Hg ) ( P Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24 % in diabetes related end points ( 95 % confidence interval 8 % to 38 % ) ( P=0.0046 ) , 32 % in deaths related to diabetes ( 6 % to 51 % ) ( P=0.019 ) , 44 % in strokes ( 11 % to 65 % ) ( P=0.013 ) , and 37 % in microvascular end points ( 11 % to 56 % ) ( P=0.0092 ) , predominantly owing to a reduced risk of retinal photocoagulation . There was a non-significant reduction in all cause mortality . After nine years of follow up the group assigned to tight blood pressure control also had a 34 % reduction in risk in the proportion of patients with deterioration of retinopathy by two steps ( 99 % confidence interval 11 % to 50 % ) ( P=0.0004 ) and a 47 % reduced risk ( 7 % to 70 % ) ( P=0.004 ) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study ( ETDRS ) chart . After nine years of follow up 29 % of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures . Conclusion : Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinical ly important reduction in the risk of deaths related to diabetes , complications related to diabetes , progression of diabetic retinopathy , and deterioration in visual acuity",
"BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure",
"Recent reports suggest a possible link between nifedipine ( but not diltiazem ) and an increased risk of cancer in patients being treated with calcium antagonists",
"BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications . Because this issue remains controversial , we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were r and omly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study . METHODS The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve , r and omized , blinded trial comparing the effects of moderate control of blood pressure ( target diastolic pressure , 80 to 89 mm Hg ) with those of intensive control of blood pressure ( diastolic pressure , 75 mm Hg ) on the incidence and progression of complications of diabetes . The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes . In the current study , we analyzed data on a secondary end point ( the incidence of myocardial infa rct ion ) in the subgroup of patients in the ABCD Trial who had hypertension . RESULTS Analysis of the 470 patients in the trial who had hypertension ( base-line diastolic blood pressure , > or = 90 mm Hg ) showed similar control of blood pressure , blood glucose and lipid concentrations , and smoking behavior in the nisoldipine group ( 237 patients ) and the enalapril group ( 233 patients ) throughout five years of follow-up . Using a multiple logistic-regression model with adjustment for cardiac risk factors , we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infa rct ions ( a total of 24 ) than enalapril ( total , 4 ) ( risk ratio , 9.5 ; 95 percent confidence interval , 2.7 to 33.8 ) . CONCLUSIONS In this population of patients with diabetes and hypertension , we found a significantly higher incidence of fatal and nonfatal myocardial infa rct ion among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril . Since our findings are based on a secondary end point , they will require confirmation",
"BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe . In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common",
"BACKGROUND In 1988 , the Systolic Hypertension in China ( Syst-China ) Collaborative Group initiated the placebo-controlled Syst-China trial to investigate whether antihypertensive drug treatment could reduce the incidence of fatal and nonfatal stroke in older Chinese patients with isolated systolic hypertension . OBJECTIVES To explore ( 1 ) whether the benefits of active treatment were evenly distributed across 4 strata , prospect ively defined according to sex and previous cardiovascular complications , and ( 2 ) whether the morbidity and mortality results were influenced by age , level of systolic or diastolic blood pressure ( BP ) , smoking or drinking habits , or diabetes mellitus at enrollment . METHODS Eligible patients had to be 60 years or older with a sitting systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg . After stratification for center , sex , and previous cardiovascular complications , 1253 patients were assigned to active treatment starting with nitrendipine ( 10 - 40 mg/d ) , with the possible addition of captopril ( 12.5 - 50.0 mg/d ) , and /or hydrochlorothiazide ( 12.5 - 50 mg/d ) . In the 1141 control patients , matching placebos were used similarly . RESULTS Male sex , previous cardiovascular complications , older age , higher systolic BP or lower diastolic BP , living in northern China , smoking , and diabetes mellitus significantly and independently increased the risk of 1 or more of the following end points : total or cardiovascular mortality , all fatal and nonfatal cardiovascular end points , all strokes , and all cardiac end points . In the placebo-control group diabetes raised the risk of all end points 2- to 3-fold ( P excess risk associated with diabetes to a nonsignificant level ( P values ranging from .12-.86 ) except for cardiovascular mortality ( P = .04 ) . Cox regression with adjustments applied for significant covariates suggested that active treatment may reduce total mortality more ( P = .06 ) in women and stroke more ( P = .07 ) in men and that it may provide better protection against cardiac end points in nonsmokers than smokers ( P = .04 ) . Otherwise , the benefits of active treatment were equally manifest , regardless of the enrollment characteristics of the patients , and regardless of whether active treatment consisted of only nitrendipine or of nitrendipine associated with other active drugs . CONCLUSIONS In elderly Chinese patients with isolated systolic hypertension , stepwise antihypertensive drug treatment , starting with the dihydropyridine calcium channel blocker nitrendipine , improved prognosis . The benefit was particularly evident in diabetic patients ; for cardiac end points it tended to be larger in nonsmokers . Otherwise , the benefit of active treatment was not significantly influenced by the characteristics of the patients at enrollment in the trial",
"OBJECTIVES We sought to evaluate the influence of pretreatment systolic blood pressure ( SBP ) on the efficacy and safety of carvedilol in patients with chronic heart failure ( CHF ) . BACKGROUND Although beta-blockers reduce the risk of death in CHF , there is little reported experience with these drugs in patients with a low pretreatment SBP , who may respond poorly to beta-blockade . METHODS We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospect i ve R and omized Cumulative Survival ( COPERNICUS ) trial . RESULTS Compared with placebo , carvedilol improved the clinical status and reduced the risk of death and the combined risk of death or hospitalization for any reason , for a cardiovascular reason , or for worsening heart failure ( p 0.10 ) . However , because patients with the lowest SBP were at highest risk of an event , they experienced the greatest absolute benefit from treatment with carvedilol . The lower the pretreatment SBP , the more likely that patients would report an adverse event , be intolerant of high doses of the study drug , or require permanent withdrawal of treatment ( p carvedilol . CONCLUSIONS The current study provides little support for concerns about using beta-blockers ( particularly those with vasodilatory actions ) in patients with severe CHF who have a low SBP . Pretreatment blood pressure can identify patients who have the greatest need for risk reduction with carvedilol",
"The incidence of ESRD is increasing dramatically . Progression to end-stage may be halted or slowed when kidney damage is detected at an early stage . Kidney damage is frequently asymptomatic but is indicated by the presence of proteinuria , hematuria , or reduced GFR . Population -based studies relating to the prevalence of kidney damage in the community are limited , particularly outside of the United States . Therefore , the prevalence of proteinuria , hematuria , and reduced GFR in the Australian adult population was determined using a cross-sectional study of 11,247 noninstitutionalized Australians aged 25 yr or over , r and omly selected using a stratified , cluster method . Subjects were interviewed and tested for proteinuria-spot urine protein to creatinine ratio ( abnormal : > /=0.20 mg/mg ) ; hematuria-spot urine dipstick ( abnormal : 1 + or greater ) confirmed by urine microscopy ( abnormal : > 10,000 red blood cells per milliliter ) or dipstick ( abnormal : 1 + or greater ) on midstream urine sample ; and reduced GFR-Cockcroft-Gault estimated GFR ( abnormal : kidney damage were examined . Proteinuria was detected in 2.4 % of cases ( 95 % CI : 1.6 % , 3.1 % ) , hematuria in 4.6 % ( 95 % CI : 3.8 % , 5.4 % ) , and reduced GFR in 11.2 % ( 95 % CI : 8.6 % , 13.8 % ) . Approximately 16 % had at least one indicator of kidney damage . Age , diabetes mellitus , and hypertension were independently associated with proteinuria ; age , gender , and hypertension with hematuria ; and age , gender , and hypertension with reduced GFR . Approximately 16 % of the Australian adult population has either proteinuria , hematuria , and /or reduced GFR , indicating the presence of kidney damage . Identifying and targeting this section of the population may provide a means to reduce the burden of ESRD",
"The 2014 Evidence -Based Guideline for the Management of High Blood Pressure In Adults : Report From the Panel Members Appointed to the Eighth Joint National Committee ( JNC 8) recommends several major changes from the JNC 7 report ( 1 , 2 ) . The 2014 guideline is based on a systematic review of r and omized , controlled trials ( RCTs ) by a multidisciplinary panel using a process informed by Institute of Medicine recommendations for guideline development ( 3 ) . Although there was almost unanimous agreement on nearly all recommendations , a minority of the panel ( the authors of this commentary ) disagreed with the recommendation to increase the target systolic blood pressure ( SBP ) from 140 to 150 mm Hg in persons aged 60 years or older without diabetes mellitus ( DM ) or chronic kidney disease ( CKD ) . This target guides both the initiation of therapy and treatment goals . Although this issue has major clinical and public health implication s , the guideline only briefly summarized the concerns underlying the minority opinion to maintain the target of less than 140 mm Hg . The Institute of Medicine recommendation for guideline development encourages guidelines to provide a description and explanation of any differences of opinion regarding the recommendation ( 3 ) . This summarizes the evidence and rationale underlying the minority opinion to maintain the SBP target of 140 mm Hg or lower in persons aged 60 years or older until there is greater certainty of the risks and benefits of a higher target . First , increasing the target will probably reduce the intensity of antihypertensive treatment in a large population at high risk for cardiovascular disease ( CVD ) ( Table 1 ) . The higher SBP goal would apply to some of the groups at highest cardiovascular risk , such as African Americans , hypertensive patients with multiple CVD risk factors other than DM or CKD , and those with clinical CVD . Second , the evidence supporting increasing the SBP target from 140 to 150 mm Hg in persons aged 60 years or older was insufficient and inconsistent with the evidence supporting the panel 's recommendations for an SBP target of less than 140 mm Hg in persons younger than 60 years and those aged 60 years or older with DM or CKD . Third , the higher SBP goal in individuals aged 60 years or older may reverse the decades-long decline in CVD , especially stroke mortality ( 4 ) . In the absence of definitive evidence defining the optimum SBP target , observational studies and RCT data that the panel did not systematic ally review more strongly support the SBP goal of less than 140 mm Hg , especially in high-risk individuals . Other recent guideline groups review ing similar evidence have recommended a goal of less than 140 mm Hg , particularly in persons aged 80 years or younger ( 59 ) . Table 1 . U.S. Cardiovascular Disease Death Rates for Persons Younger and Older Than 65 y Persons Aged 60 Years or Older With Hypertension and SBP Controlled to 140 mm Hg or Lower More than half of the 72 million persons with hypertension in the United States are aged 60 years or older ( 10 , 11 ) . Among these individuals , the 2014 guideline recommends the SBP goal of 140 mm Hg or lower only for those with DM and those younger than 70 years with CKD ( 2 ) . Although the prevalence of hypertension in this age group ( 65 % to 67 % ) did not change between 1999 and 2010 , the percentage with adequate blood pressure control increased from 27.4 % ( 19992000 ) to 50.5 % ( 20112012 ) , with 82.2 % now receiving antihypertensive medications ( 10 , 12 ) . Data from NHANES ( National Health and Nutrition Examination Survey ) from 2001 to 2008 show that among treated and untreated hypertensive adults aged 60 years or older , median SBPs were 136 mm Hg and 152 mm Hg , respectively ( 13 ) , and SBPs have been decreasing in this age group over the past 5 decades ( Figure ) ( 4 ) . Thus , a target of less than 150 mm Hg would likely increase blood pressures in the treated hypertensive population and would suggest that nearly half of the untreated hypertensive patients in this age range should remain untreated . The large population at high risk for CVD , with most currently at an SBP of 140 mm Hg or lower , creates concern that a higher SBP target will adversely affect public health . Figure . Smoothed weighted frequency distribution , median , and 90th percentile of systolic blood pressure for persons aged 60 to 74 y : United States , 19592010 . Reproduced from Lackl and and colleagues ( 4 ) . NHANES = National Health and Nutrition Examination Survey ; NHES = National Health Examination Survey . High Risk in Persons With the Higher Goal Age substantially increases risk for cardiovascular events ( Table 1 ) , so differences in cardiovascular risk do not justify different targets for patients older and younger than 60 years . The risk range for white and African American men aged 60 years is 9 % to 30 % , depending on risk factor profile . For men of both ethnicities who are aged 70 years or older and have SBP controlled to 140 mm Hg , even without clinical CVD or DM , the 10-year risk exceeds 20 % ( 14 ) . Thus , on the basis of absolute risk , using an age threshold of 60 years to define eligibility for less aggressive treatment lacks consistency . Persons aged 60 to 79 years are at higher risk than those who are younger , even if the younger persons have DM . Insufficient Evidence for Differential Hypertension Treatment Benefit for Patients Older and Younger Than 60 Years The 2014 guideline panel failed to identify evidence of differential benefits or harms of treatment using an SBP goal of 140 mm Hg with an age threshold of 60 years . There is little RCT evidence of risk or benefit in treating persons younger than 60 years to this target , except in those with diastolic hypertension . The guideline indicates that no qualifying evidence was found comparing an SBP less than 140 mm Hg to any other SBP goal for persons younger than 60 years ( 2 ) . However , in persons aged 60 years or older , the SHEP ( Systolic Hypertension in the Elderly Program ) trial showed benefit of treating hypertension to an SBP goal between 140 and 145 mm Hg ( Table 2 ) ( 15 ) . HYVET ( Hypertension in the Very Elderly Trial ) found a benefit of an SBP target of less than 150 mm Hg on health outcomes , including mortality in persons aged 80 years or older ( 16 ) . Patients in the HYVET treatment group achieved an SBP of 144 mm Hg at 2 years compared with 159 mm Hg in the control group , and blood pressures continued to decrease in both groups until the end of the trial . Therefore , HYVET and the SHEP trial provide evidence that reducing SBP to around 140 mm Hg has substantial benefit without major harm in older persons . Thus , the best evidence available for an SBP target around 140 mm Hg , which meets the guideline RCT criteria , is in persons older than 60 years . The lack of benefit seen in 2 Japanese trials in older individuals ( JATOS [ Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients ] [ 17 ] and the VALISH [ Valsartan in Elderly Isolated Systolic Hypertension ] trial [ 18 ] ) was cited by some to rationalize the higher SBP target , but these trials were underpowered ( Table 2 ) . The SHEP trial and HYVET together reported 365 strokes and more than 285 coronary heart disease events , whereas JATOS and the VALISH trial only had a combined total of 125 strokes and 67 coronary heart disease events . In addition , the much larger FEVER ( Felodipine Event Reduction ) trial ( 19 ) did not meet criteria for inclusion in the panel 's deliberation ( Table 2 ) . This trial , which was conducted in a Chinese population ( age range , 50 to 79 years ; mean age , 62 years ) , reported a significant 27 % reduction in its primary outcome , as well as significant reductions in all CVD , total mortality , coronary heart disease , and heart failure in patients treated to an SBP of 137 mm Hg with a thiazide diureticcalcium-channel blocker combination versus 143 mm Hg with a thiazide diuretic plus placebo ( 19 ) . Table 2 . Trials Comparing Different Systolic Blood Pressure Thresholds In addition , generalizability of the Japanese trials to other population s of patients older than 60 years , such as African Americans , is uncertain . African Americans are at highest risk for all complications of hypertension and are historically undertreated . Thus , we believe that recommending less aggressive targets in this or other high-risk population s requires stronger justification than the guideline cites . Three recent guidelines from other countries have concluded that the appropriate cut point for an age-related differential SBP goal is 80 years or older ( 57 ) . We agree that this higher treatment target in frail hypertensive patients aged 80 years or older better reflects existing evidence . Safety and Adverse Event Risk in Hypertensive Patients Aged 60 Years or Older Despite the limited number of end points in JATOS and the VALISH trial , their size and duration provide evidence of safety of the SBP target of less than 140 mm Hg . The VALISH investigators concluded that this target was safe in relatively healthy patients aged 70 years or older with isolated systolic hypertension ( 18 ) . In JATOS , adverse events requiring treatment discontinuation were reported in only 36 patients , with no differences in discontinuation rate between groups ( 17 ) . This evidence and the favorable results at slightly higher blood pressures in the SHEP trial and HYVET provide reassurance of the safety of an SBP goal of less than 140 mm Hg in older , nonfrail persons . Other Trial Evidence of Benefit of Treatment at an SBP of 140 mm Hg or Lower Results of the SPS3 ( Secondary Prevention of Small Subcortical Strokes ) trial indicated that an SBP target of less than 130 mm Hg versus 144 mm Hg in 3020 patients ( mean age , 63 years ) reduced subsequent strokes by 19 % ( P= 0.08 ) and hemorrhagic strokes by nearly 50 % ( P all strokes in a subgroup analysis of patients older than 65 years ( 17 ) . Finally , 2 meta-analyses",
"In 1972 - -1973 , 785 symptom-free men , aged 40 to 49 years , without target organ damage , with systolic blood pressures between 150 and 179 mm Hg and diastolic blood pressure below 110 mm Hg , were assigned at r and om to one of two groups : ( 406 to a drug treatment group and 379 to a control group ) for a five-year controlled drug treatment trial to evaluate the effect of therapy on cardiovascular complications . Drug treatment started with hydrochlorothiazide . If systolic blood pressure remained above 140 mm Hg and /or diastolic blood pressure above 90 mm Hg , alphamethyldopa was added . If there were side effects , methyldopa was replaced with propranolol . The control group was not given a placebo . The mean observation time was 66 months ( range 60 to 78 months ) . A difference in blood pressure between groups of about 17 mm Hg systolic and 10 mm Hg diastolic was maintained throughout the study . The study protocol had a rather low \" ethical \" blood pressure roof , 180 mm Hg systolic and /or 110 mm Hg diastolic . Seventeen percent of the control group had an increase in blood pressure above this level during the trial , and drug treatment was started . There was no effect on major cardiovascular morbidity comparing groups as established by r and omization , with 18 events in the treatment group and 20 events in the control group . There was no difference between the groups in total mortality and mortality from cardiovascular events . However , in the subgroups with diastolic blood pressure greater than or equal to 100 mm Hg before r and omization , there was a probable reduction in total morbidity from cardiovascular events in favor or the group receiving drug therapy , 7.6 and 16.4 percent events in the treated and control groups , respectively . Cerebrovascular events occurred only in the control group , 7 versus 0 . Two cases of fatal aortic aneurysms also occurred in the control group . Other \" pressure \" complications , such as marked left ventricular hypertrophy in the electrocardiogram and left ventricular failure , occurred only in the control group . However , regarding coronary heart disease , including sudden death , the incidence tended to be higher in the treated group , although it was not statistically significant . Only 13 men ( 1.7 percent ) failed to meet for regular examinations . At the end of the study these men were also followed up with regard to possible cardiovascular events",
"OBJECTIVE --To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke , coronary heart disease , and death . DESIGN --R and omised , placebo controlled , single blind trial . SETTING --226 general practice s in the MRC general practice research framework . SUBJECTS--4396 patients aged 65 - 74 r and omised to receive diuretic , beta blocker , or placebo . Patients had mean systolic pressures of 160 - 209 mm Hg and mean diastolic pressures less than 115 mm Hg during an eight week run in and were not taking antihypertensive treatment . INTERVENTION-- Patients were r and omised to atenolol 50 mg daily ; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily ; or placebo . The regimens were adjusted to achieve specified target pressures . Mean follow up was 5.8 years . MAIN OUTCOME MEASURES --Strokes , coronary events , and deaths from all causes . RESULTS --Both treatments reduced blood pressure below the level in the placebo group . Compared with the placebo group , actively treated subjects ( diuretic and beta blocker groups combined ) had a 25 % ( 95 % confidence interval 3 % to 42 % ) reduction in stroke ( p = 0.04 ) , 19 % ( -2 % to 36 % ) reduction in coronary events ( p = 0.08 ) , and 17 % ( 2 % to 29 % ) reduction in all cardiovascular events ( p = 0.03 ) . After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke ( 31 % ( 3 % to 51 % ) p = 0.04 ) , coronary events ( 44 % ( 21 % to 60 % ) , p = 0.0009 ) , and all cardiovascular events ( 35 % ( 17 % to 49 % ) , p = 0.0005 ) compared with the placebo group . The beta blocker group showed no significant reductions in these end points . The reduction in strokes was mainly in non-smokers taking the diuretic . CONCLUSION --Hydrochlorothiazide and amiloride reduce the risk of stroke , coronary events , and all cardiovascular events in older hypertensive adults ",
"BACKGROUND Although several important studies have been performed in hypertensive type 2 diabetic patients , it is not known whether lowering blood pressure in normotensive ( BP offers any beneficial results on vascular complications . The current study evaluated the effect of intensive versus moderate diastolic blood pressure ( DBP ) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients . METHODS The current study was a prospect i ve , r and omized controlled trial in normotensive type 2 diabetic subjects . The subjects were r and omized to intensive ( 10 mm Hg below the baseline DBP ) versus moderate ( 80 to 89 mm Hg ) DBP control . Patients in the moderate therapy group were given placebo , while the patients r and omized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication . The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion , progression of retinopathy and neuropathy and the incidence of cardiovascular disease . RESULTS The mean follow-up was 5.3 years . Mean BP in the intensive group was 128 + /- 0.8/75 + /- 0.3 mm Hg versus 137 + /- 0.7/81 + /- 0.3 mm Hg in the moderate group , P creatinine clearance ( P = 0.43 ) , a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria ( P = 0.012 ) and microalbuminuria to overt albuminuria ( P = 0.028 ) . The intensive BP control group also demonstrated less progression of diabetic retinopathy ( P = 0.019 ) and a lower incidence of strokes ( P = 0.03 ) . The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent . CONCLUSION Over a five-year follow-up period , intensive ( approximately 128/75 mm Hg ) BP control in normotensive type 2 diabetic patients : ( 1 ) slowed the progression to incipient and overt diabetic nephropathy ; ( 2 ) decreased the progression of diabetic retinopathy ; and ( 3 ) diminished the incidence of stroke",
"OBJECTIVES We attempted to compare the effect of an angiotensin-converting enzyme ( ACE ) inhibitor and angiotensin receptor blocker ( ARB ) on atherosclerotic events . BACKGROUND Angiotensin-converting enzyme inhibitors and ARBs interrupt the renin-angiotensin system by distinct mechanisms . It is not clear whether ARBs reduce atherosclerotic events such as myocardial infa rct ion ( MI ) like ACE inhibitors . This evidence gap may reflect the nature of the studies conducted , to date . Placebo-controlled studies enrolled cohorts at low risk of atherosclerotic events ( e.g. , patients with chronic heart failure , most treated with an ACE inhibitor ) . One of the main active controlled trials was confounded by a blood pressure difference between treatments . METHODS We compared the effects of captopril , valsartan , and their combination on atherosclerotic events in 14,703 patients r and omized in the Valsartan in Acute Myocardial Infa rct ion Trial ( VALIANT ) . RESULTS The number of individuals adjudicated as having a fatal or non-fatal MI in the captopril group was 559 ( total investigator reported events 798 ) , 587 ( 796 ) in the valsartan group , and 554 ( 756 ) in the combination group ; valsartan versus captopril , p = 0.651 ( 0.965 ) ; combination versus captopril , p = 0.187 ( 0.350 ) . Overall , all atherosclerotic events examined occurred at a similar frequency in the captopril and valsartan groups . CONCLUSIONS Angiotensin receptor blockers appear to be as effective as ACE inhibitors in reducing atherosclerotic events , even when used in addition to other secondary preventive treatments . These data , although not conclusive , also support the hypothesis that adding an ARB to an ACE inhibitor may have a small additional anti-infa rct ion effect , a possibility that needs to be prospect ively tested",
"BACKGROUND It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk . The objective of the study was to compare the efficacy of these treatments in elderly , high-risk Japanese hypertensive patients . METHODS The OlmeSartan and Calcium Antagonists R and omized ( OSCAR ) study was a multicenter , prospect i ve , r and omized , open-label , blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease . Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were r and omly assigned to receive 40 mg/d olmesartan ( high-dose angiotensin II receptor blocker ) or a calcium channel blocker + 20 mg/d olmesartan ( angiotensin II receptor blocker + calcium channel blocker ) . The primary end point was a composite of cardiovascular events and noncardiovascular death . RESULTS During a 3-year follow-up , blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group . Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group . More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group ( 58 vs 48 events , hazard ratio [ HR ] , 1.31 , 95 % confidence interval , 0.89 - 1.92 ; P=.17 ) . In patients with cardiovascular disease at baseline , more primary events occurred in the high-dose angiotensin II receptor blocker group ( HR , 1.63 , P=.03 ) ; in contrast , fewer events were observed in the subgroup without cardiovascular disease ( HR , 0.52 , P=.14 ) . This treatment-by-subgroup interaction was significant ( P=.02 ) . CONCLUSION The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease . The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent",
"Background Isolated systolic hyprtension occurs in around 8 % of Chinese people aged 60 years or older . In 1988 , the Systolic Hypertension in China ( Syst-China ) Collaborative Group started to investigate whether active treatment could reduce the incidence of stroke and other cardiovascular complications in older patients with isolated systolic hypertension . Methods All patients were initially started on masked placebo . After stratification for centre , sex and previous cardiovascular complications , alternate patients ( n = 1253 ) were assigned nitrendipine at 10–40 mg daily , with the addition of captopril at 12.5–50.0 mg daily or hydrochlorothiazide at 12.5–50.0 mg daily , or both , if a sufficient blood pressure fall was not obtained . In the remaining 1141 control patients , matching placebos were administered similarly . Results At entry , sitting blood pressure averaged 170.5 mmHg systolic and 86.0 mmHg diastolic , age averaged 66.5 years and total serum cholesterol was 5.1 mmol/l . After 2 years of follow-up , sitting systolic and diastolic blood pressures had fallen by 10.9 mmHg and 1.9 mmHg in the placebo group and by 20.0 mmHg and 5.0 mmHg in the active treatment group . The intergroup differences were 9.1 mmHg systolic ( 95 % confidence interval 7.6–10.7 mmHg ) and 3.2 mmHg diastolic ( 95 % confidence interval 2.4–4.0 ) . Active treatment reduced total strokes by 38 % ( from 20.8 to 13.0 endpoints per 1000 patient-years , P = 0.01 ) , all-cause mortality by 39 % ( from 28.4 to 17.4 endpoints per 1000 patient-years , P = 0.003 ) , cardiovascular mortality by 39 % ( from 15.2 to 9.4 endpoints per 1000 patient-years , P = 0.03 ) , stroke mortality by 58 % ( from 6.9 to 2.9 endpoints per 1000 patient-years , P = 0.02 ) , and all fatal and nonfatal cardiovascular endpoints by 37 % ( from 33.3 to 21.4 endpoints per 1000 patient-years , P = 0.004 ) . Conclusions Antihypertensive treatment prevents stroke and other cardiovascular complications in older Chinese patients with isolated systolic hypertension . Treatment of 1000 Chinese patients for 5 years could prevent 55 deaths , 39 strokes or 59 major cardiovascular endpoints ",
"Men aged 40 - 64 years with mild to moderate hypertension [ diastolic blood pressure ( DBP ) 100 - 130 mmHg ] were r and omized to treatment with a diuretic ( n = 3272 ) or a beta-blocker ( n = 3297 ) , with additional drugs if necessary , to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease ( CHD ) events and death . Patients with previous CHD , stroke or other serious diseases , or with contraindications to diuretics or beta-blockers were excluded . If normotension ( DBP less than 95 mmHg ) was not achieved by monotherapy , other antihypertensive drugs were added , but the two basic drugs were not crossed over . Patients were assessed at 6-monthly intervals . The mean follow-up for end-points was 45.1 months . Blood pressure ( BP ) side effects and end-points were recorded in a st and ardized manner . Entry characteristics and the BP reduction achieved were very similar in both treatment groups . All analyses were made on an intention-to-treat basis . The incidence of CHD did not differ between the two treatment groups . The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group . Total mortality and the total number of end-points were similar in both groups . The percentage of patients withdrawn due to side effects was similar , whereas the number of reported symptoms , according to a question naire , was higher for patients on beta-blockers . The incidence of diabetes did not differ between the two groups . Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers , and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD . Beta-blockers and thiazide diuretics were approximately equally well tolerated . The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group . Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications , including CHD , to a different extent",
"ABCD : Appropriate Blood pressure Control in Diabetes ABI : ankle – brachial index ABPM : ambulatory blood pressure monitoring ACCESS : Acute C and esartan Cilexetil Therapy in Stroke Survival ACCOMPLISH : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ACCORD : Action to Control Cardiovascular Risk in Diabetes ACE : angiotensin-converting enzyme ACTIVE I : Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ADVANCE : Action in Diabetes and Vascular Disease : Preterax and Diamicron-MR Controlled Evaluation AHEAD : Action for HEAlth in Diabetes ALLHAT : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack ALTITUDE : ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints ANTIPAF : ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation APOLLO : A R and omized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People ARB : angiotensin receptor blocker ARIC : Atherosclerosis Risk In Communities ARR : aldosterone renin ratio ASCOT : Anglo-Sc and inavian Cardiac Outcomes Trial ASCOT-LLA : Anglo-Sc and inavian Cardiac Outcomes Trial — Lipid Lowering Arm ASTRAL : Angioplasty and STenting for Renal Artery Lesions A-V : atrioventricular BB : beta-blocker BMI : body mass index BP : blood pressure BSA : body surface area CA : calcium antagonist CABG : coronary artery bypass graft CAPPP : CAPtopril Prevention Project CAPRAF : C And esartan in the Prevention of Relapsing Atrial Fibrillation CHD : coronary heart disease CHHIPS : Controlling Hypertension and Hypertension Immediately Post-Stroke CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease — EPIdemiology collaboration CONVINCE : Controlled ONset Verapamil INvestigation of CV Endpoints CT : computed tomography CV : cardiovascular CVD : cardiovascular disease D : diuretic DASH : Dietary Approaches to Stop Hypertension DBP : diastolic blood pressure DCCT : Diabetes Control and Complications Study DIRECT : DIabetic REtinopathy C and esartan Trials DM : diabetes mellitus DPP-4 : dipeptidyl peptidase 4 EAS : European Atherosclerosis Society EASD : European Association for the Study of Diabetes ECG : electrocardiogram EF : ejection fraction eGFR : estimated glomerular filtration rate ELSA : European Lacidipine Study on Atherosclerosis ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease EXPLOR : Amlodipine – Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine – Atenolol Combination FDA : U.S. Food and Drug Administration FEVER : Felodipine EVent Reduction study GISSI-AF : Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation HbA1c : glycated haemoglobin HBPM : home blood pressure monitoring HOPE : Heart Outcomes Prevention Evaluation HOT : Hypertension Optimal Treatment HRT : hormone replacement therapy HT : hypertension HYVET : HYpertension in the Very Elderly Trial IMT : intima-media thickness I-PRESERVE : Irbesartan in Heart Failure with Preserved Systolic Function INTERHEART : Effect of Potentially Modifiable Risk Factors associated with Myocardial Infa rct ion in 52 Countries INVEST : INternational VErapamil SR/T Tr and olapril ISH : Isolated systolic hypertension JNC : Joint National Committee JUPITER : Justification for the Use of Statins in Primary Prevention : an Intervention Trial Evaluating Rosuvastatin LAVi : left atrial volume index LIFE : Losartan Intervention For Endpoint Reduction in Hypertensives LV : left ventricle/left ventricular LVH : left ventricular hypertrophy LVM : left ventricular mass MDRD : Modification of Diet in Renal Disease MRFIT : Multiple Risk Factor Intervention Trial MRI : magnetic resonance imaging NORDIL : The Nordic Diltiazem Intervention study OC : oral contraceptive OD : organ damage ONTARGET : ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial PAD : peripheral artery disease PATHS : Prevention And Treatment of Hypertension Study PCI : percutaneous coronary intervention PPAR : peroxisome proliferator-activated receptor PREVEND : Prevention of REnal and Vascular ENdstage Disease PROFESS : Prevention Regimen for Effectively Avoiding Secondary Strokes PROGRESS : Perindopril Protection Against Recurrent Stroke Study PWV : pulse wave velocity QALY : Quality adjusted life years RAA : renin-angiotensin-aldosterone RAS : renin-angiotensin system RCT : r and omized controlled trials RF : risk factor ROADMAP : R and omized Olmesartan And Diabetes MicroAlbuminuria Prevention SBP : systolic blood pressure SCAST : Angiotensin-Receptor Blocker C and esartan for Treatment of Acute STroke SCOPE : Study on COgnition and Prognosis in the Elderly SCORE : Systematic COronary Risk Evaluation SHEP : Systolic Hypertension in the Elderly Program STOP : Swedish Trials in Old Patients with Hypertension STOP-2 : The second Swedish Trial in Old Patients with Hypertension SYSTCHINA : SYSTolic Hypertension in the Elderly : Chinese trial SYSTEUR : SYSTolic Hypertension in Europe TIA : transient ischaemic attack TOHP : Trials Of Hypertension Prevention TRANSCEND : Telmisartan R and omised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease UKPDS : United Kingdom Prospect i ve Diabetes Study VADT : Veterans ' Affairs Diabetes Trial VALUE : Valsartan Antihypertensive Long-term Use Evaluation WHO : World Health Organization # # # 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension ( ESH ) and the European Society of Cardiology",
"Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient"
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OBJECTIVE To provide information and recommendations to assist women with breast cancer and their physicians in making decisions regarding the use of locoregional post-mastectomy radiotherapy ( PMRT ) . OUTCOMES Locoregional control , disease-free survival , overall survival and treatment-related toxicities . EVIDENCE This guideline is based on a review of all meta-analyses , consensus statements and other guidelines published between 1966 and November 2002 . Search es of MEDLINE and CANCERLIT for English- language r and omized controlled trials published between 1995 and November 2002 were also conducted to supplement the literature previously review ed by the American Society of Clinical Oncology ( ASCO ) Health Services Research Committee panel in its published guideline . A non systematic review of the literature was continued through June 2003 . RECOMMENDATIONS Locoregional PMRT is recommended for women with an advanced primary tumour ( tumour size 5 cm or greater , or tumour invasion of the skin , pectoral muscle or chest wall ) . Locoregional PMRT is recommended for women with 4 or more positive axillary lymph nodes . The role of PMRT in women with 1 to 3 positive axillary lymph nodes is unclear . These women should be offered the opportunity to participate in clinical trials of PMRT . Locoregional PMRT is generally not recommended for women who have tumours that are less than 5 cm in diameter and who have negative axillary nodes . Other patient , tumour and treatment characteristics , including age , histologic grade , lymphovascular invasion , hormone receptor status , number of axillary nodes removed , axillary extracapsular extension and surgical margin status , may affect locoregional control , but their use in specifying additional indications for PMRT is currently unclear . PMRT should encompass the chest wall and the supraclavicular , infraclavicular and axillary apical lymph node areas . To reduce the risk of lymphedema , radiation of the entire axilla should not be used routinely after complete axillary dissection of level I and II lymph nodes . A definite recommendation regarding the inclusion of the internal mammary lymph nodes in PMRT can not be made because of limited and inconsistent data . The use of modern techniques in radiotherapy planning is recommended to minimize excessive normal tissue exposure , particularly to the cardiac and pulmonary structures . Common short-term side effects of PMRT , including fatigue and skin erythema , are generally tolerable and not dose-limiting . Severe long-term side effects , including lymphedema , cardiac and pulmonary toxicities , brachial plexopathy , rib fractures and secondary neoplasms , are relatively rare . The optimal sequencing of PMRT and systemic therapy is currently unclear . Regimens containing anthracyclines or taxanes should not be administered concurrently with radiotherapy because of the potential for increased toxicity . VALIDATION The authors ' original text was su bmi tted for review , revision and approval by the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer . Subsequently , feedback was provided by 11 oncologists from across Canada . The final document was approved by the steering committee . SPONSOR The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada . COMPLETION DATE : November 2003
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"Two hundred patients with node positive stage II breast cancer were r and omised to four groups after radical mastectomy and axillary evacuation : ( 1 ) Postoperative radiotherapy , ( 2 ) Adjuvant chemotherapy with eight courses of CAFt ( cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1 - 14 ) every fourth week , ( 3 ) Postoperative radiotherapy and adjuvant chemotherapy and ( 4 ) postoperative radiation , adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years . Thirty-two per cent of the patients discontinued treatment due to GI-toxicity , while 26 % required dose reductions due to leukopenia . Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy . There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone ( P = 0.05 ) , which was highly significant in a multivariate Cox analysis ( P = 0.004 ) . No significant survival differences were seen . Tamoxifen had no clear overall effect but there were better relapse-free ( P = 0.04 ) and overall ( P = 0.004 ) survival with tamoxifen in estrogen receptor positive patients , while estrogen receptor negative patients had a somewhat poorer survival ( P = 0.07 ) after tamoxifen . Local control was better ( NS ) after the combination ( 93 % ) radiotherapy and chemotherapy compared to either treatment alone ( 76 % with radiotherapy and 74 % with chemotherapy at 5 years )",
"In a prospect i ve study of 622 women with breast cancer , those with one to three histologically positive axillary lymph nodes were r and omised after mastectomy to receive cyclophosphamide 100 mg/m2 orally on days 1 - 14 , methotrexate 40 mg/m2 intravenously on days 1 and 8 , and fluorouracil 600 mg/m2 intravenously on days 1 and 8 every 28 days for six cycles ( CMF x six ) , or for twelve cycles of the same chemotherapy ( CMF x 12 ) . Those with > or = four positive nodes were r and omised to one of these two groups or to 5000 cGy of postmastectomy regional radiotherapy ( RT ) followed by six cycles of the same chemotherapy ( RT + CMF x six ) . With about 10 years median follow-up , there was no significant difference in survival or disease-free survival among the three groups . There was evidence of decreased locoregional recurrence in patients with > or = four nodes who received RT + CMF x six ( relative risk 0.53 , P = 0.067 ) . Multivariate analysis indicated that the presence of > or = four positive nodes ( negatively ) and the percentage of ideal ( full ) dose of CMF received ( positively ) were the strongest factors predictive of survival . This study shows no advantage for 12 over six cycles of CMF chemotherapy in women with breast cancer and positive axillary nodes . There was a suggestion of decreased locoregional recurrence but no improvement in survival with radiotherapy for women with > or = four positive nodes",
"OBJECTIVE To provide information and recommendations for women and their physicians when making decisions about the management of lymphedema related to breast cancer . OPTIONS Compression garments , pneumatic compression pumps , massage and physical therapies , other physical therapy modalities , pharmaceutical treatments . OUTCOMES Symptom control , quality of life , cosmetic results . EVIDENCE Systematic review of English- language literature retrieved primarily from MEDLINE ( 1966 to April 2000 ) and CANCERLIT ( 1985 to April 2000 ) . Non systematic review of breast cancer literature published to October 2000 . RECOMMENDATIONS Pre- and postoperative measurements of both arms are useful in the assessment and diagnosis of lymphedema . Circumferential measurements should be taken at 4 points : the metacarpal-phalangeal joints , the wrists , 10 cm distal to the lateral epicondyles and 15 cm proximal to the lateral epicondyles . Clinicians should elicit symptoms of heaviness , tightness or swelling in the affected arm . A difference of more than 2.0 cm at any of the 4 measurement points may warrant treatment of the lymphedema , provided that tumour involvement of the axilla or brachial plexus , infection and axillary vein thrombosis have been ruled out . Practitioners may want to encourage long-term and consistent use of compression garments by women with lymphedema . One r and omized trial has demonstrated a trend in favour of pneumatic compression pumps compared with no treatment . Further r and omized trials are required to determine whether pneumatic compression provides additional benefit over compression garments alone . Complex physical therapy , also called complex decongestive physiotherapy , requires further evaluation in r and omized trials . In one r and omized trial no difference in outcomes was detected between compression garments plus manual lymph drainage versus compression garments alone . Clinical experience supports encouraging patients to consider some practical advice regarding skin care , exercise and body weight . [ A patient version of these guidelines appears in Appendix 2 . ] VALIDATION An initial draft of this document was developed by a task force sponsored by the BC Cancer Agency . It was up date d and revised substantially by a writing committee and then su bmi tted for further review , revision and approval by the Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer . SPONSOR The steering committee was convened by Health Canada . COMPLETION DATE : October 2000",
"UNLABELLED A prospect i ve r and omized study was made of 270 patients with unilateral stage I or II invasive breast cancer treated by segmental resection , axillary dissection and radiation at the University Hospital of Tampere , Finl and , between 1989 and 1991 . The aim of the study was to determine whether there is any advantage or disadvantage if the internal mammary chains ( IMC ) are included in the radiation target volume . The medial and lateral two-field technique was used and the target volumes were determined r and omly either to include the internal mammary chain ( IMC-RT ) or not ( no-IMC-RT ) . The prevalence of radiation pneumonitis was 16 % and there was no significant difference between the IMC- and no-IMC-groups ( 18 vs. 14 % ) . Skin reactions were equal in both groups . Lung fibrosis was more common in the IMC-RT group . IN CONCLUSION radiation of internal mammary chain after conservative surgery does not lead to an increase in clinical ly important skin or pulmonary complications . Whether it prevents recurrences or new primaries of the opposite breast is too early to say because of the short follow-up time",
"Summary 158 evaluable patients with stage II , lymph node positive , carcinoma of the breast were r and omized to adjuvant therapy with either melphalan ( L-PAM ) or cyclophosphamide , methotrexate , and fluorouracil ( CMF ) after mastectomy . In addition , patients were r and omized to be treated with or without post-operative irradiation therapy ( RT ) in addition to their chemotherapy . At a median follow-up time of 11 years , there is no difference in time to relapse ( P=0.69 ) or survival ( P=0.55 ) among the four treatment groups . Multivariate analysis including treatment arm , age , race , tumor size , histologic type , performance status , time to onset of treatment , menopausal status , and number of positive nodes , revealed that only the number of positive nodes ( to disease-free and overall survival . Ten year relapse-free survival for patients with and overall survival 63 % versus 41 % , respectively . Patients who received post-operative radiation therapy had significantly less local recurrence than those treated with chemotherapy alone ( P=0.03 ) but without improvement in relapse-free or overall survival . In this trial , post-operative radiation therapy when added to chemotherapy decreased the risk of local recurrence without adverse effects on survival . Treatment outcome was not influenced by chemotherapy regimen , but differences may have been obscured by the small sample size",
"We studied loco-regional recurrence during follow-up ( median observation time 8 years ) in 1,153 patients , who underwent modified mastectomy and were r and omly assigned to one of the following postoperative treatments ; Premenopausal patients : radiotherapy , cyclophosphamide , or both ; Post-menopausal patients : radiotherapy , tamoxifen , or both . Recurrence occurred in a total of 419 patients , 123 of whom had loco-regional recurrence with or without distant metastasis . The loco-regional recurrence rate was 7 % in the irradiated subgroups and 17 % in the non-irradiated subgroups , the corresponding cure rates being 43 % and 58 % . Complete remission of all local recurrence was obtained after the first treatment in 67 % of the cases , and was persistent in 67 % of them ( 44 % overall ) . Complete remission was obtained in all patients with local recurrence who received local treatment only , and was persistent in 65 % . Of local recurrences treated with a combination of surgery , radiotherapy and hormone therapy , complete response was obtained in 94 % of the patients , and was persistent in 94 % of them ( 88 % overall ) . Complete remission of all regional recurrence was obtained after the first treatment in 58 % of the patients and was persistent in 67 % of them ( 39 % overall ) . Postoperative radiotherapy reduced not only the total number of loco-regional recurrences but also the number of uncontrolled loco-regional recurrences . Aggressive local treatment would appear to yield both satisfactory initial control and , when combined with the hormone therapy , a high rate of persistent loco-regional control",
"The efficacy of adjuvant treatment with tamoxifen was evaluated in protocol DBCG 77 C. Postmenopausal high risk patients ( tumor greater than 5 cm , positive axillary nodes , or invasion to skin/fascia ) were r and omized after total mastectomy and axillary sampling to postoperative radiotherapy ( control ) or to radiotherapy plus treatment with tamoxifen ( TAM ) , 30 mg daily for 1 year . A total of 1,716 patients entered the study . At 8 years of follow-up , ( 7 years median time of observation ) , we observed a significant increase of recurrence-free survival for the TAM treated group and a reduction in mortality , which is significant for patients less than 70 years of age . Retrospectively , an increased recurrence-free survival in TAM treated patients was significant in the following subgroups : tumor less than 5 cm , positive lymph nodes , anaplasia grade II and estrogen receptor level greater than 100 fmol/mg cytosol protein . In the subsequent trial ( DBCG 82 C ) , 1,347 postmenopausal patients less than 70 years were r and omized to one of the following 3 regimens : radiotherapy + tamoxifen , 30 mg daily for 1 year ( TAM ) , TAM alone , or TAM + CMF ( CMF i.v . day 1 every 4 weeks x 9 ) . The survival is similar in the 3 groups at 4 years ( 2 years median time of observation )",
"The purpose of this study was to test the role of radiotherapy following total mastectomy , axillary dissection , and adjuvant systemic therapy in the management of operable locally advanced breast carcinoma",
"BACKGROUND Tamoxifen is an anti-estrogen with proven efficacy and low toxicity in the treatment of breast cancer . However , tamoxifen has been shown to exert a number of nonhormonal as well as hormonal effects . One nonhormonal effect of tamoxifen is the induction of transforming growth factor-beta ( TGF-beta ) secretion . TGF-beta has been implicated in the pathogenesis of radiation-induced fibrosis . PURPOSE We investigated the development of lung fibrosis in breast cancer patients who were treated after mastectomy with radiotherapy , with or without simultaneous adjuvant treatment with tamoxifen . METHODS Data from 196 women were included in the analysis . Eighty-four women were postmenopausal patients who participated in a r and omized trial testing tamoxifen as an adjuvant to postmastectomy radiotherapy . The radiotherapy technique employed an 8-MV photon field covering the axillary and the infraclavicular and supraclavicular regions of the affected side of the chest ; the chest wall was treated with an abutted electron field . Optical density changes in pretreatment and post-treatment chest x-ray films were used to monitor the development of lung fibrosis ; lung reactions were assessed in the photon-irradiated field only . Logistic regression analysis was used to explore relationships between radiation dose and the development of lung fibrosis in patients either receiving or not receiving tamoxifen . All P values are from two-sided tests . RESULTS Among the 84 women who participated in the r and omized trial of radiotherapy plus tamoxifen ( n = 38 ) versus radiotherapy alone ( n = 46 ) , there was a significant association between tamoxifen treatment and the incidence of marked lung fibrosis ( relative risk = 2.0 ; 95 % confidence interval [ CI ] = 1.2 - 3.5 ; P = .01 ) . When logistic regression analysis was used to evaluate data from all 196 patients , a highly significant relationship was found between the incidence of lung fibrosis and total radiation dose ( P = .0005 ) . In the full analysis , an increased risk of marked lung fibrosis was found again for patients who received tamoxifen simultaneously with radiotherapy ( with patients receiving radiotherapy alone as the referent , odds ratio = 2.9 ; 95 % CI = 1.3 - 6.3 ; P = .007 ) . Patient age and menopausal status did not significantly influence the results . CONCLUSION Tamoxifen treatment during postmastectomy radiotherapy enhances the risk of radiation-induced lung fibrosis . IMPLICATION S In view of pre-existing data , we hypothesize that tamoxifen mediates the enhancement of radiation-induced lung fibrosis through the induction of TGF-beta secretion . If this hypothesis is correct , new strategies might be devised for preventing or reducing radiation-induced fibrosis . Because we studied a relatively small portion of the irradiated lung , we can not recommend changes in current therapeutic measures ; however , we strongly encourage additional studies of lung fibrosis in patients receiving tamoxifen and radiotherapy",
"BACKGROUND AND PURPOSE Some types of radiation therapy have been associated with an increased risk of cardiac mortality and morbidity in patients with early-stage breast cancer . A relationship has been observed between cardiac radiation dose-volume and the level of excess risk of cardiac mortality . However , relatively few data are available on the morbidity from myocardial infa rct ion associated with adjuvant radiotherapy . PATIENTS AND METHODS From 1971 to 1976 , a total of 960 patients with operable breast cancer were r and omly allocated to preoperative radiation therapy , postoperative radiation therapy or to surgery alone . A previous analysis of the cardiac dose-volumes with the treatment techniques used in the trial indicated that the irradiated patients could roughly be divided into three groups . Information on the number of myocardial infa rct ions was obtained through computerized record linkage with a population -based registry of myocardial infa rct ions in Stockholm County . Information on cause-specific mortality was obtained from the Swedish Cause-of-Death Registry . The median follow-up was 20 years ( range 17 - 23 years ) . RESULTS A total of 58 patients developed an acute myocardial infa rct ion during the period of follow-up . The number of myocardial infa rct ion cases was not significantly different between the three treatment groups . When analyzed according to estimated cardiac radiation dose-volumes , patients in the highest dose-volume subgroup exhibited a hazard of myocardial infa rct ion of 1.3 ( 95 % CI 0.7 - 2.6 ) relative to that of the surgical controls , whereas the corresponding relative hazard for the intermediate and low dose-volume subgroups was below unity . Data on death due to cardiovascular disease showed that patients in the high dose-volume group exhibited a hazard of 2.0 ( 95 % CI 1.0 - 3.9 , P = 0.04 ) relative to that of the surgical controls . Concerning death due to ischemic heart disease , the relative hazard for the same subgroup was 2.5 ( 95 % CI 1.1 - 5.7 , P = 0.03 ) . The difference between the groups was established after 4 - 5 years . The cumulative incidence curves continued to diverge up to about 10 - 12 years . No further divergence appeared after 12 years , but the number of events was low . CONCLUSIONS This analysis confirms and extends previous results from the trial . Cardiac mortality was positively correlated with the cardiac dose-volume . Patients receiving high dose-volumes exhibited an increased mortality of ischemic heart disease , but not of myocardial infa rct ion , which implies another mechanism , e.g. radiation-induced microvascular damage to the heart",
"BACKGROUND Patients with early-stage breast cancer who are at substantial risk for systemic metastases are increasingly treated with breast-conserving therapy and adjuvant chemotherapy . However , the optimal sequencing of chemotherapy and radiation therapy is not clear . METHODS Two hundred forty-four patients with stage I or II breast cancer who were at substantial risk for distant metastases were r and omly assigned to receive a 12-week course of chemotherapy either before or after radiation therapy . All had had breast-conserving surgery . The median length of follow-up in surviving patients was 58 months ( range , 10 to 124 ) . RESULTS The five-year actuarial rates of cancer recurrence at any site and of distant metastases in the radiotherapy-first group and the chemotherapy-first group were 38 percent and 31 percent ( P = 0.17 ) and 36 percent and 25 percent ( P = 0.05 ) , respectively . Overall survival was 73 percent and 81 percent ( P = 0.11 ) , respectively . The five-year crude rates of first recurrence according to site in the radiotherapy-first and chemotherapy-first groups , respectively , were 5 percent and 14 percent for local recurrence and 32 percent and 20 percent for distant or regional recurrence or both . This difference in the pattern of recurrence was of borderline statistical significance ( P = 0.07 ) . CONCLUSIONS This study suggests that for patients ar substantial risk for systemic metastases , it is preferable to give a 12-week course of chemotherapy followed by radiation therapy , rather than radiation therapy followed by chemotherapy",
"PURPOSE To assess the cardiac effects of two different cumulative doses of adjuvant doxorubicin and radiation therapy ( RT ) in breast cancer patients . PATIENTS AND METHODS Two hundred ninety-nine breast cancer patients were prospect ively r and omized to receive either five cycles ( CA5 ) or 10 cycles ( CA10 ) of adjuvant treatment with cyclophosphamide ( 500 mg/ m2 ) and doxorubicin ( 45 mg/m2 ) administered by intravenous bolus every 21 days . One hundred twenty-two of these patients also received RT . Estimates of the cardiac RT dose-volume were retrospectively categorized as low , moderate , or high . The risk of major cardiac events ( congestive heart failure , acute myocardial infa rct ion ) was assessable in 276 patients ( 92 % ) , with a median follow-up time of 6.0 years ( range , 0.5 to 19.4 ) . RESULTS The estimated risk ( 95 % confidence interval ) of cardiac events per 100 patient-years was significantly higher for CA10 than for CA5 [ 1.7 ( 1.0 to 2.8 ) v 0.5 ( 0.1 to 1.2 ) ; P=.02 ] . The risk of cardiac events in CA5 patients , irrespective of the cardiac RT dose-volume , did not differ significantly from rates of cardiac events predicted for the general female population by the Framingham Heart Study . In CA10 patients , the incidence of cardiac events was significantly increased ( relative risk ratio , 3.6 ; P adjuvant doxorubicin as delivered in the CA5 regimen by itself , or in combination with locoregional RT , was not associated with a significant increase in the risk of cardiac events . Higher doses of adjuvant doxorubicin ( CA10 ) were associated with a threefold to fourfold increased risk of cardiac events . This appears to be especially true in patients treated with higher dose-volumes of cardiac RT . Larger studies with longer follow-up periods are needed to confirm these results",
"Few studies have evaluated the role of concurrent chemoradiation therapy in the management of locally advanced breast cancer . The availability of radiosensitizing chemotherapeutic agents that are effective in breast cancer and the encouraging results achieved by concurrent chemoradiation in other malignancies have prompted us to investigate this approach . Paclitaxel is a promising agent for use with concurrent radiotherapy because of its single-agent efficacy profile and its radiosensitizing effects . A clinical protocol of preoperative paclitaxel and radiation in locally advanced breast cancer is ongoing at our institution to test feasibility , measure pathologic response at mastectomy , and explore association of pathologic response with molecular tumor markers . Initially , the study was design ed to test weekly paclitaxel at a dose of 60 mg/m2 during radiation therapy , delivered 5 days a week at 200 cGy fractions to a total dose of 50 Gy over 5 weeks . Due to severe skin toxicity in the first two patients , the protocol was amended to change the scheduling of paclitaxel to 30 mg/m2 twice weekly and to reduce the radiation to 180 cGy fractions to a total dose of 45 Gy , delivered 5 days a week over 5 weeks . Presently , 13 patients have been accrued ; preliminary data indicate good tolerance to twice-weekly paclitaxel , and four of eight evaluable patients have achieved pathologic response ( one patient who received the weekly regimen and three who received the twice-weekly regimen ) . In addition , sequential fine-needle aspirations of palpable breast cancers were obtained in patients enrolled in a parallel study of preoperative single-agent paclitaxel ( 200 mg/m2 every 2 weeks , for a total of four cycles before breast surgery ) . Preliminary results suggest that a steep increase in the mitotic index occurs during the first day after paclitaxel administration and plateaus between the second and the third day , then decreases to pretreatment values . The peak apoptotic index occurs at approximately 72 hours after paclitaxel administration and decreases at approximately 98 hours . These initial findings suggest that twice-weekly dosing of paclitaxel may optimize recruitment of cells into the G2/M phase of the cell cycle , the most radiosensitive phase",
"Late treatment-related morbidity after mastectomy and adjuvant systemic treatment with and without postoperative irradiation was assessed in 84 patients r and omized in the Danish Breast Cancer Cooperative Group Trials 82b and c. A structured interview and physical examination , using a st and ardized assessment sheet , constructed on the basis of the late effects normal tissues ( LENT ) scoring system , was used . The median length of follow-up from mastectomy was 9 years ( range 6 - 13 years ) . Lymphedema was measured in 14 % , of the irradiated patients versus 3 % of the non-irradiated patients ( NS ) . Slightly decreased shoulder morbidity was measured in 45 % of the irradiated women versus 15 % of the non-irradiated patients , but moderate or more severe impairment was seen in only 5 % of the irradiated patients and in none of the non-irradiated patients ( p = 0.004 ) . Seventeen percent of the irradiated patients and 2 % of the non-irradiated patients found that impairment of shoulder movement caused symptoms ( p = 0.001 )",
"The lymph nodes of the internal mammary chain represent a primary station draining the lymph from the breast and their removal or their irradiation has been considered an important step in breast cancer treatment . From January 1964 to January 1968 , 737 patients with breast cancer were r and omised at the National Cancer Institute in Milan to undergo either Halsted mastectomy or extended mastectomy with internal mammary node dissection . Patients with non-disseminated carcinoma classified as T1 , T2 , T3 , N0 , N1 were eligible for the study . No patients received postoperative radiotherapy or systemic therapy . After 30 years of follow-up , the overall survival curves and the specific survival curves do not show any difference between the patients of the two groups . Among the 558 patients who died in the 30 year interval period , 395 ( 71 % ) died from breast carcinoma ( 201 in the Halsted group and 194 in the extended mastectomy group ) and 163 from other causes . This study shows that the removal of internal mammary nodes does not improve the survival of patients treated for breast carcinoma . This finding supports the theory that treatment of regional nodes does not influence the survival of cancer patients . The prognostic value of internal mammary node status is , however , high and a biopsy on a selected lymph node should be considered for staging purpose",
"PURPOSE There is concern that breast cancer patients treated with left-sided radiation therapy ( XRT ) and doxorubicin ( DOX ) may have an increased risk of cardiac toxicity . In addition , the effect of different sequencing of XRT and chemotherapy ( CT ) on the likelihood of cardiotoxicity , as well as cellulitis , arm edema , or brachial plexopathy , is not well understood . We review ed the records of patients treated on a r and omized trial testing the sequencing of CT and XRT to determine if there was an increase in cardiac events or other complications in patients treated with a total dose of DOX of 180 mg/m2 and XRT , comparing patients with treatment to the left breast and the right breast , and comparing patients treated with initial CT and initial RT . MATERIAL S AND METHODS From June 1984 to December 1992 , 244 patients with clinical stage I or II breast cancer were r and omized following conservative surgery to receive CT ( 4 cycles of CAMFP at 3 week intervals ) either before or after XRT ( 45 Gy to the entire breast , followed by a boost of 16 Gy ; nodal radiation therapy was optional ) . Two hundred thirty-one patients were evaluable for the development of cardiac toxicity . The median age at diagnosis was 45 years ( range , 20 - 68 ) . CT doses were : doxorubicin , 45 mg/m2 IV bolus , d 3 ; methotrexate , 200 mg/m2 IV , d 1 and 15 ; 5-fluorouracil , 500 mg/m2 IV , d 1 ; cyclophosphamide , 500 mg/m2 IV , d 1 ; prednisone 40 mg p.o . , d 1 - 5 . A cardiac event was defined as a myocardial infa rct ion or clinical evidence of congestive heart failure . Median follow-up time was 53 months . RESULTS No cardiac events were observed for patients with either left- or right-sided breast cancer . The sequencing of CT and XRT had no significant effect on the risk of cardiac toxicity , cellulitis , arm edema or brachial plexopathy . CONCLUSIONS We observed no evidence of an increased risk of cardiac toxicity from the addition of left breast tangential irradiation to DOX at a total dose of 180 mg/m2 . Additional follow-up is needed to exclude possible late events . In addition , the sequencing of CT and XRT does not appear to affect the risk of cellulitis , arm edema , or brachial plexopathy",
"PURPOSE To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure ( LRF ) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation . PATIENTS AND METHODS The study population consisted of 2,016 patients entered onto four r and omized trials conducted by the Eastern Cooperative Oncology Group . The median follow-up time for patients without recurrence was 12.1 years ( range , 0.07 to 19.1 years ) . RESULTS A total of 1,099 patients ( 55 % ) experienced disease recurrence . The first sites of failure were as follows : isolated LRF , 254 ( 13 % ) ; LRF with simultaneous distant failure ( DF ) , 166 ( 8 % ) ; and distant only , 679 ( 34 % ) . The risk of LRF with or without simultaneous DF at 10 years was 12.9 % in patients with one to three positive nodes and 28.7 % for patients with four or more positive nodes . Multivariate analysis showed that increasing tumor size , increasing numbers of involved nodes , negative estrogen receptor protein status , and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF . CONCLUSION LRF after mastectomy is a substantial clinical problem , despite the use of chemotherapy with or without tamoxifen . Prospect i ve r and omized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens",
"The use of adjuvant radiation therapy in breast cancer patients treated with mastectomy and adjuvant chemotherapy has been controversial . In order to assess the necessity and effectiveness of adjuvant radiation therapy in this setting , we review ed the results in 510 patients with T1-T3 tumors and pathologically positive nodes or tumors larger than 5 cm and negative nodes who were treated with adjuvant chemotherapy . Patients with four or more positive nodes or at least one positive apical node were r and omized to receive either five or ten cycles of cyclophosphamide/Adriamycin ( Adria Laboratories , Columbus , OH ) ( CA ) and patients with one to three positive nodes or operable tumors larger than 5 cm and pathologically negative nodes were r and omized to receive eight cycles of either cyclophosphamide , methotrexate , and 5-fluorouracil ( 5-FU ) ( CMF ) or methotrexate and 5-FU ( MF ) chemotherapy . Two hundred six of these patients were subsequently rer and omized to receive either no further treatment or adjuvant radiotherapy . Thirty-five patients withdrew after r and omization , including 34 who declined to receive radiotherapy . Radiation therapy consisted of 4,500 cGy in 5 weeks to the chest wall and appropriate draining lymph nodes . Median follow-up from chemotherapy r and omization is 45 months for patients in the CA arm and 53 months for those in the CMF/MF arm . The crude rate of local failure ( chest wall or draining lymph node areas ) as first site of failure for patients r and omized to receive chemotherapy only was 14 % ; for those r and omized to receive both chemotherapy and radiotherapy it was 5 % ( P = .03 ) . For patients in the CMF/MF arm , the rate of local failure as the first site of failure was nearly the same for patients r and omized to chemotherapy only as for those r and omized to adjuvant radiotherapy as well ( 5 % v 2 % ) . For patients in the CA arm , the crude rate of local failure was 20 % for patients r and omized to receive chemotherapy only , and 6 % for those r and omized to both types of adjuvant treatment ( P = .03 ) . Among the 43 patients treated with CA who actually received radiotherapy , there was only one local failure , compared with 12 local failures among the 59 patients ( 20 % ) who actually did not receive radiotherapy ( P = .007 ) . No significant difference was seen in disease-free survival or overall survival in either the CA or the CMF/MF arm between patients r and omized to receive radiation therapy and those r and omized to no further treatment . ( ABSTRACT TRUNCATED AT 400 WORDS",
"One hundred fifty‐eight evaluable patients with Stage II carcinoma of the breast with positive lymph nodes were treated either with adjuvant chemotherapy or irradiation therapy followed by chemotherapy . Patients were r and omized to test the effectiveness of L‐phenylalanine mustard ( L‐PAM ) with and without postoperative irradiation therapy ( R.T. ) against cyclophosphamide , 5‐fluorouracil , and methotrexate ( CMF ) with and without postoperative irradiation therapy in decreasing the frequency of recurrence . No significant difference was observed between L‐PAM as compared with R.T. plus L‐PAM ( P = 0.85 ) . The difference between CMF and R.T. plus CMF was significant in support of CMF alone ( P = 0.04 ) . The frequency of recurrence between R.T. plus L‐PAM and R.T. plus CMF showed no difference . A comparison of the chemotherapy only regimens showed an advantage of CMF over L‐PAM ( P = 0.05 ) . Both the delay in starting chemotherapy and the significant decrease in percent optimal drug dosage during the first six cycles of therapy are factors that may influence the high frequency of relapse observed in the R.T. plus chemotherapy groups . Of the four treatments , CMF has the lowest frequency of recurrence ",
"BACKGROUND AND PURPOSE This study was performed to investigate whether the tamoxifen ( TAM ) induced the development of pulmonary fibrosis after post-mastectomy cobalt-60 ( Co-60 ) irradiation of chest wall and regional lymphatics in patients with breast cancer along with patient age , menopausal status , body weight , observation time and adjuvant chemotherapy regimens . MATERIAL S AND METHODS In this prospect i ve study , 74 patients treated with post-mastectomy adjuvant radiotherapy ( RT ) and TAM and 37 patients treated with RT were evaluated by axial computerized tomography ( CT ) . CT was first performed before initiation of radiotherapy and TAM treatment . A total of 824 thorax CT sections were evaluated by a radiologist blindly . Comparison of pre-treatment and post-treatment CT sections was used to monitor the development of pulmonary fibrosis . RESULTS Pulmonary fibrosis developed in 26 of 74 patients who were treated with RT and TAM combination . It was found in five of 37 women treated only with RT . The difference was statistically significant ( P median time for the development of pulmonary fibrosis was 8 months in TAM-treated patients whereas it was 10 months in non-TAM-treated patients . Among 111 patients who participated in that study , 65 were in the post-menopausal state and 46 in pre-menopausal state . In the multivariate analysis , the independent prognostic factors were age ( P=0.010 ) and menopausal status ( P=0.019 ) . Advanced age and post-menopausal status predisposed to pulmonary fibrosis . The time interval in the development of lung fibrosis and body weight did not significantly influence the results . The time interval which is one independent prognostic factor was found to be associated with lung fibrosis under only-RT group in multivariate analysis ( P cancer patients significantly increases the risk of the development of lung fibrosis along with the patient age and menopausal status",
"PURPOSE The objective of this study was to determine locoregional recurrence ( LRR ) patterns after mastectomy and doxorubicin-based chemotherapy to define subgroups of patients who might benefit from adjuvant irradiation . PATIENTS AND METHODS A total of 1,031 patients were treated with mastectomy and doxorubicin-based chemotherapy without irradiation on five prospect i ve trials . Median follow-up time was 116 months . Rates of isolated and total LRR ( + /- distant metastasis ) were calculated by Kaplan-Meier analysis . RESULTS The 10-year actuarial rates of isolated LRR were 4 % , 10 % , 21 % , and 22 % for patients with zero , one to three , four to nine , or > /= 10 involved nodes , respectively ( P . T stage ( P tumor size ( P /= 2-mm extranodal extension ( P patients with T1 or T2 primary disease and one to three involved nodes ( n = 404 ) . Those with fewer than 10 nodes examined were at increased risk of LRR compared with those with > /= 10 nodes examined ( 24 % v 11 % ; P = .02 ) . Patients with tumor size greater than 4.0 cm or extranodal extension > /= 2 mm experienced rates of isolated LRR in excess of 20 % . Each of these factors continued to significantly predict for LRR in multivariate analysis by Cox logistic regression . CONCLUSION Patients with tumors > /= 4 cm or at least four involved nodes experience LRR rates in excess of 20 % and should be offered adjuvant irradiation . Additionally , patients with one to three involved nodes and large tumors , extranodal extension > /= 2 mm , or inadequate axillary dissections experience high rates of LRR and may benefit from postmastectomy irradiation",
"Grade III , node-positive breast cancer carries a high risk of loco-regional relapse after simple mastectomy . A r and omised trial was conducted to assess whether this would be significantly reduced by postoperative radiotherapy . Between 1985 and 1991 , 76 patients who had undergone a simple mastectomy and axillary sampling , and whose tumours had been found to be grade III and node-positive , were r and omised to receive postoperative radiotherapy to the chest wall and axilla or no further loco-regional treatment . Radiotherapy was delivered with 8 MV X-rays to the axilla and supraclavicular fossa and with 8 MeV electrons to the chest wall , to a dose of 45 Gy in 15 fractions over 3 weeks . All patients have been followed-up until death , or for a minimum of 10 years . All loco-regional recurrences occurred within the first 4 years after mastectomy . There were 26 such events in the 40 patients r and omised to the ' watch ' policy ( 65 % ) , as opposed to 9 out of 36 ( 25 % ) who received radiotherapy ( P Ten-year survival was 39 % in the radiotherapy arm as opposed to 25 % in the no radiotherapy arm . Recruitment to the trial was closed in 1991 , when a preliminary safety analysis revealed the size of the effect of radiotherapy , and from then on all node-positive patients with grade III tumours have routinely been given this treatment . Further follow-up has confirmed this finding , as borne out by these 10-year results , which shows that radiotherapy has a significant impact on reducing loco-regional recurrence in patients at high risk after mastectomy . There is an apparent survival benefit although , because of the small numbers in this trial , this has not reached statistical significance",
" Three hundred and twenty‐two women with involvement of axillary lymph nodes following surgery for operable breast cancer were r and omized to receive either postoperative radiotherapy , chemotherapy ( CMF ) or radiotherapy followed by chemotherapy . There was an increase in disease free interval in pre‐ and postmenopausal patients receiving radiotherapy and chemotherapy regardless of the number of nodes involved . However , there was a trend towards an improvement in disease related survival only in those patients with more than three nodes involved",
"BACKGROUND Postmastectomy radiotherapy is associated with a lower locoregional recurrence rate and improved disease-free and overall survival when combined with chemotherapy in premenopausal high-risk breast-cancer patients . However , whether the same benefits apply also in postmenopausal women treated with adjuvant tamoxifen for similar high-risk cancer is unclear . In a r and omised trial among postmenopausal women who had undergone mastectomy , we compared adjuvant tamoxifen alone with tamoxifen plus postoperative radiotherapy . METHODS Between 1982 and 1990 , postmenopausal women with high-risk breast cancer ( stage II or III ) were r and omly assigned adjuvant tamoxifen ( 30 mg daily for 1 year ) alone ( 689 ) or with postoperative radiotherapy to the chest wall and regional lymph nodes ( 686 ) . Median follow-up was 123 months . The endpoints were first site of recurrence ( locoregional recurrence , distant metastases , or both ) , and disease-free and overall survival . FINDINGS Locoregional recurrence occurred in 52 ( 8 % ) of the radiotherapy plus tamoxifen group and 242 ( 35 % ) of the tamoxifen only group ( p Disease-free survival was 36 % in the radiotherapy plus tamoxifen group and 24 % in the tamoxifen alone group ( p Overall survival was also higher in the radiotherapy group ( 385 vs 434 deaths ; survival 45 vs 36 % at 10 years , p=0.03 ) . INTERPRETATION Postoperative radiotherapy decreased the risk of locoregional recurrence and was associated with improved survival in high-risk postmenopausal breast-cancer patients after mastectomy and limited axillary dissection , with 1 year of adjuvant tamoxifen treatment . Improved survival in high-risk breast cancer can best be achieved by a strategy of both locoregional and systemic tumour control",
"PURPOSE The purpose was to assess the incidence and clinical manifestations of radiation-induced brachial plexopathy in breast cancer patients , treated according to the Danish Breast Cancer Cooperative Group protocol s. METHODS AND MATERIAL S One hundred and sixty-one recurrence-free breast cancer patients were examined for radiation-induced brachial plexopathy after a median follow-up period of 50 months ( 13 - 99 months ) . After total mastectomy and axillary node sampling , high-risk patients were r and omized to adjuvant therapy . One hundred twenty-eight patients were treated with postoperative radiotherapy with 50 Gy in 25 daily fractions over 5 weeks . In addition , 82 of these patients received cytotoxic therapy ( cyclophosphamide , methotrexate , and 5-fluorouracil ) and 46 received tamoxifen . RESULTS Five percent and 9 % of the patients receiving radiotherapy had disabling and mild radiation-induced brachial plexopathy , respectively . Radiation-induced brachial plexopathy was more frequent in patients receiving cytotoxic therapy ( p = 0.04 ) and in younger patients ( p = 0.04 ) . The clinical manifestations were paraesthesia ( 100 % ) , hypaesthesia ( 74 % ) , weakness ( 58 % ) , decreased muscle stretch reflexes ( 47 % ) , and pain ( 47 % ) . CONCLUSION The brachial plexus is more vulnerable to large fraction size . Fractions of 2 Gy or less are advisable . Cytotoxic therapy adds to the damaging effect of radiotherapy . Peripheral nerves in younger patients seems more vulnerable . Radiation-induced brachial plexopathy occurs mainly as diffuse damage to the brachial plexus",
"One hundred twenty pathologically confirmed operable Stage III ( T3N0–2 ) breast cancer patients were r and omized to receive either postoperative radiotherapy or chemotherapy , or a combination of these , with or without levamisole immunotherapy . Radiotherapy was given to regional lymph node areas and chest wall . Chemotherapy consisted of 6 cycles of Adriamycin ( doxorubicin ) ( 45 mg/m2 ) , vincristine ( 1.2 mg/m2 ) intravenously , and cyclophosphamide ( 200 mg/m2 for 5 days ) perorally every 4 weeks . Peroral levamisole , 150 mg a day , 2 days weekly , was given as an immunotherapy . The 3‐year results are described in this article . The effect of levamisole on the prognosis can not be evaluated yet because of the short follow‐up period . The disease‐free survival was almost equal in each patient group , however , some benefit was achieved by levamisole ( a shift of disease‐free survival from 12 to 18 months ) . The patients receiving radiotherapy alone had the poorest prognosis : 68 % had a recurrent tumor , and 57 % were alive . In the chemotherapy group , the figures were 53 % and 72 % , respectively . Patients who received a combined treatment had the best prognosis : 13 % had a recurrent tumor , and 90 % survived 3 years . There was a statistically significant difference in the recurrence rate between any single therapy and the combined treatment ( radiotherapy to combined treatment , P chemotherapy to combined treatment , P ± 0.01 chi‐square test ) . In overall survival , a statistically significant difference was reached between radiotherapy and combination treatment groups ( P . Radiotherapy gave a good local control of the tumor , and chemotherapy decreased the number of metastases . The nonmetastatic axillary lymph node status and secondary amenorrhea or severe menstrual disturbances were of positive prognostic value . The side effects due to radiotherapy and chemotherapy were moderate and tolerable . The dose of Adriamycin had to be reduced only in four patients . All of the patients receiving chemotherapy had a transient total alopecia . Three of them had nonlethal arrhythmias , and one had skin rash . Levamisole was found very toxic with 9 cases of transient agranulocytosis , leading to the discontinuation of immunotherapy in 22 of 59 patients . Our results show that radiotherapy controls the tumor only locally and chemotherapy systematic ally , but the best patient‐saving results are achieved with a combination of radiotherapy and chemotherapy . The disease‐free and overall survival are statistically significant , and favor the combined therapy",
"PURPOSE To investigate long-term cardiac sequelae associated with anthracycline use in adjuvant chemotherapy of patients with early breast cancer . PATIENTS AND METHODS All 1,000 patients from three prospect i ve trials of adjuvant chemotherapy containing doxorubicin ( n = 637 , median total dose of 294 mg/m(2 ) ) or not containing the anthracycline ( cyclophosphamide , methotrexate , and fluorouracil [ CMF ] regimen alone , n = 363 ) were analyzed for the relative incidence of congestive heart failure ( CHF ) and myocardial infa rct ion ( MI ) during 14 years of follow-up . The 462 women continuously free of disease as of February 1996 were recalled , and 355 consented to undergo evaluation including 12-lead ECG and cardiac ultrasound with determination of left ventricular ejection fraction ( LVEF ) to assess the relative incidence of abnormalities in long-term survivors . RESULTS Among the 1,000 patients , there were six cases of CHF and three cases of MI . Cumulative cardiac mortality accounted for 0.4 % ( doxorubicin-treated = 0.6 % ; CMF-treated = 0 ) . Eighteen ( 5 % ) of the 355 patients undergoing cardiac evaluation after median 11 years of follow-up presented systolic dysfunction as defined by pathologic ( Systolic dysfunction was higher in doxorubicin-treated ( 15 of 192 ; 8 % ) than in CMF-treated patients ( three of 150 ; 2 % ) . Breast irradiation had a significant impact on the occurrence of early CHF ( four of 116 ; 3 % ) , but not on systolic dysfunctions . CONCLUSION At longer than 10 years of follow-up , the use of doxorubicin at a total dose commonly applied in regimens of adjuvant chemotherapy does not lead to cardiac clinical sequelae that counter-balance the benefit of treatment in patients with operable breast cancer who may be cured of their disease",
"Background . This analysis was conducted to evaluate the impact of selected clinical , histopathologic , and flow cytometric factors on sites of initial tumor relapse after postmastectomy adjuvant systemic therapy",
"One concern with adjuvant radiation therapy for early breast cancer is the potential risk of increasing intercurrent mortality due to radiation-induced damage of the myocardium . The paper presents an analysis of long-term survival among 960 patients with primary breast cancer included in a r and omized trial of pre- or postoperative radiation therapy ( 45 Gy/5 weeks ) versus surgery alone . All patients were treated with a modified radical mastectomy . The mean follow-up was 16 years ( range : 13 - 19 years ) . During the entire follow-up period there was an overall survival difference in favor of the irradiated patients that was of borderline significance ( p = 0.09 ) . There was no increase in intercurrent mortality due to any cause . However , when the results were analyzed according to estimated doses of radiation to the myocardium , the subset of patients who received the highest doses , that is , those treated with tangential 60Co fields for left-sided tumors , were found to have a significantly increased risk of death due to ischemic heart disease compared to the surgical controls ( relative hazard : 3.2 , p less than 0.05 ) . No such increase was observed among the patients who received less radiation to the myocardium , that is , whose chest wall and internal mammary nodes were treated with electrons or those with right-sided tumors , irrespective of the treatment technique . It is concluded that cardiovascular mortality associated with radiation therapy for early breast cancer is correlated with the biological dose of radiation to the heart and the irradiated volume . All of the following factors are thus important : laterality of the tumor , portal arrangements , radiation energy , fractionation , and total dose . The study illustrates that an increased cardiovascular mortality can be avoided by the use of appropriate techniques and avoidance of excessive treatment",
"One hundred twenty pathologically confirmed operable Stage III breast cancer patients were r and omized to receive either postoperative radiotherapy or chemotherapy , or a combination of these , with or without levamisole immunotherapy . Radiotherapy was given to regional lymph nodes and chest wall . Chemotherapy consisted of six cycles of vincristine , doxorubicin , and cyclophosphamide . Radiotherapy provided local and chemotherapy systemic control over the tumor , but the best patient‐saving results were achieved with a combination of radiotherapy and chemotherapy . This clinical trial was commenced in 1976 , and the first 60 of 120 patients also received oral levamisole , 150 mg/day , on 2 consecutive days weekly as immunotherapy . All patients were followed for at least 5 years . At this stage levamisole seems to increase disease‐free and overall survival in all three treatment arms ( radiotherapy , chemotherapy , combined treatment ) . Significance is reached in disease‐free survival ( P = 0.035 ) and overall survival , adjusted for all other treatment modalities ( P = 0.019 )",
" From 1963 to 1968 , the international group collected 1580 cases of breast cancer , r and omized into two therapeutic groups : radical mastectomy and extended mastectomy . The data were processed on the UNIVAC 1107 computer of the I.N.S.E.R.M. Computing Center . No significant difference was observed between the two groups in the overall five‐year survival rate . However , a more detailed analysis , according to certain prognostic features , showed that extended mastectomy improved the results in one subgroup : cancers of inner or medial quadrants , axillary N+ . Within this group the difference was highly significant for a smaller subgroup ( 190 patients ) including only tumors T1 and T2 . In conclusion , there is no indication for extended mastectomy in any cancers of the outer quadrants or in those of the inner or medial quadrants without axillary involvement . A limited indication for extended mastectomy may be provisionally retained for T1 and T2 cancers of the inner or medial quadrants with axillary involvement",
"In 1971 we began a r and omized trial to compare alternative local and regional treatments of breast cancer , all of which employ breast removal . Life-table estimates were obtained for 1665 women enrolled in the study for a mean of 126 months . There were no significant differences among three groups of patients with clinical ly negative axillary nodes , with respect to disease-free survival , distant-disease -- free survival , or overall survival ( about 57 per cent ) at 10 years . The patients were treated by radical mastectomy , total ( \" simple \" ) mastectomy without axillary dissection but with regional irradiation , or total mastectomy without irradiation plus axillary dissection only if nodes were subsequently positive . Similarly , no differences were observed between patients with clinical ly positive nodes treated by radical mastectomy or by total mastectomy without axillary dissection but with regional irradiation . Survival at 10 years was about 38 per cent in both groups . Our findings indicate that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival . The data also demonstrate that the results obtained at five years accurately predict the outcome at 10 years . We conclude that the variations of local and regional treatment used in this study are not important in determining survival of patients with breast cancer",
"BACKGROUND In women with breast cancer , the role of radical mastectomy , as compared with less extensive surgery , has been a matter of debate . We report 25-year findings of a r and omized trial initiated in 1971 to determine whether less extensive surgery with or without radiation therapy was as effective as the Halsted radical mastectomy . METHODS A total of 1079 women with clinical ly negative axillary nodes underwent radical mastectomy , total mastectomy without axillary dissection but with postoperative irradiation , or total mastectomy plus axillary dissection only if their nodes became positive . A total of 586 women with clinical ly positive axillary nodes either underwent radical mastectomy or underwent total mastectomy without axillary dissection but with postoperative irradiation . Kaplan-Meier and cumulative-incidence estimates of outcome were obtained . RESULTS No significant differences were observed among the three groups of women with negative nodes or between the two groups of women with positive nodes with respect to disease-free survival , relapse-free survival , distant-disease-free survival , or overall survival . Among women with negative nodes , the hazard ratio for death among those who were treated with total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.08 ( 95 percent confidence interval , 0.91 to 1.28 ; P=0.38 ) , and the hazard ratio for death among those who had total mastectomy without radiation as compared with those who underwent radical mastectomy was 1.03 ( 95 percent confidence interval , 0.87 to 1.23 ; P=0.72 ) . Among women with positive nodes , the hazard ratio for death among those who underwent total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.06 ( 95 percent confidence interval , 0.89 to 1.27 ; P=0.49 ) . CONCLUSIONS The findings vali date earlier results showing no advantage from radical mastectomy . Although differences of a few percentage points can not be excluded , the findings fail to show a significant survival advantage from removing occult positive nodes at the time of initial surgery or from radiation therapy",
" Two HUNDRED NINETY-THREE PATIENTS were r and omly assigned to three treatment regimens following mastectomy for operable but prognostically unfavorable breast cancer : L-PAM , CFP , or CFP with radiation therapy . For premenopausal patients an increased risk of recurrence was associated with the presence of unfavorable local signs , large number of lymph nodes involved , greater body weight , younger age , and L-PAM treatment . For the postmenopausal patients only three factors were associated with an increased risk of recurrent disease : large tumor size , large number of lymph nodes involved , and inner/ central location of the primary lesion . Specifically , the treatment employed has shown no effect . Of particular importance is the fact that for neither group of patients does our experience presently demonstrate clear association of recurrent disease with the level of drug dose administered . Furthermore , evidence suggests that although patients who experience little or no myelosuppression have significantly worse disease-free intervals than patients who experience moderate or severe myelosuppression , there is no benefit for severe myelosuppression over moderate , myelosuppression",
"BACKGROUND Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer , but whether it prolongs survival remains controversial . We conducted a r and omized trial of radiotherapy after mastectomy in high-risk premenopausal women , all of whom also received adjuvant systemic chemotherapy with cyclophosphamide , methotrexate , and fluorouracil ( CMF ) . METHODS A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were r and omly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes ( 852 women ) or nine cycles of CMF alone ( 856 women ) . The median length of follow-up was 114 months . The end points were locoregional recurrence , distant metastases , disease-free survival , and overall survival . RESULTS The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone ( P probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF ( P Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone ( P irradiation after mastectomy significantly improved disease-free survival and overall survival , irrespective of tumor size , the number of positive nodes , or the histopathological grade . CONCLUSIONS The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer",
"PURPOSE To determine the prevalence of and contributing factors for chronic arm morbidity including lymphedema in breast cancer patients after treatment and to assess the impact of arm morbidity on quality of life ( QOL ) . PATIENTS AND METHODS A four- question screening question naire was developed and mailed to a r and om sample of 744 breast cancer patients treated curatively in two cancer centers from 1993 to 1997 . Patients were without recurrence and at least 2 years from diagnosis . Respondents were classified as with or without arm-related symptoms on the basis of the survey . Stratified r and om sample s from each group were then invited for a detailed assessment of their symptoms and signs , including the presence of lymphedema . Their QOL was assessed by the European Organization for Research and Treatment of Cancer QOL Question naire C-30 and by a detailed arm problem question naire that assessed various aspects of daily arm functioning . RESULTS Approximately half of all screened patients were symptomatic and 12.5 % of all assessed patients had lymphedema . Axillary dissection ( AD ) and axillary radiotherapy ( RT ) after dissection were statistically significantly related to the occurrence of arm symptoms ( odds ratio for AD = 3.3 , P impaired QOL compared with asymptomatic patients . CONCLUSION Treatment for breast cancer is associated with considerable arm morbidity , which has a negative impact on QOL . Arm morbidity should be carefully monitored in future studies involving local treatment modalities for breast cancer",
"PURPOSE To explore prognostic factors for locoregional failures ( LRF ) among women treated for invasive breast cancer within clinical trials of adjuvant therapies . PATIENTS AND METHODS The study population consisted of 5,352 women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group r and omized trials . A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy , and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months ' duration and /or tamoxifen . Median follow-up is 12 to 15.5 years . RESULTS In women with node-negative disease , factors associated with increased risk of LRF were vascular invasion ( VI ) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients . Of the 1,275 patients , 345 ( 27 % ) met criteria for the highest risk groups , and the 10-year cumulative incidences of LRF with or without distant metastases were 16 % for premenopausal and 19 % for postmenopausal women . For the node-positive cohort , number of nodes and tumor grade were factors for both menopausal groups , with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients . Of the 4,077 patients , 815 ( 20 % ) met criteria for the highest risk groups , and 10-year cumulative incidences were 35 % for premenopausal and 34 % for postmenopausal women . CONCLUSION LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer , as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease . In addition to number of positive lymph nodes , predictors of LRF include tumor-related factors , such as vascular invasion , higher grade , and larger size",
"In 1984 the GBSG started a multicenter r and omized trial to compare the effectiveness of 6 cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) with or without radiotherapy ( RT ) as adjuvant treatment in node-positive breast-cancer patients treated by mastectomy . During 5 years , 199 patients were r and omized . After a median follow-up of about 9 years , the treatment groups 6 x CMF and 6 x CMF + RT were compared regarding time to recurrence and death . As the first event of failure , we observed locoregional recurrence in 22 patients , distant metastases in 66 patients , a secondary malignancy in 9 patients and death without previous event in 5 patients . For event-free survival ( EFS ) , no significant difference was observed [ relative risk ( RR ) 6 x CMF + RT vs. 6 x CMF 0.82 , 95 % confidence interval ( CI ) 0.55 - 1.21 ] . Event-specific analysis showed a significant decreased risk after radiotherapy for locoregional recurrence . The risk for distant metastases was estimated as slightly decreased and the risk for secondary malignancy and for death without previous event was estimated as increased in treatment group 6 x CMF + RT in comparison with treatment group 6 x CMF , but these effects were not significant . For overall survival ( OS ) and breast-cancer-specific survival ( BCS ) , no significant treatment effect could be demonstrated . There is a beneficial effect of radiotherapy on locoregional recurrence . For EFS and BCS , a tendency in favour of radiotherapy is observed , but this is not significant ; for OS , no difference can be demonstrated , but the power of the study is too low to detect small treatment effects"
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BACKGROUND Anxiety disorders are common and disabling conditions , with a lifetime prevalence of 17 % in the general population . Due to high rates of treatment resistance , there is interest in new pharmacological treatment options such as second-generation antipsychotics . OBJECTIVES To evaluate the efficacy and tolerability of second-generation antipsychotics as monotherapy or adjunctive treatment for people with anxiety disorders . SEARCH STRATEGY The Cochrane Depression , Anxiety and Neurosis Group 's controlled trial registers ( CCDANCTR- Studies and CCDANCTR-References ) were search ed up to 21 July 2010 . The author team ran complementary search es on Clinical Trials.gov . SELECTION CRITERIA We included all r and omised trials ( RCTs ) comparing second-generation antipsychotic drugs with placebo , benzodiazepines , pregabalin or antidepressants . Participants were people with generalised anxiety disorder , panic disorder and specific phobias including social phobia . DATA COLLECTION AND ANALYSIS Two authors extracted data independently . For dichotomous data we calculated odds ratios ( OR ) and their 95 % confidence intervals ( CI ) . For continuous data we calculated mean differences ( MD ) based on a r and om-effects model . MAIN RESULTS The review currently includes eleven RCTs with 4144 participants on three second-generation antipsychotics ( olanzapine , quetiapine , risperidone ) . Nine studies investigated the effects of second-generation antipsychotics in generalised anxiety disorder , only two studies investigated the effects in social phobia . There were no studies on panic disorder or any other primary anxiety disorder . Seven studies investigated the effects of quetiapine . Participants with generalised anxiety disorder responded significantly better to quetiapine than to placebo ( 4 RCTs , N = 2265 , OR = 2.21 , 95 % CI 1.10 to 4.45 ) . However , they were more likely to drop out due to adverse events , to gain weight , to suffer from sedation or to suffer from extrapyramidal side effects . When quetiapine was compared with antidepressants , there was no significant difference in efficacy-related outcomes , but more participants in the quetiapine groups dropped out due to adverse events , gained weight and feeling se date d. Only two very small studies with a total of 36 participants examined olanzapine and found no difference in response to treatment . Two trials compared adjunctive treatment with risperidone with placebo and found no difference in response to treatment . AUTHORS ' CONCLUSIONS We identified eligible trials on quetiapine , risperidone and olanzapine . The available data on olanzapine and risperidone are too limited to draw any conclusions . Monotherapy with quetiapine seems to be efficacious in reducing symptoms of generalised anxiety disorder and this effect may be similar to that of antidepressants . However , quetiapine 's efficacy must be weighed against its lower tolerability
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"OBJECTIVE To address the lack of a simple and st and ardized instrument to assess overall panic disorder severity , the authors developed a scale for the measurement of panic disorder severity . METHOD Ten independent evaluators used the seven-item Panic Disorder Severity Scale to assess 186 patients with principal DSM-III-R diagnoses of panic disorder ( with no or mild agoraphobia ) who were participating in the Multicenter Collaborative Treatment Study of Panic Disorder . In addition , 89 of these patients were reevaluated with the same scale after short-term treatment . A subset of 24 patients underwent two independent assessment s to establish interrater reliability . Internal consistency , convergent and discriminant validity , and sensitivity to change were also determined . RESULTS The Panic Disorder Severity Scale was associated with excellent interrater reliability , moderate internal consistency , and favorable levels of validity and sensitivity to change . Individual items showed good convergent and discriminant validity . Analysis suggested a two-factor model fit the data best . CONCLUSIONS The Panic Disorder Severity Scale is a simple , efficient way for clinicians to rate severity in patients with established diagnoses of panic disorder . However , further research with more diverse groups of panic disorder patients and with a broader range of convergent and discriminant validity measures is needed",
"Background Because a large proportion of patients with panic attacks receiving approved pharmacotherapy do not respond or respond poorly to medication , it is important to identify additional therapeutic strategies for the management of panic symptoms . This article describes a r and omized , rater-blind study comparing low-dose risperidone to st and ard-of-care paroxetine for the treatment of panic attacks . Methods Fifty six subjects with a history of panic attacks were r and omized to receive either risperidone or paroxetine . The subjects were then followed for eight weeks . Outcome measures included the Panic Disorder Severity Scale ( PDSS ) , the Hamilton Anxiety Scale ( Ham-A ) , the Hamilton Depression Rating Scale ( Ham-D ) , the Sheehan Panic Anxiety Scale-Patient ( SPAS-P ) , and the Clinical Global Impression scale ( CGI ) . Results All subjects demonstrated a reduction in both the frequency and severity of panic attacks regardless of treatment received . Statistically significant improvements in rating scale scores for both groups were identified for the PDSS , the Ham-A , the Ham-D , and the CGI . There was no difference between treatment groups in the improvement in scores on the measures PDSS , Ham-A , Ham-D , and CGI . Post hoc tests suggest that subjects receiving risperidone may have a quicker clinical response than subjects receiving paroxetine . Conclusion We can identify no difference in the efficacy of paroxetine and low-dose risperidone in the treatment of panic attacks . Low-dose risperidone appears to be tolerated equally well as paroxetine . Low-dose risperidone may be an effective treatment for anxiety disorders in which panic attacks are a significant component . Trial Registration Clinical Trials.gov Identifier :",
"The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate ( quetiapine XR ) as maintenance monotherapy for patients with generalized anxiety disorder ( GAD ) . Time-to-event ( anxiety symptom recurrence ; maximum 52 weeks ) multicenter , r and omized-withdrawal , parallel-group , double-blind , placebo-controlled study of quetiapine XR ( 50–300 mg/day ) following open-label run-in ( 4–8 weeks ) and open-label stabilization ( ≥12 weeks ) . Primary variable : time from r and omization to anxiety event . Secondary variables included : Hamilton Anxiety Rating Scale ( HAM-A ) total , HAM-A psychic/somatic anxiety factors , Clinical Global Impression-Severity of Illness ( CGI-S ) , and Quality of Life , Enjoyment and Satisfaction Question naire ( Q-LES-Q ) scores ; adverse events ( AE ) reporting . Four hundred and thirty-two patients , stabilized on quetiapine XR , were r and omized to continue quetiapine XR ( N=216 ) or switch to placebo ( N=216 ) . Risk of anxiety symptom recurrence was significantly reduced by 81 % for quetiapine XR versus placebo : hazard ratio=0.19 ( 95 % confidence interval 0.12–0.31 ; P receiving quetiapine XR ( N=22 , 10.2 % ) than placebo ( N=84 , 38.9 % ) experienced anxiety symptom recurrence . Significant differences were observed between quetiapine XR and placebo in : HAM-A total , psychic/somatic , CGI-S ( all P Q-LES-Q ( P 10 % ) during open-label treatment were dry mouth , sedation , somnolence , dizziness , fatigue , and constipation . During r and omized treatment , the most common AEs for quetiapine XR were headache and nasopharyngitis . Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR , with tolerability results consistent with the known profile of quetiapine ",
"The efficacy and tolerability of extended-release quetiapine fumarate ( quetiapine XR ) once-daily monotherapy in generalized anxiety disorder ( GAD ) was assessed . This multicentre , double-blind , r and omized , placebo- and active-controlled , phase III trial consisted of a 1- to 4-wk enrolment/wash-out period and a 10-wk ( 8-wk active treatment , 2-wk post-treatment drug-discontinuation ) study period ; 873 patients were r and omized to 50 mg or 150 mg quetiapine XR , 20 mg paroxetine , or placebo . Primary endpoint was change from r and omization at week 8 in Hamilton Rating Scale for Anxiety ( HAMA ) total score . At week 8 , all active agents produced significant improvements in HAMA total and psychic subscale scores vs. placebo ; HAMA somatic subscale scores were significantly reduced only by 150 mg quetiapine XR . Significant separation from placebo ( -2.90 ) in HAMA total score was observed at day 4 for 50 mg quetiapine XR ( -4.43 , p quetiapine XR ( -3.86 , p paroxetine ( -2.69 ) . Remission ( HAMA total score 7 ) rates at week 8 were significantly higher for 150 mg quetiapine XR ( 42.6 % , p paroxetine ( 38.8 % , p adverse events ( AEs ) were dry mouth , somnolence , fatigue , dizziness , and headache , for quetiapine XR , and nausea , headache , dizziness for paroxetine . A lower proportion of patients reported sexual dysfunction with quetiapine XR [ 0.9 % ( 50 mg ) , 1.8 % ( 150 mg ) ] than with placebo ( 2.3 % ) or paroxetine ( 7.4 % ) . The incidence of AEs potentially related to extrapyramidal symptoms was : quetiapine XR : 50 mg , 6.8 % , 150 mg , 5.0 % ; placebo , 1.8 % ; and paroxetine , 8.4 % . Once-daily quetiapine XR is an effective and generally well-tolerated treatment for patients with GAD , with symptom improvement seen as early as day 4",
"BACKGROUND Depression and anxiety are common disorders and have substantially overlapping symptom complexes . Not surprisingly , treatment approaches are similar for both conditions with the selective serotonin reuptake inhibitors ( SSRIs ) as the initial therapy of choice . However , after first line treatments have been deployed , residual symptoms are often problematic . Augmentation strategies to address these difficulties are an area of active investigation . This study assessed aripiprazole as adjunctive therapy to SSRIs for patients with persistent anxiety symptoms complicating a depression or anxiety disorder . METHODS Ten patients who had been receiving SSRIs for at least 6 weeks , but still had clinical ly significant anxiety symptoms , were enrolled in an open label , flexibly-dosed study of adjunctive aripiprazole . Clinical status was assessed with the Hamilton Anxiety Rating Scale ( HAM-A ) , Montgomery Asberg Rating Scale ( MADRS ) , and Sheehan Disability Scale ( SDS ) . RESULTS Eighty percent of the subjects had a greater than 50 % reduction of symptoms on these outcome measures by week 2 of therapy , and continued with further decrements in symptoms throughout the course of the study . CONCLUSIONS The results of this trial provide preliminary evidence that aripiprazole may be an effective adjunctive treatment in individuals on SSRIs with residual symptoms of anxiety or depression . More rigorous double-blind studies are warranted to confirm and eluci date the potential role of aripiprazole in these conditions",
"The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more . ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas",
"The purpose of our study was to evaluate the efficacy and tolerability of low-dose olanzapine augmentation in selective serotonin reuptake inhibitor (SSRI)-resistant panic disorder ( PD ) with or without agoraphobia . In this 12-week , open-label study , 31 adult out patients with treatment-resistant PD who had previously failed to respond to SSRI treatment were treated with fixed dose of olanzapine ( 5 mg/d ) in addition to SSRI . Efficacy was assessed using the Panic Attack and Anticipatory Anxiety Scale ( PAAAS ) , the Agoraphobic Cognitions Question naire ( ACQ ) , the Hamilton Rating Scale for Anxiety ( HAM-A ) , the Hamilton Rating Scale for Depression ( HAM-D ) , the Global Assessment of Functioning Scale ( GAF ) , and the Clinical Global Impression of Improvement ( CGI-I ) . Twenty-six patients completed the trial period with a dropout rate of 16.1 % . At week 12 , 21 patients were responders ( 81.8 % ) , and an overall improvement on all rating scales was observed in all patients both with or without agoraphobia . Fifteen patients ( 57.7 % ) achieved remission . Olanzapine was well tolerated and the most frequent adverse effects were mild-to-moderate weight gain and drowsiness . No extrapyramidal symptoms were reported . Olanzapine appears to be effective as augmentation strategy in the treatment of SSRI-resistant PD , but study limitations must be considered and placebo-controlled studies are needed",
"Rationale More data are needed to guide “ next step ” strategies for patients with generalized anxiety disorder ( GAD ) remaining symptomatic despite initial pharmacotherapy . Objective This study prospect ively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD remaining symptomatic with initial paroxetine CR pharmacotherapy . Material s and methods Adult out patients with GAD were recruited from 2004 to 2007 at two academic centers . Phase 1 consisted of 10 weeks of open-label paroxetine CR flexibly dosed to a maximum of 62.5 mg/day . Those remaining symptomatic ( Hamilton Anxiety Scale [ HAM-A ] ≥ 7 ) at week 10 were r and omized to quetiapine or placebo augmentation flexibly dosed from 25 to 400 mg/day . Results For participants receiving paroxetine CR ( n = 50 ) , there was a significant reduction in HAM-A scores ( baseline mean ± SD = 22.4 ± 4.2 to endpoint mean ± SD = 11.2 ± 6.9 ; paired t = 12.1 , df = 49 , t for quetiapine augmentation of continued paroxetine CR ( HAM-A reduction mean ± SD = 2.6 ± 5.8 points quetiapine , 0.3 ± 5.5 points placebo ; t = 0.98 , df = 20 , p = n.s . ) in the r and omized sample ( n = 22 ) with relatively minimal additional improvement overall in phase 2 . Conclusions Although conclusions are considered preliminary based on the relatively small sample size , our data do not support the addition of quetiapine to continued paroxetine CR for individuals with GAD who remain symptomatic after 10 weeks of prospect i ve antidepressant pharmacotherapy and suggest that further research examining strategies for GAD refractory to antidepressants is needed",
"More than half of anxiety and depression patients treated with an adequate course of antidepressants fail to fully improve . We retrospectively examined whether treatment-resistant depression and anxiety disorder patients responded to and tolerated augmentation with the atypical antipsychotic , aripiprazole . We report on patients with depression and anxiety disorders , including panic disorder , generalized anxiety disorder , social anxiety and post-traumatic stress disorder , who had an incomplete response to a variety of selective serotonin reuptake inhibitors ( SSRIs ) and who received augmentation with aripiprazole . The primary outcome measure was the Clinical Global Impression of Improvement ( CGI-I ) . In the intent-to-treat analysis , the mean±SD CGI-S was 3.8±1.3 at endpoint . Fifty-nine percent of subjects received CGI-I ratings of 1 or 2 , ‘ much improved ’ or ‘ very much improved , ’ in terms of their depression and anxiety symptoms at the end of 12 weeks . Several patients showed an early ( weeks 1–5 ) , as well as sustained , response to augmentation with doses of aripiprazole between 15 and 30 mg/day . The results suggest that aripiprazole may be effective as an augmentation for patients with persistent depressive and anxiety disorders despite initial SSRI treatment . Because this is a retrospective case review , further prospect i ve studies are required to confirm these findings",
"Social anxiety disorder ( SAD ) is one of the most common anxiety disorders . Reports have suggested an effect of the atypical antipsychotic quetiapine in anxiety disorders . Given these considerations , we conducted a controlled trial of quetiapine monotherapy in SAD . Fifteen patients were r and omized to quetiapine ( up to 400 mg/day ) or placebo for 8 weeks . The Brief Social Phobia Scale ( BSPS ) and the Clinical Global Impression of Improvement Scale ( CGI-I ) were the primary outcome measures , while the Social Phobia Inventory ( SPIN ) and the Sheehan Disability Inventory ( SDI ) were secondary measures . There was no significant difference on the BSPS score at endpoint between the quetiapine and placebo groups . There was a significant time effect but not a significant time x treatment group interaction , indicating that both the quetiapine and placebo patients did better over the course of the trial . 20 % of the quetiapine patients had a 50 % or greater drop in BSPS score at the end of the trial compared to baseline , while 0 % had such a drop in the placebo group . There was no significant difference in responders ( CGI-I score of 1 or 2 ) versus non-responder ( CGI-I score of 3 or more ) across the groups . However , 40 % of quetiapine patients and 0 % of the placebo patients showed much or very much improvement on the CGI-I. The Number Needed to Treat ( NNT ) to be a responder on the CGI-I was 3 . Significant time effects were noted for the SPIN and SDI , as well as a significant time x treatment effect in favor of quetiapine on the SPIN . Additionally , quetiapine showed a large effect size on the SPIN",
"The novel atypical antipsychotic ziprasidone has a pharmacologic profile notable for potent agonism of serotonin (5-HT)1A receptors , antagonism at 5-HT1D receptors , and reuptake inhibition of norepinephrine . 5-HT1A receptor agonism , in particular , suggests anxiolytic activity , and ziprasidone has shown preliminary efficacy in treating the symptoms of anxiety associated with psychotic disorders . In this study , the anxiolytic efficacy of ziprasidone was evaluated in nonpsychotic subjects who were anxious before undergoing minor dental surgery . We compared a single oral dose of 20 mg ziprasidone ( N = 30 ) with that of 10 mg diazepam ( N = 30 ) and placebo ( N = 30 ) in a r and omized , parallel-group , double-blind study . The peak anxiolytic effect of ziprasidone compared with that of placebo was similar to that of diazepam but had a later onset . At 3 hours postdose , the anxiolytic effect of ziprasidone was significantly greater than that of placebo ( p greater anxiolytic effect than placebo at 1 hour ( p sedative effect of ziprasidone was never greater than that of placebo , whereas that of diazepam was significantly greater than that of placebo 1 to 1.5 hours postdose . Ziprasidone was generally well tolerated . Only one patient reported treatment-related adverse events ( nausea and vomiting ) and , unlike diazepam , ziprasidone did not cause reductions in blood pressure . Dystonia , extrapyramidal syndrome , akathisia , and postural hypotension were not seen with ziprasidone . Thus , ziprasidone may possess anxiolytic effects in addition to its antipsychotic properties",
"BACKGROUND Residual symptoms despite treatment are common in generalized anxiety disorders ( GAD ) . The Patient-Rated Troubling Symptoms for Anxiety ( PaRTS-A ) is a newly created and vali date d instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms . METHODS Primary care and psychiatry clinicians enrolled adults ( n = 417 ) with GAD and a Clinical Global Impressions of Severity rating ≥ 4 despite ≥ 8 weeks of anxiolytic treatment . Subjects were r and omized to adjunctive risperidone or placebo . The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A. RESULTS Improvement from baseline to week 4 endpoint in PaRTS-A total score ( mean + /-SE ) was similar between treatment groups ( -8.54 [ 0.63 ] and -7.61 [ 0.64 ] for adjunctive risperidone and placebo , respectively ; P = .265 ) . Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures . A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo ( P = .04 ) . Headache , weight increase , and increased appetite were the most frequently reported adverse events in both groups . CONCLUSIONS Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo . Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinical ly meaningful information on patient-rated symptoms . Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated",
"This study evaluated once-daily , extended-release quetiapine fumarate ( quetiapine XR ) monotherapy in generalized anxiety disorder ( GAD ) . This was a 10-week ( 8-week active treatment/2-week posttreatment drug-discontinuation/tapering phase ) , double-blind , r and omized , placebo-controlled study ( D1448C00009 ) . Primary end point was change from r and omization at week 8 in Hamilton Anxiety Rating Scale ( HAM-A ) total score . Overall , 951 patients with GAD were r and omized ( quetiapine XR : 50 mg/d , n = 234 ; 150 mg/d , n = 241 ; 300 mg/d , n = 241 ; placebo , n = 235 ) . At week 8 , HAM-A total scores significantly ( P with quetiapine XR 50 mg/d ( −13.31 ) and 150 mg/d ( −13.54 ) , but not 300 mg/d ( −11.87 ; P = 0.240 ) . At week 1 , HAM-A total scores significantly improved versus placebo ( −5.94 ) with quetiapine XR 50 mg/d ( −7.47 ; P Versus placebo at week 8 , quetiapine XR 50 and 150 mg/d significantly improved HAM-A psychic ( P 0.001 , respectively ) and somatic ( P 0.01 , respectively ) cluster scores , HAM-A response ( ≥50 % total score reduction ; P , and Clinical Global Impression-Improvement categorical changes ( P For quetiapine XR 150 mg/d , significant ( P seen for HAM-A remission ( total score , ≤7 ) and Clinical Global Impression-Severity of Illness scores . For quetiapine XR 300 mg/d , improvements in these secondary variables were not significantly different versus placebo . Pittsburgh Sleep Quality Index global scores improved with all 3 doses ( quetiapine : XR 50 mg/d , −4.07 [ P . Adverse events ( > 10 % with quetiapine XR ) were dry mouth , somnolence , sedation , dizziness , headache , and fatigue . Quetiapine XR ( 50/150 mg/d ) monotherapy was effective at week 8 in patients with GAD ; symptom improvement was seen at week 1 for all doses ( 50/150/300 mg/d ) . Safety and tolerability were consistent with the known profile of quetiapine",
"BACKGROUND This article presents results of the acute treatment phase of a 2-site study comparing cognitive behavioral group therapy ( CBGT ) and treatment with the monoamine oxidase inhibitor phenelzine sulfate for social phobia . METHODS One hundred thirty-three patients from 2 sites received 12 weeks of CBGT , phenelzine therapy , pill placebo administration , or educational-supportive group therapy ( an attention-placebo treatment of equal credibility to CBGT ) . The \" allegiance effect , \" ie , the tendency for treatments to seem most efficacious in setting s of similar theoretical orientation and less efficacious in theoretically divergent setting s , was also examined by comparing responses to the treatment conditions at both sites : 1 known for pharmacological treatment of anxiety disorders and the other for cognitive behavioral treatment . RESULTS After 12 weeks , phenelzine therapy and CBGT led to superior response rates and greater change on dimensional measures than did either control condition . However , response to phenelzine therapy was more evident after 6 weeks , and phenelzine therapy was also superior to CBGT after 12 weeks on some measures . There were few differences between sites , suggesting that these treatments can be efficacious at facilities with differing theoretical allegiances . CONCLUSIONS After 12 weeks , both phenelzine therapy and CBGT were associated with marked positive response . Although phenelzine therapy was superior to CBGT on some measures , both were more efficacious than the control conditions . More extended cognitive behavioral treatment and the combination of modalities may enhance treatment effect",
"INTRODUCTION Individuals with anxiety disorders often remain symptomatic despite treatment with a first-line pharmacologic agent . More research examining pharmacotherapy augmentation strategies to improve outcomes is needed . METHODS In an 8-week , open-label , prospect i ve augmentation study , we examined the efficacy and tolerability of the novel antipsychotic agent aripiprazole for adult out patients with generalized anxiety disorder ( n=13 ) or panic disorder ( n=10 ) who remained symptomatic despite treatment for at least 8 weeks with an adequate ( or maximally tolerated ) dose of typical pharmacotherapy . RESULTS Aripiprazole augmentation was associated with a significant reduction in Clinical Global Impressions-Severity scores ( paired t=4.41 , df=22 , P sample of 23 individuals . Three subjects ( 13 % ) discontinued due to sedation , chest discomfort , and restlessness , respectively . CONCLUSION These data provide preliminary evidence that aripiprazole may be a useful augmentation strategy for individuals with generalized anxiety disorder or panic disorder who show a limited response to initial pharmacotherapy",
"BACKGROUND There is a paucity of data to support \" next-step \" treatments for the many patients with anxiety disorders who remain symptomatic after initial pharmacotherapy . METHOD Thirty patients with a primary diagnosis of an anxiety disorder-panic disorder ( PD ) , social anxiety disorder ( SAD ) , or generalized anxiety disorder (GAD)-refractory to initial pharmacotherapy with an adequate ( or maximally tolerated ) antidepressant and /or benzodiazepine trial of at least 8 weeks ' duration prior to study initiation received open-label augmentation with flexibly dosed risperidone for 8 weeks . Participants were diagnosed using the Structured Clinical Interview for DSM-IV . RESULTS Risperidone augmentation at a mean + /- SD dose of 1.12 + /- 0.68 mg/day ( range , 0.25 - 3.00 mg/day ) result ed in a significant reduction in anxiety symptoms across disorders as measured by the Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Anxiety ( HAM-A ) scores and for each disorder-specific primary outcome measure-the Panic Disorder Severity Scale , the Liebowitz Social Anxiety Scale , and HAM-A-in the intent-to-treat sample . Seventy percent ( 21/30 ) of participants completed the 8-week trial , with premature discontinuation due primarily to sedation and weight gain . CONCLUSIONS Although conclusions are limited by the open-label , relatively brief nature of this trial , our data suggest that augmentation with low-dose risperidone may be a useful option for patients with PD , SAD , or GAD refractory to adequate initial intervention with antidepressants and /or benzodiazepines . Longer-term , controlled safety and efficacy data are needed to underst and the place of risperidone augmentation in the algorithm of treatment options for refractory anxiety disorders",
"BACKGROUND There has been little systematic study of \" next-step \" interventions for patients with generalized anxiety disorder ( GAD ) who remain symptomatic despite initial pharmacotherapy . We present one of the first r and omized controlled trials for refractory GAD , comprising double blind augmentation with olanzapine or placebo for patients remaining symptomatic on fluoxetine . METHODS Patients remaining symptomatic after 6 weeks of fluoxetine ( 20 mg/day ) were r and omized to 6 weeks of olanzapine ( mean dose 8.7 + /- 7.1 mg/day ) or placebo augmentation . RESULTS Twenty-four of 46 fluoxetine-treated patients were r and omized . Olanzapine result ed in a greater proportion of treatment responders based on a Clinical Global Impression-Severity Scale ( CGI-S ) end point score of 1 or 2 ( Fisher 's exact test [ FET ] p Hamilton Anxiety Scale ( HAMA-A ) score ( FET p olanzapine compared with placebo augmentation in outcome measures , though rates of remission ( HAM-A olanzapine were higher at the level of a trend ( FET , p = .1 ) . Average weight gain for completers was greater with olanzapine than placebo augmentation ( 11.0 + /- 5.1 vs. -0.7 + /- 2.4 pounds : t = 6.32 , p Olanzapine may have a salutary effect on anxiety for some GAD patients remaining symptomatic despite initial serotonin selective reuptake inhibitor ( SSRI ) therapy , but the emergence of significant weight gain represents an important clinical consideration",
"OBJECTIVE Although significant advances have been made in recent years in the treatment of generalized anxiety disorder ( GAD ) , many patients remain symptomatic despite ongoing treatment , underscoring the need for adjunctive new treatments to help improve response . METHOD Forty patients with a primary diagnosis of DSM-IV GAD , who continued to experience GAD symptoms despite current anxiolytic treatment of at least 4 weeks ' duration , as evidence d by Hamilton Rating Scale for Anxiety ( HAM-A ) total score > or = 18 and Clinical Global Impressions-Severity of Illness scale score of moderate or greater , completed a 1-week screening phase and were then r and omly assigned to 5 weeks of double-blind adjunctive treatment with placebo or risperidone at flexible doses of 0.5 to 1.5 mg/day . Patients continued to take their anxiolytics throughout the study . The study was conducted from June 2001 through March 2003 . RESULTS Adjunctive risperidone was associated with statistically significant improvements in core anxiety symptoms , as demonstrated by greater reductions in HAM-A total scores ( p = .034 ) and HAM-A psychic anxiety factor scores ( p = .047 ) compared with placebo . Although change scores on other outcome variables , including response rates , were higher in the risperidone group , differences did not achieve statistical significance . CONCLUSION Study findings suggest that risperidone at low doses may represent a useful tool in the management of symptomatic GAD patients",
"Treatment of depression and anxiety disorders with selective serotonin reuptake inhibitors ( SSRIs ) has been shown by numerous studies to be generally effective . Less well understood is how clinical ly to address the residual anxiety symptoms a significant minority of such patients treated with SSRIs continue to experience . We assessed quetiapine as adjunctive therapy to SSRIs for patients with anxiety symptoms complicating a depressive or anxiety disorder . Patients receiving a stable dosage of an SSRI for at least 6 weeks who also had persistent anxiety symptoms ( Hamilton Anxiety scale [ HAM‐A ] ≥16 ) , were enrolled in a 9‐week , open‐label , variable dose study . Changes in clinical status were assessed with the Hamilton Depression Rating Scale ( HAM‐D ) , HAM‐A , and State Anxiety Inventory ( SAI ) . Statistically and clinical ly significant reductions of ≥50 % in the HAM‐D and HAM‐A occurred by the second week of treatment in 10 of the 11 patients . These improvements continued throughout the study along with a significant improvement on the SAI scale . The most frequent side effects reported were mild dry mouth , constipation , and transient drowsiness with dose escalation . The results provide evidence that quetiapine may be an effective adjunctive treatment for recalcitrant anxiety symptoms in individuals treated with SSRIs for either anxiety or depressive disorders . Given the open‐label design of the trial , more rigorous studies are clearly indicated . Depression and Anxiety 19:121‐126 , 2004 . © 200 Wiley‐Liss ,",
"This 8-week , r and omized , double-blind , placebo-controlled , flexible-dose trial assessed the efficacy , safety , and tolerability of ziprasidone in adults with treatment-resistant generalized anxiety disorder ( GAD ) . Seventy-three subjects with treatment-resistant GAD were recruited , and 62 were r and omized to either ziprasidone or placebo treatment at a ratio of 2:1 using a flexible dosing strategy ( 20 - 80 mg daily ) . R and omization was stratified into 2 subtypes of patients , those in whom the study drug was used as augmentation and those who have stopped their ineffective medications before entering the present trial ( nonaugmented group ) . The subjects ' clinical status was monitored weekly throughout the course of the study and included the Hamilton Anxiety Scale ( primary outcome measure ) , the Clinical Global Impression Improvement and Severity of Illness scales , the Hamilton Depression Scale , the Sheehan Disability Scale , the Hospital Anxiety and Depression Scale , and the Abnormal Involuntary Movements Scale . Sixty-two patients were r and omized to ziprasidone ( n = 41 ) or placebo ( n = 21 ) . The dropout rate was 24 % , consisting of 2 placebo patients and 13 ziprasidone patients . There was no statistically significant difference in the Hamilton Anxiety Scale score reduction between the drug and placebo groups . However , statistical trends were observed for an augmentation- study medication interaction effect , with ziprasidone patients producing more improvement in the nonaugmented than in the augmented group . This study provides pilot data for an augmentation- study medication interaction effect with ziprasidone patients producing more improvement in the nonaugmented than in the augmented group . Based on the data obtained in this trial and the subsequent power analyses , a future double-blind placebo-controlled trial should include at least 150 treatment-resistant GAD nonaugmented patients r and omized to ziprasidone and placebo in a 1:1 ratio",
"Based on evidence suggesting anxiolytic properties of the atypical antipsychotic olanzapine , this study was conducted to evaluate whether olanzapine may be efficacious in treating social anxiety disorder ( SAD ) . This study was an 8-week , double-blind , placebo-controlled evaluation of olanzapine as monotherapy in which 12 patients with the DSM-IV diagnosis of SAD were r and omized to either olanzapine ( n= 7 ) or placebo ( n= 5 ) . An initial dose of 5 mg/day was titrated to a maximum of 20 mg/day . Baseline to endpoint scores from the Brief Social Phobia Scale ( BSPS ) , Social Phobia Inventory ( SPIN ) , Liebowitz Social Anxiety Scale and Sheehan Disability Scale , as well as Clinical Global Impression-Improvement ratings , were compared for olanzapine versus placebo . Seven subjects completed all 8 weeks of the study , four in the olanzapine group and three in the placebo group . In the intent-to-treat analysis , olanzapine yielded greater improvement than placebo on the primary measures : BSPS ( p= 0.02 ) and SPIN ( p= 0.01 ) . Both treatments were well tolerated , although the olanzapine group had more drowsiness and dry mouth . Olanzapine and placebo were both associated with negligible weight gain . Olanzapine was superior to placebo on the primary outcome measures in this preliminary study of SAD . Additional studies of olanzapine as a treatment for SAD are warranted",
"To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results",
"BACKGROUND The treatment of bipolar disorder is often complicated by the presence of a co-occuring anxiety disorder . Although second generation antipsychotics are being used with increasing frequency in bipolar patients , their anxiolytic effects have not been well studied in this population . METHODS The anxiolytic effect of risperidone 0.5 - 4 mg/day was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 111 patients with bipolar disorder and a co-occuring panic disorder or generalized anxiety disorder ( GAD ) . The primary outcome measure was the Clinician Global Improvement-21 Anxiety scale ( CGI-21 Anxiety ) . Secondary measures included the Hamilton Anxiety Scale ( HAM-A ) and the Sheehan Panic Disorder Scale . RESULTS On the last-observation-carried forward analysis of repeated measures analysis of variance ( ANOVA ) , risperidone was not more effective than placebo for the CGI-21 Anxiety score or the other anxiety outcome measures . Risperidone was well tolerated , with only two patients withdrawing because of adverse events . LIMITATIONS The risperidone treated group had more patients with mixed states and lifetime panic disorder at r and omization than the placebo group . The study was limited to 8 weeks and to individuals with bipolar and comorbid panic disorder or GAD . The results may not be applicable to risperidone as an add-on treatment to mood stabilizers , or to bipolar disorder comorbid with anxiety disorders other than panic disorder or GAD . CONCLUSIONS Risperidone monotherapy was not an effective anxiolytic for bipolar patients with comorbid panic disorder or GAD in doses of 0.5 - 4 mg/day over 8 weeks of treatment . The efficacy of other second generation antipsychotics and mood stabilizers on anxiety in patients with bipolar disorder and a co-occuring anxiety disorder should be investigated in double-blind , placebo-controlled studies"
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4117d1b0-06ff-11f0-808a-c43d1ab1c353
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BACKGROUND Physicians diagnose and treat suspected hypogonadism in older men by extrapolating from the defined clinical entity of hypogonadism found in younger men . We conducted a systematic review to estimate the accuracy of clinical symptoms and signs for predicting low testosterone among aging men . METHODS We search ed the MEDLINE and Embase data bases ( January 1966 to July 2014 ) for studies that compared clinical features with a measurement of serum testosterone in men . Three of the authors independently review ed articles for inclusion , assessed quality and extracted data . RESULTS Among 6053 articles identified , 40 met the inclusion criteria . The prevalence of low testosterone ranged between 2 % and 77 % . Threshold testosterone levels used for reference st and ards also varied substantially . The summary likelihood ratio associated with decreased libido was 1.6 ( 95 % confidence interval [ CI ] 1.3 - 1.9 ) , and the likelihood ratio for absence of this finding was 0.72 ( 95 % CI 0.58 - 0.85 ) . The likelihood ratio associated with the presence of erectile dysfunction was 1.5 ( 95 % CI 1.3 - 1.8 ) and with absence of erectile dysfunction was 0.83 ( 95 % CI 0.76 - 0.91 ) . Of the multiple-item instruments , the AND ROTEST showed both the most favourable positive likelihood ratio ( range 1.9 - 2.2 ) and the most favourable negative likelihood ratio ( range 0.37 - 0.49 ) . INTERPRETATION We found weak correlation between signs , symptoms and testosterone levels , uncertainty about what threshold testosterone levels should be considered low for aging men and wide variation in estimated prevalence of the condition . It is therefore difficult to extrapolate the method of diagnosing pathologic hypogonadism in younger men to clinical decisions regarding age-related testosterone decline in aging men
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"Little is known about the descriptive epidemiology of and rogen deficiency . In this study , we sought to address this issue by providing estimates of the crude and age-specific prevalence and incidence rates of and rogen deficiency in a r and omly sample d population -based cohort of middle-aged and older men . Data on and rogen deficiency ( defined using both signs/symptoms plus total and calculated free testosterone ) were available for n = 1691 ( baseline ) and n = 1087 ( follow-up ) men from the Massachusetts Male Aging Study . Crude and age-specific prevalence and incidence rates were calculated . Based on these estimates , projections for the number of cases of and rogen deficiency in the 40- to 69-yr-old U.S. male population were computed . Estimates of the crude prevalence of and rogen deficiency at baseline and follow-up were 6.0 and 12.3 % , respectively . Prevalence increased significantly with age . From baseline age-specific prevalence data , it is estimated that there are approximately 2.4 million 40- to 69-yr-old U.S. males with and rogen deficiency . The crude incidence rate of and rogen deficiency was 12.3 per 1,000 person-years , and the rate increased significantly ( P deficiency per year in U.S. men 40 - 69 yr old",
"Background — The relation between endogenous testosterone concentrations and health in men is controversial . Methods and Results — We examined the prospect i ve relationship between endogenous testosterone concentrations and mortality due to all causes , cardiovascular disease , and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003 . Among those without prevalent cancer or cardiovascular disease , 825 men who subsequently died were compared with a control group of 1489 men still alive , matched for age and date of baseline visit . Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes ( 825 deaths ) , cardiovascular disease ( 369 deaths ) , and cancer ( 304 deaths ) . Odds ratios ( 95 % confidence intervals ) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 ( 0.55 to 1.00 ) , 0.62 ( 0.45 to 0.84 ) , and 0.59 ( 0.42 to 0.85 ) , respectively ( P serum testosterone ( ≈1 SD ) was associated with a 0.81 ( 95 % confidence interval 0.71 to 0.92 , P odds ratio for mortality . Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years . Conclusions — In men , endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes . Low testosterone may be a predictive marker for those at high risk of cardiovascular disease",
"CONTEXT Despite recognition that and rogen deficiency in men should be defined according to biochemical and clinical criteria , most prevalence estimates are based on low testosterone levels alone . OBJECTIVE The objective of this study was to examine the association between symptoms of and rogen deficiency and low total and calculated free testosterone levels and estimate the prevalence of symptomatic and rogen deficiency in men . DESIGN This study was a population -based , observational survey . PARTICIPANTS A total of 1,475 Black , Hispanic , and white men , between the ages of 30 - 79 yr , with complete data on testosterone , SHBG , and symptoms of and rogen deficiency , and who are not taking medications that impact sex steroid levels were r and omly selected from the Boston Area Community Health Survey . OUTCOME Outcomes were measured as symptomatic and rogen deficiency , defined as low total ( ) and free ( or two or more of following symptoms : sleep disturbance , depressed mood , lethargy , or diminished physical performance . RESULTS Mean age of the sample was 47.3 + /- 12.5 yr . Approximately 24 % of subjects had total testosterone less than 300 ng/dl , and 11 % of subjects had free testosterone less than 5 ng/dl . Prevalence of symptoms were as follows : low libido ( 12 % ) , erectile dysfunction ( 16 % ) , osteoporosis/fracture ( 1 % ) , and two or more of the nonspecific symptoms ( 20 % ) . Low testosterone levels were associated with symptoms , but many men with low testosterone levels were asymptomatic ( e.g. in men 50 + yr , 47.6 % ) . Crude prevalence of symptomatic and rogen deficiency was 5.6 % ( 95 % confidence interval : 3.6 % , 8.6 % ) , and was not significantly related to race and ethnic group . Prevalence was low in men less than 70 yr ( 3.1 - 7.0 % ) and increased markedly with age to 18.4 % among 70 yr olds . Projection of these estimates to the year 2025 suggests that there will be as many as 6.5 million American men ages 30 - 79 yr with symptomatic and rogen deficiency , an increase of 38 % from 2000 population estimates . CONCLUSIONS Prevalence of symptomatic and rogen deficiency in men 30 and 79 yr of age is 5.6 % and increases substantially with age . The aging of the U.S. male population will cause a large increase in the burden of symptomatic and rogen deficiency . Future work should address the clinical significance of low testosterone levels in asymptomatic men",
"BACKGROUND Gonadal steroid levels decline with age in men . Whether low testosterone levels affect the development of common age-related disorders , including physical functioning and falling , is unclear . METHODS This longitudinal , observational follow-up study sought to determine whether low testosterone levels are associated with physical performance and fall risk in older men . A total of 2587 community-based men aged 65 to 99 years were selected using a stratified r and om sampling scheme from a study cohort of 5995 volunteers . Bioavailable testosterone and estradiol levels and physical performance measures were determined from baseline . Incident falls were ascertained every 4 months during 4 years of follow-up . Generalized estimating equations were used to estimate risk ratios for the relation of sex steroids to falls . RESULTS Fifty-six percent of the men reported at least 1 fall ; many fell frequently . Lower bioavailable testosterone levels were associated with increased fall risk . Men with testosterone levels in the lowest quartile had a 40 % higher fall risk than those in the highest quartile . The effect of low testosterone levels was most apparent in younger men ( 65 - 69 years ) ( relative risk , 1.8 ; 95 % confidence interval , 1.2 - 2.7 ) ; testosterone level was not associated with falls in the oldest men ( > /=80 years ) . Lower testosterone concentrations were associated with reduced physical performance . However , the association between low testosterone levels and fall risk persisted despite adjustment for performance . CONCLUSIONS Falls were common among older men . Fall risk was higher in men with lower bioavailable testosterone levels . The effect of testosterone level was independent of poorer physical performance , suggesting that the effect of testosterone on fall risk may be mediated by other and rogen actions",
"To prospect ively compare serum hormone levels and the incidence of hormonal pathologies between men with and without erectile dysfunction , and investigate risk factors that might predict hormonal pathologies in men complaining of erectile dysfunction . The study included 262 men with erectile dysfunction and 53 healthy men with no erectile dysfunction as a control group . All men enrolled in the study were evaluated with a detailed history , physical examination , international index of erectile function ( IIEF-5 ) , and serum hormone measurement . Hypotestosteronemia was considered as serum total testosterone value of serum prolactin level of > 18 ng/mL. Serum hormone levels and the incidence of hormonal abnormalities were compared between the two groups . In addition , risk factors for hormonal abnormalities were investigated . There were no significant differences in the mean serum FSH ( p = 0.212 ) , LH ( p = 0.623 ) , testosterone ( p = 0.332 ) and prolactin values ( p = 0.351 ) between the men with and without erectile dysfunction . Hypotestosteronemia was detected in 29 ( 11 % ) of the erectile dysfunction group and in 2 ( 3.7 % ) of the control group , revealing no significant difference ( p = 0.104 ) . Hyperprolactinemia was detected in 25 ( 9.5 % ) of the erectile dysfunction group and in 2 ( 3.7 % ) of the control group , revealing no significant difference ( p = 0.171 ) . To investigate risk factors that might predict hormonal pathologies , there were no significant differences in the patient age , duration of the sexual dysfunction , smoking history and duration , the presence of chronic disease and the type of erectile dysfunction . Our findings suggest that hormonal measurement should not be routinely performed in the initial evaluation of men presenting with erectile dysfunction , and may be necessary based only on the findings obtained with a careful history and physical examination",
"BACKGROUND The association between aging-related testosterone deficiency and late-onset hypogonadism in men remains a controversial concept . We sought evidence -based criteria for identifying late-onset hypogonadism in the general population on the basis of an association between symptoms and a low testosterone level . METHODS We surveyed a r and om population sample of 3369 men between the ages of 40 and 79 years at eight European centers . Using question naires , we collected data with regard to the subjects ' general , sexual , physical , and psychological health . Levels of total testosterone were measured in morning blood sample s by mass spectrometry , and free testosterone levels were calculated with the use of Vermeulen 's formula . Data were r and omly split into separate training and validation sets for confirmatory analyses . RESULTS In the training set , symptoms of poor morning erection , low sexual desire , erectile dysfunction , inability to perform vigorous activity , depression , and fatigue were significantly related to the testosterone level . Increased probabilities of the three sexual symptoms and limited physical vigor were discernible with decreased testosterone levels ( ranges , 8.0 to 13.0 nmol per liter [ 2.3 to 3.7 ng per milliliter ] for total testosterone and 160 to 280 pmol per liter [ 46 to 81 pg per milliliter ] for free testosterone ) . However , only the three sexual symptoms had a syndromic association with decreased testosterone levels . An inverse relationship between an increasing number of sexual symptoms and a decreasing testosterone level was observed . These relationships were independently confirmed in the validation set , in which the strengths of the association between symptoms and low testosterone levels determined the minimum criteria necessary to identify late-onset hypogonadism . CONCLUSIONS Late-onset hypogonadism can be defined by the presence of at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter ( 3.2 ng per milliliter ) and a free testosterone level of less than 220 pmol per liter ( 64 pg per milliliter )",
"OBJECTIVES To determine the relationship between the ADAM question naire and the sexual hormonal levels in a male population older than 50 yr , and to know the predictive capacity of this question naire with regard to biochemical hypogonadism in the ageing male . METHODS A prospect i ve study was carried out on 230 Spanish men . Patients were evaluated by clinical history . The ADAM question naire and the Yesavage 's Geriatric Depression Scale were completed by each patient . Blood tests were performed including total testosterone , SHBG , free testosterone ( FT ) , dehidroepi and rosterone sulfate ( DHEA-S ) , and rostenedione , 17-beta-estradiol , FSH , LH , and prolactin . The relationship between positive ADAM question naire and age , clinical and sociodemographic background s , and hormone levels was analysed by means of uni- and multivariate tests . The capacity of the ADAM question naire to predict biochemical hypogonadism was determined with a chi-square test . RESULTS ADAM question naire ( excluding men with positive Yesavage 's Scale ) was positive in 140 patients ( 67.9 % ) . With respect to clinical background s , diabetes mellitus and age had a significant relationship with an ADAM-positive question naire . With respect to hormones , FT and DHEA-S levels were significantly lower when the ADAM question naire was positive . In the multivariate analysis , age , FT , and diabetes were independently related to an ADAM-positive question naire . Prevalence of biochemical hypogonadism ( FT ADAM test had a sensitivity of 84.0 % and a specificity of 36.6 % to detect biochemical hypogonadism . CONCLUSIONS FT is inversely related to the ADAM-positive question naire , independently of age . The ADAM question naire is a valid test to detect hypogonadism but has low specificity",
"Objective . The aim of this study was to evaluate the association between serum levels of testosterone and free testosterone to lifestyle in aging males . Methods . Men between 45 and 85 years were assessed regarding body mass index ( BMI ) , nicotine and alcohol consumption , stress level , physical and social activity , and sleeping quality by a self-administered question naire . In parallel , serum levels of testosterone ( T ) , free testosterone ( fT ) , LH , FSH , DHEA-S , E2 and SHBG were obtained . Results . In total , 375 men with a mean age of 59.9 years ( 9.2 ± SD ) entered this study ; 25.4 % and 27.4 % had hypogonadal testosterone or free testosterone serum levels , respectively . Nicotine consumption ( smokers had higher levels of T and fT ; p with serum levels of testosterone or free testosterone . Physical and social activity , nicotine and alcohol consumption , stress level and sleep quality did not show a significant association with serum and rogen levels . Conclusion . This prospect i ve study of 375 men aged 45 to 85 years confirms the correlation between age , BMI and smoking with serum levels of testosterone and free testosterone , whereas the investigated variety of lifestyle factors did not show a significant association to serum and rogen levels",
"We used longitudinal data from the Massachusetts Male Aging Study , a large population -based r and om- sample cohort of men aged 40 - 70 yr at baseline , to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends . Of 1,709 men enrolled in 1987 - 1989 , 1,156 were followed up 7 - 10 yr afterward . By repeated- measures statistical analysis , we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data , the cross-sectional trend between subjects within the follow-up data , and the longitudinal trend within subjects between baseline and follow-up . Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data , whereas both free and albumin-bound T declined at about 2%/yr , all significantly more steeply than within the baseline data . Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data , similarly to baseline . The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T ( 1.6%/yr ) and bioavailable T ( 2 - 3%/yr ) . Dehydroepi and rosterone , dehydroepi and rosterone sulfate , cortisol , and estrone showed significant longitudinal declines , whereas dihydrotestosterone , pituitary gonadotropins , and PRL rose longitudinally . Apparent good health , defined as absence of chronic illness , prescription medication , obesity , or excessive drinking , added 10 - 15 % to the level of several and rogens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends . The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in and rogen levels",
"OBJECTIVE Experts recommend r and om effects bivariate logitnormal sensitivity and specificity estimates , rather than directly summarized univariate likelihood ratios ( LRs ) for diagnostic test meta-analyses . We assessed whether bivariate measures might cause different clinical conclusions compared with those from simpler univariate measures . STUDY DESIGN From two articles that described the benefits of bivariate r and om effects measures , we reanalyzed results and compared outcomes to univariate r and om effects summary estimates of sensitivity , specificity , and LRs . We also reanalyzed data from two published clinical examination studies to assess differences in the two methods . RESULTS The median difference between bivariate and univariate methods for sensitivity was 1.5 % ( range : 0 - 6 % ) and for specificity was 1.5 % ( range : 0 - 4 % ) . Using a pretest probability of 50 % , the median difference in posterior probability was 2.5 % ( interquartile range : 2.2 - 3.2 % , overall range : 0 - 11 % ) . For sparse data , continuity adjustment affected the differences . Adding 0.5 to each cell of studies containing at least one cell with zero patients provided the most consistent result . CONCLUSIONS Bivariate estimates of sensitivity and specificity generate summary LRs similar to those derived with univariate methods . Our empiric results suggest that recalculating LRs in published research will not likely create dramatic changes as a function of the r and om effects measure chosen",
"CONTEXT The cause of declining testosterone ( T ) in aging men and their relationships with risk factors are unclear . OBJECTIVE The objective of the study was to investigate the relationships between lifestyle and health with reproductive hormones in aging men . DESIGN This was a baseline cross-sectional survey on 3200 community-dwelling men aged 40 - 79 yr from a prospect i ve cohort study in eight European countries . RESULTS Four predictors were associated with distinct modes of altered function : 1 ) age : lower free T ( FT ; -3.12 pmol/liter.yr , P total T ( TT ; -2.32 nmol/liter ) and FT ( -17.60 pmol/liter ) for body mass index ( BMI ; > or = 25 to LH , indicating hypothalamus/pituitary dysfunction ; 3 ) comorbidity : lower TT ( -0.80 nmol/liter , P LH in younger men but higher LH in older men ; and 4 ) smoking : higher SHBG ( 5.96 nmol/liter , P TT ( 1.31 nmol/liter , P T-LH-negative feedback due to elevated SHBG . CONCLUSIONS Complex multiple alterations in the hypothalamic-pituitary-testicular axis function exist in aging men against a background of progressive age-related testicular impairment . These changes are differentially linked to specific risk factors . Some risk factors operate independently of but others interact with age , in contributing to the T decline . These potentially modifiable risk factors suggest possible preventative measures to maintain T during aging in men",
"Diabetes mellitus is a common chronic disease , affecting 0.5–2 % worldwide . The Massachusetts Male Aging Study reported that up to 75 % of men with diabetes have a lifetime risk of developing ED . Type 2 diabetes is associated with low total serum testosterone ( TT ) identified in several cross‐sectional studies and systemic analyses . There is a lack of consensus regarding what constitutes the lowest level of testosterone within the boundaries of normality . In this retrospective study , we sought to evaluate the effect of associated co‐morbidities on serum total testosterone ( TT ) level in men with type 2 diabetes DM , either with or without erectile dysfunction ( ED ) . Three hundred and ninety‐one patients were evaluated for erectile function using an abridged , five‐item version of the International Index of Erectile Function‐5 . Measurements of TT , fasting lipid profile , blood sugar and glycated haemoglobin ( HbA1c ) were conducted . Penile hemodynamics was assessed using intracavernosal injection and penile duplex study . Hypogonadism was found in 126 cases ( 33.2 % ) , and normal TT was observed in 254 ( 66.8 % ) . ED was detected in 119 cases in the hypogonadal group ( 94.4 % ) as compared to 155/254 ( 61.0 % ) in eugonadal group , P = 0.0001 . TT was lower in diabetic men with ED as compared to those with normal erectile function ( EF ) , 392.4 ± 314.9 versus 524.3 ± 140.2 ng dl−1 , respectively , P patients with hypertension and dyslipidaemia , 185 men were evaluated , and there was no difference in the mean TT level among men with ED 490.6 ± 498.2 ng dl−1 versus normal EF 540.6 ± 133.4 ng dl−1 although , HbA1c remained lower in men with normal erectile function . Receiver operating characteristic ( ROC ) curve of TT in men without associated co‐morbidities showed that EF was compromised at TT = 403.5 ng dl−1 or less . Sensitivity of 63.3 % and a specificity of 94.0 % were detected . At this level , ED was found in 33/38 ( 86.8 % ) men with TT 403.5 ng dl−1 , whereas ED was observed in 57/147 ( 38.8 % ) men with TT ≥ 403.5 ng dl−1 ( P of TT blood levels as an indicator for initiation of testosterone replacement therapy in diabetic men with ED . Further prospect i ve controlled trials are recommended",
"Transdermal testosterone ( T ) delivery represents an effective alternative to injectable and rogens . We studied 163 hypogonadal men who applied 5 , 7.5 , or 10 g And roGel ( T gel ) 1 % CIII per day for up to 42 months . Efficacy data were presented in 123 subjects considered evaluable . Continuous And roGel treatment normalized mean serum T and free T levels . Mean serum 5alpha-dihydrotestosterone concentrations and 5alpha-dihydrotestosterone/T ratio slightly increased , mean serum estradiol/T ratio doubled , and mean serum FSH and LH levels were suppressed by T replacement . Sexual function and mood parameters improved rapidly and were maintained throughout T treatment . Lean body mass increased ( P = 0.0001 ) and fat mass decreased ( P = 0.0001 ) , and these changes were maintained with treatment but were not accompanied by significant increases in muscle strength . Increases in serum bone markers suggestive of increased bone formation were followed by gradual and progressive increases in bone mineral density more in the spine ( P = 0.0001 ) than the hip ( P = 0.0004 ) . Mild local skin irritation occurred in 12 subjects , result ing in discontinuation in only one subject . Except for the anticipated increase in hematocrit and hemoglobin , there were no clinical ly significant changes in blood counts or biochemistry . In three subjects with elevated serum prostate-specific antigen , prostate biopsies showed cancer . We conclude that continued application of And roGel result ed in beneficial effects similar to those with injectables and other transdermal preparations . This study was neither placebo controlled nor powered to determine the effects of T treatment on prostate cancer risk . Thus , monitoring for prostatic disease and assessment for erythrocytosis are strongly advised to reduce the risk of adverse events with T treatment of hypogonadal men",
"CONTEXT Risk factors for low testosterone and symptomatic and rogen deficiency ( AD ) may be modifiable . OBJECTIVE Our objective was to examine demographic , anthropometric , and medical correlates of low testosterone and symptomatic AD . DESIGN Data were used from the Boston Area Community Health Survey , an epidemiological study conducted from 2002 - 2005 . SETTING Data were obtained from a community-based r and om sample of racially and ethnically diverse men . PATIENTS OR OTHER PARTICIPANTS Data were available for 1822 men . MAIN OUTCOME MEASURES Multivariate logistic regression was used to estimate odds ratios ( OR ) and 95 % confidence intervals ( CI ) for associations of covariates with 1 ) low testosterone and 2 ) symptomatic AD . The operational definition of low testosterone was serum total testosterone less than 300 ng/dl and free testosterone less than 5 ng/dl ; symptomatic AD was defined as the additional presence of symptoms : any of low libido , erectile dysfunction , or osteoporosis or two or more of sleep disturbance , depressed mood , lethargy , or diminished physical performance . RESULTS Factors associated with low testosterone included age ( OR = 1.36 ; 95 % CI= 1.11 - 1.66 , per decade ) , low per-capita income ( $ 6000 or less per household member vs. more than $ 30,000 ; OR = 2.86 ; 95 % CI = 1.39 - 5.87 ) , and waist circumference ( per 10-cm increase ; OR = 1.75 ; 95 % CI = 1.45 - 2.12 ) . Only age ( OR = 1.36 ; 95 % CI = 1.04 - 1.77 ) , waist circumference ( OR = 1.88 ; 95 % CI = 1.44 - 2.47 ) , and health status ( OR = 0.21 ; 95 % CI = 0.05 - 0.92 , excellent vs. fair/poor ) were associated with our construct of symptomatic AD . Of all variables , waist circumference was the most important contributor in both models . CONCLUSIONS Waist circumference is a potentially modifiable risk factor for low testosterone and symptomatic AD . Manifestation of symptoms may be a consequence of generally poor health status",
"You are back where we put you in the previous article1 on diagnostic tests in this series on how to use the medical literature : in the library study ing an article that will guide you in interpreting ventilation-perfusion ( V/Q ) lung scans . Using the criteria in Table 1 , you have decided that the Prospect i ve Investigation of Pulmonary Diagnosis ( PIOPED ) study 2 will provide you with valid information . Just then , another"
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4117d1ec-06ff-11f0-808a-c43d1ab1c353
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Purpose of review This review provides an appraisal of recent evidence for or against selenium supplementation in patients with autoimmune thyroid diseases , and discusses possible effect mechanisms . Recent findings Epidemiological data suggest an increased prevalence of autoimmune thyroid diseases under conditions of low dietary selenium intake . Two systematic review s have evaluated controlled trials among patients with autoimmune thyroiditis and report that selenium supplementation decreases circulating thyroid autoantibodies . The immunomodulatory effects of selenium might involve reducing proinflammatory cytokine release . However , clinical ly relevant effects of selenium supplementation , including improvement in quality of life , are more elusive . In Graves ’ disease , some , but not all , trials indicate that adjuvant selenium supplementation enhances the restoration of biochemical euthyroidism , and might benefit patients with mild Graves ’ orbitopathy . Summary The use of selenium supplementation as adjuvant therapy to st and ard thyroid medication may be widespread , but a growing body of evidence yields equivocal results . The available evidence from trials does not support routine selenium supplementation in the st and ard treatment of patients with autoimmune thyroiditis or Graves ’ disease . However , correction of moderate to severe selenium deficiency may offer benefits in preventing , as well as treating , these disorders . Molecular mechanisms have been proposed , but further studies are needed
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"BACKGROUND The effect of supplementation with a fixed combination of antioxidants ( vitamins C and E , beta-carotene and selenium ) was monitored on the speed of attaining euthyroidism in a group of patients with Graves ' disease , treated with methimazole . METHODS The activity of glutathione peroxidase in whole blood and the concentrations of selenium , pituitary and thyroid hormones in serum were measured , prior to commencement of therapy and after 30 and 60 days . RESULTS Patients who received supplementation with antioxidants in addition to therapy with methimazole ( Group A , n=29 ) attained euthyroidism faster than the patients treated with only methimazole ( Group B , n=28 ) . The concentration of selenium in the serum of patients in Group A increased significantly during treatment ( p concentration of selenium in the serum between the groups differed statistically significantly 30 days ( p Activity of glutathione peroxidase in whole blood increased during treatment in both groups of patients . However , a statistically more significant increase occurred in Group A compared to Group B , 30 days after the commencement of therapy ( p antioxidants in the treatment of Graves ' disease is justified , particularly those containing selenium",
"We recently conducted a prospect i ve , placebo‐controlled clinical study , where we could demonstrate , that a substitution of 200 μg sodium selenite for three months in patients with autoimmune thyroiditis reduced thyroid peroxidase antibody ( TPO‐Ab ) concentrations significantly . Forty‐seven patients from the initially 70 patients agreed to participate in a follow‐up cross‐over study for further six months . One group ( n = 13 ) , which initially received selenium continued to take 200 μg sodium selenite ( Se‐Se ) , one group stopped taking selenium ( Se‐0 ) ( n = 9 ) , another group which received placebo started to take 200 μg selenium ( n = 14 ) ( Plac‐Se ) and the last group was without selenium substitution ( Plac‐0 ) ( n = 11 ) . TPO‐Ab concentrations were measured at beginning and the end of the study . In the Se‐Se group , the TPO‐Ab concentrations further significantly p = 0.004 ) decreased from 625 ± 470 U/ml to 354 ± 321 U/ml , in the Se‐0 group the TPO‐Ab concentrations increased significantly p = 0.017 ) from 450 ± 335 to 708 ± 313 U/ml . In the placebo group , the TPO‐Ab concentrations in those patients who were followed without selenium substitution were unchanged ( 1351 ± 940 vs. 1724 ± 1112 U/ml , p = 0.555 ) . In contrast , the patients who received 200 μg sodium selenite after placebo , the TPO‐Ab concentrations decreased significantly ( p = 0.029 ) from 1182 ± 723 to 643 ± 477 U/ml",
"The effect of selenium supplementation on recurrent hyperthyroidism caused by Graves ' disease is unclear . Our study aim ed to assess the efficacy of selenium supplementation therapy on recurrent Graves ' disease . Forty-one patients with recurrent Graves ' disease were enrolled in this study . All patients received the routine treatment using methimazole ( MMI ) , while patients allocated to the selenium group received additional selenium therapy for 6 months . The influence of selenium supplementation on the concentrations of thyroid stimulating hormone ( TSH ) , anti-TSH-receptor antibodies ( TRAb ) , free thyroxine ( FT4 ) , and free triiodothyronine ( FT3 ) were assessed . The remission rate was also compared between 2 groups . There was no obvious difference in the demographic data and the levels of serum FT4 , FT3 , TSH , and TRAb between the 2 groups at baseline . Both FT4 and FT3 decreased more at 2 months in the selenium group than the controls , while the TSH level increased more in patients receiving selenium supplementation ( p TRAb level was significantly lower in patients receiving selenium supplementation ( 2.4 IU/l vs. 5.6 IU/l , p=0.04 ) . The percentages of patients with normal TRAb level at 6 months was also significantly higher in the selenium group ( 19.0 vs. 0 % , p=0.016 ) . Kaplan-Meier survival curve showed patients receiving selenium supplementation had a significantly higher rate of remission than controls ( Log-rank test p=0.008 ) . In conclusion , selenium supplementation can enhance the effect of antithyroid drugs in patients with recurrent Graves ' disease . R and omized trials with large number of participants are needed to vali date the finding above",
"OBJECTIVE We studied the effects of selenium ( Se ) treatment on serum anti-thyroid peroxidase ( TPO ) levels in Greek patients with Hashimoto 's thyroiditis ( HT ) . DESIGN We prospect ively studied 80 women with HT , median age 37 ( range 24 - 52 ) years , for 1 year . All patients received 200 microg Se in the form of l-selenomethionine orally for 6 months . At the end of the 6-month period , 40 patients continued taking 200 microg Se ( Group A ) and 40 patients stopped ( Group B ) . Serum thyrotropin ( TSH ) , free triiodothyronine ( FT(3 ) ) , free thyroxine ( FT(4 ) ) , anti-TPO , and anti-thyroglobulin ( Tg ) levels were measured at baseline and at the end of each 3-month period . MAIN OUTCOME There was a significant reduction of serum anti-TPO levels during the first 6 months ( by 5.6 % and 9.9 % at 3 and 6 months , respectively ) . An overall reduction of 21 % ( p serum anti-TPO levels were increased by 4.8 % ( p HT patients 6 months of Se treatment caused a significant decrease in serum anti-TPO levels , which was more profound in the second trimester . The extension of Se supplementation for 6 more months result ed in an additional 8 % decrease , while the cessation caused a 4.8 % increase , in the anti-TPO concentrations",
"Background Patients with chronic autoimmune thyroiditis have impaired health-related quality of life . The thyroid gl and has a high selenium concentration , and specific selenoprotein enzyme families are crucial to immune function , and catalyze thyroid hormone metabolism and redox processes in thyroid cells . Previous r and omized controlled trials have found that selenium supplementation decreases thyroid-disease-specific antibody levels . We hypothesize that selenium might be beneficial in the treatment of chronic autoimmune thyroiditis . Methods / Design The CATALYST trial is an investigator-initiated r and omized , blinded , multicentre clinical trial of selenium supplementation versus placebo in patients with chronic autoimmune thyroiditis . Inclusion criteria : age ≥18 years ; serum thyroid peroxidase antibody level ≥100 IU/ml within the previous 12 months ; treatment with levothyroxine and written informed consent . Exclusion criteria : previous diagnosis of toxic nodular goitre , Graves ’ hyperthyroidism , postpartum thyroiditis , Graves ’ orbitopathy ; previous antithyroid drug treatment , radioiodine therapy or thyroid surgery ; immune-modulatory or other medication affecting thyroid function ; pregnancy , planned pregnancy or breastfeeding ; allergy towards any intervention or placebo component ; intake of selenium supplementation > 55 μg/day ; inability to read or underst and Danish or lack of informed consent . The trial will include 2 × 236 participants . The experimental intervention and control groups will receive 200 μg selenium-enriched yeast or matching placebo tablets daily for 12 months . The experimental supplement will be SelenoPrecise ® . The primary outcome is thyroid-related quality of life assessed by the Thyroid Patient-Reported Outcome ( ThyPRO ) question naire . Secondary outcomes include serum thyroid peroxidase antibody concentration ; serum triiodothyronine/thyroxine ratio ; levothyroxine dosage ; adverse reactions and serious adverse reactions and events . Discussion In this pragmatic trial , participating patients follow their usual treatment at their usual hospitals . In order to collect high- quality data on the clinical course and quality of life , and to minimize missing data , an elaborate trial management system has been design ed . 12 months intervention duration was selected in consideration of the primary outcome , thyroid-related quality of life . Trial registration Clinical Trials.gov ID : NCT02013479",
"BACKGROUND Thyroid function depends on the essential trace mineral selenium , which is at the active center of the iodothyronine deiodinase enzymes that catalyze the conversion of the prohormone thyroxine ( T(4 ) ) to the active form of thyroid hormone , triiodothyronine ( T(3 ) ) . OBJECTIVE Because selenium intake in the United Kingdom has fallen during the past 25 y , we wanted to determine whether current selenium status might be limiting conversion of T(4 ) to T(3 ) in the elderly , in whom marginal hypothyroidism is relatively common . DESIGN We investigated the effect of selenium supplementation in a double-blind , placebo-controlled trial in 501 elderly UK volunteers . Similar numbers of men and women from each of 3 age groups , 60 - 64 y , 65 - 69 y , and 70 - 74 y , were r and omly allocated to receive 100 , 200 , or 300 microg Se/d as high-selenium yeast or placebo yeast for 6 mo . As part of the study , plasma selenium , thyroid-stimulating hormone , and total and free T(3 ) and T(4 ) were measured . Data from 368 euthyroid volunteers who provided blood sample s at baseline and 6 mo were analyzed . RESULTS Although selenium status at baseline correlated weakly with free T(4 ) ( r = -0.19 , P ratio of free T(3 ) to free T(4 ) ( r = 0.12 , P = 0.02 ) , we found no evidence of any effect of selenium supplementation on thyroid function , despite significant increases in plasma selenium . However , baseline plasma selenium in our study ( x : 91 microg/L ) was somewhat higher than in previous supplementation studies in which apparently beneficial effects were seen . CONCLUSION We found no indication for increasing selenium intake to benefit T(4 ) to T(3 ) conversion in the elderly UK population",
"Introduction : In areas with severe selenium deficiency higher incidence of thyroiditis has been reported due to a decreased activity of selenium-dependent glutathione peroxidase enzyme within thyroid cells . Aims and Objective : To study the effect of selenium supplementation in patients with autoimmune thyroid disease . Material s and Methods : This is a blinded placebo-controlled prospect i ve study done in 60 patients with autoimmune thyroid disease ( as defined by an anti-thyroid peroxidase antibody ( TPOAb ) level more than 150 IU/ml ) irrespective of the baseline thyroid status . Patients with overt hyperthyroidism who are on antithyroid drugs , patients on any other medication , which may alter the immunity status of the patients , and pregnant patients were excluded from the study . Patients were r and omized into two age and TPOAb-matched groups ; 30 patients received 200 μg of sodium selenite/day , orally , for 3 months , and 30 patients received placebo . All hypothyroid patients were given l-thyroxine replacement . Results : Of 30 patients in the selenium treated group , 6 patients were overtly hypothyroid , 15 were sub clinical hypothyroid , 6 were euthyroid , and 3 were sub clinical hyperthyroid . The mean TPOAb concentration decreased significantly by 49.5 % ( P Conclusion : Selenium substitution has a significant impact on inflammatory activity in thyroid-specific autoimmune disease . It would be of interest to determine whether early treatment with selenium in patients with newly developed autoimmune thyroiditis may delay or even prevent the natural course of these diseases",
"Background Graves ’ hyperthyroidism is an autoimmune disease causing hyperfunction of the thyroid gl and . The concentration of selenium is high in the thyroid gl and and two important groups of enzymes within the thyroid are selenoproteins , that is , they depend on selenium . Selenium may have beneficial effects on autoimmune hypothyroidism and on Graves ' orbitopathy , but the effects of selenium on Graves ' hyperthyroidism is unknown . We hypothesize that adjuvant selenium may be beneficial in the treatment of Graves ' hyperthyroidism . The objective is to investigate if selenium supplementation plus st and ard treatment with anti-thyroid drugs versus st and ard treatment with anti-thyroid drugs will lead to a decrease in anti-thyroid drug treatment failure ( that is , failure to remain euthyroid , without further treatment , one year after cessation of anti-thyroid drug treatment ) , faster and longer lasting remission ( that is , anti-thyroid drug treatment success ) , and improved quality of life in patients with Graves ’ hyperthyroidism . Methods and design The trial is an investigator-initiated , r and omised , blinded , multicentre clinical trial . Inclusion criteria are : age 18 years or older ; diagnosis of active Graves ' hyperthyroidism within the last two months ; and informed consent . Exclusion criteria are major co-morbidity ; previous radioactive iodine treatment ; ongoing anti-thyroid drug treatment for more than two months ; treatment with immunomodulatory drugs ; known allergy towards the components in the selenium and placebo pills ; pregnancy or breast-feeding ; and intake of selenium supplementation above 70 μg per day . We plan to include 492 participants , r and omised ( 1:1 ) to two tablets of 100 μg selenium once daily for the 24 to 30 months intervention period versus two identical placebo tablets once daily . The primary outcome is the proportion of participants with anti-thyroid drug treatment failure ( see above ) at the end of the intervention period ( 24 to 30 months ) . Secondary outcomes are : thyroid-specific quality of life during the first year after r and omisation ; level of thyroid stimulating hormone-receptor antibodies at 18 months after r and omisation and at the end of the intervention period ( 24 to 30 months ) ; hyperthyroid symptoms during the first year after r and omisation ; eye symptoms during the first year after r and omisation , and at the end of the intervention period ( 24 to 30 months ) ; adverse reactions during the intervention period ; and serious adverse events during the intervention period . Discussion It was of great importance to the initiators of this trial , that the results would be directly applicable to daily clinical practice . Therefore , it was design ed as a pragmatic trial : the patients follow their usual treatment at their usual hospitals . In order to still collect high quality data on the clinical course and quality of life , an elaborate trial management system was design ed to keep track of patient input , need for trial personnel input and action , and to collect data from medical chart systems . Meticulous follow-up on missing responses to the QoL measurements has been incorporated into the system , to minimise missing quality of life data . Monitoring of adverse reactions and events is achieved by thorough instruction of the participants , surveillance of patient-reported outcomes , and integration with national data bases regarding hospitalizations . A very long intervention period was necessary , since patients are not considered in remission until one year after stopping anti-thyroid drugs . Usually , patients are treated for 12 to 18 months with anti-thyroid drugs , yielding a total intervention period of 24 to 30 months . Trial registration Clinical Trials.gov : NCT01611896",
"Background Hypothyroidism is often diagnosed , and subsequently treated , due to health-related quality of life ( HRQL ) issues . However , HRQL following treatment has never previously been assessed in longitudinal descriptive studies using vali date d instruments . Objective To investigate disease-specific ( ThyPRO ) and generic ( SF-36 ) HRQL , following levothyroxine therapy in patients with hypothyroidism due to autoimmune thyroiditis . Methods This prospect i ve cohort study was set at endocrine outpatient clinics at two Danish university hospitals . Seventy-eight consecutive patients were enrolled and completed HRQL question naires before , six weeks , and six months after initiation of levothyroxine therapy . Normative ThyPRO ( n = 739 ) and SF-36 ( n = 6,638 ) data were available for comparison and changes in HRQL following treatment were estimated and quantified . Results Prior to treatment , all ThyPRO scales were significantly impacted ( p Bodily Pain . Tiredness ( ThyPRO ) and Vitality ( SF-36 ) were the most markedly impacted scales . After six weeks of treatment , nine of thirteen ThyPRO scales had significantly improved . ThyPRO improvements were consistent at six months , where five of eight SF-36 scales had also significantly improved , but deficits persisted for a subset of both ThyPRO and SF-36 scales . Conclusions In this population of hypothyroid patients , HRQL was widely affected before treatment , with tiredness as the cardinal impairment according to both ThyPRO and SF-36 . Many aspects of HRQL improved during the first six months of LT4 therapy , but full recovery was not obtained . Our results may help clinicians inform patients about expected clinical treatment effects",
"Background : Several studies have suggested that selenium may influence the natural history of autoimmune thyroiditis ( AIT ) . Recently , IFNγ-inducible chemokines ( CXCL-9 , -10 and -11 ) were shown to be elevated in AIT patients . Objective : This prospect i ve , r and omized , controlled study was conducted to evaluate the effect of two doses of selenomethionine ( Semet ; 80 or 160 µg/day ) versus placebo in euthyroid women with AIT , in terms of reduction of anti-thyroid antibodies , CXCL-9 , -10 and -11 and improvement of thyroid echogenicity , over 12 months . Patients and Methods : Sixty patients , aged 21 - 65 years , were equally r and omized into 3 groups : placebo , 80 µg/day of Semet ( 80-Semet ) or 160 µg/day of Semet ( 160-Semet ) . Results : Anti-thyroperoxidase antibody ( TPOAb ) levels remained unaffected by Semet supplementation ; anti-thyroglobulin antibody levels showed a significant reduction in the 160-Semet and the placebo group at 12 months . No significant change in thyroid echogenicity , thyroid volume and quality of life was observed within and between the groups . Sub clinical hypothyroidism was diagnosed in 2 patients of the placebo group versus 1 patient in each Semet group . Serum CXCL-9 and -10 were significantly reduced in both Semet groups at 6 and 12 months , while they remained unchanged or increased in the placebo group . CXCL-11 , TNFα and IFNγ showed a transient decrease at 6 months in both Semet groups but returned nearly to the basal levels at 12 months . Conclusions : Semet supplementation had no positive effect on thyroid echogenicity or TPOAb in our patients . However , we observed a Semet-dependent downregulation of the IFNγ-inducible chemokines , especially CXCL-9 and -10 , which may serve as helpful biomarkers in future selenium supplementation trials",
"Purpose Selenium is an essential trace mineral and a component of selenoproteins that are involved in the production of thyroid hormones and in regulating the immune response . We aim ed to explore the effect of low-dose selenium supplementation on thyroid peroxidase antibody ( TPO-Ab ) concentration and thyroid function in pregnant women from a mild-to-moderate iodine-deficient population . Methods Sample s and data were from a secondary analysis of Selenium in PRegnancy INTervention ( SPRINT ) , a double-blind , r and omized , placebo-controlled study that recruited 230 women with singleton pregnancies from a UK antenatal clinic at 12 weeks of gestation . Women were r and omized to receive 60 µg/day selenium or placebo until delivery . Serum thyroid peroxidase antibodies ( TPO-Ab ) , thyrotropin ( TSH ) and free thyroxine ( FT4 ) were measured at 12 , 20 and 35 weeks and thyroglobulin antibodies ( Tg-Ab ) at 12 weeks . Results 93.5 % of participants completed the study . Se supplementation had no more effect than placebo in decreasing TPO-Ab concentration or the prevalence of TPO-Ab positivity during the course of pregnancy . In women who were either TPO-Ab or Tg-Ab negative at baseline ( Thy-Ab−ve ) , TSH increased and FT4 decreased significantly throughout gestation ( P baseline , TSH tended to decrease and was lower than placebo at 35 weeks ( P = 0.050 ) . FT4 fell more on Se than placebo supplementation and was significantly lower at 35 weeks ( P = 0.029 ) . Conclusions Low-dose selenium supplementation in pregnant women with mild-to-moderate deficiency had no effect on TPO-Ab concentration , but tended to change thyroid function in Thy-Ab+ve women",
"CONTEXT Pregnant women who are positive for thyroid peroxidase antibodies [ TPOAb(+ ) ] are prone to develop postpartum thyroid dysfunction ( PPTD ) and permanent hypothyroidism . Selenium ( Se ) decreases thyroid inflammatory activity in patients with autoimmune thyroiditis . OBJECTIVE We examined whether Se supplementation , during and after pregnancy , influences the thyroidal autoimmune pattern and function . DESIGN This was a prospect i ve , r and omized , placebo-controlled study . SETTING The study was conducted in the Department of Obstetrics and Gynecology and Department of Endocrinology . PATIENTS A total of 2143 euthyroid pregnant women participated in the study ; 7.9 % were TPOAb(+ ) . INTERVENTIONS During pregnancy and the postpartum period , 77 TPOAb(+ ) women received selenomethionine 200 microg/d ( group S1 ) , 74 TPOAb(+ ) women received placebo ( group S0 ) , and 81 TPOAb(- ) age-matched women were the control group ( group C ) . MAIN OUTCOME MEASURES We measured the prevalence of PPTD and hypothyroidism . RESULTS PPTD and permanent hypothyroidism were significantly lower in group S1 compared with S0 ( 28.6 vs. 48.6 % , P Se supplementation during pregnancy and in the postpartum period reduced thyroid inflammatory activity and the incidence of hypothyroidism",
"AIMS To test whether selenium administration affects autoantibodies to thyroid peroxidase ( anti-TPO ) and thyroglobulin ( anti-TG ) titres in chronic autoimmune ( Hashimoto 's - HT ) thyroiditis . METHODS A prospect i ve , open-label , quasi-r and omised study in 86 HT patients ( n = 86 ) assigned to either selenomethionine ( Seme ) 200μg daily for 3 months ( Se3 , n = 15 ) or 6 months ( Se6 , n = 46 ) or placebo ( Control , n = 25 ) . Serum Se , anti-TPO , anti-TG and thyroid hormones were measured in all patients at baseline , 3 and 6 months . A subgroup of 18 patients ( twelve on Se6 and six controls ) were subjected in thyroid fine-needle biopsy at baseline and 6 months to detect changes in lymphocyte infiltration . RESULTS No significant difference in anti-TPO levels was recorded after 3 ( p = 0.88 ) or 6 months ( p = 0.62 ) on Seme . Anti-TG levels decreased both at 3 months ( p = 0.001 ) and 6 months ( p = 0.001 ) . No significant changes in thyroid stimulating hormone , free thyroxine and free triiodothyronine levels or in the lymphocytes ' number in thyroid cytology specimens were detected . Age , gender , duration of disease , baseline anti-TPO levels and per cent change in Se levels could not predict the response of anti-TPO levels to Seme administration . CONCLUSION Our data suggest that Seme administration in pharmacological doses for a period of 6 months seems to have no significant effect on serum thyroid auto-antibodies ' levels or lymphocyte infiltration of the thyroid gl and",
"Objective In spite of previous conflicting results , an adjuvant role of selenium in the treatment of Graves ’ disease ( GD ) hyperthyroidism has been proposed . To address this issue , a r and omized clinical trial was carried out aim ed at investigating whether selenium is beneficial on the short-term control of GD hyperthyroidism treated with methimazole ( MMI ) . Methods Thirty newly diagnosed hyperthyroid GD patients were r and omly assigned to treatment with : ( i ) MMI or ( ii ) MMI plus selenium . Primary outcomes were : control of hyperthyroidism and clinical and biochemical manifestations of hyperthyroidism [ heart rate , cholesterol , sex hormone-binding globulin ( SHBG ) , hyperthyroidism symptoms ] at 90 days . Results Baseline features of the two groups did not differ . Serum selenium at baseline was similar in the two groups and within the recommended range to define selenium sufficiency . Selenium increased with treatment in the MMI-selenium group and became significantly higher than in the MMI group . Serum malondialdehyde , a marker of oxidative stress , was similar in the two groups and decreased significantly with treatment , with no difference between groups . Administration of MMI was followed by a reduction of FT3 and FT4 , with no difference between groups . Heart rate , SHBG and symptoms of hyperthyroidism decreased , whereas total cholesterol increased in both groups with no difference between groups . Conclusions Our study , carried out in a selenium-sufficient cohort of GD patients , failed to show an adjuvant role of selenium in the short-term control of hyperthyroidism . However , selenium might be beneficial in patients from selenium-deficient areas , as well as in the long-term outcome of antithyroid treatment",
"Abstract Background The real efficacy of selenium supplementation in Hashimoto ’s thyroiditis ( HT ) is still an unresolved issue . Objectives We studied the short-term effect of l-selenomethionine on the thyroid function in euthyroid patients with HT . Our primary outcome measures were TSH , thyroid hormones , thyroid peroxidase antibody ( TPOAb ) , thyroglobulin antibody ( TGAb ) levels and thyroid echogenicity after 6 months of l-selenomethionine treatment . The secondary outcome measure was serum CXCL10 levels . Methods In a placebo-controlled r and omized prospect i ve study , we have enrolled untreated euthyroid patients with HT . Seventy-six patients were r and omly assigned to receive l-selenomethionine 166 µg/die ( SE n = 38 ) or placebo ( controls n = 38 ) for 6 months . TSH , free T4 ( FT4 ) , free T3 ( FT3 ) , TPOAb and CXCL10 serum levels were assayed at time 0 , after 3 and 6 months . An ultrasound examination of the left and right thyroid lobe in transverse and longitudinal sections was performed . A rectangular region , the region of interest , was selected for analysis . Results TSH , FT4 , FT3 , TPOAb , thyroid echogenicity and CXCL10 were not statistically different between SE and control groups at time 0 , after 3 and 6 months . In the SE group , FT4 levels were significantly decreased ( P the FT3 decreased after 3 and 6 months ( P short-term l-selenomethionine supplementation has a limited impact on the natural course in euthyroid HT . Our results tip the balance toward the ineffectiveness of short-term l-selenomethionine supplementation in HT",
"UNLABELLED Selenium as an essential trace element is capable of exerting complex effects on the endocrine and immune system by its antioxidant capacity . The role of selenium is important because the level of free oxygen radicals is elevated in the physiological thyroid hormone synthesis . THE AIM OF STUDY was to determine whether selenium therapy can influence the level of antithyroid peroxidase and antithyroglobulin antibodies or whether there is a correlation between antioxidant capacity and the titer of autoantibodies . METHOD 132 patient with autoimmune thyroiditis were investigated in a prospect i ve , blind and placebo-controlled study . L-thyroxine substitution therapy was made in both groups and the level of TSH remained in the normal range . The selenium-treated group ( n = 70 patients , 68 female , mean age 41,4 + /- 9,5 year ) was compared with the placebo-treated group ( n = 62 patients , 61 female , mean age 42,7 + /- 8,3 year ) . Selenium therapy was continued by L-seleno-methionine ( per os 2 x 100 microg/day ) for one year . Determination of TSH , fT4 , fT3 and autoantibodies was carried out by chemiluminescence method . Total antioxidant capacity was determined by R and ox kit , the level of selenium in the sera by atomic absorption technique was measured . In the follow-up study , patients were controlled every third month and at the end of a one-year observation period . RESULTS The level of selenium in the untreated patients was significantly lower than in treated patients and controls . The fT3/fT4 ration proved to be higher in patients after selenium therapy . The titer of antithyroid antibodies ( mostly the antithyroid peroxidase ) significantly decreased at the end of the study . An inverse correlation was found between antioxidant capacity and the level of antithyroid peroxidase antibodies . The volume of thyroid gl and slightly diminished in treated patients . Side effects were not observed . CONCLUSIONS Selenium completed with L-thyroxine is a suitable therapy for patients with autoimmune thyroiditis",
"Purpose To analyze the impact of selenium supplementation on serum antiTPO levels and thyroid echogenicity in patients with CAT , evaluating the response in subgroups with different GPx1 genotypes . Methods CAT patients ( n = 55 ) with positive antiTPO were r and omized to selenomethionine ( SeMet ) 200 μg daily ( n = 28 ) or placebo ( n = 27 ) for 3 months . Assessment s included GPx1 genotyping at baseline and serum levels of plasma selenium , erythrocyte GPx1 activity , antiTPO and thyroid echogenicity at baseline , and 3 and 6 months . Results In the SeMet group , the increase in plasma levels of selenium and erythrocyte GPx1 activity was similar among patients with different GPx1 genotypes . In the overall cohort , patients r and omized to SeMet showed a 5 % decrease in antiTPO levels at 3 months ( p = non-significant ) and 20 % at 6 months ( p in antiTPO levels at any time point . Subgroup analysis showed that patients with different GPx1 genotypes presented comparable responses in antiTPO levels and echogenicity index to SeMet . Conclusions Selenium supplementation decreased serum antiTPO levels in CAT patients , with similar response among patients with different GPx1 genotypes",
"OBJECTIVE Selenium is present in the active site of proteins important for thyroid hormone synthesis and metabolism . The objective of this study is to investigate the effect of selenium supplementation in different doses on thyroid function , under conditions of suboptimal dietary selenium intake . DESIGN The Danish PREvention of Cancer by Intervention with SElenium pilot study ( DK-PRECISE ) is a r and omized , double-blinded , placebo-controlled trial . A total of 491 males and females aged 60 - 74 years were r and omized to 100 μg ( n=124 ) , 200 μg ( n=122 ) , or 300 μg ( n=119 ) selenium-enriched yeast or matching yeast-based placebo tablets ( n=126 ) . A total of 361 participants , equally distributed across treatment groups , completed the 5-year intervention period . METHODS Plasma sample s were analyzed for selenium and serum sample s for TSH , free triiodothyronine ( FT3 ) , and free thyroxine ( FT4 ) at baseline , and after 6 months , and 5 years of supplementation . RESULTS Plasma selenium concentrations increased significantly and dose-dependently in treatment groups receiving selenium ( P ) . Serum TSH and FT4 concentrations decreased significantly and dose-dependently by 0.066 mIU/l ( P=0.010 ) and 0.11 pmol/l ( P=0.015 ) , respectively , per 100 μg/day increase , with insignificant differences between 6 months and 5 years . No significant effects were found for FT3 and FT3:FT4 ratio . CONCLUSIONS In euthyroid subjects , selenium supplementation minutely and dose-dependently affects thyroid function , when compared with placebo , by decreasing serum TSH and FT4 concentrations . Based on these findings , selenium supplementation is not warranted under conditions of marginal selenium deficiency . However , a role for selenium supplementation in the treatment of autoimmune thyroid diseases is still unresolved",
"BACKGROUND Recent clinical studies have demonstrated the suppressive effect of selenium ( Se ) treatment on serum thyroid-specific antibody titers in patients with autoimmune thyroiditis ( AIT ) , but the mechanism underlying this process is not clear . The aim of the present study was to investigate the effects of selenium on the incidence and severity of AIT , titers of thyroid autoantibodies , and selenoprotein expression in thyroid in a spontaneous autoimmune thyroiditis ( SAT ) model . METHODS NOD.H-2(h4 ) mice at four weeks of age were r and omly divided into control , iodine supplement ( SAT ) , and selenium supplement groups ( SAT+Se ) . Mice were given 0.005 % sodium iodide water for eight weeks to induce SAT and then 0.3 mg/L sodium selenite in drinking water for 8 weeks and 16 weeks . The severity of lymphocytic infiltration in the thyroid , serum thyroglobulin antibody ( TgAb ) titers , serum selenium concentration , expression of glutathione peroxidase-1 ( GPx1 ) , thioredoxin reductase-1 ( Txnrd1 ) , and peroxiredoxin 5 were measured . RESULTS Serum selenium concentration significantly increased after selenium supplementation . Serum TgAb levels were significantly lower in the selenium group compared with the SAT group ( p prevalence of thyroiditis and the degree of infiltration of lymphocytes decreased gradually over time in the group provided with selenium supplementation . The expression of GPx1 and Txnrd1 by Western blotting were found to be significantly higher in the SAT+Se group than in other groups ( p selenium treatment can increase the function of antioxidation by upregulating the expression of selenoproteins in the thyroid and have an inhibitory effect on TgAb titers , which may have an impact on AIT",
"In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells . Selenium-dependent enzymes also have several modifying effects on the immune system . Therefore , even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases . We performed a blinded , placebo-controlled , prospect i ve study in female patients ( n = 70 ; mean age , 47.5 + /- 0.7 yr ) with autoimmune thyroiditis and thyroid peroxidase antibodies ( TPOAb ) and /or Tg antibodies ( TgAb ) above 350 IU/ml . The primary end point of the study was the change in TPOAb concentrations . Secondary end points were changes in TgAb , TSH , and free thyroid hormone levels as well as ultrasound pattern of the thyroid and quality of life estimation . Patients were r and omized into 2 age- and antibody (TPOAb)-matched groups ; 36 patients received 200 microg ( 2.53 micromol ) sodium selenite/d , orally , for 3 months , and 34 patients received placebo . All patients were substituted with L-T(4 ) to maintain TSH within the normal range . TPOAb , TgAb , TSH , and free thyroid hormones were determined by commercial assays . The echogenicity of the thyroid was monitored with high resolution ultrasound . The mean TPOAb concentration decreased significantly to 63.6 % ( P = 0.013 ) in the selenium group vs. 88 % ( P = 0.95 ) in the placebo group . A subgroup analysis of those patients with TPOAb greater than 1200 IU/ml revealed a mean 40 % reduction in the selenium-treated patients compared with a 10 % increase in TPOAb in the placebo group . TgAb concentrations were lower in the placebo group at the beginning of the study and significantly further decreased ( P = 0.018 ) , but were unchanged in the selenium group . Nine patients in the selenium-treated group had completely normalized antibody concentrations , in contrast to two patients in the placebo group ( by chi(2 ) test , P = 0.01 ) . Ultrasound of the thyroid showed normalized echogenicity in these patients . The mean TSH , free T(4 ) , and free T(3 ) levels were unchanged in both groups . We conclude that selenium substitution may improve the inflammatory activity in patients with autoimmune thyroiditis , especially in those with high activity . Whether this effect is specific for autoimmune thyroiditis or may also be effective in other endocrine autoimmune diseases has yet to be investigated",
"OBJECTIVE Selenium ( Se ) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase ( Gpx ) and of the iodothyronine selenodeiodinases that catalyse the extrathyroidal production of tri-iodothyronine ( T(3 ) ) . Thus , Se deficiency may seriously influence the generation of free radicals , the conversion of thyroxine ( T(4 ) ) to T(3 ) and the autoimmune process . Therefore , we performed a r and omised , placebo-controlled prospect i ve study to investigate the effects of Se treatment on patients with autoimmune thyroiditis ( AIT ) . DESIGN AND METHODS Sixty five patients aged 22 - 61 years ( median age 48 years ) with AIT were recruited into two groups . Group I ( Gr I ) ( n=34 ) was treated with selenomethionine ( Seme ) 200 microg , plus L-thyroxine ( LT(4 ) ) to maintain TSH levels between 0.3 - 2.0 mU/l , whereas group II ( Gr II ) ( n=31 ) received LT(4 ) plus placebo over a period of 6 months . Moreover , the pharmacokinetics of Seme were studied in 10 patients and eight volunteers at baseline and 2 h , 4 h , 6 h and 24 h after oral administration of a 200 microg tablet of Seme . Finally , Se levels were measured at the end of the study in some patients of both groups and their results were correlated with thyroid hormone levels . RESULTS In the pharmacokinetics study , basal serum concentration of Se ( 75+/-6 microg/l ) was within the reference range ( 70 - 125 microg/l ) , it promptly increased at 2 h , peaked at 4 h ( 147+/-17 microg/l ; P antibodies against thyroid peroxidase ( anti-TPO ) levels showed an overall decrease of 46 % at 3 months ( from 1875+/-1039 U/l to 1013+/-382 U/l ; P anti-TPO amounted to 21 % at 3 months and to 27 % at 6 months ( from 1758+/-917 U/l to 1284+/-410 U/l ; P against thyroglobulin levels between the groups . At the end of this study Se levels were found to be statistically significantly increased in Gr I ( n = 9/34 ) compared with Gr II ( n=11/31 ) ( 97+/-8.4 vs 79+/-8 ; P LT(4 ) in the treatment of AIT . The exact mechanism(s ) is not very well determined , it might enhance the activity of detoxifying enzymes and enforce the defense against oxidative stress",
"BACKGROUND Selenium , a potential cancer prevention agent currently being tested against prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) , plays an integral role in thyroid metabolism . The effects of long-term selenium supplementation on thyroid hormone concentrations are unknown . OBJECTIVE The objective was to investigate the effects of long-term selenium supplementation on thyroid hormone concentrations . DESIGN Twenty-eight healthy adults took 200 microg selenomethionine/d for 28 mo . The thyroid hormones triiodothyronine ( T3 ) , thyroxine ( T4 ) , and thyrotropin ( TSH ) were measured in plasma for 4 mo before supplementation and quarterly during supplementation . The assay methods were changed mid study ; the results of the 2 methods were not comparable . Therefore , one analysis was conducted based on the results of the first method , and a second analysis was based on all of the data , adjusted for the change . Serial data collection permitted a test for trends rather than simply a difference between initial and final values . RESULTS By 9 mo , mean ( + /-SEM ) plasma selenium concentrations had increased from 1.78 + /- 0.07 micromol/L at baseline to 2.85 + /- 0.11 micromol/L for men and from 1.64 + /- 0.04 to 3.32 + /- 0.1.2 micromol/L for women . T3 concentrations in men increased 5 % per year ( P = 0.01 ) . T4 and TSH concentrations were unchanged . CONCLUSIONS Selenium supplementation produced no clinical ly significant changes in thyroid hormone concentrations . A small but statistically significant increase in T3 concentrations was noted in men , with no corresponding decreases in TSH . A subset of SELECT subjects might be monitored periodically for changes during long-term selenium supplementation",
"The aim of this study is to investigate the long-term ( 9 months ) effects of variable doses ( 200/100 microg/day ) of L-selenomethionine on autoimmune thyroiditis ( AIT ) and the parameters affecting the success rate of this therapy . The present study was design ed in three steps : ( 1 ) 88 female patients with AIT ( mean age = 40.1 + /- 13.3 years ) were r and omized into two groups according to their initial serum TSH , thyroid peroxidase antibody ( TPOAb ) concentrations , and age . All the patients were receiving L-thyroxine to keep serum TSH 200 microg L-selenomethionine per day , orally for 3 months , and group C ( n = 40 , mean TPOAb = 770.3 + /- 406.2 IU/ml ) received placebo . ( 2 ) 40 volunteers of group S2 were r and omized into two age- and TPOAb-matched groups . Group S22 ( n = 20 ) went on taking L-selenomethionine 200 microg/day , while others ( group S21 ) lowered the dose to 100 microg/day . ( 3 ) 12 patients of group S22 ( group S222 ) went on taking L-selenomethionine 200 microg/day , while 12 patients of group S21 ( S212 ) increased the dose to 200 microg/day . Serum titers of TPOAb decreased significantly in group S2 ( 26.2 % , P 0.05 ) . TPOAb titers increased significantly in group S21 ( 38.1 % , P thyroglobulin antibody titers was only noted in group S2 ( 5.2 % , P L-selenomethionine substitution suppresses serum concentrations of TPOAb in patients with AIT , but suppression requires doses higher than 100 microg/day which is sufficient to maximize glutathione peroxidase activities . The suppression rate decreases with time",
"INTRIDUCTION The thyroid is an organ with one of the highest selenium concentrations , containing many selenoproteins implicated in thyroid hormone metabolism . Treatment with levothyroxine has been recommended for all sub clinical hypothyroid patients with TSH levels > 10 mU/L , whereas for those with TSH treatment remains controversial . AIM A r and omised controlled prospect i ve study was performed to investigate the effects of Se treatment on patients with autoimmune thyroiditis and mild sub- clinical hypothyroidism ( TSH MATERIAL AND METHODS A total of 196 patients with autoimmune thyroiditis were recruited in the study . Patients were assigned to receive ( case ) or not receive ( control ) an oral selenomethionine treatment . Cases received 83 mcg selenomethionine/day orally for four months . All the patient 's charts were su bmi tted to thyroid hormonal profile ( TSH , fT4 ) and TPOAb evaluation upon enrolment and at the end of the study . RESULTS In total 192 patients completed the study . Cases and controls were superimposable for age , gender , thyroid hormonal profile , and TPOAb levels . At the end of the study , 33/192 ( 17.2 % ) participants restored euthyroidism ( Responders ) . Responders were significantly more frequent among Cases than Controls ( 30/96 [ 31.3 % ] vs. 3/96 [ 3.1 % ] , p euthyroidism in one third of sub clinical hypothyroidism patients with autoimmune thyroiditis . ( Endokrynol Pol 2016 ; 67 ( 6 ) : 567 - 571 )",
"An antioxidant mixture ( LAROTABE ) was evaluated in the treatment of Graves disease . Fifty-six hyperthyroid patients were treated with methimazol ( MMI ) ( A ) , LAROTABE ( B ) , or MMI plus LAROTABE ( C ) . According to a clinical score , improvement was obtained at 8 weeks in A and 4 weeks in B and C. Group A diminished their thyroid hormone concentration to normal levels , while patients with LAROTABE did not reduce T3 and T4 unless MMI was introduced . Hyperthyroid patients had increased malondialdehyde ( MDA ) content and SOD activity and decreased catalase activity compared to controls . Within group A , MDA decreased to control values while SOD was reduced 38.3 % and catalase increased 21.6 % . Similar results were obtained for MDA and for both enzymes after treatment with LAROTABE . Signs and symptoms of Graves disease might be related to an increase in free radicals ; antioxidants could be a new therapeutic tool to improve the clinical manifestation of this illness",
"The aim of this prospect i ve study was to investigate for the first time whether levothyroxine and selenomethionine , administered alone or in combination , affect coagulation and fibrinolysis in Hashimoto 's thyroiditis patients with normal thyroid function tests . A group of 155 ambulatory women with recently diagnosed and previously untreated Hashimoto 's thyroiditis , of whom 149 completed the study , were r and omly assigned in a double-blind fashion to six months of treatment with levothyroxine , selenomethionine , levothyroxine plus selenomethionine , or placebo . The control group included 39 matched healthy women . The prothrombin time ratio , the activated partial thromboplastin time , and plasma levels/activities of fibrinogen , factor VII , von Willebr and factor , factor X and plasminogen activator inhibitor-1 ( PAI-1 ) were assessed at baseline and after three and six months of treatment . Compared with the healthy subjects , Hashimoto 's thyroiditis patients exhibited higher plasma levels/activities of all of the parameters studied , as well as were characterised by the abnormal prothrombin time ratio and activated partial thromboplastin time . All these haemostatic disturbances were reduced or normalised by levothyroxine + selenomethionine treatment , while the effect of levothyroxine or selenomethionine was limited to fibrinogen and PAI-1 , respectively . Our results demonstrate that euthyroid women with Hashimoto 's thyroiditis are characterised by abnormal coagulation and fibrinolysis . Levothyroxine and selenomethionine , especially if administered together , produce a beneficial effect on haemostasis in euthyroid patients with this disorder",
"CONTEXT No previous study determined monocyte- and lymphocyte-suppressing effects of levothyroxine and selenomethionine and assessed whether their coadministration is superior to treatment with only one of these drugs . OBJECTIVE Our objective was to compare the effect of levothyroxine and selenomethionine on monocyte and lymphocyte cytokine release and systemic inflammation in patients with Hashimoto 's thyroiditis . DESIGN , SETTING , PARTICIPANTS , AND INTERVENTION We conducted a r and omized clinical trial involving a group of 170 ambulatory euthyroid women with recently diagnosed and previously untreated Hashimoto 's thyroiditis and 41 matched healthy subjects . Participants were r and omized in a double-blind fashion to receive a 6-month treatment with levothyroxine , selenomethionine , levothyroxine plus selenomethionine , or placebo . One hundred sixty-five patients completed the study . MAIN OUTCOME MEASURES Monocyte and lymphocyte release of proinflammatory cytokines and plasma levels of C-reactive protein ( CRP ) were assessed . RESULTS Compared with the control subjects , monocytes and lymphocytes of Hashimoto 's thyroiditis patients released greater amounts of all cytokines studied . Levothyroxine reduced monocyte release of TNF-α , IL-1β , IL-6 , and monocyte chemoattractant protein-1 , whereas selenomethionine inhibited lymphocyte release of IL-2 , interferon-γ , and TNF-α , which was accompanied by a reduction in plasma CRP levels . The decrease in cytokine release and in plasma CRP levels was strongest when both drugs were given together . CONCLUSIONS Despite affecting different types of inflammatory cells , levothyroxine and selenomethionine exhibit a similar systemic antiinflammatory effect in euthyroid females with Hashimoto 's thyroiditis . This action , which correlates with a reduction in thyroid peroxidase antibody titers , may be associated with clinical benefits in the prevention and management of Hashimoto 's thyroiditis , particularly in subjects receiving both agents",
"Background : In Graves ' thyrotoxicosis tachycardia , weight loss and mental symptoms are common . Recovery takes time and varies between patients . Treatment with methimazole reduces thyroid hormone levels . According to previous research , this reduction has been faster if selenium ( Se ) is added . Objective : The objective was to investigate whether supplementing the pharmacologic treatment with Se could change the immune mechanisms , hormone levels and /or depression and anxiety . Methods : We prospect ively investigated 38 patients with initially untreated thyrotoxicosis by measuring the thyroid-stimulating hormone ( TSH ) , free thyroxine ( FT4 ) , free triiodothyronine ( FT3 ) , thyroid receptor antibodies and thyroid peroxidase auto-antibodies before medication and at 6 , 18 and 36 weeks after commencing treatment with methimazole and levo-thyroxine , with a r and omized blinded oral administration of 200 µg Se/day or placebo . The selenoprotein P concentration was determined in plasma at inclusion and after 36 weeks . The patients were also assessed with question naires about depression , anxiety and self-rated symptoms before medication was started and after 36 weeks . Results : FT4 decreased more in the Se group at 18 weeks ( 14 vs. 17 pmol/l compared to the placebo group , p = 0.01 ) and also at 36 weeks ( 15 vs. 18 pmol/l , p = 0.01 ) . The TSH increased more in the Se group at 18 weeks ( 0.05 vs. 0.02 mIU/l , p = 0.04 ) . The depression and anxiety scores were similar in both groups . In the Se group , the depression rates correlated negatively with FT3 and positively with TSH . This was not seen in the placebo group . Conclusions : Se supplementation can enhance biochemical restoration of hyperthyroidism , but whether this could shorten clinical symptoms of thyrotoxicosis and reduce mental symptoms must be investigated further"
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OBJECTIVE The aim of this meta- analysis was to determine the psychological impact associated with motor vehicle crash (MVC)-related physical injuries . DESIGN Systematic review and meta- analysis . DATA SOURCES Multiple search engines included MEDLINE ( via OVID ) , PsycINFO and Embase , and studies were source d from scientific journals , conference papers and doctoral theses . STUDY SELECTION A high-yield search strategy was employed . Terms like ' psychological distress ' , ' depression ' , ' PTSD ' and ' motor vehicle accident ' were employed . These key words were run primarily and secondary search es were then conducted in association with the major injury types . Studies needed to compare psychological distress in people injured in an MVC with uninjured controls who had not recently experienced an MVC . DATA EXTRACTION Search es result ed in the identification of 2537 articles , and after eliminating duplicates and studies not meeting inclusion criteria , 24 studies were selected involving 4502 injured participants . These studies were entered into separate meta-analyses for mild to moderate traumatic brain injury ( mTBI ) , whiplash-associated disorder ( WAD ) and spinal cord injury ( SCI ) . RESULTS Elevated psychological distress was associated with MVC-related injuries with a large summary effect size in WAD ( 0.90 ) , medium to large effect size in SCI ( 0.69 ) and small to medium effect size in mTBI ( 0.23 ) . No studies meeting inclusion criteria were found for burns , fractures and low back injury . Increased psychological distress remains elevated in SCI , mTBI and WAD for at least 3 years post-MVC . CONCLUSIONS Rehabilitation strategies are needed to minimise distress subsequent to MVC-related physical injuries and the scientific robustness of studies requires improvement
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"To investigate the frequency and risk factors of major depressive disorder ( MDD ) after mild to moderate traumatic brain injury ( TBI ) , 69 TBI and 52 general trauma ( GT ) patients were prospect ively recruited and studied at 3-months postinjury . There was a nonsignificant difference in the proportion of MDD patients in the TBI and GT groups . Therefore , a composite MDD group ( TBI and GT patients ) was compared to patients who were nondepressed . Female gender was related to MDD , but no other risk factors were identified . MDD was associated with disability ( Glasgow Outcome Scale , Community Integration Question naire ) and cognitive impairment . MDD was comorbid with posttraumatic stress disorder . Implication s for postacute management of mild to moderate TBI are discussed",
"OBJECTIVE To conduct a prospect i ve study of the occurrence of psychological disorders and comorbidities after spinal cord injury ( SCI ) , determine psychotropic medication usage , and establish predictors of psychological disorders after transition to the community . DESIGN Longitudinal design with multiple measures . SETTING Assessment occurred in SCI units and the community . PARTICIPANTS Adults with SCI ( N=88 ) admitted over a period of 32 months into 3 SCI units . INTERVENTIONS Participants completed inpatient rehabilitation for an acute SCI . Longitudinal assessment occurred up to 6 months postdischarge . MAIN OUTCOME MEASURES Measures were chosen that had a theoretical and clinical foundation for contributing to recovery after SCI . The Mini International Neuropsychiatric Interview , a structured diagnostic psychiatric interview , was conducted to determine the presence of psychological disorders . Medical measures included severity of secondary conditions or complications . Psychological measures included measures of anxiety and depressive mood , resilience , pain catastrophization , self-efficacy , and cognitive capacity . RESULTS Rates of psychological disorders of 17 % to 25 % were substantially higher than rates found in the Australian community . The occurrence of psychological disorder comorbidities was also very high . Anxiety was significantly elevated in those with a psychological disorder . Psychotropic medications were prescribed to more than 36 % of the sample , with most being antidepressants . Factors predictive of psychological disorders included years of education , premorbid psychiatric/psychological treatment , cognitive impairment , secondary complications , resilience , and anxiety . CONCLUSIONS SCI can have a substantial negative impact on mental health that does not change up to 6 months postdischarge . Findings suggest a substantial minority experience increased psychosocial distress after the injury and after transitioning into the community . Additional re sources should be invested in improving the mental health of adults with SCI",
"Background There is considerable evidence showing that injured people who are involved in a compensation process show poorer physical and mental recovery than those with similar injuries who are not involved in a compensation process . One explanation for this reduced recovery is that the legal process and the associated retraumatization are very stressful for the cl aim ant . The aim of this study was to empower injured cl aim ants in order to facilitate recovery . Methods Participants were recruited by three Dutch cl aims settlement offices . The participants had all been injured in a traffic crash and were involved in a compensation process . The study design was a r and omized controlled trial . An intervention website was developed with ( 1 ) information about the compensation process , and ( 2 ) an evidence -based , therapist-assisted problem-solving course . The control website contained a few links to already existing websites . Outcome measures were empowerment , self-efficacy , health status ( including depression , anxiety , and somatic symptoms ) , perceived fairness , ability to work , cl aims knowledge and extent of burden . The outcomes were self-reported through online question naires and were measured four times : at baseline , and at 3 , 6 , and 12 months . Results In total , 176 participants completed the baseline question naire after which they were r and omized into either the intervention group ( n = 88 ) or the control group ( n = 88 ) . During the study , 35 participants ( 20 % ) dropped out . The intervention website was used by 55 participants ( 63 % ) . The health outcomes of the intervention group were no different to those of the control group . However , the intervention group considered the received compensation to be fairer ( P injured cl aim ants in compensation processes , it increased the perceived fairness of the compensation amount . Trial registration Netherl and s Trial Register",
"OBJECTIVE To compare differences in functional outcomes between urban and rural patients with traumatic brain injury ( TBI ) . DESIGN A longitudinal , prospect i ve , multicentre study of a 2-year cohort from the Brain Injury Rehabilitation Program ( BIRP ) for New South Wales , with follow-up at 18 months after injury . PARTICIPANTS 198 patients ( 147 urban , 51 rural ) with severe TBI from the 11 participating rehabilitation units . MAIN OUTCOME MEASURES Demographic and injury details collected prospect ively using a st and ardised question naire , and measures from five vali date d instruments ( Disability Rating Scale , Mayo-Portl and Adaptability Inventory , Sydney Psychosocial Reintegration Scale , Medical Outcomes Study Short Form and the General Health Question naire--28-item version ) administered at follow-up to document functional , psychosocial , emotional and vocational outcomes . RESULTS Demographic details , injury severity , lengths of stay in intensive and acute care wards were similar for both rural and urban groups . There were no significant group differences in functional outcomes , including return to work , at follow-up . CONCLUSIONS Our findings contrast with previous research that has reported poorer outcomes after TBI for rural residents , and suggest that the integrated network of inpatient , outpatient and outreach services provided throughout NSW through the BIRP provides effective rehabilitation for people with severe TBI regardless of where they live",
"& NA ; Psychological distress is a feature of chronic whiplash‐associated disorders , but little is known of psychological changes from soon after injury to either recovery or symptom persistence . This study prospect ively measured psychological distress ( General Health Question naire 28 , GHQ‐28 ) , fear of movement/re‐injury ( TAMPA Scale of Kinesphobia , TSK ) , acute post‐traumatic stress ( Impact of Events Scale , IES ) and general health and well being ( Short Form 36 , SF‐36 ) in 76 whiplash subjects within 1 month of injury and then 2 , 3 and 6 months post‐injury . Subjects were classified at 6 months post‐injury using scores on the Neck Disability Index : recovered ( 30 ) . All whiplash groups demonstrated psychological distress ( GHQ‐28 , SF‐36 ) to some extent at 1 month post‐injury . Scores of the recovered group and those with persistent mild symptoms returned to levels regarded as normal by 2 months post‐injury , parallelling a decrease in reported pain and disability . Scores on both these tests remained above threshold levels in those with ongoing moderate/severe symptoms . The moderate/severe and mild groups showed elevated TSK scores at 1 month post‐injury . TSK scores decreased by 2 months in the group with residual mild symptoms and by 6 months in those with persistent moderate/severe symptoms . Elevated IES scores , indicative of a moderate post‐traumatic stress reaction , were unique to the group with moderate/severe symptoms . The results of this study demonstrated that all those experiencing whiplash injury display initial psychological distress that decreased in those whose symptoms subside . Whiplash participants who reported persistent moderate/severe symptoms at 6 months continue to be psychologically distressed and are also characterised by a moderate post‐traumatic stress reaction",
"Abstract Dysregulations of the hypothalamus – pituitary – adrenal ( HPA ) axis have been discussed as a physiological substrate of chronic pain and fatigue . The aim of the study was to investigate possible dysregulations of the HPA axis in chronic whiplash‐associated disorder ( WAD ) . In 20 patients with chronic WAD and 20 healthy controls , awakening cortisol responses as well as a short circadian free cortisol profile were assessed before and after administration of 0.5 mg dexamethasone . In comparison to the controls , chronic WAD patients had attenuated cortisol responses to awakening , normal cortisol levels during the day , and showed enhanced and prolonged suppression of cortisol after the administration of 0.5 mg dexamethasone . Dysregulations of the HPA axis in terms of reduced reactivity and enhanced negative feedback suppression exist in chronic WAD . The observed endocrine abnormalities could serve as a systemic mechanism of symptoms experienced by chronic WAD patients",
"The question as to whether mild traumatic brain injury ( mTBI ) results in persisting sequelae over and above those experienced by individuals sustaining general trauma remains controversial . This prospect i ve study aim ed to document outcomes 1 week and 3 months post-injury following mTBI assessed in the emergency department ( ED ) of a major adult trauma center . One hundred and twenty-three patients presenting with uncomplicated mTBI and 100 matched trauma controls completed measures of post-concussive symptoms and cognitive performance ( Immediate Post-Concussion Assessment and Cognitive Testing battery ; ImPACT ) and pre-injury health-related quality of life ( SF-36 ) in the ED . These measures together with measures of psychiatric status ( the Mini-International Neuropsychiatric Interview [ MINI ] ) pre- and post-injury , the Hospital Anxiety and Depression Scale , Visual Analogue Scale for Pain , Functional Assessment Question naire , and PTSD Checklist-Specific , were re-administered at follow-up . Participants with mTBI showed significantly more severe post-concussive symptoms in the ED and at 1 week post-injury . They performed more poorly than controls on the Visual Memory subtest of the ImPACT at 1 week and 3 months post-injury . Both the mTBI and control groups recovered well physically , and most were employed 3 months post-injury . There were no significant group differences in psychiatric function . However , the group with mild TBI was more likely to report ongoing memory and concentration problems in daily activities . Further investigation of factors associated with these ongoing problems is warranted",
"OBJECTIVE To conduct a descriptive study investigating the effect of access to motor vehicle accident ( MVA ) compensation on recovery outcomes at 24 months after injury . DESIGN AND SETTING Longitudinal cohort study conducted in two Level 1 trauma hospitals in Victoria , Australia . Participants were 391 r and omly selected injury patients with moderate-to-severe injuries . Compensable and non-compensable patients were compared at 24 months after injury on a number of health outcomes . MAIN OUTCOME MEASURES Health outcomes at 24 months , including anxiety and depression severity , quality of life and disability . RESULTS Medical records identified two groups of compensation patients : MVA-compensable and non-compensable patients . After controlling for baseline variables , the MVA-compensable patients , at 24 months , had higher levels of post-traumatic stress disorder , anxiety and depression , and were less likely to have returned to their pre-injury number of work hours . However , some patients in the non-compensable group had accessed other forms of compensation ( eg , private health care or compensation for victims of crime ) . When these were removed from the non-compensable group , the differences between MVA-compensable and non-compensable groups all but disappeared . CONCLUSION Our findings do not support previous research showing that access to compensation is associated with poor recovery outcomes . The relationship between access to compensation and health outcomes is complex , and more high-level research is required",
"PURPOSE To examine change in resilience in people with spinal cord injury ( SCI ) when group cognitive behavior therapy ( GCBT ) was added to routine psychosocial rehabilitation ( RPR ) . RESEARCH METHOD / DESIGN A prospect i ve repeated- measures cohort design was used to determine the efficacy of the addition of GCBT ( n = 50 ) . The control group consisted of individuals receiving RPR , which included access to individual CBT ( ICBT ) when required ( n = 38 ) . Groups were assessed on 3 occasions : soon after admission , within 2 weeks of discharge , and 6-months postdischarge . Measures included sociodemographic , injury , and psychosocial factors . The outcome variable was resilience , considered an important outcome measure for recovery . To adjust for baseline differences in self-efficacy , depressive mood and anxiety between the 2 groups , these factors were entered into a repeated measures multivariate analysis of covariance ( MANCOVA ) as covariates . Latent class analysis was used to determine the best-fitting model of resilience trajectories for both groups . RESULTS The MANCOVA indicated that the addition of GCBT to psychosocial rehabilitation did not result in improved resilience compared with the ICBT group . Trajectory data indicated over 60 % were demonstrating acceptable resilience irrespective of group . CONCLUSION / IMPLICATION S Changes in resilience mean scores suggest the addition of GCBT adds little to resilience outcomes . Latent class modeling indicated both groups experienced similar trajectories of improvement and deterioration . Results highlight the importance of conducting multivariate modeling analysis that isolates subgroups of related cases over time to underst and complex trajectories . Further research is needed to clarify individual differences in CBT intervention preference as well as other factors which impact on resilience",
"Importance : Each year , millions of persons worldwide seek compensation for transport accident and workplace injuries . Previous research suggests that these cl aim ants have worse long-term health outcomes than persons whose injuries fall outside compensation schemes . However , existing studies have substantial method ological weaknesses and have not identified which aspects of the cl aim ing experience may drive these effects . Objective : To determine aspects of cl aims processes that cl aim ants to transport accident and workers ’ compensation schemes find stressful and whether such stressful experiences are associated with poorer long-term recovery . Design , Setting , and Participants : Prospect i ve cohort study of a r and om sample of 1010 patients hospitalized in 3 Australian states for injuries from 2004 through 2006 . At 6-year follow-up , we interviewed 332 participants who had cl aim ed compensation from transport accident and workers ’ compensation schemes ( “ cl aim ants � ? ) to determine which aspects of the cl aim ing experience they found stressful . We used multivariable regression analysis to test for associations between compensation-related stress and health status at 6 years , adjusting for baseline determinants of long-term health status and predisposition to stressful experiences ( via propensity scores ) . Main Outcomes and Measures : Disability , quality of life , anxiety , and depression . Results : Among cl aim ants , 33.9 % reported high levels of stress associated with underst and ing what they needed to do for their cl aim ; 30.4 % , with cl aim delays ; 26.9 % , with the number of medical assessment s ; and 26.1 % , with the amount of compensation they received . Six years after their injury , cl aim ants who reported high levels of stress had significantly higher levels of disability ( 6.94 points , World Health Organization Disability Assessment Schedule sum score ) , anxiety and depression ( 1.89 points and 2.61 points , respectively , Hospital Anxiety and Depression Scale ) , and lower quality of life ( -0.73 points , World Health Organization Quality of Life instrument , overall item ) , compared with other cl aim ants . Adjusting for cl aim ants ’ vulnerability to stress attenuated the strength of these associations , but most remained strong and statistically significant . Conclusions and Relevance : Many cl aim ants experience high levels of stress from engaging with injury compensation schemes , and this experience is positively correlated with poor long-term recovery . Intervening early to boost resilience among those at risk of stressful cl aims experiences and re design ing compensation processes to reduce their stressfulness may improve recovery and save money",
"OBJECTIVE To determine the incidence , course , and prognosis of adult mild traumatic brain injury ( MTBI ) caused by motor vehicle collisions . DESIGN Prospect i ve , population -based , inception cohort study . SETTING The province of Saskatchewan , Canada , with a population of about 1,000,000 inhabitants . PARTICIPANTS All adults ( N=1716 ) incurring an MTBI in a motor vehicle collision between November 1997 and December 1999 in Saskatchewan . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Age- and sex-stratified incidence rates , time to self-reported recovery , and prognostic factors over a 1-year follow-up . RESULTS Of 7170 adults injured in a motor vehicle collision over the 2-year inception period , 1716 ( 24 % ) met our cohort definition of MTBI . There were more women affected ( 53 % ) , and MTBI was most common in the 18- to 23-year-old group . Most were not hospitalized ( 73 % ) , but 28 % reported loss of consciousness and 23 % reported posttraumatic amnesia . The annual incidence of MTBI per 100,000 adults was 106.1 ( 95 % confidence interval [ CI ] , 98.9 - 113.6 ) in the first year and 118.3 ( 95 % CI , 110.8 - 126.3 ) in the second year of the study . The 1-year follow-up rate was 84 % . The median time to recovery was 100 days ( 95 % CI , 97 - 103 ) , and about 23 % reported not having recovered by 1 year . Factors associated with delayed recovery included being older than 50 years , having less than a high school education , having poor expectations for recovery , having depressive symptoms , having arm numbness , having hearing problems , having headaches , having low back pain , and having thoracic back pain . Loss of consciousness and posttraumatic amnesia were not associated with recovery . CONCLUSIONS MTBI affects almost a quarter of persons reporting an injury after a traffic collision . The median time to recovery is 100 days , but 23 % have still not recovered by 1 year . A mix of biopsychosocial factors is associated with recovery , including a strong effect of poor expectations for recovery",
"OBJECTIVE To compare the early health status of people who sustained injuries during road traffic crashes ( RTC ) in which they were at fault ( AF ) , with people who sustained injuries in RTC in which they were not at fault ( NAF ) . DESIGN Prospect i ve cohort study . SUBJECTS People presenting to the emergency department with mild to moderate musculoskeletal injuries following RTC . MAIN OUTCOME MEASURES Physical Component Score ( PCS ) and Mental Component Score ( MCS ) of the Short Form 36 ( SF-36 ) health status measure ; Hospital Anxiety and Depression Scale ( HADS ) and the Functional Rating Index ( FRI ) recorded immediately post-crash . RESULTS 193 people participated in the study and were enrolled a mean of 9.3 days following the crash . The mean age was 37 years and 60 % were female . 71 % were NAF . There was a significantly higher number of females in the NAF group ( 65 % compared with 35 % males ; p Neck and back injuries were reported by 90.4 % of the NAF group compared to 69.1 % of the AF group ( p PCS , FRI or pain intensity between the two groups at a mean of 9.3 days after the crash . The mean MCS for the NAF group was significantly worse than for the AF group ( 31.4 compared to 37.3 ; p = 0.005 ) . The SF-36 domain revealed a significantly worse adjusted mean role emotional score for the NAF group ( 23.4 compared to 32.5 , p = 0.002 ) . Females had significantly worse MCS score than males ( 30.6 and 38.1 respectively ; p mean anxiety and depression scores ( 10 compared to 7.8 ; p = 0.002 and 7.6 compared to 5.5 ; p = 0.002 respectively ) . CONCLUSIONS Despite there being no difference in physical health status , the NAF group demonstrated more emotional and mental disturbance than the AF group ; and this was significantly worse for females . Treatment strategies should focus on addressing early pain and disability as well as providing appropriate psychological interventions , particularly for people not at fault following RTC",
"OBJECTIVES Spinal cord injury ( SCI ) is a catastrophic event that may result in diminished physical , social , and mental health . The main objective of this research was to establish inpatient factors that contribute to social participation following discharge into the community . DESIGN Prospect i ve longitudinal design with measures taken three times , soon after admission to rehabilitation ( N = 88 ) , at discharge from the inpatient phase ( N = 81 ) and 6 months following discharge ( N = 71 ) . METHODS Participants included adults with SCI admitted into three SCI units over a 33-month period . Assessment included demographic , injury , and psychosocial health measures . Adjustment was defined by the extent of social re-integration or participation post-discharge after 6 months in the community . Social participation was measured by the Impact on Participation and Autonomy Question naire ( IPAQ ) . Logistic regression models were used to establish inpatient factors that significantly predicted social participation 6 months post-discharge . RESULTS Six months after discharge , around 55 % of the sample had difficulties with social participation . The odds against being employed for an adult with poor social participation was found to be 8.4 to 1 . Factors that predicted social participation included a younger age , having less severe secondary medical complications like bladder and bowel dysfunction , having a higher cognitive capacity , perceiving one has control ( self-efficacy ) over one 's life and environment , and having greater perceived social support . CONCLUSIONS These results provide direction for enhancing existing psychosocial health strategies within SCI rehabilitation , affording an opportunity for every person who sustains a permanent SCI to have optimal capacity for social participation . Statement of contribution What is already known on this subject ? Spinal cord injury ( SCI ) is associated with significant challenges to wellbeing , including a high risk of secondary chronic illnesses , risk of co-morbid mental health problems , financial insecurity and social isolation . Research has shown poor social participation can lead to problems in re-integration into society following discharge from inpatient rehabilitation . Research to date has examined various factors related to poor social participation , but the majority of this research has been survey based with convenience sample s. What does this study add ? This study adds results of prospect i ve longitudinal research on adjustment following SCI , where adjustment was defined by the rate of social participation when living in the community . About one-third of SCI participants were found to have very poor social participation , and only one-third had found some form of employment 6 months after discharge . Multiple factors were found to predict and contribute to poor social participation , including older age when injured , more severe medical complications , cognitive deficits , poor perceptions of control or self-efficacy , and poor social support",
"& NA ; This study evaluated the course of psychological variables during a 2‐year follow‐up in patients after common whiplash of the cervical spine . From a sample of 117 non‐selected patients with common whiplash ( investigated on average 7.2 ± 4.2 days after trauma ) a total of 21 suffered trauma‐related symptoms over 2 years following initial injury . These patients ( symptomatic group ) were compared with 21 age , gender and education pair‐matched patients , who showed complete recovery from trauma‐related symptoms during the 2‐year follow‐up ( asymptomatic group ) . Both groups underwent st and ardised testing procedures ( i.e. , Freiburg Personality Inventory and Well‐Being Scale ) at referal , and at 3 , 6 and 24 months . In the symptomatic group during follow‐up no significant changes in ratings of neck pain or headache were found . Significant differences between the groups and significant deviation of scores over time were found on the Well‐Being and Nervousness Scales . There was a lack of significant difference between the groups on the Depression Scale , indicating a possible somatic basis for changes in psychological functioning in the investigated sample . With regard to scales of Extraversion or Neuroticism , there were neither significant differences between the groups nor significant deviation over time . These results highlight that patients ' psychological problems are rather a consequence than a cause ; of somatic symptoms in whiplash",
"OBJECTIVE To identify the frequency and manifestations of depression after traumatic brain injury ( TBI ) and the factors that contribute to developing this mood disorder . DESIGN A prospect i ve , nationwide , multicenter study ; 17 centers supplied data from medical records and patient responses on a st and ardized criterion instrument . SETTING Traumatic Brain Injury Model Systems programs . PARTICIPANTS A demographically diverse sample of 666 out patients with TBI was evaluated 10 to 126 months after injury . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Depressive symptoms were characterized with the Neurobehavioral Functioning Inventory by using the Diagnostic and Statistical Manual of Mental Disorders ( 4th ed ; DSM-IV ) diagnostic framework . Analysis of variance and Pearson correlations were used to identify factors that were significantly related to depression . RESULTS Fatigue ( 29 % ) , distractibility ( 28 % ) , anger or irritability ( 28 % ) , and rumination ( 25 % ) were the most commonly cited depressive symptoms in the sample . Twenty-seven percent of patients with TBI met the prerequisite number ( > /=5 ) of criterion A symptoms for a DSM-IV diagnosis of major depressive disorder . Feeling hopeless , feeling worthless , and difficulty enjoying activities were the 3 symptoms that most differentiated depressed from nondepressed patients . Patients who were unemployed at the time of injury and who were impoverished were significantly more likely to report DSM-IV criterion A symptoms than patients who were employed , were students , or were retired due to age . Time after injury , injury severity , and postinjury marital status were not significantly related to depression . CONCLUSIONS Patients with TBI are at great risk for developing depressive symptoms . Findings provide empirical support for the inclusion of depression evaluation and treatment protocol s in brain injury programs . Unemployment and poverty may be substantial risk factors for the development of depressive symptoms . Future research should develop biopsychosocial predictive models to identify high-risk patients and examine the efficacy of treatment interventions",
"IMPORTANCE Delayed-onset posttraumatic stress disorder ( PTSD ) accounts for approximately 25 % of PTSD cases . Current models do not adequately explain the delayed increases in PTSD symptoms after trauma exposure . OBJECTIVE To test the roles of initial psychiatric reactions , mild traumatic brain injury ( MTBI ) , and ongoing stressors on delayed-onset PTSD . DESIGN , SETTING , AND PARTICIPANTS In this prospect i ve cohort study , patients were selected from recent admissions to 4 major trauma hospitals across Australia . A total of 1084 traumatically injured patients were assessed during hospital admission from April 1 , 2004 , through February 28 , 2006 , and 785 ( 72.4 % ) were followed up at 3 , 12 , and 24 months after injury . MAIN OUTCOME AND MEASURE Severity of PTSD was determined at each assessment with the Clinician-Administered PTSD Scale . RESULTS Of those who met PTSD criteria at 24 months , 44.1 % reported no PTSD at 3 months and 55.9 % had subsyndromal or full PTSD . In those who displayed subsyndromal or full PTSD at 3 months , PTSD severity at 24 months was predicted by prior psychiatric disorder , initial PTSD symptom severity , and type of injury . In those who displayed no PTSD at 3 months , PTSD severity at 24 months was predicted by initial PTSD symptom severity , MTBI , length of hospitalization , and the number of stressful events experienced between 3 and 24 months . CONCLUSIONS AND RELEVANCE These data highlight the complex trajectories of PTSD symptoms over time . This study also points to the roles of ongoing stress and MTBI in delayed cases of PTSD and suggests the potential of ongoing stress to compound initial stress reactions and lead to a delayed increase in PTSD symptom severity . This study also provides initial evidence that MTBI increases the risk of delayed PTSD symptoms , particularly in those with no acute symptoms",
"OBJECTIVE Traumatic injury affects millions of people each year . There is little underst and ing of the extent of psychiatric illness that develops after traumatic injury or of the impact of mild traumatic brain injury ( TBI ) on psychiatric illness . The authors sought to determine the range of new psychiatric disorders occurring after traumatic injury and the influence of mild TBI on psychiatric status . METHOD In this prospect i ve cohort study , patients were drawn from recent admissions to four major trauma hospitals across Australia . A total of 1,084 traumatically injured patients were initially assessed during hospital admission and followed up 3 months ( N=932 , 86 % ) and 12 months ( N=817 , 75 % ) after injury . Lifetime psychiatric diagnoses were assessed in hospital . The prevalence of psychiatric disorders , levels of quality of life , and mental health service use were assessed at the follow-ups . The main outcome measures were 3- and 12-month prevalence of axis I psychiatric disorders , levels of quality of life , and mental health service use and lifetime axis I psychiatric disorders . RESULTS Twelve months after injury , 31 % of patients reported a psychiatric disorder , and 22 % developed a psychiatric disorder that they had never experienced before . The most common new psychiatric disorders were depression ( 9 % ) , generalized anxiety disorder ( 9 % ) , posttraumatic stress disorder ( 6 % ) , and agoraphobia ( 6 % ) . Patients were more likely to develop posttraumatic stress disorder ( odds ratio=1.92 , 95 % CI=1.08 - 3.40 ) , panic disorder ( odds ratio=2.01 , 95 % CI=1.03 - 4.14 ) , social phobia ( odds ratio=2.07 , 95 % CI=1.03 - 4.16 ) , and agoraphobia ( odds ratio=1.94 , 95 % CI=1.11 - 3.39 ) if they had sustained a mild TBI . Functional impairment , rather than mild TBI , was associated with psychiatric illness . CONCLUSIONS A significant range of psychiatric disorders occur after traumatic injury . The identification and treatment of a range of psychiatric disorders are important for optimal adaptation after traumatic injury",
"Objective . To compare health status , effect on family , occupational consequences , and quality of life ( QOL ) 1 year after an accident between patients with whiplash versus other mild injuries , and to explore the relationship between initial injury ( whiplash vs other ) and QOL . Methods . This was a prospect i ve cohort study . The study used data from the ESPARR cohort ( a representative cohort of road accident victims ) and included 173 individuals with “ pure ” whiplash and 207 with other mild injuries . QOL at 1-year followup was assessed on the World Health Organization Quality of Life question naire . Correlations between explanatory variables and QOL were explored by Poisson regression to provide adjusted relative risks , with ANOVA for the various QOL scores explored . Results . One year post-accident , more patients who had whiplash than other casualties complained of nonrecovery of health status ( 56 % vs 43 % ) and of the occupational effect of pain ( 31 % vs 23 % ) . QOL and posttraumatic stress disorder ( PTSD ) were similar in the 2 groups . Impaired QOL did not correlate with whiplash when models were adjusted on sociodemographic variables and history of psychological distress . Whatever the initial lesion , PTSD was a determining factor for poorer QOL . Conclusion . Sociodemographic factors , preaccident psychological history prior to the accident , and PTSD were the main factors influencing QOL , rather than whether the injury was whiplash . PTSD may also be related to pain"
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Aims Despite widespread adoption of contact force ( CF ) sensing technology in atrial fibrillation ( AF ) ablation , r and omized data suggests lack of improvement in clinical outcomes . We aim ed to assess the safety and efficacy of CF-guided vs. non CF-guided AF ablation . Methods and results Electronic data bases were search ed for r and omized controlled trials ( RCTs ) and controlled observational studies ( OS ) comparing outcomes of AF ablation performed with vs. without CF guidance . The primary efficacy endpoint was freedom from AF at follow-up . The primary safety endpoint was major peri-procedural complications . Secondary endpoints included procedural , fluoroscopy , and ablation duration . Subgroup analyses were performed by AF type and study design . Nine RCTs ( n = 903 ) and 26 OS ( n = 8919 ) were included . Overall , CF guidance was associated with improved freedom from AF [ relative risk ( RR ) 1.10 ; 95 % confidence interval ( CI ) 1.02 - 1.18 ] , and reduced total procedure duration [ mean difference ( MD ) 15.33 min ; 95 % CI 6.98 - 23.68 ] , ablation duration ( MD 3.07 min ; 95 % CI 0.29 - 5.84 ) , and fluoroscopy duration ( MD 5.72 min ; 95 % CI 2.51 - 8.92 ) . When restricted to RCTs however , CF guidance neither improved freedom from AF ( RR 1.03 ; 95 % CI 0.95 - 1.11 ) , independent of AF type , nor did it reduce procedural , fluoroscopy , or ablation duration . Contact force guidance did not reduce the incidence of major peri-procedural complications ( RR 0.89 ; 95 % CI 0.64 - 1.24 ) . Conclusion Meta- analysis of r and omized data demonstrated that CF guidance does not improve the safety or efficacy of AF ablation , despite initial observational data showing dramatic improvement . Rigorous evaluation in r and omized trials is needed before widespread adoption of new technologies
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"Introduction Pulmonary vein isolation ( PVI ) is an effective therapy for paroxysmal atrial fibrillation ( AF ) , but it has limitations . The two most significant recent advances have centred on the integration of real-time quantitative assessment of catheter contact force into focal radio frequency ( RF ) ablation catheters and the development of dedicated ablation tools capable of achieving PVI with a single ablation lesion ( A rct ic Front cryoballoon , Medtronic , Minneapolis , MN , USA ) . Although each of these holds promise for improving the clinical success of catheter ablation of AF , there has not been a rigorous comparison of these advanced ablation technologies . Moreover , the optimal duration of cryoablation ( freezing time ) has not been determined . Methods and analysis Patients undergoing an initial PVI procedure for paroxysmal AF will be recruited . Patients will be r and omised 1:1:1 between contact-force irrigated RF ablation , short duration cryoballoon ablation ( 2 min applications ) and st and ard duration cryoballoon ablation ( 4 min applications ) . The primary outcome is time to first documented AF recurrence on implantable loop recorder . With a sample size of 111 per group and a two-sided 0.025 significance level ( to account for the two main comparisons ) , the study will have 80 % power ( using a log-rank test ) to detect a difference of 20 % between contact force RF catheter ablation and either of the two cryoballoon ablation groups . Factoring in a 4 % loss to follow-up , 116 patients per group should be r and omised and followed for a year ( total study population of 348 ) . Ethics and dissemination The study was approved by the University of British Columbia Office of Research ( Services ) Ethics Clinical Research Ethics Board . Results of the study will be su bmi tted for publication in a peer- review ed journal . Trial registration number NCT01913522 ; Pre-",
"Aims Contact force ( CF ) catheters provide catheter-tissue contact information to improve outcome of pulmonary vein isolation ( PVI ) in paroxysmal atrial fibrillation ( PAF ) . We evaluated different target-CF values for achievement of the additional endpoint of an unexcitable ablation line . Methods A total of 106 patients undergoing PVI were r and omized into three groups ( G ) ( G1 : target-CF 15 g , G2 : target-CF 10 g , G3 : CF concealed from operator ) . The PVI encircling line was divided into predefined sections . Excitable tissue along the PVI-line identified by high output pacing ( 10 V , 2 ms ) was targeted for further ablation . Results Mean average CF was 17.4 ± 4.7 g ( G1 ) vs. 12.3 ± 6.0 g ( G2 ) vs. 11.1 ± 6.5 g ( G 3 ) ( p 0.001 ) . Primary unexcitable ablation lines were found in 38.6 , 19.4 and 5.7 % ( G1 , G2 , G3 respectively ; G1 vs. G2 p Additional radiofrequency (RF)-energy to achieve unexcitability was lowest in G1 ( 3.6 ± 3.1 kJ vs. 8.6 ± 7.2 kJ ( G2 ) and 10.4 ± 6.7 ( G3 ) , p ≤ 0.001 , G2 vs. G3 ns ) with accordingly lowest additional RF applications in G1 ( 3.0 ± 2.6 vs. 7.0 ± 5.4 in G2 and 8.4 ± 4.0 in G3 ; G1 vs. G2 and G3 , p . Single procedure success was 81.9 vs. 73.5 vs. 71.4 % ( G 1 , 2 and 3 , p = 0.6 ) during 437 ± 254 day follow-up . Conclusion Higher tip-to-tissue CF during PVI facilitates the achievement of an unexcitable ablation line , requiring less additional RF-energy",
"BACKGROUND Pulmonary vein isolation ( PVI ) is a well-established treatment of atrial fibrillation ( AF ) , with contact force (CF)-sensing catheters joining 3-dimensional mapping systems and image integration as technological advancements over the last decade . OBJECTIVE The purpose of this study was to analyze trends in radiation exposure for AF ablation over the last 12 years at our center . METHODS We review ed prospect ively collected data of 2344 consecutive PVI procedures for either paroxysmal or persistent AF between January 2004 and December 2015 . During this period , all cases used 3-dimensional mapping systems , with 8 software and 2 hardware up grade s. Primary endpoints were fluoroscopy time , absorbed dose ( Air Kerma in mGy ) , and effective dose ( mSv ) . RESULTS In total , 1914 patients underwent initial PVI , and 430 patients underwent redo PVI using radiofrequency energy . Fluoroscopy time , and absorbed and effective doses significantly and progressively decreased over the 12-year period for initial PVI as follows : 2004 - 2006 : 61 ± 27 minutes ; 2007 - 2009 : 46 ± 14 minutes , 1365 ± 1369 mGy , 11.3 ± 12.5 mSv ; 2010 - 2012 : 31 ± 11 , 464 ± 339 mGy , 9.0 ± 10.4 mSv ; and 2013 - 2015 : 17 ± 9 minutes , 304 ± 758 mGy , 5.5 ± 6.7 mSv . CF-sensing catheters were used for 357/508 PVI only cases between 2014 and 2015 . Fluoroscopy times ( 11 ± 5 vs 21 ± 8 minutes ; P and absorbed dose ( 200 ± 524 vs 470 ± 1326 mGy ; P = .004 ) were significantly shorter with this catheter . CONCLUSION Radiation exposure has dramatically decreased over the last decade for PVI and is related to operator experience , annual case volume , technology evolution , and more recently CF-sensing catheters . This has significant implication s for both patient and operator long-term risk",
"BACKGROUND Contact force ( CF ) information may improve the safety and efficacy of ablation for paroxysmal atrial fibrillation ( PAF ) . OBJECTIVE The purpose of this study was to assess the impact of CF data on ablation for PAF . METHODS Patients undergoing first-time PAF ablation were r and omized at 7 UK centers to ablation with ( CF-on ) or without ( CF-off ) CF data available to the operator , using the same ablation catheter and mapping system . An ablation CF of 5 - 40 g was targeted . Pulmonary vein ( PV ) reconnection was assessed with adenosine at 60 minutes . Follow-up for arrhythmia recurrence was for 1 year with 7-day Holter recordings at 6 and 12 months . RESULTS One hundred seventeen patients were studied ( 59 CF-on , 58 CF-off ) . In the CF-on group , a reduction in acute PV reconnection rates ( 22 % vs 32 % , P = .03 ) but no significant difference in 1-year success rates off antiarrhythmic drugs ( 49 % vs 52 % , P = .9 ) was observed . There was no difference in major complication rates : 2 of 59 ( 3 % ) CF-on , 3 of 58 ( 5 % ) CF-off ( P = .7 ) . Procedural and fluoroscopy times were not significantly different ( P>.5 ) . Overall mean CFs per ablation were not different between groups ( 13.4 [9.1 - 19.6]g CF-on , 13.4 [7.4 - 22.4]g CF-off , P = .5 ) , but a greater proportion of readings in the CF-on group were in the target range ( 80 % vs 68 % , P acute PV reconnection but not improved 1-year success rates , procedural and fluoroscopy times , or complication rates . There was a reduction in extremes of CF , above and below the study target range , suggesting greater CF control during ablation",
"BACKGROUND Contact force ( CF ) monitoring could be useful in accomplishing circumferential pulmonary vein ( PV ) isolation ( CPVI ) for atrial fibrillation ( AF ) . OBJECTIVE The purpose of this study was to compare procedure parameters and outcomes between CF-guided and non-guided CPVI . METHODS Thirty-eight consecutive AF patients ( mean age 60 ± 11 years , 28 paroxysmal AF ) undergoing CPVI were r and omized to non-CF-guided ( n = 19 ) and CF-guided ( n = 19 ) groups . CPVI was performed with the ThermoCool SmartTouch catheter in both groups . The end-point was bidirectional block between the left atrium ( LA ) and PV . In the CF group , CF was kept between 10 and 20 g during CPVI , whereas in the non-CF group , all CF information was blanked . Radiofrequency energy at 30 W in the anterior and 25 W in the posterior LA wall was applied for 20 - 25 seconds at each point . RESULTS CPVI was successfully accomplished without any major complications in both groups . Mean CF in the non-CF and CF groups were 5.9 ± 4.5 g and 11.1 ± 4.3 g , respectively , for left-side CPVI , and 9.8 ± 6.6 g and 12.1 ± 4.8 g , respectively , for right-side CPVI ( both P The procedure and fluoroscopy times for CPVI in the non-CF and CF groups were 96 ± 39 minutes and 59 ± 16 minutes , respectively ( P respectively . Total number of residual conduction gaps was 6.3 ± 3.0 in the non-CF group and 2.8 ± 1.9 in the CF group ( P free from any atrial tachyarrhythmias ( P = .34 ) . CONCLUSION CF-guided CPVI is effective in reducing procedure time and additional touch-up ablation and may improve long-term outcome ",
"Background The aim of this study was to evaluate the impact of contact force ( CF ) visualization on the incidence of low and high CF during left atrial ( LA ) mapping and pulmonary vein isolation ( PVI ) . Methods CF was assessed in 70 patients who underwent PVI . Three highly experienced operators performed all procedures . The operators were blinded to CF in group A ( 35 patients ) , and CF was displayed in group B ( 35 patients ) . In group B , optimal CF was defined as mean CF between 10 and 39 g , and operators attempted to acquire points and ablate within this range . Results A total of 8401 mapping points were analyzed during LA mapping ( group A : 4104 , group B : 4297 ) . Low CF , CF was significantly lower ( 7.7 vs. 12.2 g , P PVI was successfully achieved in all patients . There were significant site-dependent CF differences between the two groups . Optimal CF was achieved in significantly more applications in group B ( P in atrial fibrillation ( AF ) recurrence rates after a minimum follow-up of 1 year between the two groups in this cohort ( P = 0.24 ) . No significant peri-procedural complications occurred in either group . Conclusions CF visualization can assist in avoiding both low and high CF , which may have the potential to improve lesion formation and patient safety profile . In this study , CF-guided ablation did not affect AF recurrence",
"Purpose We prospect ively investigated the differences in pulmonary vein reconnections ( PVRs ) and clinical outcomes between contact force (CF)-guided and conventional circumferential PV isolation ( CPVI ) of atrial fibrillation ( AF ) . Methods One hundred twenty consecutive AF patients ( 63 ± 10 years ; 88 males ) undergoing an initial CPVI were r and omized to ablation with a target CF of 20 g ( CF group ; n = 60 ) or that with operators blinded to the CF information ( blind group ; n = 60 ) . Results The CF group had fewer PVRs ( 0.67 ± 0.91/patient vs. 1.16 ± 1.16/patient ; P = 0.007 ) , a lower incidence of persistent PVRs ( 13.2 vs. 41.2 % ; P shorter procedural time for the CPVI ( 50 vs. 56 min ; P = 0.019 ) than the blind group . The mean CF was higher in the CF group than the blind group ( 18.0 vs. 16.1 g ; P the mean CF was a negative predictor of PVRs along the P-RPVs and A-LPVs in the blind group ( odds ratios , 0.728 and 0.786 ; P , the arrhythmia-free survival rate at 12 months was 89.9 % in the CF group and 88.2 % in the blind group , respectively ( P = 0.624 ) . Conclusions CF-guided CPVI can reduce PVRs and the procedural time and be particularly beneficial along regions where a relatively low CF tends to be applied : the P-RPVs and A-LPVs . The comparable clinical outcomes may be due to the learning curve effect obtained by the CF-guided technique and repeated provocation of dormant PV conduction",
"Purpose Lesion formation is a critical determinant of technical and clinical success of pulmonary vein isolation . Different catheter design s aim to enhance tissue contact during ablation to enable optimized lesion formation . We analyzed procedural characteristics and predictors of clinical success in patients ablated with three different contemporary ablation catheters . Methods Two hundred sixty-eight sequentially included patients receiving pulmonary vein isolation ( PVI ) with conventional ( n = 122 ) , contact-force ( n = 96 ) and flexible-tip ( n = 60 ) catheters were followed for a median of 14.1 months with 7d-Holter-monitoring and TTE at 3 , 6 , 12 , and 24 months . Baseline characteristics and follow-up times were homogeneous across all groups . Results Multivariable Cox proportional hazard regression for arrhythmia recurrence demonstrated a favorable hazard ratio for contact-force and flexible-tip catheters vs. conventional open irrigation catheters . Procedure time and fluoroscopy time were shorter for contact-force and flexible-tip catheters versus conventional catheters , but equal between . Linear lesions were applied in 58 % of contact-force and 66 % of flexible-tip cases , and CFAEs were targeted in 26 % of either . Conclusions Our non-r and omized prospect ively collected data do not show a difference in observed procedure characteristics and in clinical outcome for flexible-tip versus contact-force catheter design s , while both display improved performance against conventional open irrigated-tip catheters . Linear lesions and CFAEs ablation were not associated with improved arrhythmia-free survival",
"AIMS The aim of this study was to evaluate the ' real-world ' impact of a novel contact force (CF)-sensing ( SmartTouch ™ , Biosense Webster , Diamond Bar , CA , USA ) catheter coupled with an advanced catheter location ( ACL ) system on fluoroscopy time and fluoroscopy dose during atrial fibrillation ( AF ) ablation . METHODS AND RESULTS This was a retrospective observational cohort study of prospect ively collected data of 1515 consecutive patients undergoing paroxysmal AF ( PAF ) and persistent AF ( PerAF ) ablation at a single institution between 2009 and 2014 . Patients undergoing AF ablation with the SmartTouch catheter and the ACL system ( SmartTouch group , n = 510 ) were compared with those undergoing AF ablation without this technology ( control group , n = 1005 ) . The primary outcomes were total fluoroscopy time ( min ) and fluoroscopy dose as measured by the dose-area product ( mGy cm(2 ) ) . Secondary endpoints included total procedure time , total ablation time , and major cardiac complications ( tamponade , pericardial effusion , and urgent cardiac surgery ) . The SmartTouch group had significantly lower fluoroscopy times ( 9.5 vs. 41 min , P radiation doses ( 1044 vs. 3571 mGy cm(2 ) , P shorter procedural time ( 195 vs. 240 min , P a median fluoroscopy time of 3.5 min ( interquartile range 6 ) for all AF ablations was achieved . There was no difference in the rate of cardiac complications ( ∼ 1.5 % ) . CONCLUSION SmartTouch ™ CF-sensing catheter use with ACL ™ during AF ablation significantly reduces fluoroscopy times by 77 % , radiation dose by 71 % , and procedural time by 19 % but does not improve overall safety or the risk of cardiac complications",
"Aims : Late recovery of ablated tissue leading to reconnection of pulmonary veins remains common following radiofrequency catheter ablation for AF . Ablation Index ( AI ) , a novel ablation quality marker , incorporates contact force ( CF ) , time , and power in a weighted formula . We hypothesized that prospect i ve use of our previously published derived AI targets would result in better outcomes when compared to CF‐guided ablation . Methods : Eighty‐nine consecutive drug‐refractory AF patients ( 49 % paroxysmal ) underwent AI‐guided ablation ( AI‐group ) . AI targets were 550 for anterior/roof and 400 for posterior/inferior left atrial segments . Procedural and clinical outcomes of these patients were compared to 89 propensity‐matched controls who underwent CF‐guided ablation ( CF‐group ) . All 178 procedures were otherwise similar , and both groups were followed‐up for 12 months . The last 25 patients from each group underwent analysis of all VisiTags ™ for ablation duration , CF , Force‐Time Integral , and impedance drop . Results : First‐pass pulmonary vein isolation ( PVI ) was more frequent in AI‐group than in CF‐group ( 173 [ 97 % ] vs. 149 [ 84 % ] circles , P 0.001 ) , and acute PV reconnection was lower ( 11 [ 6 % ] vs. 24 [ 13 % ] circles , P = 0.02 ) . Mean PVI ablation time was similar ( AI‐group : 42 ± 9 vs. CF‐group : 45 ± 14 minutes , P = 0.14 ) . Median impedance drop for AI‐group was significantly higher than in CF‐group ( 13.7 [ 9‐19 ] Ω vs. 8.8 [ 5.2‐13 ] Ω , P Two major complications occurred in CF‐group and none in AI‐group . Atrial tachyarrhythmia recurrence was significantly lower in AI‐group ( 15 of 89 [ 17 % ] ) than in CF‐group ( 33 of 89 [ 37 % ] , P = 0.002 ) . Conclusion : AI‐guided ablation is associated with significant improvements in the incidence of acute PV reconnection and atrial tachyarrhythmia recurrence rate compared to CF‐guided ablation , potentially due to creation of better quality lesions as suggested by greater impedance drop",
"BACKGROUND Electrode-tissue contact is crucial for adequate lesion formation in radiofrequency catheter ablation ( RFCA ) . OBJECTIVE We assessed the impact of direct catheter force measurement on acute procedural parameters during RFCA of atrial fibrillation ( AF ) . METHODS Fifty consecutive patients ( 28 male ) with paroxysmal AF who underwent their first procedure of circumferential pulmonary vein ( PV ) isolation ( PVI ) were assigned to either RFCA using ( 1 ) a st and ard 3.5-mm open-irrigated-tip catheter or ( 2 ) a catheter with contact force measurement capabilities . Using the endpoint of PVI with entry and exit block , acute procedural parameters were assessed . RESULTS Procedural data showed a remarkable decline in ablation time ( radiofrequency time needed for PVI ) from 50.5 ± 15.9 to 39.0 ± 11.0 minutes ( P = 0.007 ) with a reduction in overall procedure duration from 185 ± 46 to 154 ± 39 minutes ( P = 0.022 ) . In parallel , the total energy delivered could be significantly reduced from 70,926 ± 19,470 to 58,511 ± 14,655 Ws ( P = 0.019 ) . The number of acute PV reconnections declined from 36 % to 12 % ( P = 0.095 ) . CONCLUSIONS The use of contact force sensing technology is able to significantly reduce ablation and procedure times in PVI . In addition , energy delivery is substantially reduced by avoiding radiofrequency ablation in positions with insufficient surface contact . Procedural efficacy and safety of this new feature have to be evaluated in larger cohorts",
"Purpose Use of online contact force ( CF ) measurement during circumferential pulmonary vein ( PV ) isolation ( CPVI ) for atrial fibrillation ( AF ) has demonstrated improvements in procedural parameters and mid-term clinical outcome . However , it is unknown if experience gained with CF measuring catheters improves the efficacy of subsequent CPVI procedures performed without CF measurement . Methods This prospect i ve trial compared procedural results of CPVI performed without a CF measuring catheter to a control group performed with a CF measuring catheter , by an operator with prior experience with CF technology .. Results Thirty-six eligible paroxysmal ( n = 27 ) or persistent ( n = 9 ) AF patients were consecutively enrolled . Twelve patients underwent CPVI with the non-CF catheter ( CF− group ) in a recall period and 24 with the CF catheter ( CF+ group ) . After the first circumferential lesion set , the number of PV pairs requiring additional touch-up lesions to achieve electrical isolation was significantly less in the CF+ group ( 2 of 48 ( 4.2 % ) vs. 7 of 24 ( 29.2 % ) in the CF+ and CF− groups , respectively , p = 0.005 ) . The procedure time was significantly lower in the CF+ group ( 117.9 ± 23.3 vs. 134.1 ± 25.3 min , p = 0.033 ) . Radiofrequency ( RF ) and fluoroscopy time did not differ between groups ( 31.5 ± 7.1 vs. 31.8 ± 7.0 min and 11.8 ± 5.6 vs. 11.0 ± 5.8 min in the CF+ and the CF− group , respectively ) Conclusions With the use of online CF measurement , PV isolation is more frequently complete following the first circumferential lesion set . A previous learning period with direct CF feedback is not a substitute for real-time direct CF measurement to maintain this advantage",
"BACKGROUND Sufficient electrode-tissue contact is crucial for adequate lesion formation in radiofrequency catheter ablation ( RFCA ) . OBJECTIVE We assessed the impact of direct catheter force measurement on acute procedural parameters and outcome of RFCA for paroxysmal and persistent atrial fibrillation ( AF ) . METHODS Ninety-nine consecutive patients ( 70 % men ) with paroxysmal ( 63.6 % ) or persistent AF underwent left atrial RFCA using a 3.5-mm open-irrigated-tip ( OIT ) catheter with contact force measurement capabilities ( group 1 ) . For comparison a case-matched cohort with st and ard OIT catheters was used ( 99 patients ; group 2 ) . Case matching included gender , type of AF , number or RFCA procedures , and type of procedure . RESULTS Procedural data showed a significant decline in radiofrequency ablation time from 52 ± 20 to 44 ± 16 minutes ( P = 0.003 ) with a remarkable mean reduction in overall procedure time of 34 minutes ( P = 0.0001 ; 225.8 ± 53.1 vs 191.9 ± 53.3 minutes ) . In parallel , the total fluoroscopy time could be significantly reduced from 28.5 ± 11.0 to 19.9 ± 9.3 minutes ( P = 0.0001 ) as well as fluoroscopy dose from 74.1 ± 58.0 to 56.7 ± 38.9 Gy/cm(2 ) ( P = 0.016 ) . Periprocedural complications were similar in both groups . CONCLUSIONS The use of contact force sensing technology is able to significantly reduce ablation , procedure , and fluoroscopy times as well as dose in RFCA of AF in a mixed case-matched group of paroxysmal and persistent AF . Energy delivery is substantially reduced by avoiding radiofrequency ablation in positions with insufficient surface contact . Additionally 12-month outcome data showed increased efficacy . Such time saving and equally safe technology may have a relevant impact on laboratory management and increased cost effectiveness",
"BACKGROUND Catheter-based contact force sensing ( CFS ) technology gives detailed information regarding contact between the catheter tip and myocardium . This may result in more effective ablation procedures . The primary objective of this study was comparison of remote robotic navigation ( RRN ) and Manual CFS ablation . The secondary objective was to compare CFS with non-CFS ablation for both navigation modes . METHODS Prospect i ve registries of consecutive cases undergoing their first ablation for persistent atrial fibrillation ( AF ) from six hospitals in the United Kingdom and South Africa were analyzed : 50 Manual/CFS and 50 RRN/CFS cases were included . Historical control non-CFS ablation patients were matched by propensity score , giving a total 200 patient cohort . RESULTS RRN/CFS was associated with improved single procedure 1-year success rates ( 64 % vs 36 % , P = 0.01 ) and shorter fluoroscopy times ( 41 % reduction , P procedure times ( P = 0.8 ) . The mean contact force was higher in RRN/CFS than Manual/CFS cases ( 16 [ 15 - 18 g ] vs 13 [ 12 - 15 g ] , respectively , P = 0.003 ) . Compared with non-CFS historical controls , CFS cases had higher 1-year success rates for RRN ( 64 % vs 36 % , P = 0.01 ) , but not Manual ablation ( 36 % vs 38 % , P = 1 ) . Procedure times were reduced for CFS cases ( 20 % , P fluoroscopy times ( Manual : 43 % , RRN 83 % , P rates of major or minor complications for either comparison ( P > 0.5 ) . CONCLUSIONS A combination of RRN and CFS is associated with improved success rates at 1 year and fluoroscopy times for persistent AF ablation , compared with Manual ablation and non-CFS RRN ablation",
"BACKGROUND Catheter ablation is important for treatment of paroxysmal atrial fibrillation ( PAF ) . Limited animal and human studies suggest a correlation between electrode-tissue contact and radiofrequency lesion generation . OBJECTIVES The study sought to assess the safety and effectiveness of an irrigated , contact force (CF)-sensing catheter in the treatment of drug refractory symptomatic PAF . METHODS A prospect i ve , multicenter , nonr and omized study was conducted . Enrollment criteria included : ≥3 symptomatic episodes of PAF within 6 months of enrollment and failure of ≥1 antiarrhythmic drug ( Class I to IV ) . Ablation included pulmonary vein isolation with confirmed entrance block as procedural endpoint . RESULTS A total of 172 patients were enrolled at 21 sites , where 161 patients had a study catheter inserted and 160 patients underwent radiofrequency application . Procedural-related serious adverse events occurring within 7 days of the procedure included tamponade ( n = 4 ) , pericarditis ( n = 3 ) , heart block ( n = 1 , prior to radiofrequency application ) , and vascular access complications ( n = 4 ) . By Kaplan-Meier analyses , 12-month freedom from atrial fibrillation/atrial flutter/atrial tachycardia recurrence was 72.5 % . The average CF per procedure was 17.9 ± 9.4 g. When the CF employed was between investigator selected working ranges ≥80 % of the time during therapy , outcomes were 4.25 times more likely to be successful ( p = 0.0054 ; 95 % confidence interval : 1.53 to 11.79 ) . CONCLUSIONS The SMART-AF trial demonstrated that this irrigated CF-sensing catheter is safe and effective for the treatment of drug refractory symptomatic PAF , with no unanticipated device-related adverse events . The increased percent of time within investigator-targeted CF ranges correlates with increased freedom from arrhythmia recurrence . Stable CF during radiofrequency application increases the likelihood of 12-month success . ( THERMOCOOL ® SMARTTOUCH ® Catheter for Treatment of Symptomatic Paroxysmal Atrial Fibrillation ; NCT01385202 )",
"Background — Contact force ( CF ) is a major determinant of lesion size and transmurality and has the potential to improve efficacy of atrial fibrillation ablation . This study sought to evaluate the safety and effectiveness of a novel irrigated radiofrequency ablation catheter that measures real-time CF in the treatment of patients with paroxysmal atrial fibrillation . Methods and Results — A total of 300 patients with symptomatic , drug-refractory , paroxysmal atrial fibrillation were enrolled in a prospect i ve , multicenter , r and omized , controlled trial and r and omized to radiofrequency ablation with either a novel CF-sensing catheter or a non-CF catheter ( control ) . The primary effectiveness end point consisted of acute electrical isolation of all pulmonary veins and freedom from recurrent symptomatic atrial arrhythmia off all antiarrhythmic drugs at 12 months . The primary safety end point included device-related serious adverse events . End points were powered to show noninferiority . All pulmonary veins were isolated in both groups . Effectiveness was achieved in 67.8 % and 69.4 % of subjects in the CF and control arms , respectively ( absolute difference , −1.6 % ; lower limit of 1-sided 95 % confidence interval , −10.7 % ; P=0.0073 for noninferiority ) . When the CF arm was stratified into optimal CF ( ≥90 % ablations with ≥10 g ) and nonoptimal CF groups , effectiveness was achieved in 75.9 % versus 58.1 % , respectively ( P=0.018 ) . The primary safety end point occurred in 1.97 % and 1.40 % of CF patients and control subjects , respectively ( absolute difference , 0.57 % ; upper limit of 1-sided 95 % confidence interval , 3.61 % ; P=0.0004 for noninferiority ) . Conclusions — The CF ablation catheter met the primary safety and effectiveness end points . Additionally , optimal CF was associated with improved effectiveness . Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT01278953",
"INTRODUCTION The additional benefit of contact force ( CF ) technology during pulmonary vein isolation ( PVI ) for paroxysmal atrial fibrillation ( AF ) to improve mid-term clinical outcome is unclear . METHODS AND RESULTS Eligible patients with symptomatic paroxysmal AF were enrolled in this prospect i ve trial , comparing circular antral catheter ablation ( guided by Carto 3 System , Biosense Webster ) using either a new open-irrigated CF catheter ( SmartTouch Thermocool , Biosense Webster ) ( CF group ) or a non-CF open-irrigated catheter ( EZ Steer Thermocool , Biosense Webster ) ( control group ) . Overall , 30 patients were enrolled in each group , with a st and ardized 12-month follow-up , free of antiarrhythmic therapy . Demographic , cardiovascular and anatomic characteristics were similar in both groups . Though complete PVI was eventually achieved in all cases in both groups , success using an exclusive anatomic approach was 80.0 % in CF group versus 36.7 % in control group ( P fluoroscopy exposure ( P radiofrequency time ( P = 0.01 ) . The incidence rates of AF recurrence were 10.5 % ( 95 % CI , 1.38 - 22.4 ) in the CF group , and 35.9 % ( 95 % CI , 12.4 - 59.4 ) in the control group ( log rank test , P = 0.04 ) . After adjustment on potential confounders , the use of CF catheter was found to be associated with a lower AF recurrence ( OR 0.18 , 95 % CI 0.04 - 0.94 , P = 0.04 ) . CONCLUSION Our findings suggest a potential benefit of real-time CF sensing technology , in reducing AF recurrence during the first year after PVI",
"AIM To investigate the impact of using computed tomography ( CT ) and contact force ( CF ) technology on recurrence of atrial tachyarrhythmia after atrial fibrillation ( AF ) ablation . METHODS This non-r and omized study included 2 groups of patients . All patients had symptomatic recurrent paroxysmal or persistent AF and were treated with at least 1 anti arrhythmic medication or intolerant to medication . The first group included 33 patients who underwent circumferential pulmonary veins isolation ( PVI ) for AF during 2012 and 2013 guided by CT image integration ( Cartomerge , Biosense Webster , Diamond Bar , CA , United States ) of left atrium and pulmonary veins into an electroanatomic mapping ( EAM ) system ( CT group ) using st and ard irrigated radiofrequency catheter ( ThermoCool , Carto , Biosense Webster , Diamond Bar , CA , United States ) or irrigated catheter with integrated CF sensor ( Smart Touch , Carto , Biosense Webster , Diamond Bar , CA , United States ) . The second group included immediately preceding 32 patients who had circumferential PVI by st and ard irrigated catheter ( ThermoCool ) using only EAM ( Carto ) system ( EAM group ) . Linear lesions were performed according to the discretion of operator . RESULTS Sex , age , and persistent AF were not different between groups . PVI was achieved in all patients in both groups . Linear ablations including cavo-tricuspid isthmus and or roof line ablation were not different between groups . Free of atrial tachyarrhythmia during follow-up of 24 mo was significantly higher among CT group compared to EAM group ( 81 % vs 55 % ; respectively ; P = 0.027 ) . When 11 patients from CT group who had ablation using Smart Touch catheter were excluded , the difference between CT group and EAM became non significant ( 73 % vs 55 % ; respectively ; P = 0.16 ) . Sub analysis of CT group showed that patients who had ablation using Smart Touch catheter tend to be more free of atrial tachyarrhythmia compared to patients who had ablation using st and ard irrigated catheter during follow-up ( 100 % vs 73 % ; respectively ; P = 0.07 ) . Major complications ( pericardial effusion , cerebrovascular accident/transient ischemic attack , vascular access injury requiring intervention ) did not occurred in both groups . CONCLUSION These preliminary results suggest that CT image integration and CF technology may reduce the recurrence of atrial tachyarrhythmia after catheter ablation for AF",
"BACKGROUND Contact force ( CF ) sensing catheters provide advantages with regard to safety and efficacy . This study aim ed to evaluate if CF catheters reduce cardiac perforations and other major complications and offer equal safety compared to the magnetic navigation system ( MNS ) . METHODS Data from 1.517 ablation procedures from our prospect i ve registry was analyzed . Ablations were performed using either CF guided catheters ( CF group , n=248 ) , non-CF catheters ( NCF group , n=813 ) , or MNS ( n=456 ) . Four subgroups were analyzed : atrial fibrillation ( AF , n=557 ) , supraventricular tachycardia ( SVT , n=715 ) , ventricular tachycardia ( VT , n=190 ) and patients with congenital heart defects ( CHD , n=55 ) . The primary endpoint of this study was incidence of cardiac perforation . Secondary endpoints were major and minor complications within 30 days of the procedure . RESULTS Complications occurred in 11.3 % ( n=172 ) of the procedures . In 2.8 % ( n=43 ) a major complication occurred , 0.9 % ( n=13 ) had a perforation , 8.5 % ( n=129 ) had a minor complication and 2 patients died ( 0.1 % ) . No cardiac perforation occurred in the CF group , which was significantly different from NCF procedures ( 0.0 % vs. 1.6 % ; relative risk 0.76 , 95 % CI 0.74 - 0.79 , P=0.031 ) and equal to MNS ( 0.0 % ) . This was also observed in the AF subgroup ( 0.0 % vs. 3.3 % ; RR 0.67 , 95 % CI 0.63 - 0.72 , P=0.021 ) , and the occurrence of major complications was lower for CF versus NCF procedures ( 2.1 % vs. 7.8 % , P=0.010 ) . CONCLUSIONS CF-guided catheter ablation is superior to NCF with regard to procedural safety and avoidance of cardiac perforation . This difference is due to a reduction of cardiac perforation and major complications in the AF subgroup",
"BACKGROUND The impact of contact force ( CF ) monitoring in pulmonary vein ( PV ) isolation after a circumferential anatomic ablation ( CAA ) is unknown . We analyze the usefulness of CF monitoring in acute PV isolation and procedure parameters using a CAA . METHODS Fifty patients with paroxysmal atrial fibrillation were r and omized into CF-on ( CF > 10 grams ; n = 25 ) or CF-off ( CF blinded ; n = 25 ) groups . We performed a first round of CAA with a ThermoCool ( ® ) SmartTouch ( ® ) catheter blinded to the LASSO ( ® ) catheter ( Biosense Webster , Diamond Bar , CA , USA ) , with radiofrequency ( RF ) lesions tagged with the VisiTag ( ™ ) Module . After the CAA , each PV was review ed with the LASSO ( ® ) catheter recording the segments with gaps . RESULTS All the PVs were isolated with a CAA in 20 patients of the CF-on versus eight of the CF-off ( P = 0.001 ) . Of the 45 segments with gaps in the left PVs , 38 were from the CF-off ( P = 0.0001 ) . Of the eight segments with gaps in the right PVs , seven were from the CF-off ( P = 0.06 ) . The CF in the left PVs was higher in the CF-on ( 16.3 ± 3.2 grams vs 10.5 ± 4.3 grams ; P = 0.0001 ) and similar in the right PVs ( 17.6 ± 3.6 grams vs 15.2 ± 5.3 grams ; P = 0.08 ) . All of the gaps were closed with additional RF LASSO ( ® ) -guided touch-up . Procedure and fluoroscopy times were shorter in the CF-on ( 139 ± 24 minutes vs 157 ± 32 minutes and 20 ± 6 minutes vs 24 ± 7 minutes ; both P = 0.039 ) . At 12 months the patients free of AF recurrence was 84 % CF-on versus 75 % CF-off ( log-rank P = 0.4 ) [ corrected ] . CONCLUSIONS In paroxysmal atrial fibrillation , a CAA guided by CF reduces PV gaps and shortens the procedure parameters at the expense of the left PVs",
"Abstract Objective : To investigate the effect of the operator knowing the real-time contact force ( CF ) on the efficacy of pulmonary vein antrum isolation ( PVAI ) . Methods : Fifty patients with paroxysmal atrial fibrillation ( AF ) or short lasting persistent AF were r and omized to CF guided PVAI ( n = 25 ) or conventional PVAI ( n = 25 ) . In the CF guided group , CF between 10 and 40 g was aim ed at . Efficacy of PVAI was measured as reduction in AF burden ( AFB ) and time to AF recurrence detected by implantable cardiac monitor ( ICM ) , inserted three months before PVAI . Blanking period was three months and follow-up 12 months . Results : All pulmonary veins were isolated in the CF guided group and all but one in the conventional group . Mean CF was 25 g in the CF guided group and 24 g in the conventional group ( p = 0.75 ) . Compared to pre-ablation , median [ IQR ] relative reduction in AFB 3–12 months after ablation was 100 [99–100]% in the CF guided group ( p AF recurrence in the CF guided group and 13 ( 52 % ) in the conventional group ( p = 0.21 , log-rank test ) . CF differed between operators . When adjusted for operator by regression analysis , patients without recurrent AF had lower proportion of ablation time with CF No complications occurred . Conclusions : Operator knowledge of real-time CF had no significant effect on AFB reduction or time to AF recurrence . Larger trials should be done to study benefit of real-time CF",
"BACKGROUND Impact of contact force sensing ( CFS ) on ablation of persistent atrial fibrillation ( PeAF ) is unknown . OBJECTIVE The purpose of the TOUCH AF ( Therapeutic Outcomes Using Contact force H and ling during Ablation of Persistent Atrial Fibrillation ) r and omized trial was to compare CFS-guided ablation to a CFS-blinded strategy . METHODS Patients ( n = 128 ) undergoing first-time ablation for persistent AF were r and omized to a CFS-guided vs CFS-blinded strategy . In the CFS-guided procedure , operators visualized real-time force data . In the blinded procedure , force data were hidden . Wide antral pulmonary vein isolation plus a roof line were performed . Patients were followed at 3 , 6 , 9 , and 12 months with clinical visit , ECG , and 48-hour Holter monitoring . The primary endpoint was cumulative radiofrequency ( RF ) time for all procedures . Atrial arrhythmia > 30 seconds after 3 months was a recurrence . RESULTS PeAF was continuous for 26 weeks ( interquartile range [ IQR ] 13 - 52 ) , and left atrial size was 45 ± 5 mm . Force in the CFS-blinded and CFS-guided arms was 12 g [ IQR 6 - 20 ] and 14 g [ IQR 9 - 20 ] ( P = .10 ) , respectively . Total RF time did not differ between CFS-guided and CFS-blinded groups ( 49 ± 14 min vs 50 ± 20 min , respectively ; P = .70 ) . Single procedure freedom from atrial arrhythmia was 60 % in the CFS-guided arm and 63 % in the CFS-blinded arm off drugs . Lesions with gaps were associated with significantly less force ( 11.4 g [ IQR 6 - 19 ] vs 13.2 g [ IQR 8 - 20 ] , respectively ; P = .0007 ) and less force-time integral ( 174 gs [ IQR 91 - 330 ] vs 210 gs [ IQR 113 - 388 ] , respectively ; P ) . CONCLUSION CFS-guided ablation result ed in no difference to RF time or 12-month outcome . Lower force/force-time integral was associated with significantly more gaps",
"Abstract Background This study compared the efficacy of catheter ablation of atrial fibrillation ( AF ) between impedance (IMP)‐guided and contact force (CF)‐guided annotation using the automated annotation system ( VisiTag ™ ) . Methods Fifty patients undergoing pulmonary vein isolation ( PVI ) for AF were r and omized to the IMP‐guided or CF‐guided groups . The annotation criteria for VisiTag ™ were a 10 second minimum ablation time and 2 mm maximum catheter movement range . A minimum CF of 10 g was added to the criteria in the CF‐guided group . In the IMP‐guided group , a minimum IMP drop of over 5 Ω was added to the criteria . Results The rates of successful PVI after an initial ablation line were higher in the CF‐guided group ( 80 % vs 48 % , P = .018 ) . Although average CF was similar between two groups , the average force‐time integral ( FTI ) was significantly higher in the CF‐guided group ( 298.3 ± 65 . 2 g·s vs 255.1 ± 38.3 g·s , P = .007 ) . The atrial arrhythmia‐free survival at 1 year demonstrated no difference between the two groups ( 84.0 % in the IMP‐guided group vs 80.0 % in the CF‐guided group , P = .737 ) . If the use of any antiarrhythmic drug beyond the blanking period was considered as a failure , the clinical success rate at 1 year was 52.0 % for the CF‐guided group vs 56.0 % for the IMP‐guided group ( P = .813 ) . Conclusions Atrial fibrillation ablation using an automated annotation system guided by CF improved the success rate of PVI after the initial circumferential ablation . An IMP‐guided annotation combined with catheter stability criteria showed similar clinical outcomes as compared to the CF‐guided annotation"
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Objective : To investigate the psychometric properties of measures of balance and falls risk prediction in people with Parkinson ’s disease ( PD ) . Data sources : PubMed , Embase , CINAHL , Ovid Medline , Scopus , and Web of Science were search ed from inception to August 2019 . Review method : Studies testing psychometric properties of measures of balance and falls risk prediction in PD were included . The four-point COnsensus-based St and ards for the selection of health Measurement INstruments ( COSMIN ) assessed quality . Results : Eighty studies testing 68 outcome measures were review ed ; 43 measures assessed balance , 9 assessed falls risk prediction , and 16 assessed both . The measures with robust psychometric estimation with acceptable properties were the ( 1 ) Mini-Balance Evaluation Systems Test ( Mini-BEST ) , ( 2 ) Berg Balance Scale , ( 3 ) Timed Up and Go test , ( 4 ) Falls Efficacy Scale International , and ( 5 ) Activities-Specific Balance Confidence scale . These measures assess balance and falls risk prediction at the body , structure and function level , falls risk and balance , and falls risk at the activity level . The motor examination of the Unified Parkinson ’s Disease Rating Scale ( UPDRS-ME ) with robust psychometric analysis is a condition-specific measure with acceptable properties . Except the UPDRS-ME and Mini-BESTest , the responsiveness of the other four measures has yet to be established . Conclusion : Six of the 68 outcome measures have strong psychometric properties for the assessment of balance and falls risk prediction in PD . Measures assessing balance and falls risk prediction at the participatory level are limited in number with a lack of psychometric validation
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"Background and Purpose : Abnormal postural sway is associated with an increase in risk of falls but is difficult for clinicians to accurately quantify without access to laboratory equipment . Instrumenting clinical outcome measures using body-worn movement monitors is a low-cost alternative . This is the first study to compare the modified Clinical Test of Sensory Integration for Balance ( i-mCTSIB ) to the laboratory test of the Sensory Organization Test ( SOT ) with dynamic posturography in a group of participants with Parkinson 's disease ( PD ) and subtle balance limitations . The purpose of this study was to ( 1 ) determine the concurrent validity of the i-mCTSIB with the SOT ( 6 and 4 conditions ) and ( 2 ) compare the i-mCTSIB and the SOT to differentiate between individuals with and without recent falls within the previous 6 months . Methods : This cross-sectional study examined 26 participants with idiopathic PD who had a Motor Unified Parkinson 's Disease Rating Scale score of 32.7 ( 13.5 ) out of 108 . Results : The composite and conditions 1 and 4 of the i-mCTSIB and SOT scores were significantly correlated : composite scores r = −0.64 ( P ⩽ .001 ) , C1 r = −0.43 ( P = .03 ) , C3 r = −0.60 ( P ⩽ .01 ) , and C4 r = −0.54 ( P ⩽ .001 ) . A significant difference was observed in mean i-mCTSIB composite scores between fallers and nonfallers ( P = .04 ) . In contrast , the SOT composite was not significantly different between fallers and nonfallers ( P = 0.31 ) . Discussion : The results suggest that the i-mCTSIB may be a valid and clinical ly meaningful measure of sensory organization in persons with PD , even those with mild postural instability as measured by the median Hoehn and Yahr score ( 2.0 ) . Future research should evaluate predictive validity of the i-mCTSIB for prospect i ve falls . Conclusion : The instrumented mCTSIB with portable , body-worn movement allows clinicians to quantify abnormal postural sway without the ceiling effects of clinical balance testing or the expense and importability of force plate technology in the SOT . Instrumenting mCTSIB may also distinguish between fallers and nonfallers",
"Background The minimal detectable change ( MDC ) is the smallest amount of difference in individual scores that represents true change ( beyond r and om measurement error ) . The MDCs of the Timed “ Up & Go ” Test ( TUG ) and the Dynamic Gait Index ( DGI ) in people with Parkinson disease ( PD ) are largely unknown , limiting the interpretability of the change scores of both measures . Objective The purpose of this study was to estimate the MDCs of the TUG and the DGI in people with PD . Design This investigation was a prospect i ve cohort study . Methods Seventy-two participants were recruited from special clinics for movement disorders at a university hospital . Their mean age was 67.5 years , and 61 % were men . All participants completed the TUG and the DGI assessment s twice , about 14 days apart . The MDC was calculated from the st and ard error of measurement . The percentage MDC ( MDC% ) was calculated as the MDC divided by the mean of all scores for the sample . Furthermore , the intraclass correlation coefficient was used to examine the reproducibility between testing sessions ( test-retest reliability ) . Results The respective MDC and MDC% of the TUG were 3.5 seconds and 29.8 , and those of the DGI were 2.9 points and 13.3 . The test-retest reliability values for the TUG and the DGI were high ; the intraclass correlation coefficients were .80 and .84 , respectively . Limitations The study sample was a convenience sample , and the participants had mild to moderately severe PD . Conclusions The results showed that the TUG and the DGI have generally acceptable r and om measurement error and test-retest reliability . These findings should help clinicians and research ers determine whether a change in an individual patient with PD is a true change",
"Background and Purpose : Distinguishing between a clinical ly significant change and change due to measurement error can be difficult . The purpose of this study was to determine test-retest reliability and minimal detectable change for the Berg Balance Scale ( BBS ) , forward and backward functional reach , the Romberg Test and the Sharpened Romberg Test ( SRT ) with eyes open and closed , the Activities-specific Balance Confidence ( ABC ) Scale , the Six-Minute Walk Test ( 6MWT ) , comfortable and fast gait speed , the Timed “ Up & Go ” Test ( TUG ) , the Medical Outcomes Study 36-Item Short-Form Health Survey ( SF-36 ) , and the Unified Parkinson Disease Rating Scale ( UPDRS ) in people with parkinsonism . Subjects : Thirty-seven community-dwelling adults with parkinsonism ( mean age=71 years ) participated . The Hoehn and Yahr Scale median score of 2 was on the lower end of the scale ; however , the scores ranged from 1 to 4 . Methods : Subjects were tested twice by the same raters , with 1 week between tests . Test-retest reliability was calculated using intraclass correlation coefficients ( ICCs ) . Minimal detectable change was calculated using a 95 % confidence interval ( MDC95 ) . Results : The ICCs for test-retest reliability were above .90 for the BBS , ABC Scale , SRT with eyes closed , 6MWT , and comfortable and fast gait speeds . The MDC95 values for those functional tests were : BBS=5/56 , ABC Scale=13 % , SRT with eyes closed=19 seconds , 6MWT=82 m , comfortable gait speed=0.18 m/s , and fast gait speed=0.25 m/s . The ICCs for test-retest reliability of SF-36 scores were above .80 , with the exception of the social functioning subscale . The MDC95 values for the SF-36 ranged between 19 % and 45 % . The MDC95 values for the UPDRS Activities of Daily Living section , Motor Examination section , and total scores were 4/52 , 11/108 , and 13/176 , respectively . Discussion and Conclusion : Minimal detectable change values are useful to therapists in rehabilitation and wellness programs in determining whether change during or after intervention is clinical ly significant . High test-retest reliability of scores for the BBS , ABC Scale , SRT with eyes closed , 6MWT , and gait speed make them trustworthy functional assessment s in people with parkinsonism . The SF-36 and UPDRS provide quality -of-life and disease severity rating values in the ongoing assessment of people with parkinsonism",
"Introduction . We analyzed the ability of four balance assessment s to predict falls in people with Parkinson Disease ( PD ) prospect ively over six and 12 months . Material s and Methods . The BESTest , Mini-BESTest , Functional Gait Assessment ( FGA ) , and Berg Balance Scale ( BBS ) were administered to 80 participants with idiopathic PD at baseline . Falls were then tracked for 12 months . Ability of each test to predict falls at six and 12 months was assessed using ROC curves and likelihood ratios ( LR ) . Results . Twenty-seven percent of the sample had fallen at six months , and 32 % of the sample had fallen at 12 months . At six months , areas under the ROC curve ( AUC ) for the tests ranged from 0.8 ( FGA ) to 0.89 ( BESTest ) with LR+ of 3.4 ( FGA ) to 5.8 ( BESTest ) . At 12 months , AUCs ranged from 0.68 ( BESTest , BBS ) to 0.77 ( Mini-BESTest ) with LR+ of 1.8 ( BESTest ) to 2.4 ( BBS , FGA ) . Discussion . The various balance tests were effective in predicting falls at six months . All tests were relatively ineffective at 12 months . Conclusion . This pilot study suggests that people with PD should be assessed biannually for fall risk",
"PURPOSE The aims of this study were to determine test-retest reliability and responsiveness of short-distance walking speed tests for persons with Parkinson disease ( PD ) . Discriminant and convergent validity of walking speed tests were also examined . METHODS Eighty-eight participants with PD ( mean age , 66 years ) with mild to moderate severity ( stages 1 - 4 on the Hoehn and Yahr Scale ) were tested on medications . Measures of activity included the comfortable and fast 10-m walk tests ( CWT , FWT ) , 6-min walk test ( 6MWT ) , mini balance evaluations systems test ( mini-BEST Test ) , fear of falling ( FoF ) , and the Activity-Specific Balance Confidence Scale ( ABC ) . The mobility subsection of the PD quality of life-39 ( PDQ39-M ) served as a participation-based measure . RESULTS Test-retest reliability was high for both walking speed measures ( CWT , ICC(2,1 ) = 0.98 ; FWT , ICC(2,1 ) = 0.99 ) . Minimal detectable change ( MDC(95 ) ) for the CWT and FWT was 0.09 m/s and 0.13 m/s respectively . Participants at Hoehn & Yahr levels 3/4 demonstrated significantly slower walking speed with the CWT and FWT than participants at Hoehn & Yahr levels 1 and 2 ( P CWT and FWT were both significantly ( P ≤ .002 ) correlated with all activity and participation-based measures . CONCLUSIONS Short-distance walking speed tests are clinical ly useful measures for persons with PD . The CWT and FWT are highly reliable and responsive to change in persons with PD . Short distance walking speed can be used to discriminate differences in gait function between persons with mild and moderate PD severity . The CWT and FWT had moderate to strong associations with other activity and participation based measures demonstrating convergent validity",
"BACKGROUND Assessment of fall risk in an individual with Parkinson disease ( PD ) is a critical yet often time consuming component of patient care . Recently a simple clinical prediction tool based only on fall history in the previous year , freezing of gait in the past month , and gait velocity individuals with PD . METHODS We sought to externally vali date the utility of the tool by administering it to a different cohort of 171 individuals with PD . Falls were monitored prospect ively for 6 months following predictor assessment . RESULTS The tool accurately discriminated future fallers from non-fallers ( area under the curve [ AUC ] = 0.83 ; 95 % CI 0.76 - 0.89 ) , comparable to the developmental study . CONCLUSION The results vali date d the utility of the tool for allowing clinicians to quickly and accurately identify an individual 's risk of an impending fall",
"BACKGROUND AND PURPOSE The Timed \" Up & Go \" Test ( TUG ) is used to measure the ability of patients to perform sequential locomotor tasks that incorporate walking and turning . This study investigated the retest reliability , interrater reliability , and sensitivity of scores obtained with the TUG in detecting changes in mobility in subjects with idiopathic Parkinson disease ( PD ) . SUBJECTS The performance of 12 people with PD was compared with that of 12 age-matched comparison subjects without PD . METHODS The subjects with PD completed 5 trials of the TUG after withdrawal of levodopa for 12 hours ( \" off \" phase of the medication cycle ) as well as an additional 5 trials 1 hour after levodopa was administered ( \" on \" phase of the medication cycle ) . They were scored on the Modified Webster Scale at both sessions . The comparison subjects also performed 5 TUG trials . All trials were videotaped and timed by 2 experienced raters . The videotape was later rated by 3 experienced clinicians and 3 inexperienced clinicians . RESULTS For the subjects with PD , within-session performance was highly consistent , with correlations ( r ) ranging from.80 to.98 for the \" off \" phase and from.73 to.99 for the \" on \" phase . The performance of the comparison subjects across the 5 trials was also highly consistent ( r=.90-.97 ) . Comparisons showed differences between trials 1 and 2 on the TUG for both groups . Removal of data for trial 1 ( the practice trial ) further enhanced retest reliability . There was close agreement in TUG scores among raters despite different levels of experience ( intraclass correlation coefficient [3,1]=.87-.99 ) . Mean TUG scores were different between the \" on \" and \" off \" phases of the levodopa cycle and between subjects with PD and comparison subjects during the \" on \" phase . CONCLUSION AND DISCUSSION Retest reliability and interrater reliability of the TUG measurements were high , and the measurements reflected changes in performance according to levodopa use . The TUG can also be used to detect differences in performance between people with PD and elderly people without PD",
"Background The Functional Gait Assessment ( FGA ) is a vali date d measurement of gait-related activities in certain population s and may be potentially useful to assess balance and gait disorders in patients with Parkinson disease ( PD ) . Objective The purpose of this study was to determine the construct , concurrent , and predictive validity of the FGA in in patients with PD . Design This was a prospect i ve cohort study . Methods One hundred twenty-one in patients with PD were prospect ively enrolled . The FGA and other relevant appraisal s of gait , balance , disease severity , and activities of daily living were performed . Six months later , the patients were interviewed by telephone to have their fall information collected . Principal component analysis was used to determine construct validity . Spearman correlation coefficients were used to determine concurrent validity between the FGA and other measures . Cutoff point , sensitivity , specificity , and positive likelihood ratio were calculated for predictive validity based on the receiver operating characteristic curve . Results One common factor was extracted for construct validity , which cumulatively explained 64.0 % of the total variance . Correlation coefficients for the FGA compared with other measures ranged from .57 to .85 . The cutoff point for predicting falls was 18 , with sensitivity of 80.6 % , specificity of 80.0 % , and positive likelihood ratio of 4.03 . Limitations This study was limited by the length of time of follow-up and self-reports of falls without the requirement of a fall diary . Medication adjustment after the FGA evaluation may have led to a different cutoff score for identifying those patients who were at risk of falling . Conclusions The FGA demonstrated good construct validity in patients with PD . It had moderate to strong correlations with other balance and gait appraisal s. The FGA can be used to predict falls within the subsequent 6 months",
"Background Balance confidence and fear of falling are factors associated with recurrent falls in people with Parkinson disease ( PD ) . However , the accuracy for predicting falls on the basis of self-report measures has not been widely investigated . Objective The study objectives were : ( 1 ) to compare the accuracy of the Activities-specific Balance Confidence Scale ( ABC ) and the Falls Efficacy Scale – International ( FES-I ) with that of the Berg Balance Scale ( BBS ) , Dynamic Gait Index ( DGI ) , Functional Reach Test ( FRT ) , and Timed “ Up & Go ” Test ( TUG ) for predicting recurrent falls in people with PD and ( 2 ) to explore the ability of combinations of up to 3 tests to predict recurrent falls . Design This was a prospect i ve cohort study involving 225 people with PD . Methods Participants were assessed with the ABC , FES-I , BBS , FRT , TUG , and DGI . Participants who reported 2 or more falls in the 12-month follow-up period were classified as recurrent fallers . Areas under the receiver operating characteristic curves were determined , and the Akaike information criterion was used to select the best predictive model . Results Eighty-four participants ( 37.3 % ) were classified as recurrent fallers . Areas under the receiver operating characteristic curves for the ABC , FES-I , TUG , FRT , DGI , and BBS were 0.73 , 0.74 , 0.72 , 0.74 , 0.76 , and 0.79 , respectively . Two-test models provided additional discriminating ability compared with individual measures and had Akaike information criterion values similar to those of 3-test models , particularly the combination of the BBS with the FES-I. Limitations The lack of an external validation sample was a limitation of this study . Conclusions The ABC and FES-I demonstrated moderate accuracy in predicting recurrent falls and a predictive ability similar to that of performance-based balance measures , especially the FRT and the TUG . Two-test models showed performance similar to that of 3-test models , suggesting that a combination of 2 measures may improve the ability to predict recurrent falls in people with PD . Specifically , the combination of the BBS with the FES-I may be considered",
"Background The correct identification of patients with Parkinson disease ( PD ) at risk for falling is important to initiate appropriate treatment early . Objective This study compared the Fullerton Advanced Balance ( FAB ) scale with the Mini-Balance Evaluation Systems Test ( Mini-BESTest ) and Berg Balance Scale ( BBS ) to identify individuals with PD at risk for falls and to analyze which of the items of the scales best predict future falls . Design This was a prospect i ve study to assess predictive criterion-related validity . Setting The study was conducted at a university hospital in an urban community . Patients Eighty-five patients with idiopathic PD ( Hoehn and Yahr stages : 1–4 ) participated in the study . Measurements Measures were number of falls ( assessed prospect ively over 6 months ) , FAB scale , Mini-BESTest , BBS , and Unified Parkinson 's Disease Rating Scale . Results The FAB scale , Mini-BESTest , and BBS showed similar accuracy to predict future falls , with values for area under the curve ( AUC ) of the receiver operating characteristic ( ROC ) curve of 0.68 , 0.65 , and 0.69 , respectively . A model combining the items “ t and em stance , ” “ rise to toes , ” “ one-leg stance , ” “ compensatory stepping backward , ” “ turning , ” and “ placing alternate foot on stool ” had an AUC of 0.84 of the ROC curve . Limitations There was a dropout rate of 19/85 participants . Conclusions The FAB scale , Mini-BESTest , and BBS provide moderate capacity to predict “ fallers ” ( people with one or more falls ) from “ nonfallers . ” Only some items of the 3 scales contribute to the detection of future falls . Clinicians should particularly focus on the item “ t and em stance ” along with the items “ one-leg stance , ” “ rise to toes , ” “ compensatory stepping backward , ” “ turning 360 ° , ” and “ placing foot on stool ” when analyzing postural control deficits related to fall risk . Future research should analyze whether balance training including the aforementioned items is effective in reducing fall risk",
"OBJECTIVE To assess the criterion-related validity of the Berg Balance Scale ( BBS ) in subjects with Parkinson 's disease ( PD ) . DESIGN Prospect i ve , correlational analysis between the BBS and accepted measures of PD motor and functional impairment . SETTING The federally funded PD research center , an interdisciplinary center of excellence for people with PD within a Veterans Affairs medical center . PARTICIPANTS Thirty-eight men ( average + /- st and ard deviation , 71.1+/-10.5 y ) with confirmed PD . Their initial diagnosis had been made on average 5.8+/-3.6 years earlier . All could st and or walk unassisted and had mild to moderate disability . Patients who could not ambulate without assistive devices were excluded . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Correlational analyses between the BBS and the Unified Parkinson 's Disease Rating Scale ( UPDRS ) motor scale , Modified Hoehn and Yahr Staging ( Hoehn and Yahr ) Scale , and the Modified Schwab and Engl and Capacity for Daily Living Scale ( S&E ADL Scale ) . RESULTS BBS score showed significant correlations with indicators of motor functioning , stage of disease , and daily living capacity . BBS score was inversely associated with the UPDRS motor score ( -.58 , P Hoehn and Yahr Scale staging ( -.45 , P S&E ADL Scale rating ( .55 , P UPDRS scores ( indicating greater motoric or functional impairment ) . CONCLUSIONS Results support the criterion-related validity of the BBS . Its utility in other balance conditions of older adults has been established . Rehabilitation interventions have been shown to improve the balance deficits associated with PD . Early referral and periodic re assessment is vital to achieving and maintaining improvements . Our research results agree with other published research in suggesting that the BBS may be used as a screening tool and ongoing assessment tool for patients with PD",
"Falls are a major cause of morbidity in Parkinson 's disease ( PD ) . The objective of this study was to identify predictors of falls in PD and develop a simple prediction tool that would be useful in routine patient care . Potential predictor variables ( falls history , disease severity , cognition , leg muscle strength , balance , mobility , freezing of gait [ FOG ] , and fear of falling ) were collected for 205 community-dwelling people with PD . Falls were monitored prospect ively for 6 months using monthly falls diaries . In total , 125 participants ( 59 % ) fell during follow-up . A model that included a history of falls , FOG , impaired postural sway , gait speed , sit-to-st and , st and ing balance with narrow base of support , and coordinated stability had high discrimination in identifying fallers ( area under the receiver-operating characteristic curve [ AUC ] , 0.83 ; 95 % confidence interval [ CI ] , 0.77 - 0.88 ) . A clinical tool that incorporated 3 predictors easily determined in a clinical setting ( falling in the previous year : odds ratio [ OR ] , 5.80 ; 95 % CI , 3.00 - 11.22 ; FOG in the past month : OR , 2.39 ; 95 % CI , 1.19 - 4.80 ; and self-selected gait speed second : OR , 1.86 ; 95 % CI , 0.96 - 3.58 ) had similar discrimination ( AUC , 0.80 ; 95 % CI , 0.73 - 0.86 ) to the more complex model ( P = 0.14 for comparison of AUCs ) . The absolute probability of falling in the next 6 months for people with low , medium , and high risk using the simple , 3-test tool was 17 % , 51 % , and 85 % , respectively . In people who have PD without significant cognitive impairment , falls can be predicted with a high degree of accuracy using a simple , 3-test clinical tool . This tool enables individualized quantification of the risk of falling . © 2013 Movement Disorder Society",
"BACKGROUND In Parkinson 's disease ( PD ) , motor and cognitive impairments interact to affect functional performance adversely . A valid mobility test , the Four Square Step Test ( FSST ) involves multidirectional stepping over obstacles . FSST performance may also be associated with cognitive performance . OBJECTIVES This study determined the feasibility and reliability of an obstacle-based FSST in older individuals with versus without PD , and evaluated the association of PD performance of FSST with tests of cognition . METHODS Thirty-one individuals with mild-moderate PD , evaluated while ON medications , completed the obstacle-based FSST , other mobility and cognitive measures . FSST performance was compared between a PD participant sub-set ( n = 24 ) and 24 age-matched older adults . Data were analyzed with independent t-tests , correlations , and linear regression . RESULTS Obstacle-based FSST was feasible and reliable within sessions in those with PD . Median best FSST time among individuals with PD was 11.72 s ( 9.99 , 13.98 ) and FSST had concurrent validity with tests of mobility , and cognitive dual-tasking . Among cognitive tests , Trails Making Test B , which evaluates executive function , emerged as a sole contributor ( 49 % ) of variance . FSST performance did not differ between those with PD and older adults . CONCLUSION The obstacle-based FSST is feasible and reliable in those with PD . The relationship between cognitive status and performance on the FSST did not appear to be strongly disease-stage dependent . Using FSST in the clinic may help assess the health status of a motor-cognitive interaction in individuals with PD",
"Background and Purpose : Parkinson disease ( PD ) results in an increased frequency of falls relative to the frequency in neurologically healthy people . The purpose of this study was to compare the accuracy of PD fall risk diagnosis based on one test with that based on the collective interpretation of multiple tests . Participants : Seventy people with PD ( mean age=73.91 years ) participated in this study . Method : Clinical balance tests were conducted during the initial examinations of people with PD . Validity indices were calculated for individual tests and compared with validity indices calculated for a combination of multiple tests . Results : Thirty-six participants reported a fall history . Analysis of individual tests revealed broad variations in validity indices , whereas the collective interpretation of multiple tests improved sensitivity and negative likelihood ratios . Discussion and Conclusion : Collective interpretation of clinical balance tests result ed in fewer false-negative results and more substantial adjustments to the posttest probability of being a “ faller ” than the interpretation of one test alone . These results should be confirmed in a prospect i ve examination of fall risk in PD",
"Background : Impaired postural stability places individuals with Parkinson ’s at an increased risk for falls . Given the high incidence of fall-related injuries within this population , ongoing assessment of postural stability is important . Objective : To evaluate the validity of the Nintendo Wii ® balance board as a measurement tool for the assessment of postural stability in individuals with Parkinson ’s . Subjects : Twenty individuals with Parkinson ’s participated . Intervention : Subjects completed testing on two balance tasks with eyes open and closed on a Wii ® balance board and biomechanical force platform . Main Measures : Bl and –Altman plots and a two-way , r and om-effects , single measure intraclass correlation coefficient model were used to assess concurrent validity of centre-of-pressure data . Results : Concurrent validity was demonstrated to be excellent across balance tasks ( intraclass correlation coefficients = 0.96 , 0.98 , 0.92 , 0.94 ) . Conclusions : This study suggests that the Wii ® balance board is a valid tool for the quantification of postural stability among individuals with Parkinson ’s"
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Background Considering conflicting results on the consequences of all types of obesity surgery , we were to summarize them via a systematic review . Methods Electronic literature search was done via scientific search engines . After the removal of duplicates and selection of articles of interest , 771 studies were included . Results Insulin resistance indicators were significantly improved after bariatric surgery . Leptin was also significantly decreased while adiponectin was significantly increased . Although the level of metabolic hormones changed after bariatric surgery , they were not statistically significant . Inflammation indicators were significantly decreased . Significant reduction was also detected in PAI-1 and sICAM-1 . Conclusions Bariatric surgery is beneficial in morbidly obese patients . Although treating obesity in a surgical way may cause some complications , the weight loss is generally safe and effective
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"Background and objective : Systemic inflammation is a well-known risk factor for diseases such as atherosclerosis and is augmented by the presence of obesity . In addition , it has been shown that inflammation may be negatively influenced by certain macronutrients , specifically the omega-3 and omega-6 fatty acids . The primary aim of this study is to determine whether obesity modifies the association between plasma phospholipid polyunsaturated fatty acids ( PUFAs ) and markers of inflammation and endothelial activation in Multi-Ethnic Study of Atherosclerosis ( MESA ) participants .Subjects : A sample of 2848 adults ( 25 % African American , Chinese , Hispanic , and White ) r and omly selected from the MESA cohort . Measurements : Relative plasma PUFA concentrations were determined using gas chromatography-flame ionization detection . Levels of three inflammatory markers ( high-sensitivity C-reactive protein , interleukin (IL)-6 and tumor necrosis factor-receptor 1 ) and two endothelial activation markers ( soluble intercellular adhesion molecule-1 ( sICAM-1 ) and E-selectin ) were determined with enzyme immunoassays . Linear regression analysis was used to evaluate the relationship between these markers and plasma PUFAs . Results : Obesity modified the associations of linoleic acid ( Pint=0.01 ) , dihomo-γ-linolenic ( Pint=0.07 ) and eicosapentaenoic acid ( EPA ) ( Pint=0.04 ) with sICAM-1 concentrations ; in addition , obesity modified the association of IL-6 with dihomo-γ-linolenic ( Pint=0.01 ) . In obese individuals , sICAM-1 was inversely related to EPA levels ( P=0.02 ) , but directly related to linoleic acid levels ( P Conversely , sICAM-1 was inversely related to linoleic acid levels in normal weight individuals ( P=0.04 ) . IL-6 concentrations were significantly and directly related to dihomo-γ-linolenic acid ( DGLA ) in normal weight ( P=0.01 ) and obese participants ( P with IL-6 and sICAM-1 suggests differences in fatty acid metabolism and may also have implication s in dietary fatty acid intake for obese individuals , particularly for linoleic and EPAs . Further study is warranted to confirm and explain the strong associations of DGLA with inflammatory and endothelial activation markers",
"Adiponectin , the most abundant adipose-specific protein , has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other population s. Moreover , adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor ( IR ) and also increase whole-body insulin sensitivity . To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans , we examined 1 ) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2 ) the prospect i ve effect of plasma adiponectin concentration at baseline on change in insulin sensitivity . Fasting plasma adiponectin concentration , body composition ( hydrodensitometry or dual energy X-ray absorptiometry ) , insulin sensitivity ( insulin-stimulated glucose disposal , hyperinsulinemic clamp ) , and glucose tolerance ( 75-g oral glucose tolerance test ) were measured in 55 Pima Indians ( 47 men and 8 women , aged 31 + /- 8 years , body fat 29 + /- 8 % [ mean + /- SD ] ; 50 with normal glucose tolerance , 3 with impaired glucose tolerance , and 2 with diabetes ) . Group 1 ( 19 subjects ) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR ( stimulated by 100 nmol/l insulin ) . The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation . Group 2 ( 38 subjects ) had follow-up measurements of insulin-stimulated glucose disposal . Cross-sectionally , plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal ( r = 0.58 , P percent body fat ( r = -0.62 , P plasma adiponectin was negatively associated with the basal ( r = -0.65 , P = 0.003 ) and positively associated with the fold increase in IR tyrosine phosphorylation ( r = 0.69 , P = 0.001 ) before and after the adjustment for percent body fat ( r = -0.58 , P = 0.01 and r = 0.54 , P = 0.02 , respectively ) . Longitudinally , after adjustment for age , sex , and percent body fat , low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity ( P = 0.04 ) . In conclusion , our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation . Prospect ively , low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity . Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans",
"Background : The aim of this community-based study is to ascertain the effect of different obesity phenotypes on the incidence of chronic kidney disease in Iranian adults . Study Design : A prospect i ve cohort study , the Tehran Lipid Glucose Study ( TLGS ) . Setting and Participants : Adults aged ≥ 20 years with a mean age of 40.38 years ( 54.8 % female ) who were free from chronic kidney disease ( CKD ) at baseline ( phase 1 ) and were followed up at 3 time stages ( phases 2 , 3 , and 4 ) for a mean duration of 9.4 years to assess the risk for CKD . Predictor : Obesity phenotypes . Outcome : Incidence of chronic kidney disease . Measurements : Glomerular filtration rate ( GFR ) was estimated from the simplified equation developed using data from the Modification of Diet in Renal Disease ( MDRD ) Study . Results : CKD events occurred in 1162 participants . The prevalence of the 2 known obesity phenotypes ( metabolically obese normal weight [ MONW ] and metabolically healthy but obese [ MHO ] ) in the overall population was 3.5 % and 8.8 % , respectively . According to Kaplan-Meier curves , rates of freedom from CKD in the MHO and MONW obesity phenotypes were 75.3 % and 60.6 % , respectively ( p hazard ratios for participants with MHO or MONW obesity phenotype were 1.14 ( 95 % confidence interval [ CI ] , 0.91–1.43 ) and 1.43 ( 95 % CI , 1.09–1.88 ) , respectively . After further adjustment for confounder variables ( model 2 ) , multivariate-adjusted hazard ratios for CKD for participants with MHO or MONW obesity phenotypes were 1.23 ( 95 % CI , 0.93–1.62 ) and 1.43 ( 95 % CI , 1.08–1.90 ) , respectively . Conclusion : Adults with the MONW obesity phenotype compared to those with MHO obesity phenotype have a higher risk for incidence of CKD . The results indicate that having a normal weight is not the only factor to protect against incidence of CKD",
"We aim ed to evaluate the therapeutic efficacy on weight control by different bariatric surgeries and investigate the ghrelin and obestatin changes after these surgeries in obesity and nonobese type 2 diabetes mellitus ( T2DM ) rats . Obese rats were r and omly assigned to receive sleeve gastrectomy ( SG , n = 8) , minigastric bypass ( MGBP , n = 8) , roux-en-Y gastric bypass ( RYGBP , n = 8) , and sham operation ( SO , n = 4 ) . Another 4 rats served as control . Besides , Goto-Kakisaki ( GK ) rats were also r and omly divided into similar groups except for total gastrectomy ( TG , n = 8) group . The results showed that in obese rats , weigh loss in RYGBP group was similar to that in MGBP group but larger than that in SG group . Ghrelin significantly increased in RYGB group , but obestatin increased in MGBP group . Ghrelin/obestatin ratio significantly decreased in SG group . In GK rats , weight loss was most obvious in TG group . Postoperatively , ghrelin was significantly increased in MGBP and RYGB groups but decreased in TG group . Obestatin also showed an increase in MGBP and RYGB groups . Ghrelin/obestatin in TG group decreased significantly . In conclusion , RYGB and MGBP may be more suitable for obese rats , but TG may be the best strategy for T2DM rats to control weight with different mechanisms",
"Background : Human adipose tissue expresses and releases proinflammatory cytokines and these measures of chronic inflammation have recently been associated with obesity . Hypothesis : To test whether the proinflammatory state is reversible in subjects undergoing weight loss by surgical measures .Subjects and Methods : Twenty morbidly obese women participated in this prospect i ve study . Subjects were examined for fat mass , high-sensitive C-reactive protein ( hs-CRP ) , interleukin 6 ( IL-6 ) and tumor necrosis factor-alpha ( TNF-α ) before and 1 y after Swedish adjustable gastric b and ing . Results : Anthropometric measures displayed a significant reduction of the body mass index ( BMI ) from 41.6±5.4 to 30.8±6.1 kg/m2 and the fat mass from 53.9±10.3 to 29.8±12.1 kg ( mean±s.d . ) . Hs-CRP levels decreased significantly from 1.33±1.21 mg/dl in pre-gastric b and ing subjects to 0.40±0.61 mg/dl in post-gastric b and ing subjects , respectively . IL-6 and TNF-α levels did not differ significantly between pre- and post-gastric b and ing subjects . Conclusions : We speculate that in these patients the marked reduction in C-reactive protein might be beneficial in reducing their cardiovascular risk and is not solely mediated by IL-6 and TNF-α",
"Background : In obesity , metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles ( MPs ) . At sites of endothelium injury , the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth . Objectives : In obese females , we sought to evaluate the impact of a very low-calorie diet ( VLCD ) on procoagulant MP levels , fibrinolytic status , inflammation and endothelium damage . Methods : Circulating biomarkers of vascular damage , fibrinolytic status , platelet activation and inflammation were measured before , 30 and 90 days after starting a short-term VLCD . MPs were measured by flow cytometry and capture assays . Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry ( endothelium , platelet , leukocyte , lymphocyte and erythrocyte-derived MP ) or capture assays . Results : A total of 24 obese females ( 39±10 years ) with a mean body mass index of 35±4 kg m−2 were prospect ively enroled . Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline ( r=0.534 ; P=0.010 ) and at 90 days follow-up ( r=0.487 ; P=0.021 ) . At 90 days , weight reduction ( −9.8 % ) was associated with a lowering of blood pressure , improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 ( PAI-1 ) ( −38 % ) , procoagulant platelet-derived MPs ( −43 % ) , leukocyte-derived MPs ( −28 % ) and leptin ( −32 % ) levels . Conclusion : In obese females , a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels , diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels , an adipocyte-derived cytokine",
"Background —Visceral fat is a key regulator site for the process of inflammation , and atherosclerotic lesions are essentially an inflammatory response . Methods and Results —Fifty-six healthy premenopausal obese women ( age range 25 to 44 years , body mass index 37.2±2.2 , waist to hip ratio range 0.78 to 0.92 ) and 40 age-matched normal weight women were studied . Compared with nonobese women , obese women had increased basal concentrations of tumor necrosis factor-&agr ; ( TNF-&agr ; , P interleukin-6 ( IL-6 , P P-selectin ( P intercellular adhesion molecule-1 ( ICAM-1 , P vascular adhesion molecule-1 ( VCAM-1 , P ) . Vascular responses to l-arginine ( 3 g IV ) , the natural precursor of nitric oxide , were impaired in obese women : reductions in mean blood pressure ( P , platelet aggregation to adenosine diphosphate ( P , and blood viscosity ( P . Concentrations of TNF-&agr ; and IL-6 were related ( P multidisciplinary program of weight reduction ( diet , exercise , behavioral counseling ) , all obese women lost at least 10 % of their original weight ( 9.8±1.5 kg , range 7.5 to 13 kg ) . Compared with baseline , sustained weight loss was associated with reduction of cytokine ( P obese women , endothelial activation correlates with visceral body fat , possibly through inappropriate secretion of cytokines . Weight loss represents a safe method for downregulating the inflammatory state and ameliorating endothelial dysfunction in obese women",
"Different hormones and peptides involved in inflammation have been studied in and related to obesity . The aim of our work is to assess the variations of different molecules related to inflammation in obese patients during the first year following sleeve gastrectomy . This was a prospect i ve study on patients who underwent sleeve gastrectomy . The variations in different clinical , anthropometric , and analytical parameters related to inflammation were determined and analysed in all patients at the preoperative visit and at the first and fifth days , first and sixth months , and 1 year following surgery . We enrolled 20 patients to the study . The median body mass index ( BMI ) before intervention was 48.5 kg/m2 . With respect to comorbidities , 70 % of the patients had obstructive sleep apnoea syndrome ( OSA ) , 65 % high blood pressure , 45 % dyslipidaemia , and 40 % diabetes mellitus ( DM ) . The median percentage of BMI lost ( % BMI L ) 1 year after the intervention was 71 % . The dyslipidaemia healing or improvement rate was 100 % , whereas it was 87.5 % for diabetes , 84.6 % for hypertension , and 57.1 % for OSA . During the 1-year postintervention period , the average levels of adiponectin increased , although not significantly , whereas those of leptin significantly decreased . In addition , the blood levels of MCP-1 , IL-6 , CRP , ferritin , and PAI-1 significantly decreased in that period . Sleeve gastrectomy is a surgical technique that is associated with improvements in body weight and comorbid conditions from the first postoperative months , which lead to significant variations in the levels of different inflammation-related parameters and a decrease in the levels of leptin , IL-6 , CRP , MCP-1 , ferritin , and serpin ( PAI-1 )",
"BACKGROUND To our knowledge , no single investigation concerning the long-term effects of overweight status on the risk for hypertension , hypercholesterolemia , diabetes mellitus , and cardiovascular sequelae has been reported . METHODS Relations between categories of body mass index ( BMI ) , cardiovascular disease risk factors , and vascular disease end points were examined prospect ively in Framingham Heart Study participants aged 35 to 75 years , who were followed up to 44 years . The primary outcome was new cardiovascular disease , which included angina pectoris , myocardial infa rct ion , coronary heart disease , or stroke . Analyses compared overweight ( BMI [ calculated as weight in kilograms divided by the square of height in meters ] , 25.0 - 29.9 ) and obese persons ( BMI > or = 30 ) to a referent group of normal-weight persons ( BMI , 18.5 - 24.9 ) . RESULTS The age-adjusted relative risk ( RR ) for new hypertension was highly associated with overweight status ( men : RR , 1.46 ; women : RR , 1.75 ) . New hypercholesterolemia and diabetes mellitus were less highly associated with excess adiposity . The age-adjusted RR ( confidence interval [ CI ] ) for cardiovascular disease was increased among those who were overweight ( men : 1.21 [ 1.05 - 1.40 ] ; women : 1.20 [ 1.03 - 1.41 ] ) and the obese ( men : 1.46 [ 1.20 - 1.77 ] ; women : 1.64 [ 1.37 - 1.98 ] ) . High population attributable risks were related to excess weight ( BMI > or = 25 ) for the outcomes hypertension ( 26 % men ; 28 % women ) , angina pectoris ( 26 % men ; 22 % women ) , and coronary heart disease ( 23 % men ; 15 % women ) . CONCLUSIONS The overweight category is associated with increased relative and population attributable risk for hypertension and cardiovascular sequelae . Interventions to reduce adiposity and avoid excess weight may have large effects on the development of risk factors and cardiovascular disease at an individual and population level",
"Objective : To evaluate the physiologic importance of the satiety gut hormones . Background : Controversy surrounds the physiologic role of gut hormones in the control of appetite . Bariatric surgery remains the most effective treatment option for obesity , and gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass . Methods : We correlated peptide YY ( PYY ) and glucagon-like peptide 1 ( GLP-1 ) changes within the first week after gastric bypass with changes in appetite . We also evaluated the gut hormone responses of patients with good or poor weight loss after gastric bypass . Finally , we inhibited the gut hormone responses in gastric bypass patients and then evaluated appetite and food intake . Results : Postpr and ial PYY and GLP-1 profiles start rising as early as 2 days after gastric bypass ( P Changes in appetite are evident within days after gastric bypass surgery ( P appetite continues . However , in patients with poor weight loss after gastric bypass associated with increased appetite , the postpr and ial PYY and GLP-1 responses are attenuated compared with patients with good weight loss ( P return of appetite and increased food intake ( P appetite after gastric bypass is associated with elevated PYY and GLP-1 concentrations , and appetite returns when the release of gut hormones is inhibited . The results suggest a role for gut hormones in the mechanism of weight loss after gastric bypass and may have implication s for the treatment of obesity"
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4117d322-06ff-11f0-808a-c43d1ab1c353
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Purpose To determine the efficacy and safety of dutasteride , alone or in combination , versus a placebo or control , used for the treatment of benign prostatic hyperplasia . Methods Pubmed ® and the Cochrane Library were search ed for r and omized controlled trials longer than 6 months in duration . The subjects in the trials were men aged 40 or over , with moderate to severe symptoms of benign prostatic hyperplasia ( BPH ) as determined by International Prostate Symptom Score ( IPSS ) . We pooled data from a total of nine different clinical trials . Results Dutasteride was superior to placebo in improving urinary symptoms measured by IPSS ( ∆ = −1.78 , 95 % CI −3.01 to −0.55 ) , peak urinary flow ( Qmax ) ( ∆ = 1.27 mL/s , 95 % CI 0.97–1.57 ) , and change in total prostate volume ( TPV ) ( ∆ = −17.40 cm3 , 95 % CI −25.77 to −9.02 ) while it result ed in more frequent drug-related adverse events ( RR 1.35 , 95 % CI 1.19–1.54 ) . Combination therapy with dutasteride and tamsulosin result ed in significantly greater improvements in IPSS and Qmax than tamsulosin monotherapy ( ∆ = −1.80 mL/s , 95 % CI −1.81 to −1.79 and ∆ = 1.60 mL/s , 95 % CI 1.59–1.61 , respectively ) . When comparing dutasteride with finasteride , no significant differences in symptom improvement or the rate of adverse events were observed . Conclusions Dutasteride can be used to improve urinary symptoms ( IPSS and Qmax ) and reduce TPV but with awareness of its potential adverse events . Combination therapy with tamsulosin can be considered when further improvements in symptoms are desired
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"CONTEXT Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions . OBJECTIVE To explore whether the association between funding and conclusions in r and omized drug trials reflects treatment effects or adverse events . DESIGN Observational study of 370 r and omized drug trials included in meta-analyses from Cochrane review s selected from the Cochrane Library , May 2001 . From a r and om sample of 167 Cochrane review s , 25 contained eligible meta-analyses ( assessed a binary outcome ; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment ) . The primary binary outcome from each meta- analysis was considered the primary outcome for all trials included in each meta- analysis . The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect , adverse events , and additional confounding factors ( method ological quality , control intervention , sample size , publication year , and place of publication ) . MAIN OUTCOME MEASURE Conclusions in trials , classified into whether the experimental drug was recommended as the treatment of choice or not . RESULTS The experimental drug was recommended as treatment of choice in 16 % of trials funded by nonprofit organizations , 30 % of trials not reporting funding , 35 % of trials funded by both nonprofit and for-profit organizations , and 51 % of trials funded by for-profit organizations ( P funding , treatment effect , and double blinding were the only significant predictors of conclusions . Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice ( odds ratio , 5.3 ; 95 % confidence interval , 2.0 - 14.4 ) compared with trials funded by nonprofit organizations . This association did not appear to reflect treatment effect or adverse events . CONCLUSIONS Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results . Readers should carefully evaluate whether conclusions in r and omized trials are supported by data",
"BACKGROUND Combination therapy with dutasteride and tamsulosin provides significantly greater benefit than either monotherapy for various patient-reported outcomes in men with moderate-to-severe lower urinary tract symptoms ( LUTS ) due to benign prostatic hyperplasia ( BPH ) and prostatic enlargement . OBJECTIVE To investigate whether combination therapy is more effective than either monotherapy in reducing the relative risk for acute urinary retention ( AUR ) , BPH-related surgery , and BPH clinical progression over 4 yr in men at increased risk of progression . DESIGN , SETTING , AND PARTICIPANTS The Combination of Avodart and Tamsulosin ( CombAT ) study was a 4-yr , multicenter , r and omised , double-blind , parallel-group study in 4844 men > or = 50 yr of age with a clinical diagnosis of BPH , International Prostate Symptom Score > or = 12 , prostate volume > or = 30 cm(3 ) , prostate-specific antigen 1.5 - 10 ng/ml , and maximum urinary flow rate ( Q(max ) ) > 5 and or = 125 ml . INTERVENTION Oral daily tamsulosin , 0.4 mg ; dutasteride , 0.5 mg ; or a combination of both . MEASUREMENTS The 4-yr primary end point was time to first AUR or BPH-related surgery . Secondary end points included BPH clinical progression , symptoms , Q(max ) , prostate volume , safety , and tolerability . RESULTS AND LIMITATIONS Combination therapy was significantly superior to tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery . Combination therapy was also significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression . Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr . Safety and tolerability of combination therapy was consistent with previous experience with dutasteride and tamsulosin monotherapies , with the exception of an imbalance in the composite term of cardiac failure among the three study arms . The lack of placebo control is a study limitation . CONCLUSIONS The 4-yr CombAT data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe LUTS due to BPH and prostatic enlargement . CLINICAL TRIALS.GOV IDENTIFIER : NCT00090103 ( http://www . clinical trials.gov/ct2/show/NCT00090103 )",
"Abstract Background : Dutasteride is a dual inhibitor of type I and type II 5α-reductases and provides nearly complete suppression of dihydrotestosterone , which plays a key role in the aetiology and development of benign prostatic hyperplasia ( BPH ) . Most knowledge about the efficacy and safety of dutasteride in BPH derives from three pivotal phase III studies conducted primarily in Caucasian population s. Objective : This study aim ed to evaluate the efficacy and safety of dutasteride in Chinese adults with symptomatic BPH . Methods : This was a r and omized , double-blind , parallel-group , placebo-controlled study conducted over 6 months , followed by an open-label extension of 12 months . A total of 253 BPH subjects with a total prostate volume ( TPV ) of ≥30 cm3 , a maximal urinary flow rate ( Qmax ) between 5 and 15 mL/s , and an American Urology Association Symptom Index ( AUA-SI ) score of ≥12 units were r and omized to dutasteride 0.5 mg/day orally or matching placebo treatment in a 1 : 1 ratio . After 6 months , eligible subjects who volunteered to enter the open-label extension received dutasteride 0.5 mg/day orally . Changes in TPV , Qmax and AUA-SI as well as drug safety were evaluated . Results : Dutasteride significantly reduced mean TPV compared with placebo at 3 and 6 months ( both p , mean TPV decreased by 17.14 % versus 3.71 % in the dutasteride and placebo groups , respectively . Numerically higher improvements in Qmax and AUA-SI were observed in the dutasteride group at 3 and 6 months , but there was no statistically significant difference between treatment groups . However , ad hoc analysis indicated that , at 6 months , significantly higher proportions of subjects in the dutasteride group experienced a Qmax improvement of ≥3 mL/s , or an AUA-SI improvement of ≥1 unit , compared with the placebo group ( both p the Qmax responder rates were 33.63 % and 19.83 % in the dutasteride- and placebo-treated groups , respectively , and the AUA-SI responder rates were 87.61 % and 76.92 % , respectively . During the open-label extension , continuous improvements in TPV , Qmax and AUA-SI were noted in both groups . Dutasteride was well tolerated with a low incidence of treatment-related adverse events over 18 months . Conclusion : Dutasteride was effective compared with placebo in the treatment of symptomatic BPH among Chinese patients . The efficacy data from trials involving subjects of different ethnic origins showed some similarities . Dutasteride was generally well tolerated during the study period",
"BACKGROUND Dutasteride is a dual inhibitor of type I and type II 5α-reductases and provides nearly complete suppression of dihydrotestosterone , which plays a key role in the aetiology and development of benign prostatic hyperplasia ( BPH ) . Most knowledge about the efficacy and safety of dutasteride in BPH derives from three pivotal phase III studies conducted primarily in Caucasian population s. OBJECTIVE This study aim ed to evaluate the efficacy and safety of dutasteride in Chinese adults with symptomatic BPH . METHODS This was a r and omized , double-blind , parallel-group , placebo-controlled study conducted over 6 months , followed by an open-label extension of 12 months . A total of 253 BPH subjects with a total prostate volume ( TPV ) of ≥30 cm3 , a maximal urinary flow rate ( Qmax ) between 5 and 15 mL/s , and an American Urology Association Symptom Index ( AUA-SI ) score of ≥12 units were r and omized to dutasteride 0.5 mg/day orally or matching placebo treatment in a 1 : 1 ratio . After 6 months , eligible subjects who volunteered to enter the open-label extension received dutasteride 0.5 mg/day orally . Changes in TPV , Qmax and AUA-SI as well as drug safety were evaluated . RESULTS Dutasteride significantly reduced mean TPV compared with placebo at 3 and 6 months ( both p , mean TPV decreased by 17.14 % versus 3.71 % in the dutasteride and placebo groups , respectively . Numerically higher improvements in Qmax and AUA-SI were observed in the dutasteride group at 3 and 6 months , but there was no statistically significant difference between treatment groups . However , ad hoc analysis indicated that , at 6 months , significantly higher proportions of subjects in the dutasteride group experienced a Qmax improvement of ≥3 mL/s , or an AUA-SI improvement of ≥1 unit , compared with the placebo group ( both p the dutasteride- and placebo-treated groups , respectively , and the AUA-SI responder rates were 87.61 % and 76.92 % , respectively . During the open-label extension , continuous improvements in TPV , Qmax and AUA-SI were noted in both groups . Dutasteride was well tolerated with a low incidence of treatment-related adverse events over 18 months . CONCLUSION Dutasteride was effective compared with placebo in the treatment of symptomatic BPH among Chinese patients . The efficacy data from trials involving subjects of different ethnic origins showed some similarities . Dutasteride was generally well tolerated during the study period",
"PURPOSE We determined the occurrence of and risk factors for acute urinary retention in the community setting . MATERIAL S AND METHODS A cohort of 2,115 men 40 to 79 years old was r and omly selected from an enumeration of the Olmsted County , Minnesota population ( 55 % response rate ) . Participants completed a previously vali date d baseline question naire that assessed symptom severity , and voided into a portable urometer to measure peak urinary flow rates . A 25 % r and om sub sample underwent transrectal sonographic imaging of the prostate to determine prostate volume . Followup was performed through a retrospective review of community medical records to determine the occurrence of acute urinary retention in the subsequent 4 years . RESULTS During the 8,344 person-years of followup 57 men had a first episode of acute urinary retention ( incidence 6.8/1,000 person-years , 95 % confidence interval [ CI ] 5.2 , 8.9 ) . Among men with no to mild symptoms ( American Urological Association symptom index score 7 or less ) the incidence of acute urinary retention increased from 2.6/1,000 person-years among men 40 to 49 years old to 9.3/1,000 person-years among men 70 to 79 years old . By contrast , rates increased from 3.0/1,000 person-years for men 40 to 49 years old to 34.7/1,000 person-years among men 70 to 79 years old among men with moderate to severe symptoms ( American Urological Association symptom index score greater than 7 ) . Men with depressed peak urinary flow rate ( less than 12 ml . per second ) were at 4 times the risk of acute urinary retention compared with men with urinary flow rates greater than 12 ml . per second ( 95 % CI 2.3 , 6.6 ) . Men with an enlarged prostate ( greater than 30 ml . ) experienced a 3-fold increase in risk ( 95 % CI 1.0 , 9.0 , p = 0.04 ) . CONCLUSIONS Lower urinary tract symptoms , depressed peak urinary flow rates , enlarged prostates and older age are associated with an increased risk of acute urinary retention in community dwelling men . These findings may help to identify men at increased risk of acute urinary retention in whom closer evaluation may be warranted",
" OBJECTIVE : This study compared α-blocker monotherapy with combination therapy involving an α-blocker and a 5-α reductase inhibitor for benign prostatic hyperplasia ( BPH ) , according to baseline prostate volume . METHODS : Korean men diagnosed with BPH were r and omized to 12 months ' treatment with 0.2 mg tamsulosin or 0.2 mg tamsulosin plus 0.5 mg dutasteride . Prostate specific antigen ( PSA ) , prostate volume , transition zone volume ( TZV ) , International Prostate Symptom Score ( IPSS ) , maximal urinary flow rate ( Q max ) , postvoid residual urine volume and sexual function were assessed at baseline and after 12 months ' treatment . Variables were analysed based on baseline prostate volumes of ≤ 35 ml or > 35 ml . RESULTS : In total , 216 men with BPH were included . Combination therapy result ed in significant improvements in prostate volume , TZV , PSA , IPSS and Q max , which were most pronounced in men with a prostate volume > 35 ml . CONCLUSIONS : Tamsulosin monotherapy was sufficient treatment for BPH in Korean men with a prostate volume ≤ 35 ml . Combination tamsulosin and dutasteride therapy provided greater benefits than tamsulosin monotherapy in men with BPH whose prostate volume was > 35 ml",
"OBJECTIVES To assess the efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia ( BPH ) . METHODS This was a r and omized , double-blind , placebo-controlled , parallel-group study . A total of 378 subjects with clinical BPH having an International Prostate Symptom Score ( IPSS ) of 8 points or greater , a prostate volume of 30 mL or greater , and a maximal urinary flow rate ( Qmax ) of 15 mL/s or less were r and omized to receive placebo or dutasteride once daily for 52 weeks . Subjects were stratified according to tamsulosin use at baseline . The numbers of subjects with and without tamsulosin use were 242 and 136 , respectively . IPSS , Qmax , prostate volume and drug safety were evaluated . RESULTS Continued improvement in IPSS was noted in the dutasteride group , and dutasteride significantly decreased IPSS compared with placebo . At week 52 , dutasteride significantly improved Qmax and prostate volume compared with placebo . Drug-related sexual function events in the dutasteride group were infrequent and generally were not treatment limiting . CONCLUSIONS Dutasteride improves urinary symptoms and flow rate and reduces prostate volume . In Japanese men with BPH , it is effective and generally well tolerated during the one-year treatment period",
"PURPOSE We investigated whether combination therapy with dutasteride and tamsulosin is more effective than either monotherapy alone for improving symptoms and long-term outcomes in men with moderate to severe lower urinary tract symptoms and prostatic enlargement ( 30 cc or greater ) . We report preplanned 2-year analyses . MATERIAL S AND METHODS The CombAT study is an ongoing , multicenter , r and omized , double-blind , parallel group study . Men 50 years or older with a clinical diagnosis of benign prostatic hyperplasia , International Prostate Symptom Score 12 points or greater , prostate volume 30 cc or greater , total serum prostate specific antigen 1.5 ng/ml or greater to 10 ng/ml or less and peak urinary flow greater than 5 to 15 ml per second or less with a minimum voided volume of 125 ml or greater were r and omized to 0.5 mg dutasteride , 0.4 mg tamsulosin or the combination once daily for 4 years . Symptoms were assessed every 3 months and peak urinary flow was assessed every 6 months . The primary end point at 2 years was the change in International Prostate Symptom Score from baseline . RESULTS Combination therapy result ed in significantly greater improvements in symptoms vs dutasteride from month 3 and tamsulosin from month 9 , and in benign prostatic hyperplasia related health status from months 3 and 12 , respectively . There was a significantly greater improvement from baseline in peak urinary flow for combination therapy vs dutasteride and tamsulosin monotherapies from month 6 . There was a significant increase in drug related adverse events with combination therapy vs monotherapies , although most did not result in the cessation of therapy . CONCLUSIONS In men with moderate to severe lower urinary tract symptoms and prostate enlargement ( 30 cc or greater ) combination therapy provides a significantly greater degree of benefit than tamsulosin or dutasteride monotherapy",
"OBJECTIVES To study the efficacy and safety of dutasteride , a dual inhibitor of the 5-alpha-reductase isoenzymes types I and II . METHODS A total of 4325 men ( 2951 completed ) with clinical benign prostatic hyperplasia , moderate to severe symptoms ( American Urological Association-Symptom Index score of 12 points or greater ) , a peak flow rate of 15 mL/s or less , a prostate volume of 30 cm3 or greater ( as measured by transrectal ultrasonography ) , and a serum prostate-specific antigen level of 1.5 to 10.0 ng/mL ( inclusive ) were enrolled into three identical clinical trials and r and omized to 0.5 mg dutasteride daily or placebo . After a 1-month , single-blind , placebo lead-in , patients were followed up for 24 months in a double-blind trial with multiple interval assessment s. RESULTS At 24 months , serum dihydrotestosterone was reduced from baseline by a mean of 90.2 % ( median -93.7 % ; P total prostate and transition zone volumes were reduced by a mean of 25.7 % and 20.4 % , respectively ( P symptom score was improved by as early as 3 months , with pooled significance from 6 months onward ( P maximal flow rate improved significantly from 1 month ( P risk reduction of acute urinary retention was 57 % and the risk reduction of benign prostatic hyperplasia-related surgical intervention was 48 % compared with placebo . The drug was well tolerated . CONCLUSIONS Dutasteride is a potent inhibitor of dihydrotestosterone production that is safe and effective in terms of the reduction of prostate volume and symptoms , flow rate improvement , and the reduction of the risk of acute urinary retention and surgery during a 24-month study period"
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4117d35e-06ff-11f0-808a-c43d1ab1c353
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OBJECTIVE To evaluate the effect of iron supplementation on haemoglobin ( Hb ) in children through a systematic review of r and omised controlled trials . MATERIAL S AND METHODS Electronic data bases , personal files , h and search of review s , bibliographies of books , and abstract s and proceedings of international conferences were review ed . R and omised controlled trials evaluating change in Hb levels with interventions that included oral or parenteral iron supplementation or iron-fortified formula milk or cereals were analysed . RESULTS A total of 55 trials ( 56 cohorts ) provided relevant information . Publication bias was evident ( P change in Hb with iron supplementation ( weighted mean difference ) was 0.74 g/dL ( 95 % CI , 0.61 - 0.87 ; P baseline Hb level , oral medicinal iron supplementation , and malarial nonhyperendemic region were significant predictors of greater Hb response and heterogeneity . Projections suggested that , on average , between 37.9 % and 62.3 % of baseline anaemia ( Hb iron supplementation among children under 6 years of age ; the corresponding range for malarial hyperendemic regions was 5.8 % to 31.8 % . CONCLUSIONS This systematic review indicates that iron supplementation increases Hb levels in children significantly but modestly . The increase is greater in subjects who are anaemic at the start of the trial and lower in malarial hyperendemic areas and in those consuming iron-fortified food . The projected reductions in prevalence of anaemia with iron supplementation alone highlight the need for additional area-specific interventions , particularly in malaria-prone regions
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"OBJECTIVE In many developing countries , children are at high risk for both goiter and anemia . Iron ( Fe ) deficiency adversely effects thyroid metabolism and reduces efficacy of iodine prophylaxis in areas of endemic goiter . The study aim was to determine if co-fortification of iodized salt with Fe would improve efficacy of the iodine in goitrous children with a high prevalence of anemia . DESIGN AND METHODS In a 9-month , r and omized , double-blind trial , 6 - 15 year-old children ( n=377 ) were given iodized salt ( 25 microg iodine/g salt ) or dual-fortified salt with iodine ( 25 microg iodine/g salt ) and Fe ( 1 mg Fe/g salt , as ferrous sulfate microencapsulated with partially hydrogenated vegetable oil ) . RESULTS In the dual-fortified salt group , hemoglobin and Fe status improved significantly compared with the iodized salt group ( P mean decrease in thyroid volume measured by ultrasound in the dual-fortified salt group ( -38 % ) was twice that of the iodized salt group ( -18 % ) ( P serum thyroxine was significantly increased ( P prevalence of hypothyroidism and goiter decreased ( P efficacy of iodine in goitrous children with a high prevalence of anemia",
"Six-month-old breast-fed infants were r and omly allocated to a high iron ( 8.2 + /- 2.9 mg/day , n = 36 ) weaning diet or a control group ( 5.2 + /- 3.4 mg/day , n = 26 ) . We could detect no effect of increased iron intake from weaning foods on iron status of these iron-sufficient infants at 12 months",
"To assess the effects of iron therapy on developmental test scores in infants with iron deficiency anemia , 68 Guatemalan babies 6 to 24 months of age , with and without mild iron deficiency anemia , were tested with the Bayley Scales of Infant Development before and after one week of oral iron treatment . The two major findings of the study were developmental deficits in the anemic group prior to treatment , and lack of rapid improvement with short-term oral iron therapy . The mean pretreatment Mental Development Index of the anemic group was significantly lower than that of nonanemic infants . The anemic group 's pretreatment Psychomotor Development Index was also lower than that of the nonanemic control group . In a double-blind r and omized study , six to eight days of oral iron therapy did not reverse these deficits . Consequently , the deficits of the anemic group can not be unequivocably attributed to iron lack . However , no significant differences were found between anemic and nonanemic groups in birth histories , socioeconomic level , or general nutritional status which might otherwise explain the lower developmental test scores of the anemic babies ",
"We conducted a r and omized controlled trial of the effects of dietary supplements on anemia , weight and height in 136 anemic school children from a low socioeconomic background in Bagamoyo District schools in Tanzania . The aim of the current study was to investigate the impact of dietary supplements on anemia and anthropometric indices of anemic school children . The supplements were vitamin A alone , iron and vitamin A , iron alone or placebo , administered in a double-blinded design for 3 mo . All supplements were provided with local corn meals . Hemoglobin concentration , body weight and height were measured at baseline and at follow-up after supplementation . Vitamin A supplementation increased the mean hemoglobin concentration by 13.5 g/L compared with 3.5 g/L for placebo [ P mean body weight by 0.6 kg compared with 0.2 kg for placebo ( P mean height by 0.4 cm compared with 0.1 cm for placebo ( P = 0.0009 , 95 % CI 0.08 - 0.42 ) . However , the group of children who received combined vitamin A and iron supplementation had the greatest improvements in all indicators compared with placebo ( 18.5 g/L , P hemoglobin , weight and height , respectively ) . It is likely that vitamin A supplementation may have a useful role in combating the problems of vitamin A deficiency and anemia , as well as in improving children 's growth , in developing countries",
"The present study investigates the effect of iron supplementation on measures of school performance among 78 iron-deficient anemic and 41 nonanemic children in an economically deprived rural area in Central Java , Indonesia . All the subjects were treated for ancylostomiasis before iron supplementation . They were r and omly assigned to either an iron or placebo group . Hematological and behavioral measurements were obtained immediately before ( T1 ) and after ( T2 ) the iron and placebo treatments . Iron treatment for a 3-mo period result ed in substantive increases in mean Hgb , Hct , and transferrin saturation among the iron-deficient anemic children . Furthermore , changes in the iron status of iron-deficient anemic children were associated with significant changes in the school achievement test scores of iron-deficient anemic children . T2 evaluation of achievement test scores indicated that the difference between iron-treated anemic and nonanemic children was still statistically significant . However , when T1 scores were entered as a covariate , iron-deficient anemic subjects treated with iron obtained significantly higher delta achievement scores . Findings from the present study indicate that iron supplementation among iron-deficient anemic children benefits learning processes as measured by the school achievement test scores",
"Intermittent iron supplementation has been suggested as a replacement for daily iron supplements for reducing anemia in developing countries . The effects of once weekly and daily iron supplementation on hemoglobin ( Hb ) , serum ferritin ( SF ) , prevalence of anemia , weight and height are compared in this study . Primary schoolchildren ( n = 397 ) from two selected schools in the Hat Yai rural area , southern Thail and , were recruited in 1999 . All children received Albendazole and then r and omly received ferrous sulfate ( 300 mg/tablet ) either daily or weekly , or a placebo for 16 wk . The average increase in Hb was not significantly different between the daily ( mean + /- SD ; 6.5 + /- 6.0 g/L ) and weekly ( 5.7 + /- 6.3 g/L ) groups . However , the average increase in SF was greater ( P iron deficiency anemia were abolished in both daily and weekly groups , whereas no reduction in prevalence occurred in the placebo group . Height gain was greater in children who received weekly ( mean + /- SD ; 2.6 + /- 0.9 cm ) than in those who received daily iron ( mean + /- SD ; 2.3 + /- 0.8 cm ) , ( P Weight gain , weight-for-age and height-for-age were not significantly different among the intervention groups . It is concluded that a weekly iron dose is more effective than a daily dose in height gain but not in hematological improvement over 16 wk of supplementation",
"BACKGROUND Deficiencies of iron and vitamin A are prevalent worldwide . Single-micronutrient supplementation is widely used to combat these deficiencies . However , micronutrient deficiencies often occur concurrently , and there are many interactions between micronutrients . OBJECTIVE This study investigated interactions among 3 important micronutrients -- iron , vitamin A , and zinc -- when they are given as supplements . DESIGN In a r and omized , double-blind , placebo-controlled supplementation trial , 387 Indonesian infants aged 4 mo were supplemented 5 d/wk for 6 mo with 10 mg Fe , 10 mg Zn , 2.4 mg beta-carotene , 10 mg each of Fe and Zn , 10 mg Zn + 2.4 mg beta-carotene , or placebo . Complete data on micronutrient status , including hemoglobin , ferritin , retinol , zinc , and the modified relative dose response ( a measure of liver retinol stores ) , were available from 256 infants at the end of the study . RESULTS Iron-supplemented infants had significantly lower plasma retinol concentrations and a significantly higher prevalence of vitamin A deficiency , as defined by a plasma retinol concentration liver stores of vitamin A. Iron supplementation improved iron status , and zinc supplementation improved zinc status , but beta-carotene supplementation did not significantly improve vitamin A status . CONCLUSIONS In this study , iron supplementation in infants with marginal vitamin A status led to lower plasma vitamin A concentrations and simultaneously to greater vitamin A liver stores . This implies a redistribution of retinol after iron supplementation , which might induce vitamin A deficiency . Therefore , iron supplementation in infants should be accompanied by measures to improve vitamin A status",
"BACKGROUND In developing countries , incomplete resolution of anemia with iron supplementation is often attributed to poor compliance or inadequate duration of supplementation , but it could result from deficiencies of other micronutrients . OBJECTIVE Our objective was to assess children 's hematologic response to supervised , long-term iron supplementation and the relation of this response to other micronutrient deficiencies , anthropometry , morbidity , and usual dietary intake . DESIGN Rural Mexican children aged 18 - 36 mo ( n = 219 ) were supplemented for 12 mo with either 20 mg Fe , 20 mg Zn , both iron and zinc , or placebo . Children were categorized as iron-unsupplemented ( IUS ; n = 109 ) or iron supplemented ( IS ; n = 108 ) . Hemoglobin , hematocrit , mean corpuscular volume , mean cell hemoglobin , plasma concentrations of micronutrients that can affect hematopoiesis , anthropometry , and diet were assessed at 0 , 6 , and 12 mo ; morbidity was assessed biweekly . RESULTS At baseline , 70 % of children had low hemoglobin ( low hematocrit , 48 % were ferritin deficient , 10 % had deficient and 33 % had low plasma vitamin B-12 concentrations , 29 % had deficient vitamin A concentrations , and 70 % had deficient vitamin E concentrations . Iron supplementation increased ferritin from 11 + /- 14 microg/L at baseline to 31 + /- 18 microg/L after 6 mo ( P anemia persisted in 30 % and 31 % of supplemented children at 6 and 12 mo , respectively , and was not significantly different between the IUS and IS groups at 12 mo . Initial plasma vitamin B-12 , height-for-age , and dietary quality predicted the hematopoietic response to iron . CONCLUSION Lack of hemoglobin response to iron was associated with indicators of chronic undernutrition and multiple micronutrient deficiencies",
"BACKGROUND Iron deficiency anemia and recurrent infections are common among children of low socioeconomic status . OBJECTIVE The objective was to evaluate the effects of iron supplementation on iron status and morbidity in children with or without infection . DESIGN Children aged 5 - 10 y were recruited for a r and omized , controlled , double-blind study from out patients attending the Children 's Hospital , Colombo , Sri Lanka . Clinical , inflammatory , nutritional , and iron statuses were determined at baseline and after the intervention . Children with a history of recurrent upper respiratory tract infections ( URTIs ) and with laboratory and clinical evidence of a current URTI constituted the infection group ( n = 179 ) , and children without infection constituted the control group ( n = 184 ) . Subjects in both groups were supplemented with ferrous sulfate ( 60 mg Fe ) or placebo once daily for 8 wk . Morbidity from URTIs , the number of gastrointestinal infections , and compliance were recorded every 2 wk . RESULTS The overall prevalence of anemia was 52.6 % . Iron supplementation significantly improved iron status by increasing hemoglobin ( P ferritin ( P iron status in the children who received placebo . In both the infection group and the control group , the mean number of URTI episodes and the total number of days sick with an URTI during the period of intervention were significantly lower ( P iron supplements than in those who received placebo . CONCLUSION Iron supplementation significantly improves iron status and reduces morbidity from URTIs in children with or without infection ",
"A r and omized , double-blind , placebo-controlled iron supplementation trial was conducted in Kenya to examine the effect of iron supplements on appetite and growth in 87 primary school children . Sustained-release ferrous sulfate ( 150 mg ) or placebo tablets were provided daily at school for 14 wk . Prior to tablet administration , baseline anthropometry , iron nutritional status ( hemoglobin and serum ferritin ) , parasitic infections and clinical indicators of morbidity were measured . A baseline appetite test was conducted twice on each child by quantitatively measuring the ad libitum consumption of a midmorning snack . In addition , each child was asked for a subjective assessment of his or her appetite . Follow-up exams and appetite tests were identical to those at baseline . Findings indicated that provision of iron supplements result ed in improved growth and improved appetite ( in terms of both energy intake of the snack and child report of appetite ) as compared with children receiving the placebo . The increased energy intake from the snack was 10 % of the daily estimated energy intake for children of this same age group living elsewhere in Kenya . Further research into the underlying physiological mechanisms may shed light on the relationship between iron nutritional status and appetite",
"The effect of oral iron supplementation on blood Fe levels and physical growth in 119 rural Indonesian school children was assessed in this double-blind study . The children were classified into anemic and normal groups according to their initial hemoglobin and transferrin saturation levels and were r and omly assigned to either Fe or placebo treatment for 12 wk . Hematological , anthropometric , and morbidity data were collected before and after the treatment period . Before treatment , anemic subjects were smaller and had higher morbidity than normal subjects . Treatment with 10 mg ferrous sulfate.kg-1.d-1 for 12 wk result ed in a significant improvement in anemic subjects ' hematological status , growth velocity , and level or morbidity",
"BACKGROUND In many developing countries , children are at high risk of both goiter and iron deficiency anemia . Iron deficiency adversely affects thyroid metabolism and may reduce the efficacy of iodine prophylaxis in areas of endemic goiter . OBJECTIVE The aim of this study was to determine whether iron supplementation in goitrous , iron-deficient children would improve their response to iodized salt . DESIGN We conducted a r and omized , double-blind , placebo-controlled trial in 5 - 14-y-old children in Côte d'Ivoire . Goitrous , iron-deficient children ( n = 166 ) consuming iodized salt ( 10 - 30 mg I/kg salt at the household level ) were supplemented with either iron ( 60 mg Fe/d , 4 d/wk for 16 wk ) or placebo . At 0 , 1 , 6 , 12 , and 20 wk , we measured hemoglobin , serum ferritin , serum transferrin receptor , whole-blood zinc protoporphyrin , thyrotropin , thyroxine , urinary iodine , and thyroid gl and volume ( by ultrasonography ) . RESULTS Hemoglobin and iron status at 20 wk were significantly better after iron treatment than after placebo ( P mean reduction in thyroid size in the iron-treated group was nearly twice that in the placebo group ( x + /- SD percentage change in thyroid volume from baseline : -22.8 + /- 10.7 % compared with -12.7 + /- 10.1 % ; P goiter prevalence was 43 % in the iron-treated group compared with 62 % in the placebo group ( P whole-blood thyrotropin or serum thyroxine at baseline or during the intervention . CONCLUSIONS Iron supplementation improves the efficacy of iodized salt in goitrous children with iron deficiency . A high prevalence of iron deficiency among children in areas of endemic goiter may reduce the effectiveness of iodine prophylaxis",
"BACKGROUND According to our current underst and ing , iron absorption with weekly iron supplements is not higher than that with daily supplements ( ie , there is no mucosal block ) . However , community-based trials have repeatedly shown that a weekly regimen is as effective as a daily one . Furthermore , when differences in absorption are found , they are commonly smaller than would be expected on the basis of differences in the amount of iron provided . The possibility of differential compliance between the regimens needs to be evaluated to explain these findings . OBJECTIVE Taking compliance into account , we compared the efficacy and trial effectiveness of weekly and daily iron supplementation during pregnancy . DESIGN In Bangladesh , 50 antenatal centers were r and omly assigned to prescribe either 2 doses of 60 mg Fe once weekly or 1 dose of 60 mg Fe/d . Compliance was monitored by using a pill bottle equipped with an electronic counting device . Hemoglobin concentrations were measured at baseline and after 4 , 8 , and 12 wk of supplementation . RESULTS There was no differential effect per iron tablet between weekly and daily regimens . A 12-wk daily regimen ( 68 % compliance ) produced a small but significantly greater hemoglobin response than did the weekly regimen ( 104 % compliance ) . The first 20 tablets consumed produced most of the effect ; after 40 tablets , there was no further response . CONCLUSIONS There was no evidence of a mucosal block in the daily regimen . Over 12 wk , 50 % of the amount of iron in a daily regimen was sufficient for maximum hemoglobin effect . The weekly regimen provided a large part of this amount , explaining the limited difference in effect . It appears that the current international recommendation for iron supplementation in pregnancy is higher than necessary",
"We compared iron intake and iron nutritional status of two groups of healthy term infants who received meat-containing baby foods fortified with ferrous sulphate ( 2 mg Fe/100 g ) . One group received an Fe-fortified formula ( 1.6 mg Fe/100 kcal ) and the other a nonfortified formula . Fe intake of the group fed the nonfortified formula was significantly lower ( p less than 0.0001 ) . These infants received Fe mainly from fortification Fe with beikost ( 75 - 86 % ) and less than 10 % met the recommended intake of 1 mg.kg-1.d-1 ; whereas 80 - 85 % of the infants fed the Fe-fortified formula did . Hb , Hct , FEP , and ferritin were similar in both groups with the exception of lower ferritin values at age 365 d ( p less than 0.05 ) in the group fed the nonfortified formula . No infant had hemoglobin less than 100 g/L. We conclude that regular consumption of commercially prepared Fe-fortified beikost with meat prevents most healthy term infants from Fe deficiency even if Fe intake is substantially below the recommended intake",
"Ninety-nine anemic children aged 1 - 8 y were divided into four groups . Each group was supplemented for 2 mo with vitamin A , iron , vitamin A plus Fe , or a placebo . Clinical , hematological , and Fe biochemical evaluations were performed at the beginning and end of the study . Vitamin A supplementation produced significant elevations in the serum levels of retinol , blood hemoglobin , hematocrit , erythrocytes , serum Fe , and percent transferrin saturation ( % TS ) and had no effect on total Fe binding capacity ( TIBC ) or serum ferritin . Fe supplementation did not affect serum retinol . However , it improved hematological and Fe nutrition indicators , including TIBC and serum ferritin . The simultaneous administration of vitamin A and Fe result ed in a better response of serum Fe and % TS than when the supplement consisted only of vitamin A or Fe alone . Vitamin A benefits hematological condition and Fe metabolism",
"The effect of weekly iron supplementation with and without deworming on hemoglobin was investigated in a double-masked , placebo-controlled field trial . Subjects were 289 preschoolers who were r and omly divided into three groups . Groups 1 and 2 received 30 mg Fe once weekly and group 3 received a placebo . Group 1 additionally received anthelminthic treatment . Supplements were administered by the mothers , who were educated about iron deficiency beforeh and . In the iron-supplemented groups prevalence of anemia decreased from 37.2 % to 16.2 % ( P Hemoglobin increased by an average of 6.9 + /- 9.8 g/L in the two iron-supplemented groups ( n = 191 ) , which was greater ( P Iron supplements administered once weekly by mothers reduced anemia without major involvement of health staff",
"BACKGROUND Iron deficiency and its consequent anemia constitute the commonest micronutrient deficiency in the world . OBJECTIVE We investigated whether long-term , weekly iron-folate supplements administered at school would improve hemoglobin and ferritin concentrations in adolescent girls , including those with mild-to-moderate anemia and hemoglobin concentrations indicating borderline anemia . DESIGN Subjects were 266 girls with hemoglobin concentrations of 80 - 119.9 g/L ( group A ) and 358 girls with hemoglobin concentrations of 120 - 130 g/L ( group B ) who were otherwise healthy . Two hundred sixty-six girls in group A and 268 girls in group B were r and omly assigned to receive either 60 or 120 mg Fe plus 3.5 mg folic acid weekly for 22 wk . Ninety of the girls in group B were r and omly assigned to receive only 5 mg folic acid weekly . Capillary hemoglobin and plasma ferritin were measured at baseline and after 12 and 22 wk of supplementation . RESULTS By the end of the study , 2 % of the girls had dropped out and > 96 % had taken > or = 20 of the 22 tablets ; side effects were minimal . Mean plasma ferritin increased significantly in all iron-supplemented groups , independently of initial hemoglobin values and iron doses . Ferritin concentrations decreased in the girls supplemented with folic acid only . As expected , hemoglobin responses to iron were higher in group A than in group B and increases were positively correlated with initial plasma ferritin . Hemoglobin failed to respond to folate supplementation if initial plasma ferritin concentrations were low . Mean hemoglobin increased significantly and consistently in relation to the length of treatment . CONCLUSION Long-term , weekly iron-folate supplementation was found to be a practical , safe , effective , and inexpensive method for improving iron nutrition in adolescent schoolgirls",
"BACKGROUND Iron deficiency anemia is the most prevalent nutrition problem in young children . One possible strategy to prevent iron deficiency anemia in this population group is the fortification of affordable food . OBJECTIVE This study was design ed to assess whether iron-fortified c and ies can improve iron status and are acceptable to children aged 4 - 6 y. DESIGN A double-blind , placebo-controlled intervention study was conducted in Jakarta , INDONESIA : The children were r and omly assigned to 1 of 2 treatment groups : a fortified group ( n = 57 ) and a placebo group ( n = 60 ) . Every week for 12 wk , 30 g ( 10 pieces ) c and y was given to the children . The c and y given to the fortified group contained 1 mg elemental Fe/g and very small amounts of other vitamins and minerals . RESULTS The hemoglobin concentration of the fortified group increased by 10.2 g/L ( 95 % CI : 8.3 , 12 g/L ) whereas that of the placebo group increased by 4.0 g/L ( 2.0 , 6.0 g/L ; P Anemia prevalence decreased from 50.9 % at the start of the intervention to 8.8 % after 12 wk of intervention in the fortified group ( P serum ferritin concentration was 71 % higher than at baseline in the fortified group and 28 % higher in the placebo group ( P Acceptability of the iron-fortified c and ies was good . The per capita cost of the supplement was approximately US$ 0.96 - 1.20 for the 12 wk of intervention . CONCLUSION Iron-fortified c and ies were effective for improving the iron status of young children and might be an affordable way to combat iron deficiency in children of low-to-middle income groups",
"BACKGROUND Combined supplementation with iron and zinc during infancy may be effective in preventing deficiencies of these micronutrients , but knowledge of their potential interactions when given together is insufficient . OBJECTIVE The goal was to compare the effect in infants of combined supplementation with iron and zinc and of supplementation with single micronutrients on iron and zinc status . DESIGN Indonesian infants ( n = 680 ) were r and omly assigned to daily supplementation with 10 mg Fe ( Fe group ) , 10 mg Zn ( Zn group ) , 10 mg Fe + 10 mg Zn ( Fe+Zn group ) , or placebo from 6 to 12 mo of age . Venous blood sample s were collected at the start and end of the study . Five hundred forty-nine infants completed the supplementation and had both baseline and follow-up blood sample s available for analysis . RESULTS Baseline prevalences of anemia , iron deficiency anemia ( anemia and low serum ferritin ) , and low serum zinc ( higher hemoglobin ( 119.4 compared with 115.3 g/L ; P serum ferritin ( 46.5 compared with 32.3 microg/L ; P higher serum zinc ( 11.58 compared with 9.06 micromol/L ; P on serum ferritin in the Fe and Fe+Zn groups , but at different levels . There was a significant dose effect on serum zinc in the Zn group , whereas no dose effect was found in the Fe+Zn group beyond 7 mg Zn/d . CONCLUSION Supplementation with iron and zinc was less efficacious than were single supplements in improving iron and zinc status , with evidence of an interaction between iron and zinc when the combined supplement was given",
"In this study the effects of supplementation of iron and zinc , alone or combined , on iron status , zinc status and growth in Indonesian infants is investigated . Micronutrient deficiencies are prevalent in infants in developing countries , and deficiencies often coexist ; thus , combined supplementation is an attractive strategy . However , little is known about interactions between micronutrients . In a r and omized , double-blind , placebo-controlled supplementation trial , 478 infants , 4 mo of age , were supplemented for 6 mo with iron ( 10 mg/d ) , zinc ( 10 mg/d ) , iron + zinc ( 10 mg of each/d ) or placebo . Anthropometry was assessed monthly , and micronutrient status was assessed at the end of supplementation . Supplementation significantly reduced the prevalence of anemia , iron deficiency anemia and zinc deficiency . Iron supplementation did not negatively affect plasma zinc concentrations , and zinc supplementation did not increase the prevalence of anemia or iron deficiency anemia . However , iron supplementation combined with zinc was less effective than iron supplementation alone in reducing the prevalence of anemia ( 20 % vs. 38 % reduction ) and in increasing hemoglobin and plasma ferritin concentrations . There were no differences among the groups in growth . The growth of all groups was insufficient to maintain the same Z-scores for height for age and weight for height . There is a high prevalence of deficiencies of iron and zinc in these infants , which can be overcome safely and effectively by supplementation of iron and zinc combined . However , overcoming these deficiencies is not sufficient to improve growth performance in these infants",
"We report an apparently protective effect of vitamin A in infants who received iron supplements ( 15 mg/d ) for 3 mo . Those receiving iron showed increases in hemoglobin ( 8 g/L ) , ferritin ( 3.7 micrograms/L ) , and the acute-phase protein alpha 1-antichymotrypsin ( ACT ; 0.06 g/L ) . In both the placebo and iron-supplemented groups there were increases in plasma retinol , lutein , alpha-tocopherol , immunoglobulin A , and immunoglobulin G. The improvement in vitamin A status could only have been from a seasonal increase in dietary sources of vitamin A , eg , breast milk and early weaning foods , and there were no obvious effects on iron utilization ( hemoglobin concentrations ) . However , in the infants receiving iron , those whose retinol concentrations increased also showed reductions in ACT , ferritin , immunoglobulin A , and immunoglobulin M. Vitamin A is well known for its antiinfective properties and we suggest that these observations illustrate the importance of even small increases in dietary vitamin A or differences in vitamin A status in reducing the potentially toxic effects of iron supplements in persons in developing countries . These conclusions should now be confirmed with an intervention study to show that the benefits of vitamin A on iron status are due to reduced levels of infection",
"1 . The effect of fortification of food with iron to provide 10 mg elemental Fe/child per d was studied in preschool children maintained on a cereal diet , over a 5-month period . 2 . The absorption of 5 mg Fe as ferrous sulphate mixed in one meal was 3.3 % of the test dose and when 3.3 mg was given with each of three meals over a 2 d period the corresponding value was 4.8 % . 3 . The mean absorption of a test dose of ferrous ascorbate studied in twenty-four children midway through the trial was 42 % . 4 . The only beneficial effect of Fe fortification in this time-period in the experimental group was the prevention of the decrease in packed cell volume which occurred in the control groups",
"Whether children with malarial anaemia should receive supplementation with iron or folic acid is uncertain . Therefore , the effects of supplementary treatment with iron or folic acid , given together with chloroquine or pyrimethamine-sulfadoxine ( Fansidar ) , has been assessed in 600 Gambian children with uncomplicated falciparum malaria . After one month , haematological recovery was significantly better in the group treated with Fansidar than in the chloroquine-treated group ( difference in mean haemoglobin level = 0.54 g/dL , P = 0.01 ) . Children who received iron had a significantly better response than those given placebo ( differences in mean haemoglobin level after one month and at dry season follow-up = 0.70 g/dL , P = 0.006 , and 0.81 g/dL , P = 0.001 , respectively ) . Iron supplementation was not associated with increased prevalence of malaria . Supplementation with folic acid did not improve the haematological response but , among children who received Fansidar , the treatment failure rate was significantly higher among those given folic acid than among those given placebo . Thus , supplementation with iron , but not folic acid , improves haematological recovery without increasing susceptibility to malaria",
"In spite of the declining prevalence of iron-deficiency anemia , a large proportion of low-income infants have \" low-normal \" ( 11 - 11.5 g/dL ) and \" low \" ( less than 11 g/dL ) hemoglobin ( Hgb ) values . Because most of these infants are fed iron-fortified formulas , it was of interest whether additional iron supplementation would enhance Hgb values . A cohort of 334 healthy , inner-city , minority , 6-month-old infants , fed iron-fortified formulas , with Hgb values ranging from 9 to 11.5 g/dL , participated in a double-blind , r and omized , placebo-controlled trial of supplemental iron at 0 , 3 , and 6 mg/kg per day for 3 months . Hemoglobin values increased significantly with age , regardless of assignment to placebo or supplemental iron ( means for the entire cohort : 6 months 10.9 g/dL , 8 months 11.2 , 10 months 11.3 , and 12 months 11.4 ) . The proportion of \" responders \" ( Hgb level increased greater than or equal to 1 g/dL ) was 34 % and did not differ significantly by placebo or iron dose . There were no significant differences in mean corpuscular volume or levels of erythrocyte porphyrins or serum ferritin between treatment groups . The implication s of this clinical trial are twofold : ( 1 ) screening healthy infants fed iron-fortified formula at the age of 6 months is not justified , regardless of socioeconomic status ; ( 2 ) the clinical practice of routinely treating low-income , \" low-Hgb \" infants with iron supplementation , without regard to dietary considerations , is unwarranted",
"Objective : To assess the effects of iron and deworming on linear growth performance of preschoolers . Design : Three-month r and omized , double-blind and placebo-controlled trial . The children were allocated to four treatments : iron ( 60 mg elemental iron/day)+albendazole ( 200 mg/day for 3 consecutive days , repeated 1 month later ) , iron+albendazole-placebo , albendazole+iron-placebo or placebos . The supplementation was supervised . Subjects : A group of 177 children aged 3–5 y was selected from low-income households in a rural area in southern Bénin . A complete data set was analysed for 140 subjects . Many children were stunted ( 58 % had height-for-age Z-score measures : Anthropometric parameters , hemoglobin and eggs per gram feces . Results : No significant difference in changes in anthropometric parameters was observed between study groups , and also not in a sub- sample of stunted and anemic subjects . Changes in hemoglobin were highest in the iron-treated subjects at the end of the 3-month intervention period ( P=0.032 ) . The difference between the iron and the placebo groups remained significant even 7 months later ( P=0.022 ) . The difference was 5 g/l in both periods . Ascaris lumbricoides and hookworm infections decreased significantly in albendazole-treated subjects ( P children may have multiple micronutrient deficiencies . Therefore , it may be interesting to study appetite and food intake of young toddlers in relation to health and linear growth performance in poor environments . Sponsorship : The Nestlé Foundation ( Lausanne , Switzerl and ) .European Journal of Clinical Nutrition ( 2001 ) 55 ,",
"Preterm infants with birth weights between 1,001 and 1,600 gm were r and omly assigned at one week of age to three groups and fed a st and ard milk-based formula , the same formula with iron , or a soy-based formula with iron . Hematologic values and selenium status were then studied prospect ively for five weeks . Rates of decline in hematocrit and hemoglobin did not differ significantly among the three groups and did not correlate with red cell selenium values or glutathione peroxidase activity . Attainment of vitamin E sufficiency was variable among the infants , with no significant intergroup differences . Plasma selenium concentrations did not change significantly , but plasma glutathione peroxidase activity declined consistently in all three groups . Under the conditions of this study , iron at a concentration of 12 mg/L of infant formula did not accelerate hemolysis ; nor was there evidence of a direct association between selenium values and early anemia of prematurity",
"The effects of oral iron supplementation on blood iron levels and learning achievement in 130 rural Indonesian school children were assessed in this double-blind study . The children were classified into anemic and nonanemic groups according to their initial hemoglobin and transferrin saturation levels and were r and omly assigned to either iron or placebo treatment for 3 mo . Hematological , anthropometric , and learning-achievement data were collected before ( T1 ) and after ( T2 ) the treatment period and 3 mo later . The means and st and ard deviations suggest that supplementation with 10 mg ferrous sulfate per kilogram body weight per day for 3 mo result ed in an apparent improvement in anemic subjects ' hematological status and learning-achievement scores . No tests of statistical comparisons are reported",
"A double-blind clinical trial was conducted in Indonesia to assess effects of iron supplementation on performance of iron-depleted and iron-deficient anemic children in discrimination and oddity learning tasks . Half these children received elemental Fe for 8 wk ; the others received a placebo . There were significant changes from pre- to postintervention evaluations in ferritin , transferrin saturation , free erythrocyte protoporphyrin , and hemoglobin among the anemic and iron-depleted children ; no changes were observed among the placebos or any of the iron-replete children . The magnitude of hematological changes in anemic children treated with iron was small ; yet , after treatment the children 's mean ferritin , transferrin saturation , and hemoglobin values were above the cutoff points used for the definition of iron-deficiency anemia ( IDA ) . Pre- and posttreatment psychological test data show that IDA produces alterations in cognitive processes related to visual attention and concept acquisition , alterations reversed with iron treatment",
"Abstract Objective : To measure the effects of iron supplementation and anthelmintic treatment on iron status , anaemia , growth , morbidity , and development of children aged 6–59 months . Design : Double blind , placebo controlled r and omised factorial trial of iron supplementation and anthelmintic treatment . Setting : Community in Pemba Isl and , Zanzibar . Participants : 614 preschool children aged 6–59 months . Main outcome measures : Development of language and motor skills assessed by parental interview before and after treatment in age appropriate subgroups . Results : Before intervention , anaemia was prevalent and severe , and geohelminth infections were prevalent and light — Plasmodium falciparum infection was nearly universal . Iron supplementation significantly improved iron status , but not haemoglobin status . Iron supplementation improved language development by 0.8 ( 95 % confidence interval 0.2 to 1.4 ) points on the 20 point scale . Iron supplementation also improved motor development , but this effect was modified by baseline haemoglobin concentrations ( P=0.015 for interaction term ) and was apparent only in children with baseline haemoglobin concentrations iron treatment increased scores by 1.1 ( 0.1 to 2.1 ) points on the 18 point motor scale . Mebendazole significantly reduced the number and severity of infections caused by Ascaris lumbricoides and Trichuris trichiura , but not by hookworms . Mebendazole increased development scores by 0.4 ( −0.3 to 1.1 ) points on the motor scale and 0.3 ( −0.3 to 0.9 ) points on the language scale . Conclusions : Iron supplementation improved motor and language development of preschool children in rural Africa . The effects of iron on motor development were limited to children with more severe anaemia ( baseline haemoglobin concentration . Mebendazole had a positive effect on motor and language development , but this was not statistically significant . What is already known on this topic Iron is needed for development and functioning of the human brain Anaemic children show developmental delays , but it is not yet clear whether iron deficiency causes these deficits or whether iron supplementation can reverse them Helminth infections in schoolchildren are associated with cognitive deficits , but few studies have been made of helminth infection and early child development What this study adds Low doses of oral iron supplementation given daily improved language development in children aged 1–4 years in Zanzibar Iron supplementation improved motor development , but only in children with initial haemoglobin concentrations below 90 g/l The effects of routine anthelmintic treatment on motor and language milestones were positive , but non-significant , with our sample",
"A r and omized , placebo-controlled treatment trial was conducted among 546 anemic ( hemoglobin concentration , 7 - 11 g/dL ) children aged 2 - 36 months in an area with intense malaria transmission in western Kenya . All children used bednets and received a single dose of sulfadoxine-pyrimethamine ( SP ) on enrollment , followed by either intermittent preventive treatment ( IPT ) with SP at 4 and 8 weeks and daily iron for 12 weeks , daily iron and IPT with SP placebo , IPT and daily iron placebo , or daily iron placebo and IPT with SP placebo ( double placebo ) . The mean hemoglobin concentration at 12 weeks , compared with that for the double-placebo group , was 1.14 g/dL ( 95 % confidence interval [ CI ] , 0.82 - 1.47 g/dL ) greater for the IPT+iron group , 0.79 g/dL ( 95 % CI , 0.46 - 1.10 g/dL ) greater for the iron group , and 0.17 g/dL ( 95 % CI , -0.15 - 0.49 g/dL ) greater for the IPT group . IPT reduced the incidence of malaria parasitemia and clinic visits , but iron did not . The combination of IPT and iron supplementation was most effective in the treatment of mild anemia . Although IPT prevented malaria , the hematological benefit it added to that of a single dose of SP and bednet use was modest",
" Ninety two normal birthweight infants aged 6 months entered a double blind controlled trial which compared a follow on formula milk with no added iron against the same formula milk containing 1.2 mg of iron per 100 ml . There was no significant difference in the social class or demographic characteristics of the two treatment groups or in the proportion of each group completing the trial . There was no difference between the two groups in the quantity of milk taken but the amounts taken lessened between 6 and 18 months of age . There was no difference between the two groups with respect to mean haemoglobin and median serum ferritin at 6 , 9 , 12 , 15 , and 18 months of age . Very few infants developed iron deficiency anaemia in either group but there was a tendency for serum ferritin levels to fall between 6 and 18 months of age in both groups . The results suggest that iron added to follow on milk was not an important source of dietary iron in the infants studied",
"Summary Background Recent data suggest that daily iron supplementation of iron-replete children could impair their growth . If verified for weekly iron supplementation these results would markedly complicate targeting and implementing school-based weekly iron supplementation programs . Aim of the study To ascertain the effect of weekly iron supplementation on the growth and hemoglobin status of non-anemic school-age children . Subjects and methods 73 Bolivian non-anemic school-age children r and omly assigned to the treatment group ( n=37 ; receiving supplements containing FeSO4 during 18 weeks ) or the control group ( n=36 ; receiving a placebo during the same period ) . Hemoglobin concentration and anthropometric measures were determined for each child at the beginning ( T0 ) and the end ( T18 ) of the study . Results The treatment group did not show any significant variation in hemoglobin concentration between T0 and T18 ( −1.6±10.4 g/L ; P=0.40 ) whereas the control group showed a significant decrease in hemoglobin concentration ( −4.6±10.9 g/L ; P=0.03 ) . Anthropometric changes were not significantly different between the treatment and the control groups for weight , ( 1.63±1,11 kg vs 1.88±0.79 kg ; P=0.30 ) , height ( 2.35±0.94 cm vs 2.11±1.03 cm ; P=0.34 ) or mid-upper arm circumference ( 0.29±0.57 cm vs 0.22±0.54 cm ; P=0.64 ) . Conclusion In our study , weekly iron supplementation of non-anemic school-age children had no negative effect on their growth while having a positive effect in preventing significant decreases in hemoglobin concentration . These results suggest that in regions where iron deficiency anemia ( IDA ) is prevalent , a simple and cost-effective way to control IDA in school-age children is to give weekly iron supplements to all children at school",
"Objectives : This paper investigates simultaneously the growth and activity of children that received an early energy and micronutrient supplement , adjusting for all non-supplemental energy intakes . Any additional change in growth and activity after this adjustment was then compared across supplements at three points felt to be representative of the study . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Twenty children that received S belonged to the 12- and 18-month-old cohorts . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Length was measured with a portable measuring board ; a Detecto scale with an accuracy of 0.1 kg was used for the measurement of body weight . Arm and head circumferences were measured using similar fiberglass tapes . Motor activity was assessed through continuous 4 h observations at home and at day care centers . Anthropometry and activity were measured every two months over 12 months . Results : After correcting for non-supplemental sources of energy intake , the effects of the supplement on weight and activity were observed at 2 months ; effects on length and activity were observed at 6 months ; and effects on weight alone were observed at 12 months . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 ,",
"BACKGROUND Malaria and anaemia , especially that due to iron deficiency , are two leading causes of morbidity worldwide . Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas . We undertook a r and omised comparison of different strategies for control of anaemia and malaria in infants , including an assessment of the effect of iron supplementation on malaria susceptibility . METHODS 832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October , 1995 , were r and omly assigned to group DI , receiving daily oral iron ( 2 mg/kg daily ) plus weekly Deltaprim ( 3.125 mg pyrimethamine plus 25 mg dapsone ) ; group IP , receiving iron plus weekly placebo ; group DP , receiving daily placebo plus weekly Deltaprim ; or group PP . supplementation was given from 8 to 24 weeks of age , and the weekly chemoprophylaxis from 8 to 48 weeks . The frequency of severe anaemia ( packed-cell volume malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys . FINDINGS The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron ( 0.62 vs 0.87 cases per person-year ; protective efficacy 28.8 % [ 95 % CI 6.3 - 45.8 ) . Iron supplementation had no effect on the frequency of malaria ( 0.87 vs 1.00 cases per person-year ; protective efficacy 12.8 % [ -12.8 to 32.5 ] ) . The groups that received malaria prophylaxis had lower frequencies of both severe anaemia ( 0.45 vs 1.04 episodes per person-year ; protective efficacy 57.3 % [ 43.0 - 67.9 ] ) and malaria ( 0.53 vs 1.34 episodes per person-year ; protective efficacy 60.5 % [ 48.2 - 69.9 ] ) than the groups that did not receive prophylaxis . After the end of the intervention period , children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups ( relative risks 2.2 [ 1.3 - 3.7 ] and 1.8 [ 1.3 - 2.6 ] ) . INTERPRETATION Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity . Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria . Our findings support iron supplementation of infants to prevent iron-deficiency anaemia , even in malaria-endemic areas",
" A total of 502 children up to the age of 14 years were treated for iron deficiency or overt anemia . ITF 282 was prescribed to 256 children , and a commercially available ferrous polystyrene sulphonate preparation to 246 , in a r and omized double-blind , double-dummy , ten-center trial . One oral vial of ITF 282 ( 60 mg iron ) was administered once a day to children weighing up to 40 kg ; and twice a day to children with body weight equal or superior to 40 kg . In the reference group , oral vials of polystyrene sulphonate ( 52.5 mg iron ) were administered once a day to children weighing up to 40 kg , and twice a day to children weighing 40 kg or more . Treatments lasted 60 days . The treatments ' efficacy and tolerability were evaluated taking into consideration : special hematology , symptomatology , safety hematology and hematochemistry , urinalysis . At the end of treatment , the trend was detected to the normalization of the main hematologic parameters in both groups ( hemoglobin , hematocrit , ferritin , blood iron , transferrin saturation , MCHC ) . Although in the first month the reference treatment appears to provide somewhat faster results , significantly greater values of blood iron are observed at the end of the observation in the ITF 282 group , indicating a more progressive and steady therapeutic effect . The overall clinical rating was , although not significant , in favor of ITF 282 , with a failure rate of 18.0 vs 24.0 % . The general tolerance , although favorable with both treatments , was significantly more favorable with ITF 282 . With this medication , 13 patients complained of 13 events ( 1 heartburn , 6 constipation , 6 abdominal pain ) vs 48 events reported by 43 patients with the reference medication ( 1 heartburn , 2 epigastric pain , 14 constipation , 14 abdominal pain , 3 skin rash , 14 vomiting ) . These observations confirm that , although the most modern preparations of ferrous ions exhibit a relatively low frequency of adverse events of limited clinical concern , it is nevertheless possible to decrease ( with the use of more \" physiologic \" preparations in which the iron is reversibly bound to a protein carrier ) the prevalence and , tendentially , duration and intensity of such events without prejudice for the clinical efficacy . Therefore , the good clinical tolerability of ITF 282 effectively removed one of the main obstacles to the correct compliance with iron treatments ( necessarily to be taken long-term ) , as reduced the risks of undesired events in a particularly susceptible population subgroup , such as children",
"Feeding of iron (Fe)-fortified ( 12–15 mg/L ) infant formulas is an effective and convenient means to protect infants from Fe deficiency . To study lower levels of Fe fortification of infant formulas ( 3 or 6 mg/L ) compared with those currently in use , we compared Fe intake and Fe nutritional status of three groups of healthy , term infants between 90 and 274 days of age . One group received an Fe-fortified whey-predominant formula ( 3 mg/ L ) and the second group received the same formula with a higher Fe level ( 6 mg/L ) . A comparison group was breast-fed at least until 274 days of age . All infants received infant foods and cereals according to European Community recommendations . Mean Fe intake of infants fed formula fortified with 3 mg/L was significantly lower at 183 and 274 days of age ( p age . Hemoglobin , hematocrit , mean corpuscular volume , free erythrocyte protoporphyrin , and serum ferritin levels were similar in the formula-fed groups ; none of the infants had depleted Fe stores ( ferritin depleted Fe stores at 183 days of age , but only 3 % were depleted at 273 days of age , when Fe-fortified beikost was already part of the diet . No influence of Fe nutritional status was found on zinc and copper nutritional status or on growth . We conclude that regular consumption of an infant formula fortified with 3 mg Fe/L , a level substantially below present recommendations , prevents healthy , term infants from developing Fe deficiency during the first 6 months of life . It is preferable that infants 6 months of age and older receive an Fe-fortified formula and a judicious selection of beikost to ensure an adequate dietary intake of Fe",
"In a double-blind , placebo-control prospect i ve cohort study of 196 infants from birth to 15 months of age , assessment was made at 12 months of age of the relationship between iron status and psychomotor development , the effect of a short-term ( 10-day ) trial of oral iron vs placebo , and the effect of long-term ( 3 months ) oral iron therapy . Development was assessed with the mental and psychomotor indices and the infant behavior record of the Bayley Scales of Infant Development in 39 anemic , 30 control , and 127 nonanemic iron-deficient children . Anemic infants had significantly lower Mental and Psychomotor Developmental Index scores than control infants or nonanemic iron-deficient infants ( one-way analysis of variance , P less than .0001 ) . Control infants and nonanemic iron-deficient infants performed comparably . No difference was noted between the effect of oral administration of iron or placebo after 10 days or after 3 months of iron therapy . Among anemic infants a hemoglobin concentration less than 10.5 g/dL and duration of anemia of greater than 3 months were correlated with significantly lower motor and mental scores ( P less than .05 ) . Anemic infants failed specifically in language capabilities and body balance-coordination skills when compared with controls . These results , in a design in which intervening variables were closely controlled , suggest that when iron deficiency progresses to anemia , but not before , adverse influences in the performance of developmental tests appear and persist for at least 3 months despite correction of anemia with iron therapy . If these impairments prove to be long st and ing , prevention of iron deficiency anemia in early infancy becomes the only way to avoid them",
"We tested in the field an extruded rice flour , fortified with a bovine haemoglobin concentrate ( Fe:14 mg/100 g of powder ) . This cereal has a high iron bioavailability , good protein quality and amino acid score . Healthy , term breast-fed infants were prospect ively studied . One group ( n = 92 ) received the fortified cereal ( from 4 to 12 months of age ) . As control , 96 infants received regular solid foods ( cooked vegetables and meat ) from age 4 months . At the end of the field trial , a sub sample of infants in both groups was supplemented with 45 mg Fe during 90 d. Iron nutrition status was determined at 9 , 12 and 15 months . At 12 months , iron deficiency anaemia was present in 17 per cent of controls , in 10 per cent of fortified infants as a whole , but only in 6 per cent of the babies who consumed over 30 g of cereal/d . In addition , this latter group did not show any significant changes in iron nutrition status after the supplementation trial . Results demonstrate that the consumption of a haemoglobin fortified cereal is effective in markedly reducing the incidence of iron deficiency in breast-fed infants",
"Objective : To assess the impact of a daily oral iron supplementation on hematological status , cell-mediated immunity and susceptibility to infections in children living in an environment where iron deficiency , malaria and other infections are frequent . Design : R and omized , double-blind iron supplementation including a placebo group . Setting : A village in Togo , West Africa . Subjects : Of the 229 6–36-month-old children of both sexes recruited , 197 with hemoglobin concentration ≥80 g/l were included and 163 completed the study .Intervention : Children received daily a placebo ( n=79 ) or a dose of 2–3 mg of elemental iron per kg of body weight ( n=84 ) for 3 months . Hematological , nutritional and immune status were assessed at the beginning and at the end of the supplementation period , and 6 months later . Morbidity was recorded throughout the study . Results : Iron supplementation had a significant and positive effect on iron status of children and no impact on the incidence of infections , especially malaria . Its probable effect on immune status was masked by interference of infections and their treatment , which contributed to improve hematological and immune status in both groups . Conclusion : According to the negative consequences of anemia and iron deficiency on global child development , control of iron deficiency by oral iron supplementation in young children has to be conducted , associated with prophylaxis and treatment of malaria and repeated deworming . Sponsorship : Program supported by IRD.European Journal of Clinical Nutrition ( 2000 ) 54 ,",
"Iron-deficient anaemic infants perform worse in tests of mental and motor development than do iron-sufficient infants of a comparable age . A r and omised , double-blind trial was done to monitor the effects of iron supplementation on performance in the Bayley scales of mental and motor development among 12 - 18-month-old infants in Indonesia . Iron-deficient anaemic infants ( n = 50 ) were assigned r and omly to receive dietary ferrous sulphate or placebo for 4 month . Similar treatment r and omisation was done among nonanaemic iron-deficient ( n = 29 ) and iron-sufficient ( n = 47 ) infants . Before intervention , the mean mental and motor scores of the iron-deficient anaemic infants were significantly ( p developmental delays were reversed among iron-deficient anaemic infants who had received iron but they remained the same among placebo-treated iron-deficient anaemic infants . Neither ferrous sulphate nor placebo had significant effects on the scores of the other two iron-status classes . The poor performance of 12 - 18-month-old iron-deficient anaemic infants in the Bayley scales of mental and motor development can be improved to the level of performance of iron-sufficient infants by treatment with ferrous sulphate",
"We conducted a r and omized double-blind trial of a cow 's milk infant formula with increased iron fortification in order to confirm its safety and to measure its effects on iron status and immune function . A group of full-term , well nourished and healthy infants was followed from the age of 3 months to 1 year . A control group of 74 infants was given a commercially available infant formula containing 8.3 mg Fe/100 g . The test group of 75 infants received a similar formula with 40 mg Fe/100 g. The formula with the extra iron proved to be safe and , when compared with the control group , the children in the test group had significantly improved iron status as reflected by the proportion of children classed as normal ( 25 of 61 cf . 44 of 65 ; p less than 0.003 ) , and by the mean values of the haemoglobin concentration ( 11.5 cf . 11.9 g/dl ; p = 0.04 ) , red cell distribution width ( 15.5 % cf . 14.4 % ; p = 0.0005 ) , red cell zinc protoporphyrin ( 3.4 cf . 4.0 micrograms/g Hb ; p = 0.04 ) and ferritin ( 29 cf . 17.3 micrograms/l ; p = 0.004 ) . The extra iron fortification depressed zinc concentration in plasma ( 90.6 cf . 83.5 micrograms/l ; p = 0.05 ) . There was no significant difference between the two groups for laboratory measures of immune function or for incidence of infection . No adverse effects such as infection could be attributed to the increased iron . We conclude that iron fortification of cow 's milk infant formula may be safely increased to 40 mg/100 g ( i.e. by a factor of 4.8 over the common concentration of 8.3 mg/100 g ) , but that this has less than the expected effect on iron status . Further studies are required to define ( a ) the long-term role of facilitators of iron absorption such as ascorbic acid , ( b ) the interaction of iron with absorption of divalent trace elements such as zinc , and ( c ) the effect of iron status on immune function and susceptibility to infection",
"The study was conducted to determine whether provision of oral supplementary iron to primary school children in Kenya would improve their growth . Children in the two lowest grade s who satisfied study criteria were allocated to either an iron-supplementation group ( n = 29 ) or a placebo group ( n = 26 ) . At the baseline before intervention the groups did not differ significantly in age , sex ratio , prevalence and intensity of intestinal helminthic infections , most anthropometric measurements or hemoglobin levels . Although the study lasted for 32 weeks , children only took iron or placebos on school days thus omitting weekends and school holidays . Examination at the end of the study showed that the iron-supplemented children had grown significantly more in terms of weight , weight for height , arm circumference and skinfold thickness compared with the placebo group . Hemoglobin levels had also improved significantly . We conclude that where iron deficiency anemia and undernutrition are prevalent in children , iron supplementation will improve growth and hemoglobin levels",
"The effect of chronic iron intake on diarrhoeal disease was evaluated in children in a community of low socio-economic stratum in Santiago , Chile . Children were incorporated into each of two consecutive cohorts ; each cohort was divided into two groups , one receiving iron-enriched milk ( 12 mg/l ) ( monthly average = 70 children ) and the other a control milk ( 1 mg/l ) ( monthly average = 83 children ) , and each cohort was followed up for 6 months . The incidence of diarrhoea was higher among the iron-supplemented children ( 30.4 vs 25.5 episodes/100 children/month , P 3 - 8 months of age during the summer months . Supplemented infants had more bowel movements on day 1 ( P liquid or semi-liquid stools were passed for more than 15 days more frequently ( P Shigella-associated episodes were less common among iron-supplemented infants ( P Asymptomatic shedding of enteropathogens significantly increased in infants 12 - 18 months of age receiving iron-supplemented milk . In areas with inadequate environmental sanitation , chronic iron supplementation may have negative effects on diarrhoeal morbidity , despite improving iron nutritional status",
"Oral iron supplementation is often routinely given to children with malaria-associated anaemia , but its contribution to recovery is controversial . A r and omized clinical trial , evaluating such routine , was carried out among 100 children , who had a haemoglobin of All children received malaria therapy ( chloroquin + fansidar ) and were r and omly allocated to two groups , one receiving additional oral iron treatment , the other being the control . In the 12-week follow-up period the haemoglobin level and malaria indices were measured at 2 , 4 , 8 , and 12 weeks . There was a 100 per cent compliance during the follow-up period . In each group 20 children ( 40 per cent ) required a blood transfusion . In the remaining 60 children , after 2 weeks the haemoglobin had risen 3.7 g/dl in the ferrous-supplemented group compared to 3.5 g/dl in the non-ferrous group . Thereafter , the increase in haemoglobin in both groups was steady . At follow-up measurements , the groups did not differ for haemoglobin levels . The mean haemoglobin at 12 weeks was 9.2 and 9.0 g/dl , respectively . It was concluded that iron supplementation did not have any effect on the rate of parasitaemia and on parasite density during the 12 weeks . However , the iron-supplemented group had a significantly increased morbidity from other causes than malaria . It appears that iron does not have an effect on the recovery of haemoglobin level in children with malaria-associated anaemia . This study provides no evidence supporting routine iron supplementation to these children",
"OBJECTIVES To obtain baseline data on hemoglobin ( Hb ) levels of adolescent girls belonging to the low-socio-economic groups ; investigate the comparative efficacy of once ' weekly ' and ' daily ' administration of iron-folate tablets with respect to impact on the Hb levels ; and find out the effect of added ascorbic acid supplementation on the efficacy of iron-folate administration with respect to increment in Hb levels . DESIGN R and omized experimental . SETTING Adolescent girls of poor communities in urban areas of Delhi and rural parts of Bharatpur ( Rajasthan ) . METHODS The baseline investigations included measurements of height , weight , and Hb levels . The Hb levels of the participating subjects were measured again after 3 months and 6 months of supplementation . RESULTS 61.9 % of the subjects in the urban and 85.4 % in the rural area were anemic . The response of Hb levels to daily iron/folate supplementation was better in comparison to once-weekly supplementation . The increment in Hb levels of subjects due to addition of vitamin C to iron/folate supplementation was more than that with supplementation of iron/folate alone . CONCLUSIONS Considering compliance , feasibility and cost-factors , a public-health approach consisting of once-weekly distribution of iron/folate supplementation through schools and welfare centers is better and can be recommended as an appropriate strategy for combating anemia in adolescent girls of poor communities in developing countries like India",
"AIMS Iron deficiency anaemia is associated , in observational studies , with developmental disadvantage . This study tested the hypothesis that feeding iron supplemented formula from 9 to 18 months of age would improve developmental performance . SUBJECTS AND METHODS 493 healthy children aged 9 months being fed pasteurised cows ’ milk were recruited from three UK centres . They were r and omised to : cows ’ milk as before , formula containing 0.9 mg/litre iron , or formula containing 1.2 mg/litre iron , until 18 months of age . Bayley mental and psychomotor developmental indices were measured at 18 months , as were growth and haematological indices . RESULTS Children fed iron fortified formula had higher plasma ferritin concentrations , but there were no significant intergroup differences in development or growth . CONCLUSIONS There are no developmental or growth advantages in children given iron supplemented formula , but a benefit for a minority who were anaemic , or the possibility that a benefit may emerge at a later age , can not be excluded",
"A supplementation trial was carried out in 101 children , 6 - 12 years of age , in 3 primary schools in a rural area . Their hemoglobin level and PCV ( mean + /- SD ) were 11.64 + /- 1.21 g/dl and 0.356 + /- 0.028 respectively , 74 % of them were anemic and the hemoglobin level were correlated with the MCHC ( P mean hemoglobin level between those with hookworm infection and those without . The children were divided into 3 groups : Group I comprising 39 children who received placebo tablest ; Group II of 33 , who received ferrous sulphate ( 60 mg elemental iron ) ; Group III of 29 , who received ferrous sulphate ( 60 mg elemental iron ) with riboflavin ( 6 mg ) . Each child received one tablet after lunch on schooldays and evaluation was carried out after receiving 80 to 90 tablets . The mean hemoglobin change of Group II was 0.60 g/dl larger than that of Group I ( P mean hemoglobin change of Group III was 0.38 g/dl larger than that of Group II ( P < .005 ) with 86 % of them responding to iron and riboflavin . Thus additional riboflavin is beneficial in iron supplementation",
"BACKGROUND Iron deficiency continues to be a common problem among infants throughout the world . Iron-fortified formula is effective in preventing iron deficiency but the benefit of iron-fortified cereal is controversial . METHODS We compared iron-fortified rice cereal to unfortified rice cereal in infants who were exclusively breast-fed for more than 4 months and to iron-fortified formula in infants who were weaned to formula before 4 months of age . The design was double blind in respect to the presence or absence of fortification iron in the cereal or formula and included 515 infants who were followed on the protocol from 4 to 15 months of age . Rice cereal was fortified with 55 mg of electrolytic iron per 100 g of dry cereal and infant formula with 12 mg of ferrous sulfate per 100 g of dry powder , levels approximating those in use in the United States . Measures of iron status were obtained at 8 , 12 , and 15 months . Infants with hemoglobin levels of were excluded from the study and treated . RESULTS Consumption of cereal reached plateaus at means of about 30 g/d after 6 months of age in the formula-fed groups and 26 g/d after 8 months in the breast-fed groups ; these amounts are higher than the 19-g/d mean intake by the 73 % of infants who consume such cereal in the United States . Among infants weaned to formula before 4 months , the cumulative percentages of infants excluded for anemia by 15 months were 8 % , 24 % , and 4 % , respectively , in the fortified cereal , unfortified cereal and formula , and fortified formula groups ( P unfortified cereal groups ( P Mean hemoglobin level and other iron status measures were in accord with these findings . CONCLUSION Iron-fortified infant rice cereal can contribute substantially to preventing iron deficiency anemia",
"The aim of this study was to investigate the effects of different doses of iron on haematological status of breastfed infants . One hundred and thirteen infants were r and omized into four groups at 5 months of age . Iron supplementation was given at doses of 1 mg/kg/day , 2 mg/kg/day , and 2 mg/kg/every other day in the first three study groups , respectively , and the last group received placebo . The hematological values , except hemoglobin , were higher in the group supplemented with iron at a dose of 2 mg/kg/day , and ferritin values were statistically higher in the group supplemented with iron at a dose of 2 mg/kg/every other day than in the group supplemented with iron at a dose of 1 mg/kg/day . We suggest that intermittent iron supplementation is more effective than a daily regimen in equal dosages",
"Previous work at this hospital and elsewhere has shown that anaemia in toddlers is common and is associated with psychomotor delay . It seemed unclear , however , whether this association was cause and effect or merely due to the same underprivileged environment . A double blind r and omised intervention study was , therefore , performed . After an initial assessment 97 children with anaemia ( haemoglobin 8 - 11 g/dl ) aged 17 - 19 months received either iron and vitamin C or vitamin C only ( control group ) for two months and were then reassessed . The children who received the iron had an increased rate of weight gain and more of them achieved the expected rate of development . While iron deficiency anaemia is unlikely to be the only factor in the slower development of children living in underprivileged circumstances , it can at least be easily identified and treated . Routine child health surveillance in such areas should include a haemoglobin determination",
"Four studies examined impacts of iron supplementation on school children of various ages and both sexes . The first study investigated impact of iron-folic acid supplements for 60 d on cognition in 94 boys and girls aged 5 - 8 y. Improvement in total scores of the anemics was significantly higher than the nonanemics in 7 - 8-y-old children only . The second study assessed impacts of supplementation on cognition in 14 pairs of 5 - 6-y-old anemic boys , with clear beneficial effects on cognitive function . The third study investigated effects of varying dosages of elemental iron on cognitive function in 48 boys aged 8 - 15 y , with different levels of improvement . The fourth study investigated impacts of iron supplementation on 163 anemic girls aged 8 - 15 y with treatment and evaluations at 4 and 8 mo , with significantly improved scores in cognitive function after the eighth month",
"Abstract Six‐month‐old infants were recruited at 21 centres in the UK and Irel and and r and omly assigned to receive matching iron‐fortified ( 12.3 mg/l iron ) or non‐fortified ( 1.4 mg/l iron ) formula for 9 months . Infants already receiving cow 's milk continued this feed . Haematological indices and iron status were evaluated at age 6 months , 9–10 months and 15 months . Four hundred and six infants entered and 302 completed the study . There were no differences between the groups for increases in weight , head circumference or length . Significant differences between the groups were observed at 15 months for haemoglobin , serum ferritin , serum iron and total iron binding capacity . Haemoglobin levels were non‐iron‐fortified and iron‐fortified formula respectively . The corresponding figures for serum ferritin < 10 µg/l were 43 % , 22 % and 6 % . Follow‐on formula provides an acceptable vehicle for preventing iron deficiency in this vulnerable group",
"It is evident that intermittent iron supplementation is better than daily supplementation in two aspects : iron absorption is more efficient and has insignificant side effects in contrast to the daily dose . The significantly higher daily iron loss observed in the daily iron supplemented groups rats also suggests alterations in total body iron metabolism . Based on serum ferritin distribution patterns , intermittent iron supplementation avoids temporary iron overload with daily iron supplemented . We conclude that weekly iron supplementation scheme is safer and easier to administer . This feasible strategy for the control of iron deficient anemia in pregnant women and children would be an effective iron-supplementation program ( Baily et al. , 1993 )",
"Sixty-nine boys and girls between 10 and 14 years , with evidence of sub clinical vitamin deficiencies and poor iron status were enrolled into the study at the beginning of the rainy season . Children were allocated to three treatment groups to receive five times weekly either a placebo , 200 mg ferrous sulphate or 5 mg riboflavin and 150 mg ascorbic acid . Before receiving the supplement , and 9 weeks later , children performed an exercise regimen on a treadmill during which expired air was collected and heart rate measured . There was a general deterioration in the running performance of the children during the study period which was not affected by either the iron or the vitamin supplement",
"OBJECTIVE A r and omized , double-blind study was conducted comparing high-iron content ( 15 mg/L ) with low-iron content ( 3 mg/L ) premature formula given during initial hospitalization to infants with birth weights less than 1800 g to determine the influence of these differing intakes on the iron nutritional status during the first 4 months of life . A third group of similar infants received human milk mixed with an equal volume of liquid fortifier result ing in an iron content of approximately 1.7 mg/L. PATIENTS AND METHODS Mean birth weight , gestational age , age at study entry , volume of blood removed for studies , and volume of red cells transfused were not different among the three groups . After hospitalization both formula-fed groups were given a cow milk formula with an iron content of 12 mg/L , and breast-fed infants were given an iron-containing multivitamin with a result ing iron intake of 10 mg/d . Infants were observed to 8 weeks after discharge . RESULTS There were no differences in serum iron , ferritin , transferrin , transferrin saturation , hemoglobin , hematocrit , or reticulocyte count among the three groups at study entry , although mean corpuscular hemoglobin and mean corpuscular volume were lower in infants in the low-iron formula group . Mean plasma ferritin was significantly lower in infants receiving low-iron content premature formula at the time of hospital discharge compared with the other two groups . The incidence of anemia ( hemoglobin low transferrin saturation ( low plasma ferritin ( iron intake were observed . Growth was not different among the three groups . CONCLUSIONS These data indicate that preterm infants with formula benefit from formula given during initial hospitalization containing 15 mg/L iron compared with that containing 3",
" Thirty eight children with a haemoglobin concentration of 106 - 110 g/l were given either oral iron ( n = 17 ) or placebo ( n = 21 ) for two months . The treated group achieved a significantly higher rise in haemoglobin concentration ; in a quarter it was greater than 20 g/l . While those with the lower mean corpuscular volume and ferritin showed greater rises in haemoglobin these indices were of little value in predicting response in an individual child",
"We evaluated the effect of weekly doses of 400 mg of ferrous sulphate for 4 months on the iron status of adolescent girls in a controlled trial in Tanga , Tanzania . Supplementation led to a significantly greater increase in serum ferritin compared with the control group ( + 15.6 microg/l vs. 8.6 microg/l ) ( P = 0.002 ) but there was no significant difference in change in haemoglobin . Children given iron showed a significantly greater weight gain than controls ( + 2.4 kg vs. + 1.4 kg ) ( P = 0.03 ) . Weekly iron supplementation may be an effective means of increasing iron stores and growth in children vulnerable to iron deficiency",
" Adult males and children between 4 and 12 years in a subsistence farming community in The Gambia were screened for haematological status . 80 men and 80 children with initially poor status were identified and allocated to three treatment groups comprising : a placebo , ferrous sulphate , and ferrous sulphate with riboflavin . Over a period of 6 weeks of supplementation there was a general improvement in haematological status in the two supplemented groups . The inclusion of riboflavin in the supplement enhanced recovery , particularly in those individuals with strikingly low levels of haemoglobin at the outset",
"In sub-Saharan countries , although malaria and malaria-associated anaemia are major public health problems , the usefulness of supplementary iron treatment for children with malaria-associated anaemia is unknown . In a 6-week period during the 1995 rainy season , 222 Malawian children aged or = 500 parasites/microliter blood and at least 5 g haemoglobin (HB)/dl blood and whose parents gave consent , were r and omized into a prospect i ve study comparing the efficacy of sulphadoxine- pyrimethamine only ( SP ) , SP plus daily iron ( SPD ) and SP plus weekly iron ( SPW ) as treatment for malaria-associated anaemia . The patients had their HB concentrations measured on enrollment ( day 0 ) , just before antimalarial treatment , and on days 3 , 7 , 14 , 21 and 28 ; 215 ( 96.8 % ) completed the 28-day study . Among the children with 5 - 8 g HB/dl on enrolment , HB gain by the end of the study was significantly greater than in the children with > 8 g HB/dl initially ( 4.1 v. 2.2 g/dl ; P gained significantly more HB by days 21 and 28 ( 3.6 and 4.9 g/dl , respectively ) than those in either the SPW ( 2.7 and 3.7 g/dl , respectively ) or the S2 groups ( 2.6 and 3.5 g/dl , respectively ) ; there was no difference in HB gain between the SP and SPW groups . Type of treatment had no apparent effect , at any time during the study , on HB gains in those patients who had > 8 g HB/dl on enrolment . Thus the children with 5 - 8 g HB/dl on enrolment benefited from daily iron therapy whereas those with > 8 g HB/dl derived no significant benefit ; improvement in HB depended most on whether enrolment HB was HB gains , irrespective of treatment group or HB concentration at enrolment , the anaemia observed may be mostly related to malaria . However , as a larger proportion of the iron-treated patients failed to clear their parasitaemias than of those given SP alone , oral iron may inhibit SP action . It is therefore recommended that , for children with both malaria and malaria-associated anaemia , the malaria should first be cleared with an effective antimalarial drug , such as SP , before the anaemia , if it still persists , is treated with iron",
"OBJECTIVE To determine the efficacy of iron-fortified infant formula in preventing developmental delays and abnormal behavior . DESIGN Double-blind , r and omized , controlled trial . SETTING Urban hospital clinic . PARTICIPANTS A total of 283 healthy , bottle-fed infants from very low income families . Children with prematurity , low birth weight , and major anomalies and those who had received more than 2 weeks of evaporated-milk feedings were excluded . The groups were similar for sociodemographic background variables . Fifty-eight infants ( 20.5 % ) dropped out before any outcome data were gathered ; 225 , 204 , 186 , and 154 remained at 6- , 9- , 12- , and 15-month assessment s , respectively . INTERVENTION Iron-fortified formula ( 12.8 mg iron per liter ) versus regular formula ( 1.1 mg iron per liter ) . MAIN OUTCOME MEASURES Iron status was measured on venous blood by determination of hemoglobin , serum iron and iron-binding capacity , serum ferritin , and free erythrocyte protoporphyrin values . The Bayley Scales of Infant Development ( mental and psychomotor indexes ) and two factors of the Infant Behavior Record ( test affect and task orientation ) were the outcomes of interest . RESULTS All measures of iron status were significantly different between groups ( p Psychomotor development patterns differed between groups ( F3,520 , 3.4 ; p = 0.02 ) with time . Mean values were similar at 6 months but differed at 9 and 12 months of age ( p Mental development and behavior were not affected . CONCLUSIONS Iron-fortified formula significantly reduced iron deficiency in a high-risk group of infants and prevented a decline in psychomotor development quotients . This effect may be transient , and its long-term significance needs further study",
"This double-blind clinical trial was conducted in Thail and to assess the impact of iron treatment on the IQ and educational attainment of 1358 9 - 11-y-old children . The children were classified into one of three groups : iron replete , iron depleted , and iron-deficient anemic . The Raven Progressive Matrices was used to measure IQ . A Thai language and a math test were administered to assess school attainment . A 50-mg/d tablet of ferrous sulphate was given for 2 wk and a 100 mg/d tablet , for 14 wk . An anthelminthic drug was given on the day of the blood test before treatment and 3 mo after the intervention started . There is evidence of a positive association between iron status and IQ and a language school achievement test but there is no support for the internal validity of the hypothesis that this association is causal",
"The interactions between infections , malnutrition and poor iron nutritional status in infants at weaning ages are poorly defined . Therefore , four groups of infants from an area with a high incidence of malnutrition ( Lahore , Pakistan ) were enrolled in a prospect i ve , r and omized nutritional intervention study . Between 122 and 365 days of age , the infants from one community received either a milk cereal without iron fortification ( n= 29 ) , a milk cereal fortified with ferrous fumarate ( 7.5 mg/100 g ; n= 30 ) , or a milk cereal fortified with ferric‐pyrophosphate ( 7.5 mg/100 g ; n= 27 ) . Forty‐four infants from a neighbouring community did not receive a nutritional supplement and served as the control group . Calculated mean daily energy‐ and protein intake with the cereals was between 259–287 kcal , and 9.6–10.6 g at 12 months of age , respectively . Mean daily iron intake with the fortified cereals was between 4.1–5.1 mg at corresponding age . Nutritional supplementation result ed in significantly lower incidence of malnutrition and heigher weight gain . Incidence of acute diarrhoea was significantly ( p the iron‐fortified milk cereals had significantly higher hemoglobin ( mean 10.4 vs. 9.8 gdl‐1 ) and serum ferritin ( mean 13.3 vs. 8.5 ngml‐1 ) values than the infants fed the non‐fortified milk cereals . However , no differences in the incidence of infections were found between the supplemented groups . It is concluded that poor nutritional intake between 122 and 365 days of age substantially contributed to the high incidence of diarrhoea and malnutrition in Pakistani infants",
"The optimum management of children with severe malarial anaemia is still uncertain . Hence , we have undertaken a study to determine whether iron treatment is as effective at restoring haemoglobin levels one month after presentation as blood transfusion without iron treatment in children with moderately severe malarial anaemia . Two hundred and eighty-seven children with a packed cell volume ( PCV ) blood transfusion because they had a PCV to receive either blood transfusion ( 58 ) or treatment with oral iron ( 56 ) for 28 d. Twenty-four children died , 23 in the most severely anaemic group . Fifteen children ( 65 % ) died before transfusion was given and most deaths occurred within the first 4 h of admission . One child died in the iron treatment group and 10 subsequently required transfusion . Among the severely anaemic children , those with respiratory distress were at greater risk of death than those without respiratory distress . After 28 d , haematological restoration was significantly better in children who had received iron than in those treated by blood transfusion ( P = 0.02 ) . Children who received malaria chemoprophylaxis after discharge from hospital had fewer episodes of malaria and subsequent admissions to a hospital or health centre than those who did not . Children with severe anaemia and clinical signs of respiratory distress must be identified quickly and transfused as soon as possible . However , for less severely anaemic children who are clinical ly stable , iron therapy offers an alternative to transfusion provided such children can be kept under surveillance and transfused subsequently should this become necessary",
"1 . The effect of daily supplements of 20 - 30 mg inorganic iron as ferrous sulphate on the growth , activity and haematological status of preschool children was studied for 3.5 , 7 and 12 months and compared to that of children who served as controls . All children were given their daily requirements of energy and protein . In addition , they received 5 microgram cyanocobalamin and 200 microgram folic acid . 2 . Fe supplementation increased the haemoglobin , serum Fe and percentage saturation of transferrin and reduced the unsaturated Fe-binding capacity significantly compared to corresponding values for the controls . 3 . Height and activity were unaffected by Fe supplements . 4 . Of the children 45 % had haemoglobin values below 110 g/l at the end of 7 - 12 months of Fe supplementation",
"This experimental study was design ed to investigate the effects of daily versus intermittent iron supplementation on iron status of high school girls in Zahedan and Rasht cities in 1996 - 1997 . The subjects were selected r and omly from among students of grade s 1 - 3 of four high schools in each city . Anemia was determined by measuring hematological indices . 260 anemic and a similar number of non-anemic subjects of 4 high schools were selected and allocated r and omly to 4 treatment groups . During a 3-month period , the test groups were given 150 mg ferrous sulfate tablets ( 50 mg Fe ) . Subjects in group 1 received a daily dose , groups 2 & 3 received twice or once weekly doses respectively . The control group received no iron supplement . For these subjects , in addition to hematological indices biochemical iron indices were measured in the beginning and at the end of the study . The increases in hemoglobin concentration in anemic subjects were not significantly different among supplemented groups but were different from the control group ( p changes in serum ferritin levels in 3 supplemented groups were significantly different from the control group . Serum ferritin in Group 1 was also increased to a greater extent than groups 2 and 3 ( P anemia but the daily dose was more effective in improving iron stores than a weekly dose in the short run",
"BACKGROUND Up to 25 % of adolescent girls in the USA are iron deficient . This double-blind , placebo-controlled clinical trial assessed the effects of iron supplementation on cognitive function in adolescent girls with non-anaemic iron deficiency . METHODS 716 girls who enrolled at four Baltimore high schools were screened for non-anaemic iron deficiency ( serum ferritin Participants were r and omly assigned oral ferrous sulphate ( 650 mg twice daily ) or placebo for 8 weeks . The effect of iron treatment was assessed by question naires and haematological and cognitive tests , which were done before treatment started and repeated after the intervention . We used four tests of attention and memory to measure cognitive functioning . Intention-to-treat and per- protocol analyses were done . FINDINGS Of the 81 enrolled girls with non-anaemic iron deficiency , 78 ( 96 % ) completed the study ( 39 in each group ) . Five girls ( three control , two treatment ) developed anaemia during the intervention and were excluded from the analyses . Thus , 73 girls were included in the per- protocol analysis . Ethnic distribution , mean age , serum ferritin concentrations , haemoglobin concentrations , and cognitive test scores of the groups did not differ significantly at baseline . Postintervention haematological measures of iron status were significantly improved in the treatment group ( serum ferritin 27.3 vs 12.1 micrograms/L , p iron performed better on a test of verbal learning and memory than girls in the control group ( p this urban population of non-anaemic iron-deficient adolescent girls , iron supplementation improved verbal learning and memory",
"Iron nutrition in infants was studied in a double-blind trial with artificial milk formula . Statistically significant differences were observed with the iron-fortified formula . Not all haematological indices showed significant differences . The fragiligraph technique result was the only parameter showing differences not influenced by other variables examined",
"The prevalence of anemia is high in adolescent girls in India , with over 70 % anemic . Iron-folic acid ( IFA ) supplements have been shown to enhance adolescent growth elsewhere in the world . To confirm these results in India , a study was conducted in urban areas of Vadodora , India to investigate the effect of IFA supplements on hemoglobin , hunger and growth in adolescent girls 10 - 18 y of age . Results show that there was a high dem and for IFA supplements and > 90 % of the girls consumed 85 out of 90 tablets provided . There was an increment of 17.3 g/L hemoglobin in the group of girls receiving IFA supplements , whereas hemoglobin decreased slightly in girls in the control group . Girls and parents reported that girls increased their food intake . A significant weight gain of 0.83 kg was seen in the intervention group , whereas girls in the control group showed little weight gain . The growth increment was greater in the 10- to 14-y-old age group than in the 15- to 18-y-old group , as expected , due to rapid growth during the adolescent spurt . IFA supplementation is recommended for growth promotion among adolescents who are underweight",
"OBJECTIVE The objective was to study the effects of iron supplementation on hemoglobin and iron status in 2 different population s. STUDY DESIGN In a r and omized , placebo-controlled , masked clinical trial , we assigned term Swedish ( n = 101 ) and Honduran ( n = 131 ) infants to 3 groups at 4 months of age : ( 1 ) iron supplements , 1 mg/kg/d , from 4 to 9 months , ( 2 ) placebo , 4 to 6 months and iron , 6 to 9 months , and ( 3 ) placebo , 4 to 9 months . All infants were breast-fed exclusively to 6 months and partially to 9 months . RESULTS From 4 to 6 months , the effect of iron ( group 1 vs 2 + 3 ) was significant and similar in both population s for hemoglobin , ferritin , and zinc protoporphyrin . From 6 to 9 months , the effect ( group 2 vs group 3 ) was significant and similar at both sites for all iron status variables except hemoglobin , for which there was a significant effect only in Honduras . In Honduras , the prevalence of iron deficiency anemia at 9 months was 29 % in the placebo group and 9 % in the supplemented groups . In Sweden , iron supplements caused no reduction in the already low prevalence of iron deficiency anemia at 9 months ( Iron supplementation from 4 to 9 months or 6 to 9 months significantly reduced iron deficiency anemia in Honduran breast-fed infants . The unexpected hemoglobin response at 4 to 6 months in both population s suggests that regulation of hemoglobin synthesis is immature at this age",
"The growth status of anemic ( n = 117 , Hb 7 - 10 g/dl ) and normal ( n = 53 , H > or = 11 g/dl ) children 3 - 5 years of age living under similar environmental and socio-economic conditions was evaluated . The dietary intake was assessed on a r and om sub sample of the anemic and normal children . The anemic children had a poorer growth status than normal children as indicated by their significantly ( p weight , height and weight for age and significantly ( p Iron supplementation ( 40 mg elemental iron/day ) for six months produced a significant ( p Hb levels of both groups ( 1.6 g/dl in the anemic and 0.8 g/dl in the non-anemic ) compared to their respective controls who received sugar placebos . The growth performance of the anemic children supplemented with iron was superior to that of anemic placebo treated children as indicated by a better weight gain and a significantly higher weight for height ( p Weight for age was a good differentiator of the anemic from normal while weight for height was a good indicator of the impact of iron supplements on growth"
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4117d39a-06ff-11f0-808a-c43d1ab1c353
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Anorexia nervosa ( AN ) is a psychiatric disorder with a high mortality and unknown etiology , and effective treatment is lacking . For decades , cannabis has been known to cause physical effects on the human body , including increasing appetite , which may be beneficial in the treatment of AN . To systematic ally review the literature for evidence of an effect of cannabinoids on ( 1 ) weight gain , and ( 2 ) other outcomes , in AN . A systematic review was done using three data bases Embase , PubMed and Psychinfo . The review was registered in PROSPERO with ID number CRD42019141293 and was done according to PRISMA guidelines . There were 1288 studies identified and after thorough review and exclusion of copies , 4 studies met the inclusion criteria . Three studies used the same AN population and utilized data from one original study , leaving only two original studies . Both of these were R and omized Controlled Trials that explored the effects of delta-9-tetrahydrocannabinol ( Δ9-THC ) or dronabinol in AN , whereof one study was properly design ed and powered and showed a weight increase of an added 1 kg over 4 weeks over placebo . There are few studies and the level of evidence is low . The only properly design ed , low bias and highly powered study found a weight increasing effect of dronabinol in AN , while the other , using Δ9-THC at a high dose , found no effect and where the dose may have counteracted the weight gaining effects due to adverse events . More research on cannabinoids in anorexia nervosa is warranted , especially its effects on psychopathology . Level I , systematic review
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"OBJECTIVE The evidence for pharmacological treatment of severe , longst and ing anorexia nervosa ( AN ) is sparse and the few controlled pharmacologic studies have focused on a narrow range of drugs . The aim of the present study was to investigate the effects of treatment with a synthetic cannabinoid agonist on body weight and eating disorder-related psychopathological personality traits in women with severe , enduring AN . METHOD This add-on , prospect i ve , r and omized , double blind , controlled crossover study was conducted between 2008 and 2011 at a specialized care center for eating disorders . Twenty-five women over 18 years with AN of at least 5 years duration were r and omized to treatment with either dronabinol-placebo or placebo-dronabinol . In addition to the st and ardized baseline therapeutic regime , the participants received dronabinol , 2.5 mg twice daily for 4 weeks and matching placebo for 4 weeks , separated by a 4-week wash-out period . Primary outcome was the mean change in body weight . Secondary outcome was score changes on the Eating Disorder Inventory-2 ( EDI-2 ) . Data were analyzed for the 24 patients who completed the trial . RESULTS During dronabinol treatment , participants gained 0.73 kg ( t = 2.86 , df = 22 , p Dronabinol significantly predicted weight gain in a multiple linear regression including EDI-2 body dissatisfaction score and leptin . EDI-2 subscale scores showed no significant changes over time . DISCUSSION Dronabinol therapy was well tolerated . During four weeks of exposure it induced a small but significant weight gain in the absence of severe adverse events",
"The endocannabinoid system , consisting of two cannabinoid receptors ( CB1 and CB2 ) and the endogenous lig and s an and amide ( arachidonoylethanolamide ( AEA ) ) and 2-arachidonoylglycerol ( 2-AG ) , has been shown to control food intake in both animals and humans , modulating either rewarding or quantitative aspects of the eating behavior . Moreover , hypothalamic endocannabinoids seem to be part of neural circuitry involved in the modulating effects of leptin on energy homeostasis . Therefore , alterations of the endocannabinoid system could be involved in the pathophysiology of eating disorders , where a deranged leptin signalling has been also reported . In order to verify this hypothesis , we measured plasma levels of AEA , 2-AG , and leptin in 15 women with anorexia nervosa ( AN ) , 12 women with bulimia nervosa ( BN ) , 11 women with binge-eating disorder ( BED ) , and 15 healthy women . Plasma levels of AEA result ed significantly enhanced in both anorexic and BED women , but not in bulimic patients . No significant change occurred in the plasma levels of 2-AG in all the patients ' groups . Moreover , circulating AEA levels were significantly and inversely correlated with plasma leptin concentrations in both healthy controls and anorexic women . These findings show for the first time a derangement in the production of the endogenous cannabinoid AEA in drug-free symptomatic women with AN or with BED . Although the pathophysiological significance of this alteration awaits further studies to be clarified , it suggests a possible involvement of AEA in the mediation of the rewarding aspects of the aberrant eating behaviors occurring in AN and BED",
"Purpose The level of physical activity is inappropriately high in up to 80 % of the patients suffering of anorexia nervosa ( AN ) , as a result of conscious efforts to lose weight , affect regulation and biological adaptive changes to starvation induced by hypothermia and neuroendocrine mechanisms . The purpose s of this paper were to ( 1 ) assess the effect of dronabinol — a synthetic cannabinoid agonist — on physical activity in patients with chronic and stable AN , and to ( 2 ) unravel the role of leptin and cortisol in this process . Methods This prospect i ve , r and omised , double-blind , crossover study was conducted at a specialised care centre for eating disorders . Twenty-four adult women with AN of at least 5-year duration received either the dronabinol-placebo or placebo-dronabinol sequence . Physical activity was monitored during the fourth week of each intervention . Body weight , leptin and urinary free cortisol excretion were measured repeatedly during the trial . Changes in behavioural dimensions related to AN were assessed by Eating Disorder Inventory-2 . Results The total duration of physical activity did not change , while its average intensity increased by 20 % ( P = 0.01 ) during dronabinol therapy , result ing in an increased energy expenditure with 68.2 kcal/day ( P = 0.01 ) above placebo . Conclusions This r and omised , double-blind study revealed that cannabinoid agonist treatment was associated with a modest increase in physical activity in adult women with severe and longst and ing AN . Additionally , we detected a strong relationship between the circulating levels of leptin and physical activity in these chronically undernourished patients",
"OBJECTIVE Anorexia nervosa ( AN ) is characterised by complex neuroendocrine disturbances due to severe underweight , physical hyperactivity and purging behaviour . Cannabinoid agonists are used to palliate cachexia of various causes , but their interactions with the hormonal systems that are involved in energy metabolism have not been previously described in humans . Therefore we found it of interest to assess interactions between the synthetic cannabinoid agonist dronabinol and insulin-like growth factor I ( IGF-I ) , urinary free cortisol ( UFC ) and adipokines in patients with chronic AN . DESIGN This was a prospect i ve , double-blind r and omised crossover study , conducted at a specialised care centre for eating disorders . The results are based on twenty-four adult women with chronic AN , who completed the study . The participants received dronabinol ( oral capsules , 5 mg daily ) and matching placebo over four weeks , separated by a four-week washout period . Bioactive IGF was determined by a cell-based bioassay , whereas total IGF-I , IGFBP-2 and -3 and the two adipokines leptin and adiponectines were measured by immunoassays . The UFC excretion was determined by mass spectrometry . RESULTS As previously reported , dronabinol treatment caused a small , yet significant increase in BMI as compared to placebo ( + 0.23 kg/m(2 ) ; P = 0.04 ) . This modest weight gain predicted a corresponding increase in bioactive IGF-I , while the amount of daily energy expenditure due to physical activity had a comparable but opposite effect . Nevertheless , neither IGF-I , bioactive IGF nor the IGFBPs levels changed significantly during dronabinol intervention as compared to placebo . Adiponectin also remained unaffected by the weight gain , whereas plasma leptin showed a transient increase at three weeks ( P UFC levels were decreased during dronabinol intervention . CONCLUSION Our results showed that low-dosage therapy with the synthetic cannabinoid agonist dronabinol affected neither the concentration nor the activity of the circulating IGF-system in women with severe and chronic AN . However , our results suggest that such treatment may alleviate the increased hypothalamic-pituitary-adrenal axis activity seen in these patients",
"Δ9-Tetrahydrocannabinol ( Δ9-THC ) , the most prominent psychoactive cannabinoid in Cannabis sativa L. ( marijuana ) , has been reported to have properties of appetite stimulation , promotion of weight gain , and antiemetic efficacy in selected patient population s. In this 4-week , double-blind , crossover study , 11 female patients with primary anorexia nervosa ( PAN ) were evaluated on Δ9-THC and on an active placebo , diazepam . All patients participated in a st and ardized behavior modification treatment program . The following data were obtained : ( 1 ) daily weight , ( 2 ) daily caloric intake , and ( 3 ) weekly psychiatric assessment s. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales . The only significant differences found between the changes over time on Δ9-THC versus diazepam were more pathology on Δ9-THC for somatization , interpersonal sensitivity , and sleep disturbance . Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during Δ9-THC administration . One week after the study ended , each subject was given the highest dose level of Δ8-THC achieved in the study , and periodic blood sample s were obtained coincident with self-rated “ subjective high ” assessment s and pulse measurements . Quantitative analyses of these sample s indicated peak times of 1 to 5 hours postdose for Δ9- THC and for its primary active metabolite , 11-hydroxy-THC , which generally coincided with peak times for “ subjective high ” and pulse rate . The results of this clinical investigation suggest that Δ9-THC is not efficacious , in short-term administration , in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients",
"We conducted a review of systematic review s ( SRs ) and r and omized-controlled trials ( RCTs ) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders . Five data bases were systematic ally search ed ( 2006—August 2018 ) ; 4 SRs ( of 11 RCTs ) and 14 RCTs ( 1629 participants ) were included . Diagnoses were : dementia , cannabis and opioid dependence , psychoses/schizophrenia , general social anxiety , posttraumatic stress disorder , anorexia nervosa , attention-deficit hyperactivity disorder , and Tourette`s disorder . Outcome variables were too heterogeneous to conduct a meta- analysis . A narrative synthesis method was applied . The study quality was assessed using the risk-of-bias tool and SIGN-checklists . THC- and CBD-based medicines , given as adjunct to pharmaco- and psychotherapy , were associated with improvements of several symptoms of mental disorders , but not with remission . Side effects occurred , but severe adverse effects were mentioned in single cases only . In order to provide reliable treatment recommendations , more and larger RCTs with follow-up assessment s , consistent outcome measures and active comparisons are needed"
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Background This review examines the evidence for an association between computer work and neck and upper extremity disorders ( except carpal tunnel syndrome ) . Methods A systematic critical review of studies of computer work and musculoskeletal disorders verified by a physical examination was performed . Results A total of 22 studies ( 26 articles ) fulfilled the inclusion criteria . Results show limited evidence for a causal relationship between computer work per se , computer mouse and keyboard time related to a diagnosis of wrist tendonitis , and for an association between computer mouse time and forearm disorders . Limited evidence was also found for a causal relationship between computer work per se and computer mouse time related to tension neck syndrome , but the evidence for keyboard time was insufficient . Insufficient evidence was found for an association between other musculoskeletal diagnoses of the neck and upper extremities , including shoulder tendonitis and epicondylitis , and any aspect of computer work . Conclusions There is limited epidemiological evidence for an association between aspects of computer work and some of the clinical diagnoses studied . None of the evidence was considered as moderate or strong and there is a need for more and better documentation
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"BACKGROUND A prospect i ve study of computer users was performed to determine the occurrence of and evaluate risk factors for neck or shoulder ( N/S ) and h and or arm ( H/A ) musculoskeletal symptoms ( MSS ) and disorders ( MSD ) . METHODS Individuals ( n = 632 ) newly hired into jobs requiring > or = 15 hr/week of computer use were followed for up to 3 years . At study entry , workstation dimensions and worker postures were measured and medical and psychosocial risk factors were assessed . Daily diaries were used to document work practice s and incident MSS . Those reporting MSS were examined for specific MSD . Incidence rates of MSS and MSD were estimated with survival analysis . Cox regression models were used to evaluate associations between participant characteristics at entry and MSS and MSD . RESULTS The annual incidence of N/S MSS was 58 cases/100 person-years and of N/S MSD was 35 cases/100 person-years . The most common N/S MSD was somatic pain syndrome . The annual incidence of H/A MSS was 39 cases/100 person-years and of H/A MSD was 21 cases/100 person-years . The most common H/A disorder was deQuervain 's tendonitis . Forty-six percent of N/S and 32 % of H/A MSS occurred during the first month of follow-up . Gender , age , ethnicity , and prior history of N/S pain were associated with N/S MSS and MSD . Gender , prior history of H/A pain , prior computer use , and children at home were associated with either H/A MSS or MSD . CONCLUSIONS H/A and N/S MSS and MSD were common among computer users . More than 50 % of computer users reported MSS during the first year after starting a new job",
"Three groups of data entry female visual display terminal ( VDT ) workers from Norway ( n = 30 ) , Pol and ( n = 33 ) and the USA ( n = 29 ) were compared . Before intervention , the Norwegian group reported more neck pain compared with the Polish group . The Polish group reported less shoulder pain than both the U.S. and the Norwegian groups . The clinical examination documented fewer symptoms and signs of musculoskeletal illness among the Polish participants compared with the Norwegian and the U.S. groups . After intervention , the Norwegian group reported a reduction in neck pain while the U.S. group reported a reduction in shoulder pain . The Polish group reported an increase in neck , shoulder and forearm pain at follow-up compared to after intervention . The Polish group recorded higher flexion of the upper arm at follow-up parallel with an increase of pain in the upper part of the body . Visual discomfort showed variable results in the 3 countries",
" A group of routine data entry operators ( female ) was included in the Polish MEPS ( musculoskeletal — eyestrain— psychosocial — stress ) study . Before the intervention , ergonomic assessment revealed improper working conditions such as inadequate lighting , uncomfortable chairs , and lack of forearm and wrist support while medical examination revealed that trapezius muscle load along with upper arm , head and back angles were higher than advisable . Subjects complained about neck and shoulder pain , visual problems , and psychosocial conditions . The ergonomic intervention included installation of new luminaires and Venetian blinds , new chairs , repair of ventilators , and optometric corrections . The results after the intervention showed mainly improvement in chair comfort , lighting conditions , visual strain , and sitting posture . However , financial limitations did not allow satisfactory completion of the intervention leading to a mixed interpretation of the results",
"Background : Call centre work with computers is associated with increased rates of upper body pain and musculoskeletal disorders . Methods : This one year , r and omised controlled intervention trial evaluated the effects of a wide forearm support surface and a trackball on upper body pain severity and incident musculoskeletal disorders among 182 call centre operators at a large healthcare company . Participants were r and omised to receive ( 1 ) ergonomics training only , ( 2 ) training plus a trackball , ( 3 ) training plus a forearm support , or ( 4 ) training plus a trackball and forearm support . Outcome measures were weekly pain severity scores and diagnosis of incident musculoskeletal disorder in the upper extremities or the neck/shoulder region based on physical examination performed by a physician blinded to intervention . Analyses using Cox proportional hazard models and linear regression models adjusted for demographic factors , baseline pain levels , and psychosocial job factors . Results : Post-intervention , 63 participants were diagnosed with one or more incident musculoskeletal disorders . Hazard rate ratios showed a protective effect of the armboard for neck/shoulder disorders ( HR = 0.49 , 95 % CI 0.24 to 0.97 ) after adjusting for baseline pain levels and demographic and psychosocial factors . The armboard also significantly reduced neck/shoulder pain ( p = 0.01 ) and right upper extremity pain ( p = 0.002 ) in comparison to the control group . A return-on-investment model predicted a full return of armboard and installation costs within 10.6 months . Conclusion : Providing a large forearm support combined with ergonomic training is an effective intervention to prevent upper body musculoskeletal disorders and reduce upper body pain associated with computer work among call centre employees",
"Abstract . The overall aim of this study was to investigate whether time pressure and verbal provocation has any effect on physiological and psychological reactions during work with a computer mouse . It was hypothesised that physiological reactions other than muscle activity ( i.e. wrist movements , forces applied to the computer mouse ) would not be affected when working under stressful conditions . Fifteen subjects ( 8 men and 7 women ) participated , performing a st and ardised text-editing task under stress and control conditions . Blood pressure , heart rate , heart rate variability , electromyography , a force-sensing computer mouse and electrogoniometry were used to assess the physiological reactions of the subjects . Mood ratings and ratings of perceived exertion were used to assess their psychological reactions . The time pressure and verbal provocation ( stress situation ) result ed in increased physiological and psychological reactions compared with the two control situations . Heart rate , blood pressure and muscle activity in the first dorsal interosseus , right extensor digitorum and right trapezius muscles were greater in the stress situation . The peak forces applied to the button of the computer mouse and wrist movements were also affected by condition . Whether the increases in the physiological reactions were due to stress or increased speed/productivity during the stress situation is discussed . In conclusion , work with a computer mouse under time pressure and verbal provocation ( stress conditions ) led to increased physiological and psychological reactions compared to control conditions",
"OBJECTIVES Following a consensus statement from a multidisciplinary UK workshop , a structured examination schedule was developed for the diagnosis and classification of musculoskeletal disorders of the upper limb . The aim of this study was to test the repeatability and the validity of the newly developed schedule in a hospital setting . METHOD 43 consecutive referrals to a soft tissue rheumatism clinic ( group 1 ) and 45 subjects with one of a list of specific upper limb disorders ( including shoulder capsulitis , rotator cuff tendinitis , lateral epicondylitis and tenosynovitis ) ( group 2 ) , were recruited from hospital rheumatology and orthopaedic outpatient clinics . All 88 subjects were examined by a research nurse ( blinded to diagnosis ) , and everyone from group 1 was independently examined by a rheumatologist . Between observer agreement was assessed among subjects from group 1 by calculating Cohen 's κ for dichotomous physical signs , and mean differences with limits of agreement for measured ranges of joint movement . To assess the validity of the examination , a pre-defined algorithm was applied to the nurse 's examination findings in patients from both groups , and the sensitivity and specificity of the derived diagnoses were determined in comparison with the clinic 's independent diagnosis as the reference st and ard . RESULTS The between observer repeatability of physical signs varied from good to excellent , with κ coefficients of 0.66 to 1.00 for most categorical observations , and mean absolute differences of 1.4 ° –11.9 ° for measurements of shoulder movement . The sensitivity of the schedule in comparison with the reference st and ard varied between diagnoses from 58%–100 % , while the specificities ranged from 84%–100 % . The nurse and the clinic physician generally agreed in their diagnoses , but in the presence of shoulder capsulitis the nurse usually also diagnosed shoulder tendinitis , whereas the clinic physician did not . CONCLUSION The new examination protocol is repeatable and gives acceptable diagnostic accuracy in a hospital setting . Examination can feasibly be delegated to a trained nurse , and the protocol has the benefit of face and construct validity as well as consensus backing . Its performance in the community , where disease is less clear cut , merits separate evaluation , and further refinement is needed to discriminate between discrete pathologies at the shoulder",
"The Norwegian MEPS ( musculoskeletal — eyestrain — psychosocial — stress ) study included 3 groups : data entry , data dialogue ( female ) and data dialogue ( male ) . Before intervention , the data entry group reported significantly more symptoms and signs of musculoskeletal illness and had longer periods in front of the video display terminal ( VDT ) without a break . The ergonomic intervention consisted mainly of ergonomic information and training . After intervention , the data dialogue female group reported a significant reduction in shoulder pain in parallel with a reduction in trapezius load . Increasing the underst and ing in how to adjust the work st and and chair may have been contributing factors to reducing the pain level . There was a significant reduction in eye problems in all groups ; the greatest reduction in eye symptoms was seen in the groups who had new optometric corrections",
"This special issue of the International Journal of Occupational Safety and Ergonomics ( JOSE ) reports the results from an extensive multinational and multidisciplinary collaborative investigation of the impacts on visual display terminal ( VDT ) work of musculoskeletal , visual , ergonomic , and psychosocial factors . For brevity , this effort has been referred to as the MEPS project ( musculoskeletal — eyestrain — psychosocial — stress ) . This paper lays out the basic method ological structure of the study . The study was conducted in 4 countries utilizing VDT data entry workers as the primary subject population . A battery of objective and subject assessment measures , including muscle load , visual function , physical and visual strain , postural , ergonomic and psychosocial factors , were assessed at 3 different points in time . A pre-test was given prior to an ergonomic intervention . Two post-tests were given 1 month and 1 year after the ergonomic intervention",
"A prospect i ve epidemiological field study covering a 2 years period has earlier been published . The study has a parallel group design with two intervention groups ( T and S ) and one control group ( C ) of Visual Display Unit ( VDU ) operators . The present paper covers the period from 2 to 6 years of the study . After 3.5 years , the C group got the same intervention in terms of new lighting system , new workplaces and at last an optometric examination and corrections if needed . The C group reported a significant reduction in visual discomfort after interventions while the two groups ( T and S ) continued to report significant reduction of visual discomfort after 6 years . By supporting the forearm on the table top , the C group reported significant reduction of shoulder and neck pain while the T group reported significant reduction in shoulder and back pain after 6 years . Organizational and psychosocial factors at work and outside work did not show any significant changes during the study period",
"BACKGROUND Despite widespread recommendations regarding posture during computer use , associations between specific postures and musculoskeletal health are not well characterized . METHODS Six hundred and thirty-two newly hired computer users were followed prospect ively to evaluate associations between posture and neck or shoulder ( N/S ) and h and or arm ( H/A ) musculoskeletal symptoms and musculoskeletal disorders . Participants ' postures were measured at entry and they reported symptoms on weekly diaries . Participants reporting symptoms were examined for specific disorders . Multivariate Cox regression models were used to estimate associations between postural variables and risk of symptoms and disorders , controlling for confounding variables . RESULTS Keying with an inner elbow angle > 121 degrees , greater downward head tilt , and presence of armrests on the participants chair were associated with lower risk of N/S symptoms or N/S disorders . Keying with elbow height below the height of the \" J \" key and the presence of a telephone shoulder rest were associated with a greater risk of N/S symptoms or N/S disorders . Horizontal location of the \" J \" key > 12 cm from the edge of the desk was associated with a lower risk of H/A symptoms and H/A disorders . Use of a keyboard with the \" J \" key > 3.5 cm above the table surface , key activation force > 48 g , and radial wrist deviation of > 5 degrees while using a mouse was associated with a greater risk of H/A symptoms or H/A disorders . The number of hours keying/week was associated with H/A symptoms and disorders . CONCLUSIONS The results suggest that the risk of musculoskeletal symptoms and musculoskeletal disorders may be reduced by encouraging specific seated postures",
"OBJECTIVES This prospect i ve study concentrated on determining factors of computer work that predict musculoskeletal symptoms in the shoulder , elbow , and low-back regions . METHODS A question naire on ergonomics , work pauses , work techniques , and psychosocial and work factors was delivered to 5033 office workers at baseline in early 1999 ( response rate 69 % ) and to 3361 respondents at the time of the follow-up in late 2000 ( response rate 77 % ) . An increased frequency or intensity of symptoms was the outcome variable , including only nonsymptomatic respondents from the baseline question naire ( symptom frequency below 8 days within the last 12 months or intensity score below 4 within the last 3 months ) . RESULTS In the follow-up , 10 % , 18 % , and 23 % had symptoms more often in the elbow , shoulder , and low back , respectively , and 14 % , 20 % , and 22 % had more intense symptoms . Women were more likely to be afflicted than men in all regions . In the full-fit multivariate logistic regression analysis , little influence on the timing of a rest pause and being disturbed by glare or reflection were significant predictors of shoulder symptoms , screen below eye height was a significant predictor for elbow symptoms , and previous symptoms was a significant predictor for symptoms in all regions . Computer worktime and psychosocial dimensions were not significant predictors . CONCLUSIONS Influence on work pauses , reduction of glare or reflection , and screen height are important factors in the design of future computer workstations . Since previous symptoms was a significant predictor of recurrent symptoms in all three regions under study , it can be concluded that musculoskeletal symptoms are persistent",
"The United States MEPS ( musculoskeletal — eyestrain — psychosocial — stress ) study consisted of 1 group of 28 female data entry operators . The intervention was in 3 parts : workstation re design ( including advanced ergonomic chairs , motorized adjustable workstations , advanced adjustable keyboards , adjustable copyholders , adjustable footrests , monitor support surfaces ) and ergonomic training/coaching and corrective lenses . After the intervention , statistically significant reductions in physical signs ( trigger points , neck and shoulder mobility ) , subjective reports of intensity and frequency of musculoskeletal pain , and subjective reports of visual problems were observed . Static load during the work sample , as assessed by experts , improved after the intervention as did measured postural angles of head and trunk and subjective assessment of users of ergonomic characteristics of the workplaces . For all of these measures , improvements observed 1 month after intervention were also observed in the 1-year follow-up . Trapezius load , as assessed by electromyography ( EMG ) , decreased after intervention , but then increased in the follow-up . The increase was interpreted as a calibration problem",
"OBJECTIVES This study concerned the influence of 6 positions of the computer mouse on the work table on posture , muscular load , and perceived exertion during text editing . METHODS An optoelectronic 3-dimensional motion analysis system was used to register the postures of 10 men and 10 women using video display units . Muscular load was also registered ( with electromyography ) , as was perceived exertion ( with rating scales ) . RESULTS A neutral posture with a relaxed and supported arm showed the least perceived exertion , and the electromyographic results showed low activity in both trapezius muscles in this position . Short operators ( all women ) showed a numerically higher activity in the 4 examined muscles than the tall operators ( all men , except 1 ) . This finding could be related to lower muscle force among women and to anthropometric differences , which also influence biomechanic load moments . Narrow-shouldered operators ( 8 women and 1 man ) and short operators worked with larger outward rotation and abduction of the shoulder in a position of the mouse lateral to the keyboard than the broad-shouldered ( 7 men and 2 women ) and tall operators did . Arm support markedly reduced muscle load in the neck-shoulder region among the operators . CONCLUSIONS The operators using video display units in this study preferred to use the mouse on a table in a close to relaxed , neutral posture of the arm in combination with arm support . Short and narrow-shouldered operators worked in more strenuous postures of the arm when the mouse was located lateral to the keyboard",
"Aims : To quantify the relative contribution of work related physical factors , psychosocial workplace factors , and individual factors and aspects of somatisation to the onset of neck/shoulder pain . Methods : Four year prospect i ve cohort study of workers from industrial and service companies in Denmark . Participants were 3123 workers , previously enrolled in a cross sectional study , where objective measurement of physical workplace factors was used . Eligible participants were followed on three subsequent occasions with approximately one year intervals . Outcomes of interest were : new onset of neck/shoulder pain ( symptom cases ) ; and neck/shoulder pain with pressure tenderness in the muscles of the neck/shoulder region ( clinical cases ) . Results : During follow up , 636 ( 14.1 % ) participants reported neck/shoulder pain of new onset ; among these , 82 ( 1.7 % ) also had clinical signs of substantial muscle tenderness . High shoulder repetition was related to being a future symptom case , and a future clinical case . Repetition was strongly intercorrelated with other physical measures . High job dem and s were associated with future status as a symptom case , and as a clinical case . A high level of distress predicted subsequent neck/shoulder pain , and neck/shoulder pain with pressure tenderness . Conclusions : High levels of distress , and physical and psychosocial workplace factors are predictors of onset of pain in the neck and /or shoulders , particularly pain with pressure tenderness in the muscles",
"Objectives : The aim of this intervention study was to determine the effects of an alternative mouse and /or a forearm support board on the change in upper body discomfort scores and the development of incident musculoskeletal disorders . Methods : This r and omised controlled intervention trial followed 206 engineers for one year . Participants were r and omised to receive ( 1 ) a conventional mouse only , ( 2 ) an alternative mouse only , ( 3 ) a forearm support board , or ( 4 ) an alternative mouse plus forearm support board . Outcome measures included weekly upper body discomfort scores and incident musculoskeletal disorders . Results : During the study , 42 participants were diagnosed with an incident musculoskeletal disorder . The group that received the forearm support board experienced a reduction in their right upper extremity discomfort ( beta-coefficient −0.35 , 95 % CI −0.67 to −0.03 ) in comparison to those who did not receive a forearm board . The group that received the alternative mouse had a protective , but non-significant ( p = 0.20 ) , effect on incident cases of right upper extremity musculoskeletal disorders ( HR 0.57 , 95 % CI 0.24 to 1.34 ) and a non-significant reduction in neck/shoulder discomfort ( beta-coefficient −0.23 , 95 % CI −0.056 to 0.10 ) in comparison to those who received a conventional mouse . Conclusions : In engineers who use a computer for more than 20 h per week , a forearm support board may reduce right upper extremity discomfort attributed to computer use",
"OBJECTIVES A cross-sectional study was conducted to assess the association of upper extremity musculoskeletal disorders and work-related factors among employees using video display terminals at a large metropolitan newspaper . METHODS The study included 1050 r and omly selected workers from four departments . The workers were asked to complete question naires on symptoms , job tasks , and psychosocial and work organization conditions . Musculoskeletal disorders of the upper extremities were defined by frequency , duration , and intensity of symptoms not attributable to acute injury . Data were analyzed with the use of logistic regression . RESULTS A total of 973 workers completed the survey . The one-year period prevalence rate for any musculoskeletal disorder of the upper extremities was 41 % . Neck symptoms ( 26 % ) were the most frequently reported , followed by h and or wrist ( 22 % ) , shoulder ( 17 % ) , and elbow ( 10 % ) symptoms . Greater time working at the video display station was associated with increased h and or wrist symptoms in a dose-response relationship . In addition , variables corresponding to increased work-load dem and s ( eg , increased time working under deadline and increased job pressure ) were associated with increased neck , shoulder , and h and or wrist disorders . Women were more likely to report symptoms in several areas , but this finding may reflect the concentration of women in jobs involving more risk factors . CONCLUSIONS The results suggest a high prevalence of musculoskeletal disorders of the upper extremities among newspaper employees , and they provide additional evidence that increased work load , time pressure , and greater hours of computer use are related to the occurrence of work-related musculoskeletal disorders among these workers , particularly for disorders in the h and or wrist area"
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4117d412-06ff-11f0-808a-c43d1ab1c353
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Thromb Haemost 2008 ; 100 : 11–13 Atrial fibrillation ( AF ) is the commonest sustained cardiac rhythm disorder , which has particularly attracted much clinical and research interest from the mortality and morbidity associated with stroke and thromboembolism . The more chronic presentations of AF have clinical subtypes based on the temporal pattern of the arrhythmia – AF is considered recurrent when a patient experiences two or more episodes , which may be paroxysmal if they terminate spontaneously , defined by consensus as seven days , or persistent if the arrhythmia requires cardioversion for termination of the arrhythmia ( 1 ) . Although paroxysmal AF is common , the associated stroke risk is less defined , given the limited information on its clinical epidemiology and the under-representation of these patients in clinical trials . As Gladstone et al. ( 2 ) highlight , it really depends on how hard we look for paroxysmal AF in patients who present with an acute stroke or thromboembolism . It has long been recognized that paroxysmal AF is frequently asymptomatic , and it has been estimated that only 1 in 12 paroxysms of AF are symptomatic ( 3 ) . In their data from the prospect i ve Registry of the Canadian Stroke Network , Gladstone et al. ( 2 ) found that 17 % of 12,849 consecutive hospitalised ischemic stroke patients had a history of AF , and an additional 6 % had new AF detected whilst in hospital ( 4 % on admission electrocardiogram [ ECG ] and 2 % detected later in hospital ) . In a study by Jabaudon et al. ( 4 ) , a st and ard 12-lead ECG identified AF in 2.7 % of 149 acute stroke and transient ischemic attack ( TIA ) patients at admission and in 4.1 % of remaining patients within five days ; however , a 24-hour ECG recording ( Holter ) detected AF in 5 % of patients who had a normal st and ard ECG , whereas seven-day ambulatory ECG monitoring using an event-loop recording ( ELR ) device detected AF in 5.7 % of patients with a normal st and ard ECG and normal Holter . Unsurprisingly , a recent systematic review of a series of cohort studies reemphasises the importance of screening for occult AF after ischemic stroke and TIA given that an extended duration of ECG monitoring ( e.g. event loop recorder [ ELR ] , etc ) after stroke/TIA identifies many more patients with ( usually paroxysmal ) AF than st and ard ECG and Holter monitoring alone ( 5 ) . Another recent report found that in patients with acute ischemic stroke , even frequent atrial premature beats ( APBs ) recorded in 24-hour ECG ( ≥70 per 24 hours ) were a marker for subsequent paroxysmal AF ( 6 ) . Clearly , more rhythm monitoring investigations would be needed for subjects with acute stroke and /or thromboembolism , to define the relationship between paroxysmal atrial arrhythmias and stroke
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[
"OBJECTIVE This study was performed to characterize the risk of stroke in elderly patients with recurrent intermittent atrial fibrillation ( AF ) . BACKGROUND Although intermittent AF is common , relatively little is known about the attendant risk of stroke . METHODS A longitudinal cohort study was performed comparing 460 participants with intermittent AF with 1,552 with sustained AF treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and followed for a mean of two years . Independent risk factors for ischemic stroke were identified by multivariate analysis . RESULTS Patients with intermittent AF were , on average , younger ( 66 vs. 70 years , p women ( 37 % vs. 26 % p heart failure ( 11 % vs. 21 % , p annualized rate of ischemic stroke was similar for those with intermittent ( 3.2 % ) and sustained AF ( 3.3 % ) . In patients with intermittent AF , independent predictors of ischemic stroke were advancing age ( relative risk [ RR ] = 2.1 per decade , p hypertension ( RR = 3.4 , p = 0.003 ) and prior stroke ( RR = 4.1 , p = 0.01 ) . Of those with intermittent AF predicted to be high risk ( 24 % ) , the observed stroke rate was 7.8 % per year ( 95 % confidence interval 4.5 to 14 ) . CONCLUSIONS In this large cohort of AF patients given aspirin , those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors . Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation . High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF",
"Background and Purpose — For patients having suffered ischemic stroke , the current diagnostic strategies often fail to detect atrial fibrillation as a potential cause of embolic events . The aim of the study was to identify paroxysmal atrial fibrillation in stroke patients . We hypothesized that patients with frequent atrial premature beats ( APBs ) recorded in 24-hour ECG will show more often atrial fibrillation when followed by repeated long-term ECG recordings than patients without or infrequent APBs . Methods — 127 patients with acute ischemic stroke and without known AF were enrolled in a prospect i ve study to detect paroxysmal AF . Patients were stratified according to the number of APBs recorded in a 24-hour ECG ( ≥70 APBs versus serial 7-day event-recorder monitoring at 0 , 3 , and 6 months . Results — Serial extended ECG monitoring identified AF in 26 % of patients with frequent APBs but only in 6.5 % when APBs were infrequent ( P=0.0021 ) . A multivariate analysis showed that the presence of frequent APBs in the initial 24-hour ECG was the only independent predictor of paroxysmal AF during follow-up ( odds ratio 6.6 , 95 % confidence intervals 1.6 to 28.2 , P=0.01 ) . Conclusions — In patients with acute ischemic stroke , frequent APBs ( ≥70/24 hours ) are a marker for individuals who are at greater risk to develop or have paroxysmal AF . For such patients , we propose a diagnostic workup with repeated prolonged ECG monitoring to diagnose paroxysmal AF",
"AIMS To test the hypothesis that stroke and systemic embolic events ( SEE ) in the stroke prevention using an oral thrombin inhibitor in atrial fibrillation ( SPORTIF ) III and V trials are different between paroxysmal and persistent atrial fibrillation ( AF ) . METHODS Data analysis from two cohorts of patients enrolled in the prospect i ve SPORTIF III and V clinical trials ( n = 7329 ) ; 836 subjects ( 11.4 % ) with paroxysmal AF [ mean age 70.1 years ( SD = 9.5 ) ] were compared with 6493 subjects with persistent AF for this ancillary study . RESULTS The annual event rates for stroke/SEE are 1.73 % for persistent AF and 0.93 % for paroxysmal AF . In a multivariate analysis , after adjusting for stroke risk factors , gender and aspirin usage , the differences remained statistically significant with a higher hazard ratio ( HR ) for stroke/SEE in persistent AF [ vs. paroxysmal AF , HR 1.87 , 95 % confidence interval ( CI ) 1.04 - 3.36 ; P = 0.037 ] . In ' high risk ' patients ( with > or=2 stroke risk factors ) annual event rates for stroke/SEE were 2.08 % for persistent AF and 1.27 % for paroxysmal AF ( adjusted HR = 1.68 , 95 % CI 0.91 - 3.1 , P = 0.098 ) . Elderly patients had annual event rates for stroke/SEE of 2.38 % for persistent AF and 1.13 % for paroxysmal AF ( adjusted HR = 2.27 , 95 % CI 0.92 - 5.59 , P = 0.075 ) . Vitamin K antagonist (VKA)-naive paroxysmal AF patients had a 1.89%/year stroke/SEE rate , compared with 0.61 % for previous VKA takers ( HR = 0.33 , 95 % CI 0.11 - 1.01 , P = 0.052 ) . CONCLUSION In this large clinical trial cohort of anticoagulated AF patients , those with paroxysmal AF had stroke rates which were lower than for patients with persistent AF , although both groups had broadly similar stroke risk factors . Subjects with paroxysmal AF at ' high risk ' had stroke/SEE rates that were not significantly different to persistent AF subjects",
"Background — This study investigated onset scenarios of atrial fibrillation ( AF ) , the first phase of the Atrial Fibrillation Therapy ( AFT ) trial , to determine potential arrhythmogenic triggers as targets for atrial pacing algorithms that have been proposed for prevention of AF . Methods and Results — Ninety-eight patients ( 58 men ; age 65±11 years ) with recurrent , symptomatic , drug-refractory AF and a conventional pacemaker indication in 31 of 98 received a dual-chamber pacemaker . Using novel diagnostic pacemaker features AF onset scenarios were prospect ively evaluated in 612 AF episodes during a 2-month monitoring period , with atrial pacing limited to 40 bpm . The most common onset scenario was premature atrial complexes ( PACs ) before AF ( 48 % onsets per patient ) , followed by bradycardia ( 33 % ) , sudden onset ( 17 % ) , and tachycardia ( 0 % ) . Combinations of onset scenarios were frequent ( median 2 different scenarios per patient ) . A main study finding was the significance of repetitive AF , with 33 % of onsets per patient being initiated within 5 minutes of a previous AF episode . Sudden onsets were more frequent among patients with than without repetitive AF ( 24 % versus 0 % onsets per patient , P=0.011 ) , whereas the proportion of PACs before AF was not statistically different ( 50 % versus 37 % , P=0.52 ) ; however , patients with repetitive AF had more PACs per hour ( 72 versus 29 , P=0.023 ) and a higher number of AF episodes per day ( 17 versus 0 , P=0.001 ) and were more likely to have at least 1 PAC-related onset ( 90 % versus 53 % , P rate and rhythm changes before AF and thus uncovered a substantial intraindividual and interindividual variability of AF onset scenarios",
"Although infrequent , embolic occlusion to non-cerebral arteries may result in limb loss , organ failure , and death . The aim of this study was to define clinical and echocardiographic characteristics determining thromboembolism destination in non-valvular atrial fibrillation . An inception cohort of individuals ( n=72 ) were identified with incident peripheral embolism in the setting of non-valvular atrial fibrillation ( 1995 - 2005 ) . A r and omly selected group of atrial fibrillation related stroke patients ( n=100 ) were identified for comparison . Arteries of the extremities were the most common site of embolism ( 85 % ) ; lower extremity involvement was twice as common compared with the upper extremity . Clinical features distinguishing peripheral embolism from stroke included age>75 , heart failure and hypertension . Severe left ventricular dysfunction , spontaneous echo contrast and left atrial thrombus were 2 - 3 fold more common in peripheral embolism patients . Mean CHADS-2 scores were low and comparable for both groups . By multivariate analysis , age>5 years ( hazard ratio [ HR ] 2.3 , 95 % confidence interval [ CI ] 1.3 - 3.9 ; p=0.05 ) was predictive of peripheral embolism . After adjustment for age>75 years , severe left atrial enlargement ( HR 1.8 , 95 % CI 0.99 - 3.1 ; p=0.055 ) and CHADS score ( HR 1.2 , 95 % CI 0.99 - 1.6 ; p=0.06 ) were of borderline significance . In conclusion , several clinical and echocardiographic measures distinguish the clinical presentation of thromboembolism in non-valvular atrial fibrillation . Small emboli are destined to lodge in the cerebral circulation as a result of hydrodynamic , anatomic , and physical factors . Advanced age , atrial enlargement and other co-morbidities may increase the propensity for the formation of larger thrombi which may bypass the carotid orifice merely as a function of size"
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4117d44e-06ff-11f0-808a-c43d1ab1c353
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Background : Despite the widespread use of antidepressants in clinical practice , the current trial‐ and ‐error approach to medication selection contributes to treatment failure and underscores the need to identify reliable predictors of antidepressant response . Since changes in measures of cognition have been reported to occur early in treatment and prior to improvements in overall mood symptoms , the present review aims to determine whether early changes in measures of cognition can predict response in individuals with MDD . Methods : A systematic review of studies evaluating early cognitive change as a predictor of later treatment response in MDD was conducted using PubMed / Medline , Embase and PsychINFO . Results : A total of seven articles were identified . The available evidence suggests the early changes in cognition may predict treatment response in individuals with MDD . This was shown across antidepressant classes ( i.e. , SSRIs , SNRIs , NRIs , melatonergic antidepressants ) and forms of therapy ( i.e. , pharmacotherapy , rTMS ) . The results depict an emerging trend towards early changes in facial emotion recognition ( i.e. , a hot cognitive process ) as a predictor of treatment outcome . Limitations : Our qualitative analysis reflects a very limited number of studies . Moreover , there was significant heterogeneity in the evaluation of cognition across studies . Future research should aim to parse out this heterogeneity by evaluating the relative predictive value of different measures of cognition . Conclusion : The identification of reliable early treatment predictors of antidepressant response would be clinical ly significant , enabling clinicians to more accurately evaluate the efficacy of selected treatment avenues . HIGHLIGHTSCognitive dysfunction is a principal feature and determinant of health outcome in MDD.Cognitive changes have shown to occur prior to improvements in mood symptoms . Early changes in emotional processing may predict treatment response in MDD
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"OBJECTIVE Antidepressants that inhibit the reuptake of serotonin ( SSRIs ) or norepinephrine ( SNRIs ) are effective in the treatment of disorders such as depression and anxiety . Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders , but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information . The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers . METHOD Forty-two male and female volunteers were r and omly assigned to 7 days of double-blind intervention with the SSRI citalopram ( 20 mg/day ) , the SNRI reboxetine ( 8 mg/day ) , or placebo . On the final day , facial expression recognition , emotion-potentiated startle response , and memory for affect-laden words were assessed . Question naires monitoring mood , hostility , and anxiety were given before and after treatment . RESULTS In the facial expression recognition task , citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear . Citalopram also abolished the increased startle response found in the context of negative affective images . Both antidepressants increased the relative recall of positive ( versus negative ) emotional material . These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety . However , reboxetine decreased subjective ratings of hostility and elevated energy . CONCLUSIONS Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers , reducing the processing of negative relative to positive emotional material . Such effects of antidepressants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders . They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression",
"Background Antidepressant drugs such as selective serotonin re-uptake inhibitors ( SSRIs ) remediate negative biases in emotional processing in depressed patients in both behavioural and neural outcome measures . However , it is not clear if these effects occur before , or as a consequence of , changes in clinical state . Method In the present study , we investigated the effects of short-term SSRI treatment in depressed patients on the neural response to fearful faces prior to clinical improvement in mood . Altogether , 42 unmedicated depressed patients received SSRI treatment ( 10 mg escitalopram daily ) or placebo in a r and omised , parallel-group design . The neural response to fearful and happy faces was measured on day 7 of treatment using functional magnetic resonance imaging . A group of healthy controls was imaged in the same way . Results Amygdala responses to fearful facial expressions were significantly greater in depressed patients compared to healthy controls . However , this response was normalised in patients receiving 7 days treatment with escitalopram . There was no significant difference in clinical depression ratings at 7 days between the escitalopram and placebo-treated patients . Conclusions Our results suggest that short-term SSRI treatment in depressed patients remediates amygdala hyperactivity in response to negative emotional stimuli prior to clinical improvement in depressed mood . This supports the hypothesis that the clinical effects of antidepressant treatment may be mediated in part through early changes in emotional processing . Further studies will be needed to show if these early effects of antidepressant medication predict eventual clinical outcome",
"OBJECTIVE Acute administration of an antidepressant increases positive affective processing in healthy volunteers , an effect that may be relevant to the therapeutic actions of these medications . The authors investigated whether this effect is apparent in depressed patients early in treatment , prior to changes in mood and symptoms . METHOD In a double-blind , placebo-controlled , between-groups r and omized design , the authors examined the effect of a single 4-mg dose of the norepinephrine reuptake inhibitor reboxetine on emotional processing . Thirty-three depressed patients were recruited through primary care clinics and the community and matched to 31 healthy comparison subjects . Three hours after dosing , participants were given a battery of emotional processing tasks comprising facial expression recognition , emotional categorization , and memory . Ratings of mood , anxiety , and side effects were also obtained before and after treatment . RESULTS Depressed patients who received placebo showed reduced recognition of positive facial expressions , decreased speed in responding to positive self-relevant personality adjectives , and reduced memory for this positive information compared to healthy volunteers receiving placebo . However , this effect was reversed in patients who received a single dose of reboxetine , despite the absence of changes in subjective ratings of mood or anxiety . CONCLUSIONS Antidepressant drug administration modulates emotional processing in depressed patients very early in treatment , before changes occur in mood and symptoms . This effect may ameliorate the negative biases in information processing that characterize mood and anxiety disorders . It also suggests a mechanism of action compatible with cognitive theories of depression",
"Recent neuropsychological studies in healthy volunteers suggest that antidepressants enhance the processing of positive emotional information . However , the neural substrates underpinning these changes have not been fully eluci date d. The current study , therefore , used functional magnetic resonance imaging ( fMRI ) to map brain systems activated during successful categorization and subsequent recognition of self-referent positive and negative personality characteristics in healthy volunteers following short-term ( 7 days ) repeated administration of the selective noradrenergic reuptake inhibitor reboxetine . Twenty-four healthy volunteers were r and omly assigned to 7-day double-blind intervention with reboxetine or placebo . On day 7 , neural responses during the categorization and subsequent recognition of positive and negative characteristics were assessed using fMRI . Question naires monitoring mood , hostility and anxiety were given before and during this intervention . During categorization , reboxetine was associated with greater activation to positive words , relative to negative words , in left precuneus and right inferior frontal gyrus . By contrast , at subsequent recognition reboxetine was associated with reduced response to positive words , relative to negative words , in left precuneus , anterior cingulate and medial frontal gyrus . These changes in the neural processing of positive and negative words occurred in the absence of significant differences in ratings of mood and anxiety . Such adaptations in the neural processing of emotional information support the hypothesis that antidepressants have early effects on emotional processing in a manner which would be expected to reverse negative biases in depression",
"Enhancement of serotonin neurotransmission plays an important role in the antidepressant response to agents presently available to treat depression . This response forms the major evidence for the role of serotonin in affective and social behaviour in humans . The present study investigated the effects of acute administration of the selective serotonin reuptake inhibitor ( SSR1 ) , citalopram ( 10 mg , i.v . ) upon a measure of emotional processing in healthy female volunteers . Subjects completed a facial expression recognition task following infusion of citalopram or saline ( between-subjects design , double-blind ) . Facial expressions associated with five basic emotions — happiness , sadness , fearfulness , anger and disgust — were displayed . Each face had been ‘ morphed ’ between neutral ( 0 % ) and each emotional st and ard ( 100 % ) in 10 % steps , leading to a range of emotional intensities . Mood and subjective experience were also monitored throughout the testing session . Volunteers receiving citalopram detected a higher number of facial expressions of fear and happiness , with reduced response times , relative to those given the placebo . By contrast , changes in the recognition of other basic emotions were not observed following citalopram . Notable differences in mood were also not apparent in these volunteers . These results suggest that acute administration of antidepressant drugs may affect neural processes involved in the processing of social information . This effect may represent an early acute effect of SSRIs on social and emotional processing that is relevant to their therapeutic actions",
"Agomelatine is a new antidepressant with a novel profile of pharmacological action . The clinical efficacy of agomelatine has been established in major depression , but its actions on emotional bias are unknown . Consequently , the current experimental study assessed the effect of agomelatine on emotional processing in healthy volunteers using an Emotional Test Battery shown to be sensitive to serotonin and noradrenaline reuptake inhibitors . Volunteers were r and omized to receive placebo , 25 mg or 50 mg of agomelatine over a 7-day period in a double-blind parallel groups design . Emotional processing ( n = 48 ) was assessed on the morning of day 8 using the Emotional Test Battery which included facial expression recognition , emotional memory , attentional visual probe and emotion-potentiated startle . Mood and subjective state were monitored before and during treatment . Agomelatine ( 25 mg ) decreased subjective ratings of sadness , reduced recognition of sad facial expressions , improved positive affective memory and reduced the emotion-potentiated startle response . The results show that agomelatine has more selective effects on the processing of social facial cues than conventional antidepressants , which could contribute to less blunting of emotional experience . The study highlights the potential value of volunteer models in drug development for screening and profiling of novel antidepressants",
"OBJECTIVE High-frequency left-side repetitive transcranial magnetic stimulation ( rTMS ) and low-frequency stimulation to the right prefrontal cortex have both been shown to have antidepressant effects , but doubts remain about the magnitude of previously demonstrated treatment effects . The authors evaluated sequentially combined high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex for treatment-resistant depression . METHOD The authors conducted a 6-week double-blind , r and omized , sham-controlled trial in 50 patients with treatment-resistant depression . Three trains of low-frequency rTMS to the right prefrontal cortex of 140 seconds ' duration at 1 Hz were applied daily , followed immediately by 15 trains of 5 seconds ' duration of high-frequency left-side rTMS at 10 Hz . Sham stimulation was applied with the coil angled at 45 degrees from the scalp , resting on the side of one wing of the coil . The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale . RESULTS There was a significantly greater response to active than sham stimulation at 2 weeks and across the full duration of the study . A significant proportion of the study group receiving active treatment met response ( 11 of 25 [ 44 % ] ) or remission ( nine of 25 [ 36 % ] ) criteria by study end compared to the sham stimulation group ( two of 25 [ 8 % ] and none of 25 respectively ) . CONCLUSIONS Sequentially applying both high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex , has substantial treatment efficacy in patients with treatment-resistant major depression . The treatment response accumulates to a clinical ly meaningful level over 4 to 6 weeks of active treatment",
"BACKGROUND After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor ( SSRI ) , it is not known whether switching to one antidepressant is more effective than switching to another . METHODS We r and omly assigned 727 adult out patients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks : sustained-release bupropion ( 239 patients ) at a maximal daily dose of 400 mg , sertraline ( 238 patients ) at a maximal daily dose of 200 mg , or extended-release venlafaxine ( 250 patients ) at a maximal daily dose of 375 mg . The study was conducted in 18 primary and 23 psychiatric care setting s. The primary outcome was symptom remission , defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) at the end of the study . Scores on the Quick Inventory of Depressive Symptomatology - Self Report ( QIDS-SR-16 ) , obtained at treatment visits , determined secondary outcomes , including remission ( a score of 5 or less at exit ) and response ( a reduction of 50 percent or more on baseline scores ) . RESULTS Remission rates as assessed by the HRSD-17 and the QIDS-SR-16 , respectively , were 21.3 percent and 25.5 percent for sustained-release bupropion , 17.6 percent and 26.6 percent for sertraline , and 24.8 percent and 25.0 percent for extended-release venlafaxine . QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion , 26.7 percent for sertraline , and 28.2 percent for extended-release venlafaxine . These treatments did not differ significantly with respect to outcomes , tolerability , or adverse events . CONCLUSIONS After unsuccessful treatment with an SSRI , approximately one in four patients had a remission of symptoms after switching to another antidepressant . Any one of the medications in the study provided a reasonable second-step choice for patients with depression . ( Clinical Trials.gov number , NCT00021528 . )",
"BACKGROUND The amygdala is believed to play a key role in processing emotionally salient , threat-relevant , events that require further online processing by cortical regions . Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala , but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information . METHODS The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor ( SSRI ) , citalopram , on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent ( BOLD ) functional magnetic resonance imaging . A double-blind , between-groups design was used with volunteers r and omized to 20 mg/day citalopram versus placebo . RESULTS Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo . Citalopram also reduced responses within the hippocampus and medial prefrontal cortex ( mPFC ) specifically during the fear-relevant stimuli . These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan . By contrast , there was no effect of citalopram on the neural or behavioral response to the happy facial expressions . CONCLUSIONS These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans . Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety",
"The aim of this study is to investigate whether repetitive transcranial magnetic stimulation ( rTMS ) targeted to a specific site in the dorsolateral prefrontal cortex ( DLPFC ) , with a neuro-navigational method based on structural MRI , would be more effective than rTMS applied using the st and ard localization technique . Fifty-one patients with treatment-resistant depression were r and omized to receive a 3-week course ( with a potential 1-week extension ) of high-frequency ( 10 Hz ) left-sided rTMS . Thirty trains ( 5 s duration ) were applied daily 5 days per week at 100 % of the resting motor threshold . Treatment was targeted with either the st and ard 5 cm technique ( n=27 ) or using a neuro-navigational approach ( n=24 ) . This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject 's MRI scan . There was an overall significant reduction in the Montgomery – Asberg Depression Rating Scale scores over the course of the trial , and a better outcome in the targeted group compared with the st and ard localization group at 4 weeks ( p=0.02 ) . Significant differences were also found on secondary outcome variables . The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression . Further research is required to confirm this in larger sample s , or to establish whether an alternate method based on surface anatomy , including measurement from motor cortex , can be substituted for the st and ard 5 cm method",
"Background We have previously shown that single doses of serotonin-selective and noradrenaline-selective antidepressant agents produce positive biases in measures of emotional processing in healthy volunteers . The aim of the present study was to confirm and extend this finding by study ing the effects of a single dose of the selective serotonin and noradrenaline re-uptake inhibitor , duloxetine . Material s and methods Healthy volunteers were r and omly allocated to double-blind administration of either duloxetine 60 mg orally or placebo . Participants then completed a battery of emotional-processing tasks measuring facial expression recognition , emotional memory and emotion-potentiated startle . Subjective state was measured using visual analogue scales throughout the test period . Results Duloxetine enhanced the recognition of both disgusted and happy facial expressions and increased memory intrusions for positive personality characteristics in the free recall test . There were no significant effects on startle responses . However , duloxetine was not well tolerated and was associated with a high level of negative subjective effects . Conclusions Despite the induction of negative subjective effects after duloxetine administration , some positive effects on emotional processing were seen in line with acute administration of serotonin-selective and noradrenaline-selective antidepressant agents . These results confirm the induction of fast changes in emotional processing in healthy volunteer groups and suggest a mechanism by which antidepressants may act in depression . Further studies are required to assess whether positive effects on emotional processing are more selective at a lower dose of duloxetine",
"BACKGROUND The majority of studies investigating the effectiveness of repetitive transcranial magnetic stimulation ( rTMS ) as a treatment for major depression have focused on high-frequency rTMS to the left prefrontal cortex ( HFL-rTMS ) . In addition , low-frequency right prefrontal rTMS ( LFR-rTMS ) has also been shown to have antidepressant properties . To date only a small number of studies have directly compared the efficacy of these two approaches . METHODS The aim of this study , therefore , was to investigate further whether LFR-rTMS is as effective as HFL-rTMS in the treatment of major depression . Twenty-seven patients were r and omized to one of two treatment arms ( HFL-rTMS or LFR-rTMS ) for 3 weeks with a possible 1-week extension . Non-responders were offered the opportunity of crossing over to the other treatment type . Stimulation parameters for HFL-rTMS were 30 stimulation trains of 5 s duration at 100 % of the resting motor threshold ( RMT ) ; for LFR-rTMS , stimulation was applied in four trains of 180 s duration ( 30 s inter-train interval ) at 110 % of the RMT . Stimulation was provided 5-week days per week . RESULTS There were significant improvements seen from baseline to end point irrespective of group and on all clinical outcome measures . In addition , there was no deterioration in any of the measures used to assess cognitive change , and significant improvements were seen on measures of immediate verbal memory and verbal fluency . CONCLUSIONS HFL-rTMS and LFR-rTMS appear to be equally efficacious in treating major depression . This study adds to the growing literature supporting LFR-rTMS as an additional viable method of rTMS delivery in the treatment of depression",
"BACKGROUND In healthy volunteers , exposure to antidepressants increases the recognition of positive face emotions and decreases recognition of negative emotions . It has been proposed that this may underlie therapeutic effects of antidepressants , but to date this has not been tested in clinical population s. METHOD Recognition of facial emotions was measured at baseline ( N=108 ) and after 2 ( N=59 ) and 6 weeks ( N=69 ) of treatment in depressed primary care patients who had been r and omised to treatment with either citalopram ( SSRI ) or reboxetine ( NaRI ) in an open-label study . Changes in emotional processing were compared to clinical outcome after 6 weeks of treatment . RESULTS Significant increases in recognition accuracy of disgust , happiness and surprise occurred by two-weeks of treatment with both antidepressants , and did not further change at 6 weeks . There was a significant correlation between the increased accuracy in recognition of happy faces over the first two-weeks of treatment and the clinical improvement after six-weeks of treatment . LIMITATIONS There was no control group and changes over time may be due to practice effects . CONCLUSIONS Antidepressants altered emotional processing in depressed patients with some similarities to the effects seen in healthy volunteers . The largest effect seen was increased recognition of disgust that may be specific to depressed patients . The correlation between increased accurate recognition of happy faces at two-weeks of treatment and clinical outcome at six-weeks of treatment suggests that early changes in emotional processing may underlie clinical response to antidepressants"
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Scope Studies have demonstrated inconsistent effects of curcumin on glycemic outcomes and lipid parameters in patients with prediabetes and type 2 diabetes mellitus ( T2DM ) . This study aim ed to assess the effect of curcumin on glycemic control and lipid profile in prediabetes and T2DM . Methods and results A systematic search of r and omized controlled trials ( RCTs ) was conducted from inception to June 2018 in electronic sources including AMED , ANZCTR , BioMed Central , CENTRAL , CINAHL , Clinical Trials.gov , Exp and ed Academic Index , Google Scholar , IS RCT N , LILACS , MEDLINE , NCCIH , Science Direct , Scopus , Web of Science , and WHO ICTRP . H and search was also performed . Of the total 486 records , four trials ( N = 508 ) and eight trials ( N = 646 ) were eligible for the meta- analysis of individuals with prediabetes and T2DM , respectively . Curcumin significantly reduced glycosylated hemoglobin ( HbA1c ) in prediabetics ( MD : -0.9 % , 95 % CI : -1.7 to -0.1 % , p = 0.03 ) . Furthermore , T2DM subjects gained favorable reduction in both HbA1c ( MD : -0.5 % , 95 % CI : -1.0 to -0.0 % , p = 0.04 ) and fasting plasma glucose ( MD : -11.7 mg/dL , 95 % CI : -22.1 to -1.3 mg/dL , p = 0.03 ) . Tendency of lipid profile improvement was also observed . Conclusion Our findings may encourage curcumin supplementation based on its meaningful effect on glycemic control and positive trend on lipid outcomes in prediabetes and T2DM
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"Background Curry , one of the most popular foods in Japan , contains spices that are rich in potentially antioxidative compounds , such as curcumin and eugenol . Oxidative stress is thought to impair endothelial function associated with atherosclerosis , a leading cause of cardiovascular events . The aim of this study was to determine whether a single consumption of curry meal would improve endothelial function in healthy men . Methods Fourteen healthy male subjects ( BMI 23.7 ± 2.7 kg/m2 ; age 45 ± 9 years ) were given a single serving of curry meal or spice-free control meal ( 180 g of curry or control and 200 g of cooked rice ; approximately 500 kcal in total ) in a r and omized , controlled crossover design . Before and 1 hr after the consumption , fasting and postpr and ial flow-mediated vasodilation ( FMD ) responses and other parameters were measured . Results The consumption of the control meal decreased FMD from 5.8 ± 2.4 % to 5.1 ± 2.3 % ( P = 0.039 ) . On the other h and , the consumption of the curry meal increased FMD from 5.2 ± 2.5 % to 6.6 ± 2.0 % ( P = 0.001 ) , and the postpr and ial FMD after the curry meal was higher than that after the control meal ( P = 0.002 ) . Presence of spices in the curry did not alter significantly the systemic and forearm hemodynamics , or any biochemical parameters including oxidative stress markers measured . Conclusions These findings suggest that the consumption of curry ameliorates postpr and ial endothelial function in healthy male subjects and may be beneficial for improving cardiovascular health . Trial registration UMIN Clinical Trials Registry 000012012",
"Background Diabetes remains a major health problem worldwide . Low-risk low-cost alternatives to pharmaceutical interventions are needed where lifestyle modifications have failed . We conducted a double-blind r and omised placebo controlled trial to investigate the efficacy of a Chinese herbal formula , Jiangtang Xiaozhi , in treating impaired glucose control and insulin resistance in persons with prediabetes and controlled diabetes . Methods Seventy-one patients with prediabetes or ‘ controlled ’ diabetes were r and omised to receive 3 capsules of Jiangtang Xiaozhi ( n = 39 ) or placebo ( n = 32 ) three times daily for 16 weeks with a follow up eight weeks later ( week 24 ) . The primary outcome was change in glycaemic control as evidence d by fasting blood glucose ( FBG ) , post-pr and ial plasma glucose and glycosylated haemoglobin ( HbA1c ) . Other measures included change in fasting insulin , insulin resistance and sensitivity , lipids , C-reactive protein ( CRP ) , body mass index ( BMI ) , waist girth , blood pressure ( BP ) , health related quality of life ( HRQoL ) and safety . Analysis of covariance ( ANCOVA ) was used to model outcomes at 16 weeks , by treatment group corrected for baseline level of the outcome variable . Results In patients receiving Jiangtang Xiaozhi , FBG was not significantly different ( p = 0.73 ) compared to placebo after 16 weeks of treatment ( 6.3 ± 1.1 mmol/L vs 6.7 ± 1.3 mmol/L ) . There was a significant difference ( p = 0.04 ) in the mean levels of fasting insulin between the treatment group ( 11.6 ± 5.5 mmol/L ) and the placebo group ( 22.1 ± 25.9 mmol/L ) . Insulin resistance slightly decreased in the treatment group ( 1.58 ± 0.74 ) compared to that of the placebo group ( 2.43 ± 1.59 ) but this change did not reach statistical significance ( p = 0.06 ) . Patients taking Jiangtang Xiaozhi had a significant improvement in high-density lipoprotein ( HDL ) level compared to the placebo group at week 16 ( p = 0.03 ) . Mean levels of cholesterol , triglycerides , BMI , waist-girth , HRQoL , BP , CRP and insulin sensitivity were not significantly different between the two groups . The herbal medicine was well tolerated . Conclusions In the current study , the 16 week Jiangtang Xiaozhi treatment did not lower fasting blood glucose , but it improved serum insulin and HDL cholesterol in a Western population with prediabetes or controlled diabetes . Our trial may have been underpowered . Dosage needs to be considered before commencing a longer adequately powered trial . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12612000128897;https://www.anzctr.org.au/Trial/ Registration /Trial Review",
"Curcumin is a phytocompound found in the root of turmeric , a common herbal ingredient in many Asian cuisines . The compound contains anti-inflammatory activity , which is mediated through an up-regulation of adiponectin and reduction of leptin . Consumption of curcumin was shown to prevent some deteriorative conditions caused by inflammation , such as ulcerative colitis , rheumatoid arthritis and esophagitis , and so on . Inflammation-associated cardiovascular conditions such as atherosclerosis are common in diabetes patients . The anti-inflammation effect of curcumin might be beneficial to prevent such condition in these patients . We aim to evaluate an antiatherosclerosis effect of curcumin in diabetes patients . Effects of curcumin on risk factors for atherosclerosis were investigated in a 6-month r and omized , double-blinded and placebo-controlled clinical trial that included subjects diagnosed with type 2 diabetes . An atherosclerosis parameter , the pulse wave velocity , and other metabolic parameters in patients treated with placebo and curcumin were compared . Our results showed that curcumin intervention significantly reduced pulse wave velocity , increased level of serum adiponectin and decreased level of leptin . These results are associated with reduced levels of homeostasis model assessment -insulin resistance , triglyceride , uric acid , visceral fat and total body fat . In summary , a 6-month curcumin intervention in type 2 diabetic population lowered the atherogenic risks . In addition , the extract helped to improve relevant metabolic profiles in this high-risk population",
"SCOPE We previously found that curcuminoids decreased blood glucose and improved insulin resistance by reducing serum free fatty acids ( FFAs ) and increasing fatty acid oxidation in skeletal muscle of diabetic rats . This study was to investigate whether curcuminoids have beneficial effects on type 2 diabetic patients , and its possible mechanisms . METHODS AND RESULTS Overweight/obese type 2 diabetic patients ( BMI ≥ 24.0 ; fasting blood glucose ≥ 7.0 mmol/L or postpr and ial blood glucose ≥11.1 mmol/L ) were r and omly assigned to curcuminoids ( 300 mg/day ) or placebo for 3 months . Bodyweight , glycosylated hemoglobin A1c ( HbA1c , % ) , serum fasting glucose , FFAs , lipids , and lipoprotein lipase ( LPL ) were determined . A total of 100 patients ( curcuminoids , n = 50 ; placebo , n = 50 ) completed the trial . Curcuminoids supplementation significantly decreased fasting blood glucose ( p ) , HbA1c ( p = 0.031 ) , and insulin resistance index ( HOMA-IR ) ( p type 2 diabetic patients . Curcuminoids also led to a significant decrease in serum total FFAs ( p ( P = 0.018 ) , an increase in LPL activity ( p of curcuminoids in type 2 diabetes , which is partially due to decrease in serum FFAs , which may result from promoting fatty acid oxidation and utilization",
"Background The effect of an herbal formulation LI85008F on weight loss in obese human subjects was evaluated in an 8-weeks r and omized , double-blind , placebo-controlled study ( Clinical Trial Registration no. IS RCT N37381706 ) . Fifty obese subjects ( Body mass index 30 to 40 kg/m² , 29.3 % male ; 70.7 % female ; ages 27–50 years ) were r and omized into two groups ; placebo ( n = 25 ) and LI85008F formulation ( n = 25 ) . The participants received either 900 mg/day of LI85008F formulation in three divided doses or three identical placebo capsules and all of them remained on a calorie-controlled diet ( 2000 cal/day ) and 30 min walking for 5 days a week during the entire duration of the study . Results and discussion At the end of the trial period , LI85008F supplemented group showed significant net reductions in body weight and Body Mass Index ( BMI ) . The participants who received the herbal formulation , showed reduced fasting blood glucose , LDL , LDL/HDL ratio , and triglycerides . At the end of the study , LI85008F supplementation also provided 21.26 % ( p = 0.012 ) increase in serum adiponectin level , compared with the placebo group . No major adverse events were reported by the participants in the study duration . In addition , Adipokine profiling study in 3T3-L1 adipocytes demonstrates that LI85008F modulates key regulatory factors of adipogenic differentiation and insulin sensitivity , such as Adiponectin , Pref-1 , and resistin . Conclusion The herbal formulation LI85008F ( Adipromin ) is prepared from commonly used medicinal plants extracts , which provides useful and safe application for weight loss in obese humans . It also demonstrates potential promise in controlling healthy blood glucose level in obesity linked type 2 diabetes",
"BACKGROUND In the present study , the improvement of diabetic microangiopathy and retinopathy was evaluated in 38 diabetic patients treated with a novel curcumin phospholipids delivery form ( Meriva ® ) . METHODS Diabetes was diagnosed at least 5 years before inclusion and all patients had signs of retinal oedema and of peripheral microangiopathy . Meriva ® was administered at the dosage of 2 tablets/day ( each tablet containing 500 mg Meriva ® corresponding to 100 mg curcumin ) for a period of at least 4 weeks in addition to the st and ard management plan , while a comparable group of subjects ( n = 39 ) followed the st and ard management plan alone . RESULTS All subjects ( treatment and controls ) completed the follow-up period , there were no dropouts and Meriva ® showed an optimal tolerability . At 4 weeks , microcirculatory and clinical evaluations indicated an improvement of microangiopathy . In terms of peripheral microangiopathy , in the Meriva ® group , there was a significant improvement in the venoarteriolar response ( p decrease in the score of peripheral oedema ( p Meriva ® treated patients . The evaluation of retinal oedema ( Steigerwalt 's scale ) showed an improvement associated with improved visual acuity ( Snellen scale ) . There were no clinical or microcirculatory effects in controls . CONCLUSION These preliminary observations , indicate the value of curcumin , when administered in a bioavailable form as with Meriva ® , in the management of diabetic microangiopathy and retinopathy",
"Objective : Diabetes mellitus is defined as a group of metabolic diseases characterized by hyperglycemia result ing from defects in insulin secretion , insulin action , or both or insulin resistance . Curcumin inhibits NF-κB signaling pathway . The aim of this study is evaluation of the effect of Nano-curcumin on HbA1C , fast blood glucose and lipid profile in diabetic patients . Material s and Methods : Seventy type-2 diabetic patients ( fasting blood glucose ( FBG ) ≥ 126 mg/dL or 2-hr postpr and ial blood glucose ≥200 mg/dl ) r and omly receivedeither Curcumin ( as nano-micelle 80 mg/day ) or placebo for 3 months in a double blind r and omized clinical trial . Fasting blood glucose , HbA1C , and lipids profile were checked before and after the intervention . Data analyses , including parametric and nonparametric tests were done using the SPSS 11.5 software . A p value Results : Mean age , BMI , FBG , total cholesterol ( TC ) , triglyceride ( TG ) , LDL , HDL , HbA1c , and sex and had no significant difference at the baseline between the groups . In Nano-curcumin group , a significant decrease was found in HbA1C , FBG , TG , and BMI comparing results of each subject before and after the treatment ( p groups , HbA1c , eAG , LDL-C , and BMI variables showed significant differences ( p HbA1c lowering effect for Nano-curcumin in type-2 diabetes ; also , it is partially decrease in serum LDL-C and BMI ",
"Abstract It is known that there is a significant interplay of insulin resistance , oxidative stress , dyslipidemia , and inflammation in type 2 diabetes mellitus ( T2DM ) . The study was undertaken to investigate the effect of turmeric as an adjuvant to anti-diabetic therapy . Sixty diabetic subjects on metformin therapy were recruited and r and omized into two groups ( 30 each ) . Group I received st and ard metformin treatment while group II was on st and ard metformin therapy with turmeric ( 2 g ) supplements for 4 weeks . The biochemical parameters were assessed at the time of recruitment for study and after 4 weeks of treatment . Turmeric supplementation in metformin treated type 2 diabetic patient significantly decreased fasting glucose ( 95 ± 11.4 mg/dl , P 0.001 ) and HbA1c levels ( 7.4 ± 0.9 % , P 0.05 ) . Turmeric administered group showed reduction in lipid peroxidation , MDA ( 0.51 ± 0.11 µmol/l , P 0.05 ) and enhanced total antioxidant status ( 511 ± 70 µmol/l , P 0.05 ) . Turmeric also exhibited beneficial effects on dyslipidemia LDL cholesterol ( 113.2 ± 15.3 mg/dl , P ( 138.3 ± 12.1 mg/dl , P ratio ( 3.01 ± 0.61 , P , hsCRP ( 3.4 ± 2.0 mg/dl , P Turmeric supplementation as an adjuvant to T2DM on metformin treatment had a beneficial effect on blood glucose , oxidative stress and inflammation ",
"Curcuma spp . extracts , particularly the dietary polyphenol curcumin , prevent colon cancer in rodents . In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans , a dose-escalation pilot study of a novel st and ardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day , containing 36 - 180 mg of curcumin . Fifteen patients with advanced colorectal cancer refractory to st and ard chemotherapies received Curcuma extract daily for up to 4 months . Activity of glutathione S-transferase and levels of a DNA adduct ( M(1)G ) formed by malondialdehyde , a product of lipid peroxidation and prostagl and in bio synthesis , were measured in patients ' blood cells . Oral Curcuma extract was well tolerated , and dose-limiting toxicity was not observed . Neither curcumin nor its metabolites were detected in blood or urine , but curcumin was recovered from feces . Curcumin sulfate was identified in the feces of one patient . Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59 % decrease in lymphocytic glutathione S-transferase activity . At higher dose levels , this effect was not observed . Leukocytic M(1)G levels were constant within each patient and unaffected by treatment . Radiologically stable disease was demonstrated in five patients for 2 - 4 months of treatment . The results suggest that ( a ) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily , equivalent to 180 mg of curcumin ; ( b ) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism ; and ( c ) larger clinical trials of Curcuma extract are merited",
"Curcumin has a therapeutic potential in treating diabetic kidney disease ( DKD ) while potential mechanisms underlining this beneficial effect remain to be eluci date d. In the present study , curcumin intervention was performed in patients with Type II diabetes mellitus ( T2DM ) by oral intake of curcumin at the dose of 500 mg/day for a period of 15 - 30 days . Nephritic excretion of urinary micro-albumin ( U-mAlb ) and blood metabolic indexes were assessed before and after this intervention . In addition , the lipid oxidation index , malondialdehyde ( MDA ) in plasma and the status of anti-oxidative Nrf2 system in blood lymphocytes were measured . The effect of curcumin on inflammation was assessed by measuring plasma lipopolysaccharide ( LPS ) content and inflammatory signaling protein in blood lymphocytes . A self-comparison method was used for assessing statistical significance s of these measurements . Here we show that curcumin intervention markedly attenuated U-mAlb excretion without affecting metabolic control of participated patients . In addition , curcumin reduced plasma MDA level with enhanced the Nrf2 system specifically regulated protein , NAD(P)H quinone oxidoreductase 1 ( NQO-1 ) together with other anti-oxidative enzymes in patients ' blood lymphocytes . Furthermore , we observed reduced plasma LPS content and increased IκB , an inhibitory protein on inflammatory signaling in patient 's lymphocytes after curcumin administration . Finally , several gut bacterials important for maintaining gut barrier integrity and function were upregulated by curcumin . In conclusion , short-term curcumin intervention ablates DKD progress with activating Nrf2 anti-oxidative system and anti-inflammatory efficacies in patients with T2DM",
"This study aim ed to assess the possible beneficial effects of curcumin capsules as lipid-lowering effects and as a permeability glycoprotein ( P-gp ) inhibitor on the pharmacokinetics and pharmacodynamics of glyburide and as a P-gp substrate with glyburide in patients with type-2 diabetes mellitus . Open-label , r and omized control trial was carried out for 11 days on eight type-2 diabetic patients on glyburide therapy . On the first day of the study , following the administration of 5 mg of glyburide , blood sample s were collected from the patients at various time intervals ranging from 0.5 to 24 h. Blood sampling was repeated on the 11th day of the study , after treating the patients with curcumin for ten consecutive days . Glyburide concentrations changed at the second hour , Cmax was unchanged , the glucose levels were decreased , Area Under first Movement Curre ( AUMC ) was increased , and no patient has experienced the hypoglycaemia . The low-density lipoprotein , very-low-density lipoprotein and triglycerides were decreased significantly , and the high-density lipoprotein content increased . The co-administration of curcumin capsules with glyburide may be beneficial to the patients in better glycaemic control . The lipid lowering and antidiabetic properties of the curcumin show as a potential future drug molecule",
"Aims : DBCare ® ( Ace Continental Exports Inc. , London , UK ) is a traditional Indian herbal food supplement marketed as an antidiabetes remedy . This study evaluated the efficacy and safety of DBCare in patients with inadequately controlled type 2 diabetes mellitus ( T2DM ) despite oral hypoglycemic treatment . Methods : A 12-week r and omized double-blind placebo-controlled trial was conducted . Patients with T2DM on oral hypoglycemic agents with HbA1C > 7.0 % were r and omized to receive DBCare or placebo tablets . Results : Thirty-five patients ( 20 male/15 female ; mean age 61.2 ± 7.6 years ) , with a mean baseline HbA1C of 7.9 % ± 0.6 % , received DBCare ( N = 18 ) or placebo ( N = 17 ) . During the study period , HbA1C declined 0.4 ± 0.7 % in the DBCare ® group and 0.2 % ± 0.8 % in the placebo group ( p = 0.806 ) . No significant changes occurred in fasting plasma glucose , lipid profile , or homeostasis model assessment throughout the study or in body mass index , waist circumference , or blood pressure values . Hypoglycemic episodes ( glucose patients . DBCare was generally well tolerated , with mild side effects that were not different from those of the placebo group . Conclusions : This preliminary study did not demonstrate that DBCare was efficacious in improving glycemic control in inadequately controlled patients with T2DM on oral hypoglycemics . A trend toward improved glycemic control was noted in the DBCare group , which correlates with more frequent hypoglycemic episodes . Further studies are needed to eluci date DBCare 's hypoglycemic effect in patients with T2DM in general and in specific clinical setting s , such as HbA1C ≥ 8 % , short ( ≤10-year ) duration of diabetes , or young age in particular",
"Background : Nonalcoholic fatty liver disease ( NAFLD ) is one of the most common hepatic diseases in the general adult population . Dyslipidemia , hyperuricemia , and insulin resistance are common risk factors and accompanying features of NAFLD . Curcumin is a dietary natural product with beneficial metabolic effects relevant to the treatment of NAFLD . Aim : To assess the effects of curcumin on metabolic profile in subjects with NAFLD . Methods : Patients diagnosed with NAFLD ( grade s 1–3 ; according to liver sonography ) were r and omly assigned to curcumin ( 1000 mg/d in 2 divided doses ) ( n = 50 ) or control ( n = 52 ) group for a period of 8 weeks . All patients received dietary and lifestyle advises before the start of trial . Anthropometric measurements , lipid profile , glucose , insulin , glycated hemoglobin , and uric acid concentrations were measured at baseline and after 8 weeks of follow-up . Results : Eighty-seven subjects ( n = 44 and 43 in the curcumin and control group , respectively ) completed the trial . Supplementation with curcumin was associated with a reduction in serum levels of total cholesterol ( P , low-density lipoprotein cholesterol ( P ) , triglycerides ( P , non – high-density lipoprotein cholesterol ( P and uric acid ( P whereas serum levels of high-density lipoprotein cholesterol and glucose control parameters remained unaltered . Curcumin was safe and well tolerated during this study . Conclusion : Results of the present trial suggest that curcumin supplementation reduces serum lipids and uric acid concentrations in patients with NAFLD",
"Abstract Background and objective : Hyperglycaemia leads to increased oxidative stress result ing in endothelial dysfunction . ACE inhibitors , antioxidants and HMG-CoA reductase inhibitors ( statins ) have been shown to improve endothelial function . The aim of this study was to compare the effects of NCB-02 ( a st and ardized preparation of curcuminoids ) , atorvastatin and placebo on endothelial function and its biomarkers in patients with type 2 diabetes mellitus . Methods : A total of 72 patients with type 2 diabetes were r and omized to receive NCB-02 ( two capsules containing curcumin 150 mg twice daily ) , atorvastatin 10 mg once daily or placebo for 8 weeks . Endothelial function assessment was performed at baseline and post-treatment using digital volume plethysmography ( salbutamol [ albuterol ] challenge test ) to measure change in reflective index , an indicator of arterial vascular tone . Blood sample s were similarly collected at baseline and post-treatment for estimations of malondialdehyde , endothelin-1 ( ET-1 ) , interleukin-6 ( IL-6 ) and tumour necrosis factor-α ( TNFα ) . Pre- and posttreatment safety assessment s were also conducted . ANOVA and paired t-test evaluations were used for comparison . Results : A total of 67 patients completed the study . At baseline , there was no significant difference in the various parameters tested . In all three groups , the change in reflective index at baseline was improvement in endothelial function after treatment with atorvastatin ( mean ± SD : −3.63 ± 3.17 % vs −8.95 ± 6.80 % , respectively ) and NCB-02 ( −2.69 ± 3.02 % vs −8.19 ± 5.73 % , respectively ) . Similarly , patients receiving atorvastatin or NCB-02 showed significant reductions in the levels of malondialdehyde , ET-1 , IL-6 and TNFα . No significant improvements were obtained in patients administered placebo . Conclusion : NCB-02 had a favourable effect , comparable to that of atorvastatin , on endothelial dysfunction in association with reductions in inflammatory cytokines and markers of oxidative stress . Further studies are needed to evaluate the potential long-term effects of NCB-02 and its combination with other herbal antioxidants ",
"Abstract Objective . End-stage renal disease ( ESRD ) due to type 2 diabetic nephropathy is a very common condition which is increasing in prevalence , and is associated with high global levels of mortality and morbidity . Both proteinuria and transforming growth factor-β ( TGF-β ) may contribute to the development of ESRD in patients with diabetic nephropathy . Experimental studies indicate that turmeric improves diabetic nephropathy by suppressing TGF-β . Therefore , this study investigated the effects of turmeric on serum and urinary TGF-β , interleukin-8 ( IL-8 ) and tumour necrosis factor-α ( TNF-α ) , as well as proteinuria , in patients with overt type 2 diabetic nephropathy . Material and methods . A r and omized , double-blind and placebo-controlled study was carried out in the Diabetes Clinic of the Outpatient Department of Shiraz University of Medical Sciences on 40 patients with overt type 2 diabetic nephropathy , r and omized into a trial group ( n = 20 ) and a control group ( n = 20 ) . Each patient in the trial group received one capsule with each meal containing 500 mg turmeric , of which 22.1 mg was the active ingredient curcumin ( three capsules daily ) for 2 months . The control group received three capsules identical in colour and size containing starch for the same 2 months . Results . Serum levels of TGF-β and IL-8 and urinary protein excretion and IL-8 decreased significantly comparing the pre- and post-turmeric supplementation values . No adverse effects related to turmeric supplementation were observed during the trial . Conclusion . Short-term turmeric supplementation can attenuate proteinuria , TGF-β and IL-8 in patients with overt type 2 diabetic nephropathy and can be administered as a safe adjuvant therapy for these patients",
"BACKGROUND Type 2 diabetes ( T2D ) is an established risk factor for cardiovascular disease ( CVD ) and is associated with disturbed metabolism of lipids and lipoproteins . Curcuminoids are natural products with anti-diabetic and lipid-modifying actions but their efficacy in improving dyslipidemia in diabetic individuals has not been sufficiently studied . OBJECTIVE To investigate the efficacy of supplementation with curcuminoids , plus piperine as an absorption enhancer , in improving serum lipids in patients with T2D . METHODS In this 12-week r and omized double-blind placebo-controlled trial , subjects with T2D ( n=118 ) were assigned to curcuminoids ( 1000mg/day plus piperine 10mg/day ) or placebo plus st and ard of care for T2D . Serum concentrations of lipids including total cholesterol ( TC ) , low-density lipoprotein cholesterol ( LDL-C ) , high-density lipoprotein cholesterol ( HDL-C ) , triglycerides ( TG ) , lipoprotein(a ) [ Lp(a ) ] , and non-HDL-C were determined at baseline and at the end of trial . RESULTS Between-group comparison of change in the study parameters revealed significant reductions in serum levels of TC ( -21.86±25.78 versus -17.06±41.51 , respectively ; p=0.023 ) , non-HDL-C ( -23.42±25.13 versus -16.84±41.42 , respectively ; p=0.014 ) and Lp(a ) ( -1.50±1.61 versus -0.34±1.73 , respectively ; p=0.001 ) and elevations in serum HDL-C levels ( 1.56±4.25 versus -0.22±4.62 , respectively ; p=0.048 ) in the curcuminoids group as compared with the placebo group ( p changes did not show any significant difference between the study groups ( p>0.05 ) . CONCLUSION Curcuminoids supplementation can reduce serum levels of atherogenic lipid indices including non-HDL-C and Lp(a ) . Therefore , curcuminoids supplementation could contribute to a reduced risk of cardiovascular events in dyslipidemic patients with T2D",
"OBJECTIVE Previous experimental studies have suggested curcumin as a safe phytochemical that can improve insulin resistance through effects on adiponectin and leptin . This study aim ed to investigate the effect of curcumin on circulating adiponectin and leptin concentrations in patients with metabolic syndrome . METHODS In this pilot , r and omized , double-blind , placebo-controlled trial , subjects who met the criteria of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria were r and omly assigned to curcumin ( n = 59 ; 1000 mg/d ) or a placebo ( n = 58 ) for 8 wk . Serum adiponectin and leptin concentrations were determined before and after intervention . The pooled effect size for the impact of curcumin supplementation on serum adiponectin and leptin levels was also estimated using r and om-effects meta analysis . RESULTS Eight-week supplementation with curcumin was associated with a significant increase in serum adiponectin levels ( P reduction in serum leptin concentrations ( P Serum leptin : adiponectin ratio was also improved by curcumin ( P curcumin remained significant after adjustment for changes in serum lipids and glucose concentrations and baseline differences in body mass index and serum levels of glucose and glycated hemoglobin as potential confounders of treatment response . Meta analysis suggested that curcumin supplementation can increase adiponectin levels by 76.78 % ( 95 % CI : 6.14 - 147.42 ; P = 0.0330 ) , and reduce leptin by 26.49 % ( 95 % CI : -70.44 to 17.46 ) , however this latter effect size did not reach statistical significance ( P = 0.238 ) . CONCLUSIONS Curcumin can improve serum levels of adiponectin and leptin in patients with metabolic syndrome . This trial was registered at the UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ ) under Trial No. UMIN000018339",
"Non-alcoholic fatty liver disease ( NAFLD ) is a global health problem . Although many aspects of NAFLD pathogenesis have been understood , there is a paucity of effective treatments to be used as the second line when lifestyle modification is insufficient . Curcumin , a natural polyphenol from turmeric , has been shown to be effective against development of hepatic steatosis and its progression to steatohepatitis , yet these beneficial effects have not been explored in clinical practice . The aim of this study is to investigate the effects of curcumin on hepatic fat content as well as biochemical and anthropometric features of patients with NAFLD . In this r and omized double-blind placebo-controlled trial , patients with ultrasonographic evidence of NAFLD were r and omly assigned to receive an amorphous dispersion curcumin formulation ( 500 mg/day equivalent to 70-mg curcumin ) or matched placebo for a period of 8 weeks . Liver fat content ( assessed through ultrasonography ) , glycemic and lipid profile , transaminase levels , and anthropometric indices were evaluated at baseline and at the end of follow-up period . The clinical trial protocol was registered under the Iranian Registry of Clinical Trials ID : I RCT 2014110511763N18 . Compared with placebo , curcumin was associated with a significant reduction in liver fat content ( 78.9 % improvement in the curcumin vs 27.5 % improvement in the placebo group ) . There were also significant reductions in body mass index and serum levels of total cholesterol , low-density lipoprotein cholesterol , triglycerides , aspartate aminotransferase , alanine aminotransferase , glucose , and glycated hemoglobin compared with the placebo group . Curcumin was safe and well tolerated during the course of trial . Findings of the present proof-of-concept trial suggested improvement of different features of NAFLD after a short-term supplementation with curcumin . Copyright © 2016 John Wiley & Sons ,"
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Although certain risk factors can identify individuals who are most likely to develop chronic pain , few interventions to prevent chronic pain have been identified . To facilitate the identification of preventive interventions , an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain . We present general design considerations for prevention trials in population s that are at relatively high risk for developing chronic pain . Specific design considerations included subject identification , timing and duration of treatment , outcomes , timing of assessment , and adjusting for risk factors in the analyses . We provide a detailed examination of 4 models of chronic pain prevention ( ie , chronic postsurgical pain , postherpetic neuralgia , chronic low back pain , and painful chemotherapy-induced peripheral neuropathy ) . The issues discussed can , in many instances , be extrapolated to other chronic pain conditions . These examples were selected because they are representative models of primary and secondary prevention , reflect persistent pain result ing from multiple insults ( ie , surgery , viral infection , injury , and toxic or noxious element exposure ) , and are chronically painful conditions that are treated with a range of interventions . Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions . Such interventions would have the potential to reduce the prevalence of chronic pain in the population . Additionally , st and ardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic review s and improve detection of preventive strategies emerging from clinical trials
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"Background Adjustment for prognostic covariates can lead to increased power in the analysis of r and omized trials . However , adjusted analyses are not often performed in practice . Methods We used simulation to examine the impact of covariate adjustment on 12 outcomes from 8 studies across a range of therapeutic areas . We assessed ( 1 ) how large an increase in power can be expected in practice ; and ( 2 ) the impact of adjustment for covariates that are not prognostic . Results Adjustment for known prognostic covariates led to large increases in power for most outcomes . When power was set to 80 % based on an unadjusted analysis , covariate adjustment led to a median increase in power to 92.6 % across the 12 outcomes ( range 80.6 to 99.4 % ) . Power was increased to over 85 % for 8 of 12 outcomes , and to over 95 % for 5 of 12 outcomes . Conversely , the largest decrease in power from adjustment for covariates that were not prognostic was from 80 % to 78.5 % . Conclusions Adjustment for known prognostic covariates can lead to substantial increases in power , and should be routinely incorporated into the analysis of r and omized trials . The potential benefits of adjusting for a small number of possibly prognostic covariates in trials with moderate or large sample sizes far outweigh the risks of doing so , and so should also be considered",
"Abstract Psychological factors consistent with fear‐avoidance models are associated with the development of chronic low back pain ( LBP ) . As a result , grade d activity ( GA ) and grade d exposure ( GX ) have been suggested as behavioral treatment options . This clinical trial compared the effectiveness of treatment‐based classification ( TBC ) physical therapy alone to TBC augmented with GA or GX for patients with acute and sub‐acute LBP . Our primary hypothesis was that GX would be most effective for those with elevated pain‐related fear . In total , 108 patients enrolled in this clinical trial and were r and omly assigned to receive TBC , GA , or GX . Outcomes were assessed by a blinded evaluator at 4 weeks and by mail at 6 months . The primary outcomes for this trial were disability and pain intensity , and the secondary outcomes were fear‐avoidance beliefs , pain catastrophizing , and physical impairment . There were no differences in 4‐week and 6‐month outcomes for reduction of disability , pain intensity , pain catastrophizing , and physical impairment . GX and TBC were associated with larger reductions in fear‐avoidance beliefs at 6 months only . Six‐month reduction in disability was associated with reduction in pain intensity , while 6‐month reduction in pain intensity was associated with reductions in fear‐avoidance beliefs and pain catastrophizing . This trial suggests that supplementing TBC with GA or GX was not effective for improving important outcomes related to the development of chronic LBP",
"Background Perioperative administration of pregabalin , which is effective for neuropathic pain , might reduce early postoperative and chronic pain . This r and omized , double-blinded , placebo-controlled trial ( Clinical Trials.gov ID NCT00905580 ) was design ed to investigate the efficacy and safety of pregabalin for reducing both acute postoperative pain and the development of chronic pain in patients after robot-assisted endoscopic thyroidectomy . Methods Ninety-nine patients were r and omly assigned to groups that received pregabalin 150 mg or placebo 1 h before surgery , with the dose repeated after 12 h. Assessment s of pain and side effects were performed 48 h postoperatively . The incidences of chronic pain and hypoesthesia in the anterior chest were recorded 3 months after surgery . Results Ninety-four patients completed the study . Verbal numerical rating scale scores for pain and the need for additional analgesics were lower in the pregabalin group ( n = 47 ) than the placebo group ( n = 47 ) during 48 h postoperatively ( P incidences of sedation and dizziness were higher in the pregabalin group ( P incidences of chronic pain and chest hypoesthesia at 3 months after surgery . Conclusions Perioperative administration of pregabalin ( 150 mg twice per day ) was effective in reducing early postoperative pain but not chronic pain in patients undergoing robot-assisted endoscopic thyroidectomy . Caution should be taken regarding dizziness and sedation",
"Background and Objectives The transversus abdominis plane ( TAP ) block is an established technique to manage post – cesarean delivery pain . Transversus abdominis plane blocks with a local anesthetic only offer no analgesic benefits compared with intrathecal morphine . Adjuvants to extend TAP block duration and possibly reduce wound hyperalgesia , known to be a risk factor for chronic pain , have not been studied . We hypothesized that a TAP block with clonidine will affect postsurgical wound hyperalgesia and improve pain outcomes . Methods Ninety women were r and omly assigned to receive 1 of 3 TAP blocks after cesarean delivery : saline ( placebo ) , bupivacaine ( BupTAP ) , or bupivacaine + clonidine ( CloTAP ) . The primary outcome was wound hyperalgesia index at 48 hours . Secondary outcomes included pain scores , analgesic consumption , and pain descriptors up to 12 months . Results Wound hyperalgesia index at 48 hours ( median [ 25th–75th percentiles ] ) was 1.07 ( 0.48–3.26 ) in the placebo group , 1.27 ( 0.59–2.95 ) in the BupTAP group , and 0.74 ( 0.09–2.25 ) in the CloTAP group ( P = 0.48 ) . Morphine request in the postanesthesia care unit was significantly higher in the placebo group compared with the other TAP groups ( P = 0.01 ) . Postoperative pain scores and requests for breakthrough medication at 48 hours ( 30 % in the placebo group , 24 % in the BupTAP group , and 12 % in the CloTAP group , P = 0.25 ) or chronic pain descriptors reported up to 12 months did not differ significantly among groups . Conclusions Adding clonidine to a TAP block with bupivacaine did not affect wound hyperalgesia index and it did not improve short-term or long-term pain scores in women undergoing elective cesarean delivery . Further studies are warranted to determine the benefits of antihyperalgesic adjuvants in TAP solutions for specific individuals at risk for chronic pain",
"Background and objective To find out whether preoperative gabapentin use had a favourable effect on long-term postoperative pain in patients undergoing inguinal herniorrhaphy . Methods Sixty male patients – aged 20–40 years – who were scheduled for unilateral inguinal herniorrhaphy under spinal anaesthesia were included in this prospect i ve , r and omized , double-blind study . The patients were r and omly allocated to two groups : the gabapentin group ( n = 30 ) received single-dose 1.2 g oral gabapentin 1 h before surgery , and the placebo group received a placebo capsule instead . Spinal anaesthesia was performed with heavy bupivacaine , and all operations were performed by the same surgeon with the same technique . Postoperative analgesia was evaluated during sitting and lying with a visual analogue scale . Assessment of postoperative pain at 1 , 3 and 6 months was carried out with an 11-point numerical rating scale ; 0 indicating ‘ no pain ’ and 10 indicating ‘ worst pain imaginable ’ . Patients who had numerical rating scale scores of more than 0 were further evaluated with regard to the impact of pain on their daily activities . Results When compared with the placebo group , the gabapentin group displayed significantly lower visual analogue scale scores ( lying and sitting ) and total tramadol consumption at 8 , 12 , 16 , 20 and 24 h after surgery ( P higher postoperative patient satisfaction scores ( P ) . Numerical rating scale scores at 1 , 3 and 6 months after surgery were lower in the gabapentin group than in the placebo group ( P by pain was smaller in the gabapentin group at the first month ; however , the two groups were found to be similar at 3 and 6 months . Conclusion We conclude that preoperative single-dose gabapentin decreases the intensity of acute postoperative pain , tramadol consumption and the incidence and intensity of pain in the first 6 months after inguinal herniorrhaphy",
"BACKGROUND : The issue of postoperative pain after neurosurgery is controversial . It has been reported as mild to moderate and its treatment may be inadequate . Infiltration of the surgical site with local anesthetics has provided transient benefit after craniotomy , but its effect on chronic pain has not been evaluated . Accordingly , we design ed the present study to test the hypothesis that ropivacaine infiltration of the scalp reduces acute and persistent postoperative pain after intracranial tumor resection . METHODS : This was a prospect i ve , single-blinded study . Inclusion criteria were intracranial tumor resection , age ≥18 or ≤80 yr , and ability to underst and and use a visual analog scale ( VAS ) . Exclusion criteria were history of craniotomy , chronic drug abuse , and neurologic disorders . All eligible patients were r and omly included in Group I ( infiltration ) or C ( control ) . Postoperative analgesia was IV acetaminophen combined with nalbuphine . At the end of the surgery , Group I received an infiltration of the surgical site with 20 mL of ropivacaine 0.75 % . Acute pain was evaluated hourly by VAS during the first 24 h. The analgesic effect of ropivacaine was evaluated based on total consumption of nalbuphine and VAS scores . The incidence of persistent pain and neuropathic pain was assessed at the 2-mo postoperative evaluation . We used the Student ’s t-test to compare total nalbuphine consumption , repeated measures analysis of variance with post hoc Bonferroni t-test for VAS score and the Fisher ’s exact test for chronic and neuropathic pain . RESULTS : Fifty-two patients were enrolled , 25 in Group I and 27 in Group C. Demographic and intraoperative data were similar between groups . Group I showed a nonsignificant trend toward reduced nalbuphine consumption during the first postoperative day , 11.2 ± 9.2 mg vs 16.6 ± 11.0 mg for Group C ( mean ± sd , P = 0.054 ) . VAS scores were significantly higher in Group C. Two months after surgery , persistent pain was significantly lower in Group I , 2/24 ( 8 % ) vs 14/25 ( 56 % ) , P = 0.0003 . One patient ( 4.1 % ) in Group I versus six ( 25 % ) patients in Group C ( P = 0.04 ) experienced neuropathic pain . CONCLUSIONS : Because pain is moderate after intracranial tumor resection , there is limited interest in scalp infiltrations with ropivacaine in the acute postoperative period . Nevertheless , these infiltrations may be relevant for the rehabilitation of neurosurgical patients and their quality of life by limiting the development of persistent pain and particularly neuropathic pain",
"Background Fibromyalgia ( FM ) is a chronic disorder characterized by widespread , persistent pain . Prospect i ve and retrospective studies have demonstrated substantial health-care costs associated with FM in a number of countries . This study evaluated and compared health-re source use ( HRU ) and associated costs related to FM in routine clinical practice across the US , France , and Germany . Methods Two separate , cross-sectional , observational studies of subjects with FM were conducted : one in the US and one in France and Germany . HRU related to prescription medication , physician office visits , diagnostic tests , and hospitalizations was abstract ed from chart review ; patient out-of-pocket costs and lost productivity were collected via subject self-report . Costs were assigned to HRU based on st and ard algorithms . Direct and indirect costs were evaluated and compared by simple linear regression . Results A total of 442 subjects ( 203 US , 70 France , 169 Germany ) with FM were analyzed . The mean ( st and ard deviation ) age in the US , France , and Germany was 47.9 ( 10.9 ) , 51.2 ( 9.5 ) , and 49.2 ( 9.8 ) , respectively ( P = 0.085 ) . Most subjects were female ( 95 % US , 83 % France , 80 % Germany ) ( P Adjusted annual direct costs per subject for FM were significantly higher in the US ( $ 7087 ) than in France ( $ 481 , P Adjusted mean annual indirect costs per subject for FM were lower in the US ( $ 6431 ) than in France ( $ 8718 ) or Germany ( $ 10,001 ) , but represented a significant proportion of total costs in all countries . Conclusion The significant HRU and costs associated with FM in the US , France , and Germany documented in this study highlight the substantial global economic burden of FM . Indirect costs represented a significant proportion of the total costs , particularly in Europe . Comparisons between the three countries show differences in HRU , with significantly higher direct costs in the US compared with France and Germany",
"BACKGROUND : Chronic postsurgical pain ( CPSP ) affects between 5 % and 70 % of surgical patients , depending on the surgery . There is no reliable treatment for CPSP , which has led to an increased emphasis on prevention . In this study , we sought to determine whether preventive etanercept can decrease the magnitude of postoperative pain and reduce the incidence of CPSP . METHODS : We performed a multicenter , r and omized study in 77 patients comparing subcutaneous etanercept 50 mg administered 90 minutes before inguinal hernia surgery with saline . Patients , surgeons , anesthesiologists , the injecting physician , nursing staff , and evaluators were blinded . The primary outcome measure was a 24-hour numerical rating scale pain score . Secondary outcome measures were postanesthesia care unit pain scores , 24-hour opioid requirements , time to first analgesic , and pain scores recorded at 1 month , 3 months , 6 months , and 12 months . RESULTS : Mean 24-hour pain scores were 3.3 ( 95 % confidence interval [ CI ] , 3.2–4.6 ) in the etanercept and 3.9 ( 95 % CI , 2.6–4.0 ) in the control group ( P = 0.22 ) . The mean number of analgesic pills used in the first 24 hours was 4.0 ( SD , 2.8 ) in the treatment versus 5.8 ( SD , 4.2 ) in the control group ( P = 0.03 ) . At 1 month , 10 patients ( 29 % ) in the treatment group reported pain versus 21 ( 49 % ) control patients ( P = 0.08 ) . The presence of pain at 1 month was significantly associated with pain at 3 months ( hazard ratio , 0.74 ; 99 % CI , 0.52–0.97 ; P = 0.03 ) . CONCLUSION : Although preventive etanercept was superior to saline in reducing postoperative pain on some measures , the effect sizes were small , transient , and not statistically significant . Different dosing regimens in a larger population should be explored in future studies",
"Background : Ketamine potentiates intravenous or epidural morphine analgesia . The authors hypothesized that very-low-dose ketamine infusion reduces acute and long-term postthoracotomy pain . Methods : Forty-nine patients scheduled to undergo open thoracotomy were r and omly assigned to receive one of two anesthesia regimens : continuous epidural infusion of ropivacaine and morphine , along with intravenous infusion of ketamine ( 0.05 mg · kg−1 · h−1 [ approximately 3 mg/h ] , ketamine group , n = 24 ) or placebo ( saline , control group , n = 25 ) . Epidural analgesia was continued for 2 days after surgery , and infusion of ketamine or placebo was continued for 3 days . Pain was assessed at 6 , 12 , 24 , and 48 h after surgery . Patients were asked about their pain , abnormal sensation on the wound , and inconvenience in daily life at 7 days and 1 , 3 , and 6 months after surgery . Results : The visual analog scale scores for pain at rest and on coughing 24 and 48 h after thoracotomy were lower in the ketamine group than in the control group ( pain at rest , 9 ± 11 vs. 25 ± 20 and 9 ± 11 vs. 18 ± 13 ; pain on coughing , 26 ± 16 vs. 50 ± 17 and 30 ± 18 vs. 43 ± 18 , mean ± SD ; P = 0.002 and P = 0.01 , P . The numerical rating scale scores for baseline pain 1 and 3 months after thoracotomy were significantly lower in the ketamine group ( 0.5 [ 0–4 ] vs. 2 [ 0–5 ] and 0 [ 0–5 ] vs. 1.5 [ 0–6 ] , median [ range ] , respectively ; P = 0.02 ) . Three months after surgery , a higher number of control patients were taking pain medication ( 2 vs. 9 ; P = 0.03 ) . Conclusions : Very-low-dose ketamine ( 0.05 mg · kg−1 · h−1 ) potentiated morphine-ropivacaine analgesia and reduced postthoracotomy pain ",
"UNLABELLED Postmastectomy pain syndrome ( PMPS ) is a neuropathic pain syndrome that might develop after breast surgery . Like many other forms of neuropathic pain , it is relatively resistant to treatment and negatively affects the quality of life . A double-blind , r and omized , placebo-controlled pilot trial was conducted to study the analgesic efficacy of perioperative administration of the N-methyl-D-aspatrate ( NMDA ) receptor antagonist amantadine in preventing PMPS after mastectomy plus axillary lymph node dissection ( ALND ) . In the study group , a regimen of 200 mg/day of amantadine was started 1 day before surgery and continued for 14 days , whereas the control group received a placebo . Patients were required to indicate the exact location of their pain and to record its level at 1 , 3 , and 6 months after surgery . Neurologic examination and Quantitative Thermal Testing ( QTT ) were performed 1 and 6 months after surgery . On both the neurologic examination and the QTT , all patients , regardless of the perioperative intervention ( amantadine or placebo ) , presented evidence for nerve injury , manifested primarily by painful hypoesthesia ( anesthesia dolorosa ) in the axilla or inner arm . PMPS persisted for the entire duration of the study in 82 % of the patients who were available for follow-up . The average intensity of the pain was moderate in both groups and tended not to decline over time . No differences between the 2 groups in any of the outcome parameters reached statistical significance . According to the results of the present pilot study , the NMDA antagonist amantadine does not prevent the development of PMPS in patients who undergo breast surgery with ALND . PERSPECTIVE Breast surgery that involves ALND seems to uniformly cause nerve injury , which can not be prevented by the perioperative administration of 200 mg of amantadine . It is most commonly presented by painful hypoesthesia or anesthesia dolorosa in the axillary/inner arm area , which is moderate in intensity and likely to persist for at least 6 months",
"Purpose This study assessed whether gabapentin given preoperatively and for two days postoperatively ( in addition to patient-controlled analgesia [ PCA ] morphine , acetaminophen , and ketorolac ) is effective in reducing morphine requirements and moderating pain scores when compared with placebo for primary total knee arthroplasty . Methods This single-centre double-blind r and omized controlled trial was undertaken in patients who underwent primary total knee arthroplasty . All subjects received acetaminophen 1,000 mg and ketorolac 15 mg po preoperatively . Postoperatively , subjects received PCA morphine , acetaminophen 1,000 mg every six hours , and ketorolac 15 mg po every six hours . Subjects received either gabapentin 600 mg po preoperatively followed by 200 mg po every eight hours for two days or matching placebo . The primary outcome was cumulative morphine consumption at 72 hr following surgery . Secondary outcome measures included pain scores and patient satisfaction . Results There were 52 subjects in the gabapentin group and 49 subjects in the placebo group . The average cumulative morphine consumption at 72 hr postoperatively was 66.3 mg in the gabapentin group and 72.5 mg in the placebo group ( difference −6.2 mg ; 95 % confidence interval −29.1 to 16.8 mg ; P = 0.59 ) . Mean pain scores at rest , with passive movement , or with weight bearing were similar in both groups at corresponding time periods for the first three days following surgery . In addition , mean patient satisfaction scores and hospital length of stay were similar in the two groups . Conclusion Gabapentin 600 mg po given preoperatively followed by 200 mg po every eight hours for two days has no effect on postoperative morphine consumption , pain scores , patient satisfaction , or length of hospital stay . This trial is registered at Clinical Trials.gov NCT01307202.RésuméObjectifCette étude a consisté à déterminer si la gabapentine , donnée en préopératoire et pendant deux jours après l’opération ( en addition à de la morphine en analgésie contrôlée par le patient [ ACP ] , de l’acétaminophène et du kétorolac ) , était efficace pour réduire les besoins en morphine ainsi que pour diminuer les scores de douleur par rapport à un placebo pour une arthroplastie totale du genou . MéthodeCette étude r and omisée contrôlée à double insu a été réalisée dans un seul centre , auprès de patients subissant une arthroplastie totale du genou primaire . Tous les patients ont reçu 1000 mg d’acétaminophène et 15 mg de kétorolac po avant l’opération . En postopératoire , les patients ont reçu de la morphine en ACP , 1000 mg d’acétaminophène toutes les six heures et 15 mg de kétorolac po toutes les six heures . Les patients ont reçu soit 600 mg de gabapentine po en préopératoire suivis de 200 mg po aux huit heures durant deux jours , soit un placebo correspondant . Le critère d’évaluation principal était la consommation cumulée de morphine à 72 h après la chirurgie . Les critères d’évaluation secondaires étaient les scores de douleur et la satisfaction des patients .RésultatsLe groupe gabapentine comptait 52 patients et le groupe placebo en comptait 49 . La consommation cumulée moyenne de morphine à 72 h postopératoires était de 66,3 mg dans le groupe gabapentine et de 72,5 mg dans le groupe placebo ( différence −6,2 mg ; intervalle de confiance 95 % −29,1 à 16,8 mg ; P = 0,59 ) . Les scores moyens de douleur au repos , avec un mouvement passif ou avec un mouvement contre résistance , étaient semblables dans les deux groupes à des points dans le temps correspondants au cours des trois premiers jours postopératoires . En outre , les scores moyens de satisfaction des patients et la durée du séjour à l’hôpital étaient semblables dans les deux groupes . Conclusion La gabapentine 600 mg po en préopératoire suivie de 200 mg po toutes les huit heures pendant deux jours n’a aucun effet sur la consommation postopératoire de morphine , les scores de douleur , la satisfaction des patients ou la durée du séjour à l’hôpital . Cette étude est enregistrée sous Clinical Trials.gov NCT01307202",
"STUDY DESIGN A double-blind , r and omized controlled trial of a novel educational booklet compared with a traditional booklet for patients seeking treatment in primary care for acute or recurrent low back pain . OBJECTIVE To test the impact of a novel educational booklet on patients ' beliefs about back pain and functional outcome . SUMMARY OF BACKGROUND DATA The information and advice that health professionals give to patients may be important in health care intervention , but there is little scientific evidence of their effectiveness . A novel patient educational booklet , The Back Book , has been developed to provide evidence -based information and advice consistent with current clinical guidelines . METHODS One hundred sixty-two patients were given either the experimental booklet or a traditional booklet . The main outcomes studied were fear-avoidance beliefs about physical activity , beliefs about the inevitable consequences of back trouble , the Rol and Disability Question naire , and visual analogue pain scales . Postal follow-up response at 1 year after initial treatment was 78 % . RESULTS Patients receiving the experimental booklet showed a statistically significant greater early improvement in beliefs which was maintained at 1 year . A greater proportion of patients with an initially high fear-avoidance beliefs score who received the experimental booklet had clinical ly important improvement in fear-avoidance beliefs about physical activity at 2 weeks , followed by a clinical ly important improvement in the Rol and Disability Question naire score at 3 months . There was no effect on pain . CONCLUSION This trial shows that carefully selected and presented information and advice about back pain can have a positive effect on patients ' beliefs and clinical outcomes , and suggests that a study of clinical ly important effects in individual patients may provide further insights into the management of low back pain",
"Study Design . A r and omized controlled study with 12 months intervention . Objective . To study the effectiveness of a training intervention with emphases on the control of lumbar neutral zone ( NZ ) and behavior modeling as secondary prevention of low back pain ( LBP ) and disability . Summary of Background Data . Improving the control of lumbar NZ and enhancing muscle activation patterns ensuring spinal stability have been proposed as means for secondary prevention of LBP and disability . In addition , cognitive behavior interventions have been shown to lower the risk of recurrence of LBP and long-term disability . Methods . Middle-aged working men with recent LBP but without severe disability were r and omly allocated to either a training ( TG , n = 52 ) or control group ( CG , n = 54 ) . The aim was to exercise twice a week for 12 months , once guided and once independently . The outcome measures were the changes in intensity of LBP , disability , self-evaluated future work ability , and neuromuscular fitness . Results . The intensity of LBP decreased significantly more ( 39 % ) in the TG than in CG at 12 months . The proportion of subjects with negative expectations about their future work ability decreased in both groups at 6 and 12 months ; however , the proportion was significantly bigger in TG compared with CG ( P = 0.028 ) . There effects on disability indexes and fitness were not statistically significant . Conclusions . Controlling lumbar NZ is a specific form of exercise and daily self-care with potential for prevention of recurrent nonspecific LBP and disability among middle aged working men",
"Objectives : To identify risk factors for postherpetic neuralgia ( PHN ) using a vali date d definition of this chronic neuropathic pain syndrome , to determine combinations of risk factors that identify patients with a high risk of developing PHN , and to examine the characteristics of patients with subacute herpetic neuralgia , that is , pain that persists beyond the acute phase of herpes zoster but that resolves before PHN can be diagnosed . Methods : The authors examined baseline and follow-up data from 965 herpes zoster patients enrolled within 72 hours of rash onset in two clinical trials of famciclovir . Results : Univariate and multivariate analyses indicated that older age , female sex , presence of a prodrome , greater rash severity , and greater acute pain severity made independent contributions to identifying which patients developed PHN . Patients with subacute herpetic neuralgia who did not develop PHN were significantly younger and had less severe acute pain than PHN patients but were significantly more likely to have severe and widespread rash than patients without persisting pain . Conclusions : The independent contributions to the prediction of PHN made by older age , female sex , presence of a prodrome , greater rash severity , and greater acute pain severity suggest that these risk factors reflect different mechanisms that each contribute to the development of PHN . Subacute herpetic neuralgia that does not progress to PHN may reflect peripheral tissue damage and inflammation caused by a particularly severe or widespread rash",
"BACKGROUND : Gabapentin and ketamine are popular analgesic adjuvants for improving perioperative pain management . We design ed this double-blind , placebo-controlled study to test and compare the preventive effects of perioperative ketamine and gabapentin on early and chronic pain after elective hysterectomy . METHODS : Sixty patients undergoing abdominal hysterectomy were r and omly assigned to 1 of the following 3 groups : control group received oral placebo capsules and bolus plus infusion of saline ; ketamine group received oral placebo capsules and , before incision , 0.3 mg/kg IV bolus and 0.05 mg·kg−1·h−1 infusion of ketamine until the end of surgery ; and gabapentin group received oral gabapentin 1.2 g and bolus plus infusion of saline . The anesthetic technique was st and ardized , and the postoperative assessment s included verbal rating scales for pain and sedation , IV morphine usage , quality of recovery assessment , recovery of bowel function , resumption of normal activities , and patient satisfaction with their pain management . Patients were question ed at 1 , 3 , and 6 mo after surgery for chronic postoperative pain . RESULTS : Postoperative pain scores were significantly lower in the gabapentin group compared with the ketamine and control groups , and patient-controlled analgesia morphine use was significantly reduced in both treatment groups ( versus control group ) ( P 0.001 ) . Total patient-controlled analgesia morphine use was decreased by 35 % and 42 % in the ketamine and gabapentin groups , respectively , compared with the control group ( P 0.001 ) . Patient satisfaction with pain treatment was significantly improved in the ketamine and gabapentin groups compared with the control group ( P . The incidence of incisional pain and related pain scores at the 1- , 3- , and 6-mo follow-up were significantly lower in the gabapentin group compared with the ketamine and control groups ( P CONCLUSION : Gabapentin and ketamine are similar in improving early pain control and in decreasing opioid consumption ; however , gabapentin also prevented chronic pain in the first 6 postoperative months",
"In this clinical , r and omized , prospect i ve study , we compared the effects of three different analgesia techniques ( thoracic epidural analgesia [ TEA ] with and without preoperative initiation and IV patient-controlled analgesia [ IV-PCA ] ) on postthoracotomy pain in 69 patients . In two groups , a thoracic epidural catheter was inserted preoperatively . Group Pre-TEA had bupivacaine and morphine solution preoperatively and intraoperatively . Postoperative analgesia was maintained with epidural PCA with a similar solution . Group Post-TEA , with no intraoperative medication , had the same postoperative analgesia as Group Pre-TEA plus the bolus dose . Group IV-PCA received only IV-PCA with morphine for postoperative analgesia . Pain was evaluated every 4 h during the first 48 h at rest , cough , and movement . Pre-TEA was associated with decreased pain compared with the other groups . Six months later , the patients were asked about their pain . The incidence and the intensity of pain were most frequent in Group IV-PCA ( 78 % ) and were the least in Group Pre-TEA ( 45 % ) ( Group Pre-TEA versus Group IV-PCA , P = 0.0233 ; Group Pre-TEA versus Group IV-PCA , P = 0.014 ) . Patients having pain on the second postoperative day had 83 % chronic pain . TEA with preoperative initiation is a preferable method in preventing acute and long-term thoracotomy pain",
"AFTER surgical procedures such as amputation , mastectomy , and thoracotomy , as many as 60 % of patients continue to experience pain for at least 6 months , with approximately 10 % reporting severe pain . These chronic postsurgical pain conditions have major adverse effects on health-related quality of life , including physical functioning and emotional well-being . Unfortunately , the efficacy of existing treatments is limited and many patients remain refractory to currently available therapies . For this reason , the development of interventions that prevent chronic pain after surgery has the potential to have a major impact on public health . Substantial attention has been devoted to the hypothesis that the incidence of chronic postsurgical pain can be reduced by “ preventive ” analgesia , and the benefits of preoperative , intraoperative , and postoperative analgesic interventions have been investigated alone and in various combinations . Although the results of these studies suggest that reduced acute pain and analgesic consumption can extend beyond the duration of action of the preventive analgesic interventions , there is little evidence that chronic postsurgical pain can be prevented . Placebocontrolled r and omized clinical trials are needed to determine what specific analgesic interventions are efficacious for preventing chronic pain after what types of surgery for which patients . – 6 A critical component of future clinical trials will involve determining the clinical importance of the benefits of preventive analgesia . The results of recent studies and consensus recommendations provide a foundation for interpreting the benefits of chronic pain treatment ; however , little attention has been paid to determining what magnitudes of chronic pain prevention are clinical ly meaningful . As is true of treatment benefits , evaluating the importance of preventive benefits involves a frequently misunderstood distinction between the interpretation of the clinical importance of individual patient benefits and the interpretation of the clinical importance of group differences . The results of multiple studies have shown that individual patients consider chronic pain reductions of at least 30 % on numerical or visual analog scales to be moderately clinical ly important , whereas reductions of at least 50 % represent substantial improvements . These thresholds are based on ratings by patients of their own improvement at the end of chronic pain trials , and consistent results have been found across different chronic pain conditions and in patients administered active treatments as well as placebo . Criteria for identifying clinical ly meaningful individual improvements are necessary to categorize patients as “ responders ” or “ nonresponders , ” which makes it possible to compare the percentages of patients who achieve clinical ly important outcomes between different treatment and comparison groups . Unfortunately , criteria for determining clinical ly important improvements in patients being treated for chronic pain can not be extrapolated to those undergoing perioperative analgesic interventions to prevent chronic pain . Currently , there are no data that make it possible to determine whether patients who have not experienced chronic pain would consider its prevention after surgery important enough to undergo preoperative , intraoperative , and postoperative analgesic interventions . Evaluations of individual patient improvements associated with chronic pain treatments have emphasized pain reduction , but patients considering the prevention of conditions for which their risk is relatively low can also be expected to be particularly concerned with the adverse effects , safety risks , inconvenience , and costs of the preventive intervention . It is likely that an efficacious preventive analgesia would not completely prevent chronic pain but would instead partially reduce its incidence , intensity , or duration . Such partial preventive benefits would , of course , be even harder for patients to evaluate ; for example , would patients consider reducing pain intensity 6 months after surgery from a daily average of 4 to 2 on a 0–10 scale a clinical ly important benefit ? Would this evaluation change if this reduction in pain intensity at 6 months is known to last for another 2 yr , or if the preventive intervention requires that patients take a medication that causes sedation , nausea , and constipation for 7 days before and 30 days after their operation ? Evaluations of the clinical importance of preventive analgesia must reflect the magnitude of the reductions in chronic pain incidence , intensity , or duration that the intervention would provide . However , even small reductions in the incidence or intensity of a chronic pain condition that can last for months or even years might be considered clinical ly important by patients if Accepted for publication November 17 , 2009 . The authors are not supported by , nor maintain any financial interest in , any commercial activity that may be associated with the topic of this article",
"A clinical trial , aim ed at secondary prevention of low-back pain , was performed in 142 hospital employees reporting at least three annual episodes of this condition . Participants were r and omly assigned to one of three groups : a calisthenics program ( CAL ) for 3 months with biweekly sessions of flexion exercises , a back school program ( 5 sessions ) , and a control group . The effectiveness of the two intervention programs was evaluated over a 1-year period . Baseline preintervention data and evaluation at the end of 3 months of intervention and after an additional 6 months were collected . A monthly surveillance for the whole year showed a mean of 4.5 “ painful months ” in the CAL group versus 7.3 and 7.4 months in the back school and control groups , respectively ( P CAL group was achieved partly because of the significant increase in trunk forward flexion and to initial increment in abdominal muscle strength . The increased trunk flexion was associated with the rate of participation in the CAL sessions . Further research is needed to answer the question of “ intensity versus type of exercise ” by comparing different intervention programs , with similar intensity",
"The CONSORT ( Consoli date d St and ards of Reporting Trials ) statement is used worldwide to improve the reporting of r and omized , controlled trials . Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience .",
"OBJECTIVE Long-term pain is a common sequela of thoracotomy , occurring in approximately 50 % of patients 2 years after thoracic surgery . Despite this alarming statistic , little is known about the factors responsible for the transition of acute to chronic pain . The aim of the present study is to identify predictors of long-term post-thoracotomy pain . DESIGN Follow-up was for 1.5 years for patients who had participated in a prospect i ve , r and omized , controlled trial of preemptive , multimodal analgesia . SETTING Subjects were recruited from a tertiary care center . PATIENTS Thirty patients who had undergone lateral thoracotomy were followed up by telephone , administered a structured interview , and classified according to long-term pain status . MAIN OUTCOME MEASURES Present pain status was measured by a verbal rating scale ( VAS ) . Measures obtained within the first 48 h after surgery were compared between patients with and without pain 1.5 years later . These include VAS pain scores at rest and after movement , McGill Pain Question naire data , patient-controlled morphine consumption ( mg ) , and pain thresholds to pressure applied to a rib contralateral to the thoracotomy incision . RESULTS Fifty-two percent of patients reported long-term pain . Early postoperative pain was the only factor that significantly predicted long-term pain . Pain intensity 24 h after surgery , at rest , and after movement was significantly greater among patients who developed long-term pain compared with pain-free patients . A significant predictive relationship was also found at 24 and 48 h using the McGill Pain Question naire . Cumulative morphine was comparable for the two groups . Pain thresholds to pressure applied to a rib contralateral to the incision did not differ significantly between the groups . CONCLUSION Aggressive management of early postoperative pain may reduce the likelihood of long-term post-thoracotomy pain",
"Background Axonal sensory peripheral neuropathy is the major dose-limiting side effect of paclitaxel . Omega-3 fatty acids have beneficial effects on neurological disorders from their effects on neurons cells and inhibition of the formation of proinflammatory cytokines involved in peripheral neuropathy . Methods This study was a r and omized double blind placebo controlled trial to investigate the efficacy of omega-3 fatty acids in reducing incidence and severity of paclitaxel-induced peripheral neuropathy ( PIPN ) . Eligible patients with breast cancer r and omly assigned to take omega-3 fatty acid pearls , 640 mg t.i.d during chemotherapy with paclitaxel and one month after the end of the treatment or placebo . Clinical and electrophysiological studies were performed before the onset of chemotherapy and one month after cessation of therapy to evaluate PIPN based on \" reduced Total Neuropathy Score \" . Results Twenty one patients ( 70 % ) of the group taking omega-3 fatty acid supplement ( n = 30 ) did not develop PN while it was 40.7 % ( 11 patients ) in the placebo group(n = 27 ) . A significant difference was seen in PN incidence ( OR = 0.3 , .95 % CI = ( 0.10 - 0.88 ) , p = 0.029 ) . There was a non-significant trend for differences of PIPN severity between the two study groups but the frequencies of PN in all scoring categories were higher in the placebo group ( 0.95 % CI = ( −2.06 -0.02 ) , p = 0.054 ) . Conclusions Omega-3 fatty acids may be an efficient neuroprotective agent for prophylaxis against PIPN . Patients with breast cancer have a longer disease free survival rate with the aid of therapeutical agents . Finding a way to solve the disabling effects of PIPN would significantly improve the patients ’ quality of life . Trial registration This trial was registered at Clinical Trials.gov ( NCT01049295",
"Objectives Postmastectomy pain syndrome is a neuropathic pain syndrome that is known to develop after breast surgery . Preemptive analgesia has been shown to be efficacious in reducing postoperative pain , and may be effective in reducing the incidence of certain types of neuropathic pain . We investigated the analgesic efficacy of Venlafaxine and gabapentin on acute and chronic pain associated with cancer breast surgery . Patients and Methods The study was carried out on 150 patients scheduled for either partial or radical mastectomy with axillary dissection . They were r and omized in a double-blinded manner to receive , extended release Venlafaxine 37.5 mg/d , gabapentin 300 mg/d , or placebo for 10 days starting the night before operation . Pain scores were recorded at rest and movement ( visual analog scale ) at 4 , 12 , and 24 hours on the first day postoperatively , daily from the second to tenth day postoperatively and visual analog scale in addition to pain character 6 months later . Analgesic requirements were compared between the 3 groups . Results Pain after movement was reduced by gabapentin from the second to tenth postoperative day and venlafaxine group in the last 3 days but no difference was found between the groups regarding pain during rest . Gabapentin reduced morphine consumed in the first 24 hours postoperatively . The analgesic requirements from the second to tenth days for codeine and paracetamol were reduced in venlafaxine and gabapentin groups compared to the control group . Six months later , the incidence of chronic pain , its intensity , and need for analgesics were reduced in venlafaxine compared to gabapentin and the placebo group . However , burning pain was more frequent in the control groups than in the gabapentin . Conclusion Venlafaxine 37.5 mg/d extended release or gabapentin 300 mg/d have equipotent effects ( except on the first day in venlafaxine group ) in reducing analgesic requirements , although gabapentin is more effective in reducing pain after movement . Venlafaxine significantly reduced the incidence of postmastectomy pain syndromes ( chronic pain ) 6 months in women having breast cancer surgery . Gabapentin had no effect on chronic pain except decreasing incidence of burning pain",
"OBJECTIVE To evaluate the effects of thoracic epidural anesthesia ( TEA ) as an adjunct to general anesthesia ( GA ) on postoperative pain after coronary artery bypass grafting ( CABG ) . METHODS Between April 2009 and March 2010 , 40 patients with ischemic heart disease scheduled for elective CABG were prospect ively r and omized to receive either GA ( n = 20 ) or GA + TEA ( n = 20 ) . Through epidural catheters , patients received an infusion of ( 10 - 20 mg/h ) 0.25%-bupivacaine intraoperatively and during the first 24 hours after surgery . Study endpoints included assessment of postoperative pain at rest and with coughing , rescue analgesic need , and postoperative course . RESULTS The differences in pain scores were decreased at rest during 6 ( 0.1 ± 0.3 vs. 2.4 ± 1.8 ; p coughing at 6 ( 0.1 ± 0.3 vs. 5.6 ± 2.2 ; p the GA + TEA group . At one-month follow-up , pain scores were decreased in GA + TEA group ( 0.3 ± 0.7 vs. 1.6 ± 1.3 ; p = 003 ) . There was no significant difference at three and six months . Mechanical ventilation time ( 4.7 ± 1.2 vs. 2.9 ± 1.1 hours ; p stay ( 28.4 ± 9.0 vs. 22.4 ± 3.4 hours ; p 0.05 ) , and hospital stay ( 7.2 ± 1.1 vs. 6.1 ± 0.3 days ; p = 0.001 ) were reduced in the GA + TEA group . CONCLUSIONS TEA significantly reduced the intensity of postoperative pain and analgesic consumption in the early postoperative period following CABG . The delivery of effective analgesia along with conventional medications may prevent chronic pain after surgery",
"ABSTRACT The objective of the present research was to develop a single measure of the major symptoms of both neuropathic and non‐neuropathic pain that can be used in studies of epidemiology , natural history , pathophysiologic mechanisms , and treatment response . We exp and ed and revised the Short‐form McGill Pain Question naire1 ( SF‐MPQ ) pain descriptors by adding symptoms relevant to neuropathic pain and by modifying the response format to a 0–10 numerical rating scale to provide increased responsiveness in longitudinal studies and clinical trials . The reliability , validity , and subscale structure of the revised SF‐MPQ ( SF‐MPQ‐21 ) were examined in responses from 882 individuals with diverse chronic pain syndromes and in 226 patients with painful diabetic peripheral neuropathy who participated in a r and omized clinical trial . The data suggest that the SF‐MPQ‐2 has excellent reliability and validity , and the results of both exploratory and confirmatory factor analyses provided support for four readily interpretable subscales — continuous pain , intermittent pain , predominantly neuropathic pain , and affective descriptors . These results provide a basis for use of the SF‐MPQ‐2 in future clinical research , including clinical trials of treatments for neuropathic and non‐neuropathic pain conditions",
"BACKGROUND : Despite the enormous success of total knee arthroplasty ( TKA ) , chronic neuropathic pain can develop postoperatively and is both distressing and difficult to treat once established . We hypothesized that perioperative treatment with pregabalin , a chronic pain medication , would reduce the incidence of postsurgical neuropathic pain . METHODS : We performed a r and omized , placebo-controlled , double-blind trial of pregabalin ( 300 mg ) administered before TKA and for 14 days after TKA ( 150–50 mg twice daily ) . Patients were screened for the presence of neuropathic pain at 3 and 6 mo postoperatively using the Leeds Assessment of Neuropathic Symptoms and Signs scale . Secondary outcomes included postsurgical recovery and rehabilitation measures , including knee range of motion , opioid consumption , postoperative pain scores , sleep disturbance , and time to discharge as well as the occurrence of postoperative systemic complications . RESULTS : Of the 240 patients r and omly assigned to the 2 treatment groups ( 120 in each ) , data for the primary outcome were obtained from 113 pregabalin patients and 115 placebo patients . At both 3 and 6 mo postoperatively , the incidence of neuropathic pain was less frequent in the pregabalin group ( 0 % ) compared with the placebo group ( 8.7 % and 5.2 % at 3 and 6 mo , respectively ; P = 0.001 and P = 0.014 ) . Patients receiving pregabalin also consumed less epidural opioids ( P = 0.003 ) , required less oral opioid pain medication while hospitalized ( P = 0.005 ) , and had greater active flexion over the first 30 postoperative days ( P = 0.013 ) . There were no differences in the actual recorded duration of hospitalization between the 2 groups , although time to achieve hospital discharge criteria was longer for placebo patients , 69.0 ± 16.0 h ( mean ± sd ) , than that of pregabalin patients , 60.2 ± 15.8 h ( P = 0.001 ) . Sedation ( P = 0.005 ) and confusion ( P = 0.013 ) were more frequent on the day of surgery and postoperative day 1 in patients receiving pregabalin . CONCLUSION : Perioperative pregabalin administration reduces the incidence of chronic neuropathic pain after TKA , with less opioid consumption and better range of motion during the first 30 days of rehabilitation . However , in the doses tested , it is associated with a higher risk of early postoperative sedation and confusion",
"& NA ; Recently , fear – avoidance models have been quite influential in underst and ing the transition from acute to chronic low back pain ( LBP ) . Not only has pain‐related fear been found to be associated with disability and increased pain severity , but also treatment focused at reducing pain‐related fear has shown to successfully reduce disability levels . In spite of these developments , there is still a lack in well‐ design ed prospect i ve studies examining the role of pain‐related fear in acute back pain . The aim of the current study was to prospect ively test the assumption that pain‐related fear in acute stages successfully predicts future disability . Subjects were primary care acute LBP patients consulting because of a new episode of LBP ( ≤3 weeks ) . They completed question naires on background variables , fear – avoidance model variables and LBP outcome ( Grade d Chronic Pain Scale , GCPS ) at baseline , 3 , 6 , and 12 months follow‐up and at the end of the study . Two‐hundred and twenty‐two acute LBP patients were included , of whom 174 provided full follow‐up information ( 78.4 % ) . A backward ordinal regression analysis showed previous LBP history and pain intensity to be the most important predictors of end of study GCPS . Of the fear – avoidance model variables , only negative affect added to this model . Our results do not really support the longitudinal validity of the fear – avoidance model , but they do feed the discussion on the role of pain‐related fear in early stages of LBP",
"ABSTRACT Although acute pain in patients with herpes zoster can be severe and has a substantial impact on health‐related quality of life , there have been no r and omized clinical trials of oral medications specifically for its ongoing treatment . A r and omized clinical trial was conducted in which 87 subjects ⩾50 years of age with herpes zoster within 6 calendar days of rash onset and with worst pain in the past 24 h ⩾ 3 on a 0–10 rating scale initiated 7 days of treatment with famciclovir in combination with 28 days of treatment with either controlled‐release ( CR ) oxycodone , gabapentin , or placebo . Subjects were evaluated for adverse effects of treatment , acute pain , and health‐related quality of life . The results showed that CR‐oxycodone and gabapentin were generally safe and were associated with adverse events that reflect well‐known effects of these medications . Discontinuing participation in the trial , primarily associated with constipation , occurred more frequently in subjects r and omized to CR‐oxycodone ( 27.6 % ) compared with placebo ( 6.9 % ) . Treatment with CR‐oxycodone reduced the mean worst pain over days 1–8 ( p = 0.01 ) and days 1–14 ( p = 0.02 ) relative to placebo but not throughout the entire 28‐day treatment period as pain resolved in most subjects . Gabapentin did not provide significantly greater pain relief than placebo , although the data for the first week were consistent with a modest benefit . By demonstrating that CR‐oxycodone is safe , generally adequately tolerated , and appears to have efficacy for relieving acute pain , the results of this clinical trial provide a foundation for evidence ‐based treatment for acute pain in herpes zoster",
"BACKGROUND The incidence of postherpetic neuralgia ( PHN ) has been reported to be 25 % among those over the age of 50 years treated with antiviral medication . The role of sympathetic block in its prevention remains question able . OBJECTIVES The aim of this study is to determine whether early stellate ganglion blockade for acute herpes zoster of the face will reduce the intensity and duration of acute herpetic pain , and if the blockade has the potential to prevent or reduce the incidence and /or severity of PHN . STUDY DESIGN R and omized , controlled , double blind trial . SETTING Hospital , outpatient setting . METHODS Sixty-four patients over 50 years were assigned to receive a stellate ganglion block using either 8 mL saline ( Group 1 ) or 6 mL bupivacaine 0.125 % and 8 mg dexamethasone in a total volume of 8 mL ( Group 2 ) . All procedures were performed under fluoroscopy . All patients received pregabalin in a dose of 150 mg twice daily . Acetaminophen was available as needed . Pain assessment using the visual analog scale and amount of analgesic being taken was measured at the initial visit ( basal ) , weekly for 6 weeks after the procedure and after 2 , 3 , and 6 months . Once a patient reported mild pain during the trial , pregabalin was tapered by 75 mg every other day ; the patients who succeeded in this step were recorded in each group . The time of complete resolution of pain and incidence of persistent postherpetic pain was reported . Each patient 's satisfaction was evaluated . RESULTS There was a significantly shorter duration of pain noticed in Group 2 ( P = 0.002 ) . A significantly lower incidence of PHN was encountered in Group 2 after 3 months ( P = 0.043 ) and 6 months ( P = 0.035 ) . Significantly more patient satisfaction was reported in Group 2 after 3 and 6 months . By the fourth week , 29 patients in Group 2 reported no pain . Two patients reported mild pain after 3 months which was resolved by the sixth month . In Group 1 , 22 patients reported no pain by the sixth week and 8 patients reported moderate pain after 2 and 3 months ; by the sixth month , 4 out of those 8 patients showed spontaneous remission of pain . There was a significant reduction in the total doses of pregabalin and acetaminophen in Group 2 ( P serious adverse effects were reported during the study period . LIMITATIONS The sample size was determined using the incidence of PHN ( chronic pain ) as a main hypothesis . Meanwhile , this study determined the incidence of acute pain as well , which may lead to bias to the results of acute pain . CONCLUSION Early stellate ganglion blockade , in combination with an antiviral agent , is a very effective treatment modality ; it dramatically decreases the intensity of acute pain and shortens its duration and reduces the incidence of postherpetic neuralgia",
"Acute neuritis and persistent pain are the most significant clinical manifestations of herpes zoster and are end points for clinical trials therapy . In an acyclovir and prednisone study , patients were categorized according to pain severity and number of lesions at presentation . Risk categories were defined according to the magnitude of risk ratios ( RRs ) and a comparison of Kaplan-Meier survival estimates . For acute neuritis and zoster-associated pain , RRs defined rate of resolution . Patients who presented with severe or incapacitating pain and a large number of lesions were less likely to achieve resolution of both acute neuritis and zoster-associated pain ( RR , 18.0 ; 95 % confidence interval [ CI ] , 6 . 6 - 48.6 , and RR , 5.3 ; 95 % CI , 4.2 - 17.2 , respectively ) . These analyses identify the subgroups of patients for whom aggressive interventions are most strongly indicated",
"BACKGROUND Early clinical trials have suggested that glutathione ( GSH ) offers protection from the toxic effects of cisplatin . PATIENTS AND METHODS One hundred fifty-one patients with ovarian cancer ( stage I-IV ) were evaluated in a clinical trial of cisplatin ( CDDP ) + /- glutathione ( GSH ) . The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity . RESULTS When considering the proportion of patients receiving six courses of CDDP at any dose , GSH produced a significant advantage over control--58 % versus 39 % , ( P = 0.04 ) . For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control--74 % versus 62 % ( P = 0.006 ) . Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression , emesis , peripheral neurotoxicity , hair loss , shortness of breath and difficulty concentrating . As an indication of overall activity , these patients were statistically significantly more able to undertake housekeeping and shopping . Clinical ly assessed response to treatment demonstrated a trend towards a better outcome in the GSH group ( 73 % versus 62 % ) but this was not statistically significant ( P = 0.25 ) . CONCLUSIONS The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient 's quality of life is improved",
"Introduction Low back pain ( LBP ) is the leading cause of disability worldwide . Of those patients who present to primary care with acute LBP , 40 % continue to report symptoms 3 months later and develop chronic LBP . Although it is possible to identify these patients early , effective interventions to improve their outcomes are not available . This double-blind ( participant/ outcome assessor ) r and omised controlled trial will investigate the efficacy of a brief educational approach to prevent chronic LBP in ‘ at-risk ’ individuals . Methods / analysis Participants will be recruited from primary care practice s in the Sydney metropolitan area . To be eligible for inclusion participants will be aged 18–75 years , with acute LBP ( r and omly allocated to receive 2 × 1 h sessions of pain biology education or 2 × 1 h sessions of sham education from a specially trained study physiotherapist . The study requires 101 participants per group to detect a 1-point difference in pain intensity 3 months after pain onset . Secondary outcomes include the incidence of chronic LBP , disability , pain intensity , depression , healthcare utilisation , pain attitudes and beliefs , global recovery and recurrence and are measured at 1 week post-intervention , and at 3 , 6 and 12 months post LBP onset . Ethics/dissemination Ethical approval was obtained from the University of New South Wales Human Ethics Committee in June 2013 ( ref number HC12664 ) . Outcomes will be disseminated through publication in peer- review ed journals and presentations at international conference meetings . Trial registration number https://www.anzctr.org.au/Trial/ Registration /Trial Review",
"OBJECTIVES To evaluate the effect of perioperative gabapentin treatment for the prevention of persistent post-thoracotomy pain and to establish whether gabapentin has a significant therapeutic impact on acute postoperative pain . METHODS Consecutive patients with pulmonary malignancies scheduled for anterior thoracotomy were enrolled in this r and omized , double-blinded , placebo-controlled trial . Patients were given 1200 mg gabapentin or placebo 2 h before surgery followed by increasing doses during 5 postoperative days : 600 mg for day 1 ; 900 mg for day 2 ; and 1200 mg for days 3 - 5 . Effective pain relief was provided with perioperative multimodal analgesia with epidural infusion of bupivacaine and morphine for 72 h , and oral acetaminophen , ibuprofen and morphine . The main outcome was persistent post-thoracotomy pain at 6 months . Secondary outcomes included measures of early postoperative post-thoracotomy pain , morphine requirements , recovery and analgesia-related adverse effects over the first 3 weeks as well as persistent post-thoracotomy pain at 3 months . RESULTS A total of 104 patients were r and omly assigned to the intervention or control group ; 86 ( 83 % ) patients were available for the 14-day analysis , 76 ( 73 % ) for the 3-month analysis and 67 ( 64 % ) for the 6-month follow-up . At 6 months postoperatively , 47 % of patients treated with gabapentin reported persistent post-thoracotomy pain compared with 49 % in the placebo group ( P = 0.9 ) . No overall clinical ly or statistically significant differences were observed between groups receiving placebo and gabapentin , respectively , for the secondary outcome measures and treatment-related adverse events . CONCLUSIONS We found no evidence for the superiority of gabapentin over placebo for the treatment of acute pain following thoracotomy or for the prevention of persistent post-thoracotomy pain",
"Purpose To investigate interindividual variability in response to pain treatment , we characterized postoperative patients for morphine metabolism and for COMT , OPRM1 and UGT2B7 polymorphisms . Methods A total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT , OPRM1 and UGT2B7 genes . The plasma concentration of morphine and of M3G/M6 G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry . Results An association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia ( PCA ) and COMT haplotypes was found . Specifically , patients with the diplotype for average pain intensity ( APS/APS ) required the lowest morphine doses compared to the other subjects ( p = 0.011 ) . The APS haplotype contains an adenine corresponding to methionine , instead of valine , at position 158 of the COMT protein . Met/Met homozygous patients consumed significantly lower morphine doses than other subjects ( p = 0.014 ) ; accordingly , Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need . Considering both COMT Val158Met and OPRM1 A118 G polymorphisms , carriers of both the Met/Met and AA genotypes required less morphine than other subjects , although the difference was not significant . The analysis of UGT2B7 revealed the occurrence of two common haplotypes ( G_C_C_A_C and A_T_T_G_T ) that did not prove to be related with plasma morphine and M3G/M6 G concentration . Conclusions By considering COMT , OPRM1 , and UGT2B7 genotypes , as well as pharmacokinetic results , only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy",
"Thoracotomy is often responsible for chronic pain , possibly of neuropathic origin . To confirm pre clinical studies , the preventive effects of perioperative ketamine were tested in a r and omized , double‐blind , placebo‐controlled clinical trial on persistent neuropathic pain after thoracotomy . Eighty‐six patients scheduled for thoracotomy under st and ardised general anaesthesia were r and omised to receive either ketamine ( 1mgkg−1 at the induction , 1mgkg−1h−1 during surgery , then 1mgkg−1 during 24h ; n=42 ) or normal saline ( n=44 ) . Postoperative analgesia included a single dose of intrapleural ropivacaine , intravenous paracetamol and nefopam , and patient‐controlled intravenous morphine . Vital parameters and analgesia were recorded during the 48 first postoperative hours . Seventy‐three patients were followed up . The patient 's chest was examined 1–2 weeks , 6 weeks and 4 months after surgery . At the last two observations , spontaneous pain score over a one‐week period ( visual analogue scale ) , neuropathic pain score ( NPSI ) , and intake of analgesics , were assessed . No drug affecting neuropathic pain ( except opiates ) was given during the follow‐up . Two patients in each group were lost to follow‐up after the 6 week visit . Ketamine improved immediate postoperative pain , but the groups were similar in terms of neuropathic pain and intake of analgesics , 6 weeks ( NPSI score : ketamine : 1.25 [ 0–4.125 ] ; placebo : 1 [ 0–4 ] ) and 4 months after surgery . Thus , ketamine given in 24‐h infusion failed to prevent chronic neuropathic pain after thoracotomy . Other perioperative preventive long‐lasting treatments or techniques could be tested in this context",
"OBJECTIVE To evaluate the effectiveness of a program design ed to reduce back pain in nursing aides . METHODS Female nursing aides from a university hospital who had suffered episodes of back pain for at least six months were included in the study . Participants were r and omly divided into a control group and an intervention group . The intervention program involved a set of exercises and an educational component stressing the ergonomic aspect , administered twice a week during working hours for four months . All subjects answered a structured question naire and the intensity of pain was assessed before and after the program using a visual analogue scale ( VAS ) . Student 's t-test or the Wilcoxon Rank Sum Test for independent sample s , and Chi-square test or the Exact Fisher test for categorical analysis , were used . The McNemar test and the Wilcoxon matched pairs test were used to compare the periods before and after the program . RESULTS There was a statistically significant decrease in the frequency of cervical pain in the last two months and in the last seven days in the intervention group . There was also a reduction in cervical pain intensity in the two periods ( 2 months , 7 days ) and lumbar pain intensity in the last 7 days . CONCLUSIONS The results suggest that a program of regular exercise with an emphasis on ergonomics can reduce musculoskeletal symptoms in nursing personnel",
"BACKGROUND The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus ( VZV ) . We tested the hypothesis that vaccination against VZV would decrease the incidence , severity , or both of herpes zoster and postherpetic neuralgia among older adults . METHODS We enrolled 38,546 adults 60 years of age or older in a r and omized , double-blind , placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ( \" zoster vaccine \" ) . Herpes zoster was diagnosed according to clinical and laboratory criteria . The pain and discomfort associated with herpes zoster were measured repeatedly for six months . The primary end point was the burden of illness due to herpes zoster , a measure affected by the incidence , severity , and duration of the associated pain and discomfort . The secondary end point was the incidence of postherpetic neuralgia . RESULTS More than 95 percent of the subjects continued in the study to its completion , with a median of 3.12 years of surveillance for herpes zoster . A total of 957 confirmed cases of herpes zoster ( 315 among vaccine recipients and 642 among placebo recipients ) and 107 cases of postherpetic neuralgia ( 27 among vaccine recipients and 80 among placebo recipients ) were included in the efficacy analysis . The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent ( P incidence of postherpetic neuralgia by 66.5 percent ( P incidence of herpes zoster by 51.3 percent ( P Reactions at the injection site were more frequent among vaccine recipients but were generally mild . CONCLUSIONS The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults",
"BACKGROUND In this prospect i ve , r and omized , double-blind , placebo-controlled study , we investigated the effect of pregabalin on oxycodone consumption , postoperative confusion , and pain in elderly cardiac surgery patients . METHODS Seventy patients , aged ≥75 yr , were r and omized to receive either 150 mg of pregabalin before operation and 75 mg of pregabalin twice daily for 5 postoperative days or placebo . Pain intensity was measured with the Verbal Rating Scale ( VRS ) . When pain intensity was ≥2 on the VRS , patients received oxycodone either i.v . ( 0.05 mg kg(-1 ) ) or orally ( 0.10 - 0.15 mg kg(-1 ) ) . Postoperative confusion was measured with the Confusion Assessment Method for the intensive care unit ( CAM-ICU ) . Postoperative pain was assessed by a telephone interview 1 and 3 months after operation . RESULTS Cumulative consumption of parenteral oxycodone during 16 h after extubation was reduced by 44 % and total oxycodone consumption from extubation to the end of the fifth postoperative day was reduced by 48 % in the pregabalin group . Time to extubation was 138 min shorter and CAM-ICU scores were significantly lower on the first postoperative day in the placebo group , although there was no significant difference with respect to the Mini-Mental State Examination or the Richmond Agitation Sedation Score . The incidence of pain during movement was significantly lower in the pregabalin group at 3 months postoperative . CONCLUSIONS The administration of pregabalin reduced postoperative opioid consumption after cardiac surgery reduced the incidence of confusion on the first postoperative day and increased time to extubation when compared with placebo . Three months after operation , patients in the pregabalin group experienced less pain during movement",
"New and previously reported analyses of the data from a placebo-controlled trial of famciclovir are review ed in light of recently proposed recommendations for the analysis of pain in herpes zoster trials . The analyses examined the effect of famciclovir treatment on the duration of postherpetic neuralgia ( PHN ) , which was defined as pain persisting after rash healing , pain persisting > 30 days after study enrollment , or pain persisting > 3 months after study enrollment ; the baseline characteristics of patients in the famciclovir and placebo groups who developed PHN ; the impact of famciclovir treatment on the duration of PHN , while controlling for significant covariates ; and the prevalence of PHN at monthly intervals from 30 to 180 days after enrollment . The results of these analyses indicated that greater age , rash severity , and acute pain severity are risk factors for prolonged PHN . In addition , they demonstrated that treatment of acute herpes zoster patients with famciclovir significantly reduces both the duration and prevalence of PHN",
"BACKGROUND : Patient outcome after lumbar discectomy for radicular low back pain is variable and the benefit is inconsistent . Many patients continue to experience pain 3 months after surgery . Pregabalin , a membrane stabilizer , may decrease perioperative central sensitization and subsequent persistent pain . METHODS : Forty patients undergoing lumbar discectomy were r and omly allocated to receive either pregabalin ( 300 mg at 90 minutes preoperatively and 150 mg at 12 and 24 hours postoperatively ) or placebo at corresponding times in a double-blinded manner . Our primary outcome was the change in the present pain intensity ( PPI ) ( visual analog scale [ VAS ] , 0–100 mm [ PPI-VAS , McGill Pain Question naire ] ) from preoperatively to 3 months postoperatively . RESULTS : The decrease in PPI-VAS score at 3 months was greater in patients who received pregabalin ( 37.6 ± 19.6 mm ) ( mean ± SD ) than those who received placebo ( 25.3 ± 21.9 mm ) ( P = 0.08 ) . The Rol and Morris disability score at 3 months was less in patients who received pregabalin ( 2.7 ± 2.4 ) than in those who received placebo ( 5.6 ± 4.8 ) ( P = 0.032 ) . Pregabalin administration was associated with greater pain tolerance thresholds in both lower limbs compared with placebo at 24 hours postoperatively . CONCLUSION : Perioperative pregabalin administration is associated with less pain intensity and improved functional outcomes 3 months after lumbar discectomy",
"BACKGROUND The efficacy of antidepressant therapy in patients undergoing coronary artery bypass grafting ( CABG ) is not clearly established . METHODS This double-blind trial was conducted at University Hospital , Besançon , France . Adult CABG patients were r and omized ( 1:1 ) to receive escitalopram ( 10 mg daily ) or placebo from 2 to 3 weeks before to 6 months after surgery , including 12 months post-surgery follow-up . The primary composite endpoint was the occurrence of mortality or predefined morbidity events . Secondary endpoints included measures of depression , mental and physical health using Beck Depression Inventory Short Form ( BDI ) , and quality of life 36-Item Short Form ( SF-36 ) self assessment s. RESULTS The treated cohort contained 361 patients with mean age 67 years . At 12 months , the proportions of patients with the composite morbidity and mortality endpoint were not different between escitalopram and placebo ( 110 of 182 [ 60.4 % ] vs 108 of 179 [ 60.3 % ] , p = 0.984 ) . However , over the 6 months postoperative period , the BDI and SF-36 Mental Component Summary scores were better overall in the escitalopram group than in the placebo group for all patients ( p = 0.015 and p = 0.014 , respectively ) and preoperatively depressed ( BDI > 3 ) patients ( p = 0.002 and p = 0.005 , respectively ) . Moreover , the SF-36 Pain score was better overall in the escitalopram group than in the placebo group in the preoperatively-depressed subset ( p = 0.026 ) . CONCLUSIONS Antidepressant therapy had no effect on morbidity and mortality events up to 1 year after CABG . However , antidepressant therapy may provide faster improvements to mental health aspects of quality of life and reduce postoperative pain in patients with preoperative depression . Subject to contra-indications , we recommend antidepressant therapy in coronary revascularization patients who are preoperatively depressed ",
"Background Psychologically informed practice emphasizes routine identification of modifiable psychological risk factors being highlighted . Objective The purpose of this study was to test the predictive validity of the STarT Back Screening Tool ( SBT ) in comparison with single-construct psychological measures for 6-month clinical outcomes . Design This was an observational , prospect i ve cohort study . Methods Patients ( n=146 ) receiving physical therapy for low back pain were administered the SBT and a battery of psychological measures ( Fear-Avoidance Beliefs Question naire physical activity scale and work scale [ FABQ-PA and FABQ-W , respectively ] , Pain Catastrophizing Scale [ PCS ] , 11-item version of the Tampa Scale of Kinesiophobia [ TSK-11 ] , and 9-item Patient Health Question naire [ PHQ-9 ] ) at initial evaluation and 4 weeks later . Treatment was at the physical therapist 's discretion . Clinical outcomes consisted of pain intensity and self-reported disability . Prediction of 6-month clinical outcomes was assessed for intake SBT and psychological measure scores using multiple regression models while controlling for other prognostic variables . In addition , the predictive capabilities of intake to 4-week changes in SBT and psychological measure scores for 6-month clinical outcomes were assessed . Results Intake pain intensity scores ( β=.39 to .45 ) and disability scores ( β=.47 to .60 ) were the strongest predictors in all final regression models , explaining 22 % and 24 % and 43 % and 48 % of the variance for the respective clinical outcome at 6 months . Neither SBT nor psychological measure scores improved prediction of 6-month pain intensity . The SBT overall scores ( β=.22 ) and SBT psychosocial scores ( β=.25 ) added to the prediction of disability at 6 months . Four-week changes in TSK-11 scores ( β=−.18 ) were predictive of pain intensity at 6 months . Four-week changes in FABQ-PA scores ( β=−.21 ) , TSK-11 scores ( β=−.20 ) and SBT overall scores ( β=−.18 ) were predictive of disability at 6 months . Limitations Physical therapy treatment was not st and ardized or accounted for in the analysis . Conclusions Prediction of clinical outcomes by psychology-based measures was dependent upon the clinical outcome domain of interest . Similar to studies from the primary care setting , initial screening with the SBT provided additional prognostic information for 6-month disability and changes in SBT overall scores may provide important clinical decision-making information for treatment monitoring",
"OBJECTIVES Improvement in health-related quality of life is a major object of cardiac surgery . However , high stress exposure during the perioperative period of cardiac surgery can result in the formation of traumatic memories and symptoms of chronic stress or even posttraumatic stress disorder , which can have negative effects on health-related quality -of-life outcome . In this controlled study we examined whether exogenously administered stress doses of hydrocortisone during cardiac surgery reduce perioperative stress exposure and the long-term incidence of chronic stress symptoms and improve health-related quality of life after cardiac surgery . METHODS Thirty-six high-risk patients undergoing cardiac surgery were prospect ively r and omized to receive either stress doses of hydrocortisone or placebo . Of 28 available patients at 6 months after cardiac surgery , 14 had received hydrocortisone , and 14 had received placebo . Traumatic memories , chronic stress symptoms ( posttraumatic stress disorder scores ) , and health-related quality of life were measured by using vali date d question naires . RESULTS Compared with patients from the placebo group , patients from the hydrocortisone group had a significantly shorter duration of intensive care unit treatment , required lower doses of the stress hormone norepinephrine during cardiac surgery , and had significantly fewer stress symptoms and a better health-related quality of life regarding physical function , chronic pain , general health , vitality , and mental health during follow-up . The groups did not differ with regard to the number or type of intensive care unit-related traumatic memories . CONCLUSIONS The use of stress doses of hydrocortisone in high-risk cardiac surgical patients reduces perioperative stress exposure , decreases chronic stress symptoms , and improves health-related quality of life at 6 months after cardiac surgery",
"BACKGROUND Regular paracetamol is the recommended first-line analgesic for acute low-back pain ; however , no high- quality evidence supports this recommendation . We aim ed to assess the efficacy of paracetamol taken regularly or as-needed to improve time to recovery from pain , compared with placebo , in patients with low-back pain . METHODS We did a multicentre , double-dummy , r and omised , placebo controlled trial across 235 primary care centres in Sydney , Australia , from Nov 11 , 2009 , to March 5 , 2013 . We r and omly allocated patients with acute low-back pain in a 1:1:1 ratio to receive up to 4 weeks of regular doses of paracetamol ( three times per day ; equivalent to 3990 mg paracetamol per day ) , as-needed doses of paracetamol ( taken when needed for pain relief ; maximum 4000 mg paracetamol per day ) , or placebo . R and omisation was done according to a central ised r and omisation schedule prepared by a research er who was not involved in patient recruitment or data collection . Patients and staff at all sites were masked to treatment allocation . All participants received best- evidence advice and were followed up for 3 months . The primary outcome was time until recovery from low-back pain , with recovery defined as a pain score of 0 or 1 ( on a 0 - 10 pain scale ) sustained for 7 consecutive days . All data were analysed by intention to treat . This study is registered with the Australian and New Zeal and Clinical Trial Registry , number ACTN 12609000966291 . FINDINGS 550 participants were assigned to the regular group ( 550 analysed ) , 549 were assigned to the as-needed group ( 546 analysed ) , and 553 were assigned to the placebo group ( 547 analysed ) . Median time to recovery was 17 days ( 95 % CI 14 - 19 ) in the regular group , 17 days ( 15 - 20 ) in the as-needed group , and 16 days ( 14 - 20 ) in the placebo group ( regular vs placebo hazard ratio 0·99 , 95 % CI 0·87 - 1·14 ; as-needed vs placebo 1·05 , 0·92 - 1·19 ; regular vs as-needed 1·05 , 0·92 - 1·20 ) . We recorded no difference between treatment groups for time to recovery ( adjusted p=0·79 ) . Adherence to regular tablets ( median tablets consumed per participant per day of maximum 6 ; 4·0 [ IQR 1·6 - 5·7 ] in the regular group , 3·9 [ 1·5 - 5·6 ] in the as-needed group , and 4·0 [ 1·5 - 5·7 ] in the placebo group ) , and number of participants reporting adverse events ( 99 [ 18·5 % ] in the regular group , 99 [ 18·7 % ] in the as-needed group , and 98 [ 18·5 % ] in the placebo group ) were similar between groups . INTERPRETATION Our findings suggest that regular or as-needed dosing with paracetamol does not affect recovery time compared with placebo in low-back pain , and question the universal endorsement of paracetamol in this patient group . FUNDING National Health and Medical Research Council of Australia and GlaxoSmithKline Australia",
"Study Design . Prospect i ve observational study . Objective . To determine whether polymorphic variations of the guanosine triphosphate ( GTP ) cyclohydrolase 1 gene ( GCH1 ) are associated with different outcomes in patients undergoing surgical treatment for lumbar degenerative disc disease ( DDD ) . Summary of Background Data . GCH1 , the gene encoding the rate-limiting enzyme in tetrahydrobiopterin synthesis , has been strongly implicated as a determinant of pain experience in previous animal and human studies . Methods . A total of 69 patients undergoing surgical treatment for lumbar DDD were prospect ively enrolled . Genomic DNA was extracted from a venous blood sample , and DNA sequence analysis was performed of GCH1 . Surgery included 65 instrumented fusions and 4 disc arthroplasty procedures . Patients were observed prospect ively for 1 year following surgery . Allelic and genotype frequencies were calculated for each of 14 single nucleotide polymorphisms ( SNPs ) . One-year postoperative Oswestry Disability Index ( ODI ) scores were compared to preoperative scores and the absolute change in ODI score was used to perform genetic association analyses on the basis of both individual SNP markers as well as commonly observed haplotypes for the entire gene sequence . Results . Single marker analysis revealed 1 SNP ( rs998259 ; minor allele T ) that was significantly associated with improvement in both absolute ODI score ( P = 0.030 ) and Numerical Rating Scale back pain scores ( P = 0.033 ) following surgery . Haplotype analysis identified a common GCH1 haplotype ( “ CACTTGTTTGAC ” ) with a sample frequency of 12.3 % , which was highly associated with improvement in absolute ODI score ( P = 0.04 ) . This haplotype frequency reflects the existence of both heterozygous and homozygous individuals in the study population . The presence of 1 unit of this haplotype was associated with an improvement in postoperative ODI score of 15.34 relative to the absence of this haplotype ( P = 0.04 ) . Conclusion . Preliminary results from this pilot genetic study of patients undergoing surgery for DDD suggests that the T allele at rs998259 of GCH1 may be associated with improved outcomes 1 year following surgery",
"A r and omized , controlled trial was performed to assess the efficacy and safety of vitamin E supplementation for prophylaxis against paclitaxel-induced peripheral neuropathy ( PIPN ) . Thirty-two patients undergoing six courses of paclitaxel-based chemotherapy were r and omly assigned to receive either chemotherapy with vitamin E ( 300 mg twice a day , Group I ) or chemotherapy without vitamin E supplementation ( Group II ) . A detailed neurological examination and electrophysiological study was performed during and 3 months after chemotherapy . The severity of PIPN was summarized by means of a modified Peripheral Neuropathy ( PNP ) score . The incidence of neurotoxicity differed significantly between groups , occurring in 3/16 ( 18.7 % ) patients assigned to the vitamin E supplementation group and in 10/16 ( 62.5 % ) controls ( P=0.03 ) . The relative risk ( RR ) of developing PIPN was significantly higher in controls than in vitamin E group patients ( RR=0.3 , 95 % confidence interval (CI)=0.1 - 0.9 ) . Mean PNP scores were 2.25+/-5.1 ( range 0 - 15 ) for patients in Group I and 11+/-11.63 ( range 0 - 32 ) for those in Group II ( P=0.01 ) . Vitamin E supplementation was well tolerated and showed an excellent safety profile . This study shows that vitamin E effectively and safely protects patients with cancer from the occurrence of paclitaxel-induced peripheral nerve damage . A double-blind , placebo-controlled trial is needed to confirm these results",
"OBJECTIVE The objective was to evaluate the efficacy of Org 2766 ( a hexapeptide analogue of ACTH ) in the prevention or delay of cisplatin-induced neuropathy during chemotherapy in women with ovarian cancer as measured by vibration perception threshold ( VPT ) . METHODS In this r and omized , multicenter , double-blind , placebo-controlled study , 196 women with ovarian cancer were treated with cisplatin 75 - 100 mg/m2 , cyclophosphamide 600 - 1000 mg/m2 plus placebo or two dose levels of Org 2766 . The cisplatin-induced neuropathies were monitored by determining the VPT with the Vibratron II . VPT was determined for both the most sensitive great toe and the index finger on a monthly basis during treatment and months 1 , 2 , and 3 postchemotherapy . Once the blind was broken , it was found that 174 women ( 59 in placebo , 58 in 2 mg , and 57 in 4 mg ) had enough data to allow evaluation . RESULTS Over the course of follow-up , the VPT was found to increase . This is consistent with the development of cisplatin-induced peripheral neuropathies . The baseline VPT for the index finger was less than that of the great toe ( 0.65 vs 2.13 ) , but the percentage change in VPT was the same for both ( percentage increase in VPT of about 350 % ) . When the VPTs are compared according to the dose of Org 2766 given , there appears to be no difference in the rate of change or degree of neuropathies that developed in these women receiving cisplatin and cyclophosphamide . CONCLUSIONS The development of cisplatin-induced neuropathies is confirmed by measurement of the VPT . The rate of development of neuropathies seems to accelerate after the sixth course of cisplatin . When the development of neuropathies is evaluated on the basis of Org 2766 dosage , it is found that there is no difference in the rate or degree of neuropathies seen . Instead of providing protection from and delay of onset of peripheral neuropathies caused by cisplatin , these results suggest that the administration of Org 2766 appears to cause an increase in the rate of change and degree of neuropathies ( P > 0.05 )",
"Abstract Though it is clear that genomic variability plays an integral role in accounting for pain sensitivity , controversy exists over which genes are involved . While recent data suggest a “ protective ” ( i.e. , less pain ) haplotype in the GTP cyclohydrolase ( GCH1 ) gene , other research has failed to confirm this association . Possibly , the effects of single nucleotide polymorphisms ( SNPs ) vary depending on the pain task . The current investigation analyzed the association of five previously identified GCH1 SNPs with ratings of pain induced by topical high concentration ( 10 % ) capsaicin applied to the skin of 39 healthy human volunteers . Each of the GCH1 polymorphisms was associated with lower pain ratings . When combined , three of the five accounted for a surprisingly high 35 % of the inter‐individual variance in pain ratings . We conclude that SNPs of the GCH1 gene may profoundly affect the ratings of pain induced by capsaicin",
"IMPORTANCE There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy . OBJECTIVE To determine the effect of duloxetine , 60 mg daily , on average pain severity . DESIGN , SETTING , AND PATIENTS R and omized , double-blind , placebo-controlled crossover trial at 8 National Cancer Institute (NCI)-funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic setting s between April 2008 and March 2011 . Study follow-up was completed July 2012 . Stratified by chemotherapeutic drug and comorbid pain risk , patients were r and omized to receive either duloxetine followed by placebo or placebo followed by duloxetine . Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10 , representing average chemotherapy-induced pain , after paclitaxel , other taxane , or oxaliplatin treatment . INTERVENTIONS The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks . MAIN OUTCOME MEASURES The primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain . Pain severity was assessed using the Brief Pain Inventory-Short Form \" average pain \" item with 0 representing no pain and 10 representing as bad as can be imagined . RESULTS Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 ( 95 % CI , 0.72 - 1.40 ) vs 0.34 ( 95 % CI , 0.01 - 0.66 ) among those who received placebo ( P = .003 ; effect size , 0.513 ) . The observed mean difference in the average pain score between duloxetine and placebo was 0.73 ( 95 % CI , 0.26 - 1.20 ) . Fifty-nine percent of those initially receiving duloxetine vs 38 % of those initially receiving placebo reported decreased pain of any amount . CONCLUSION AND RELEVANCE Among patients with painful chemotherapy-induced peripheral neuropathy , the use of duloxetine compared with placebo for 5 weeks result ed in a greater reduction in pain . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00489411",
"Background : Pain after amputation is common but difficult to treat . Therefore , the authors examined whether postoperative treatment with gabapentin could reduce postamputation stump and phantom pain . Methods : Forty-six patients scheduled to undergo lower limb amputation were r and omly assigned to receive oral gabapentin or placebo . Treatment was started on the first postoperative day and continued for 30 days . The daily dose of gabapentin or placebo was gradually increased to 2,400 mg/day . The intensity of stump and phantom pain was recorded every day on a numeric rating scale ( 0–10 ) during the 30-day treatment period . Five interviews were performed after 7 , 14 , and 30 days and after 3 and 6 months . Results : Results from 41 patients were included in the data analysis . The risk of phantom pain ( gabapentin vs. placebo ) was 55.0 % versus 52.6 % ( risk difference , 2.4 % ; 95 % confidence interval , −28.9 to 33.7 % ; P = 0.88 ; 30 days ) and 58.8 % versus 50.0 % ( risk difference , 8.8 % ; 95 % confidence interval , −23.3 to 40.9 % ; P = 0.59 ; 6 months ) . The median intensity of phantom pain ( gabapentin vs. placebo ) was 1.5 ( range , 0–9.0 ) versus 1.2 ( range , 0–6.6 ) ( P = 0.60 ; 30 days ) and 1.0 ( range , 0–6.0 ) versus 0.5 ( range , 0–5.0 ) ( P = 0.77 ; 6 months ) . The median intensity of stump pain was 0.85 ( range , 0–8.2 ) versus 1.0 ( range , 0–5.4 ) ( P = 0.68 ; 30 days ) and 0 ( range , 0–8.0 ) versus 0 ( range , 0–5.0 ) ( P = 0.58 ; 6 months ) . Conclusion : Gabapentin administered in the first 30 postoperative days after amputation does not reduce the incidence or intensity of postamputation pain",
"BACKGROUND : Harvesting of iliac crest graft for spinal fusions is associated with a number of patients reporting residual or chronic pain at the harvest site . Various interventions , including morphine infiltration , have been proposed to minimize the associated pain . METHODS : We performed a prospect i ve , double-blind , r and omized , placebo-controlled study comparing intraoperative infiltration of 5 mg morphine ( treatment ) versus saline ( placebo ) into the iliac crest harvest site for patients undergoing elective spinal surgery . Patients with myelopathy , excessive perioperative opioid use ( 60 mg equivalent morphine/d or more ) , or multilevel ( > 3 levels ) spinal surgery were excluded . Postoperative administration of morphine ( recovery room and patient-controlled analgesia ) was st and ardized . Numerical pain scores specific for the iliac crest site were determined in the immediate postoperative period and at 3 , 6 , and 12 months . RESULTS : Of the 54 patients r and omized , 47 ( 87 % ) were available for review with a minimum of 1-year follow-up . The groups were similar in baseline age , gender , and comorbidities . There was no significant difference between groups in total use of postoperative morphine during the first 24 hours ( P = 0.48 ) . Repeated measures analysis of variance demonstrated no interacting effect of group over time for hip pain at rest ( P = 0.94 ) , hip pain while moving ( P = 0.90 ) , spine pain at rest ( P = 0.99 ) , or spine pain while moving ( P = 0.83 ) . The proportion of patients reporting iliac crest pain at 1-year follow-up was the same between groups ( P = 0.95 ) . CONCLUSIONS : This study has demonstrated that there are no additional benefits for the use of intraoperative infiltration of morphine into the iliac crest harvest site during spinal fusions",
"Chemotherapy‐induced peripheral neuropathy ( CIPN ) is a significant side effect of taxane and platinum‐based chemotherapy . Several studies have supported the potential benefit of glutathione for the prevention of platinum‐induced CIPN . The current trial was design ed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy",
"Objectives : Breast cancer surgery is associated with a high incidence of persistent postsurgical pain ( PPSP ) . The aim of this study was to evaluate the impact of intravenous ( IV ) lidocaine on acute and PPSP , analgesic requirements , and sensation abnormalities in patients undergoing surgery for breast cancer . Methods : Thirty-six patients participated in this r and omized , double-blinded study . Before induction of general anesthesia , patients received a bolus of intravenous lidocaine 1.5 mg/kg followed by a continuous infusion of lidocaine 1.5 mg/kgh ( lidocaine group ) or an equal volume of saline ( control group ) . The infusion was stopped 1 hour after the skin closure . Pain scores and analgesic consumption were recorded at 2 , 4 , 24 hours , and then daily for 1 week postoperatively . Three months later , patients were assessed for PPSP and secondary hyperalgesia . Results : Two ( 11.8 % ) patients in the lidocaine group and 9 ( 47.4 % ) patients in the control group reported PPSP at 3 months follow-up ( P=0.031 ) . McGill Pain Question naire revealed greater present pain intensity-visual analog scale in the control group ( 14.6±22.5 vs. 2.6±7.5 ; P=0.025 ) . Secondary hyperalgesia ( area of hyperalgesia/length of surgical incision ) was significantly less in the lidocaine group compared with control group ( 0.2±0.8 vs. 3.2±4.5 cm ; P=0.002 ) . The 2 groups were similar in terms of analgesic consumption during the early postoperative period . Discussion : Intravenous perioperative lidocaine decreases the incidence and severity of PPSP after breast cancer surgery . Prevention of the induction of central hyperalgesia is a potential mechanism",
"BACKGROUND : Gabapentin is effective for preventing and treating acute and chronic postoperative pain ; however , it has not been described for use in cesarean delivery . We hypothesized that preoperative gabapentin would reduce postcesarean delivery pain . METHODS : Women undergoing scheduled cesarean delivery were r and omized to receive preoperative gabapentin 600 mg , or placebo . Spinal anesthesia was achieved with 0.75 % hyperbaric bupivacaine 12 mg , fentanyl 10 & mgr;g , and morphine 100 & mgr;g . Postoperative analgesia was initiated with intraoperative ketorolac and acetaminophen , and continued with postoperative diclofenac , acetaminophen , and morphine . Patients were assessed at 6 , 12 , 24 , and 48 hours after spinal anesthesia for pain at rest and on movement using a visual analog scale ( 0 to 100 mm ) , satisfaction , opioid consumption , and side effects . Neonatal interventions , Apgar scores , umbilical artery blood gases , and breastfeeding difficulties were assessed . Chronic pain was assessed 3 months after delivery . Maternal and umbilical vein gabapentin plasma concentrations were measured in a subgroup of patients . Mixed-model analysis was used to compare the primary outcome of visual analog scale pain scores at 24 hours between groups . RESULTS : Forty-six patients were r and omized , and 2 were excluded from analysis . The mean ( 95 % confidence interval , CI ) pain scores on movement at 24 hours were 21 mm ( CI = 13–28 ) in the gabapentin and 41 mm ( CI = 31–50 ) in the placebo group ( P = 0.001 ) . Maternal satisfaction was higher in the gabapentin group . There was no difference in opioid consumption . Severe maternal sedation was more common in the gabapentin group ( 19 % vs. 0 % , P = 0.04 ) . There was no difference in neonatal Apgar scores , interventions , or umbilical artery pH. The mean ( SD ) maternal vein : umbilical vein plasma gabapentin ratio was 0.86 ( 0.12 ) . The incidence of pain at 3 months was similar in both groups . CONCLUSION : Preoperative gabapentin 600 mg in the setting of multimodal analgesia reduces postcesarean delivery pain and increases maternal satisfaction in comparison with placebo",
"We hypothesized that perioperative ketamine administration would modify acute central sensitization following amputation and hence reduce the incidence and severity of persistent post-amputation pain ( both phantom limb and stump pain ) . In a r and omized , controlled trial , 45 patients undergoing above- or below-knee amputation received ketamine 0.5 mg.kg–1 or placebo as a pre-induction bolus followed by an intravenous infusion of ketamine 0.15 mg.kg–1.h–1 or normal saline for 72 hours postoperatively . Both groups received st and ardized general anaesthesia followed by patient-controlled intravenous morphine . The surface area of allodynia over the stump was mapped at days 3 and 6 . Postamputation pain was assessed at days 3 and 6 and at 6 months postoperatively . We found no significant difference between groups in the surface area of stump allodynia or in morphine consumption . There was an unexplained , but significant , increase in the incidence of stump pain in the ketamine group at day 3 . At six-month review , the incidence of phantom pain was 47 % in the ketamine group and 71 % in the control group . This did not reach statistical significance ( P=0.28 ) as the power of the study was based on the search for a large treatment effect . The incidence of stump pain at six months was 47 % in the ketamine group and 35 % in the control group ( P=0.72 ) . There were no significant between-group differences in pain severity throughout the study period . Ketamine at the dose administered did not significantly reduce acute central sensitization or the incidence and severity of post-amputation pain",
"Acyclovir treatment of acute herpes zoster speeds rash healing and decreases pain and ocular complications . The limited oral bioavailability of acyclovir necessitates frequent dosing . Valaciclovir , the l-valyl ester of acyclovir , is rapidly and almost completely converted to acyclovir in vivo and gives three- to fivefold increases in acyclovir bioavailability . In a r and omized , double-blind , multicenter study , the safety and efficacy of oral valaciclovir given at a dosage of 1,000 mg three times daily for 7 or 14 days and oral acyclovir given at a dosage of 800 mg five times daily for 7 days were compared in immunocompetent adults aged > or = 50 years with herpes zoster . Patients were evaluated for 6 months . The intent-to-treat analysis ( 1,141 patients ) showed that valaciclovir for 7 or 14 days significantly accelerated the resolution of herpes zoster-associated pain ( P = 0.001 and P = 0.03 , respectively ) compared with acyclovir ; median pain duration s were 38 and 44 days , respectively , versus 51 days for acyclovir . Treatment with valaciclovir also significantly reduced the duration of postherpetic neuralgia and decreased the proportion of patients with pain persisting for 6 months ( 19.3 versus 25.7 % ) . However , there were no differences between treatments in pain intensity or quality -of-life measures . Cutaneous manifestations resolved at similar rates in all groups . Adverse events were similar in nature and prevalence among groups , and no clinical ly important changes occurred in hematology or clinical chemistry parameters . Thus , in the management of immunocompetent patients > or = 50 years of age with localized herpes zoster , valaciclovir given at 1,000 mg three times daily for 7 days accelerates the resolution of pain and offers simpler dosing , while it maintains the favorable safety profile of acyclovir",
"BACKGROUND Postherpetic neuralgia is the most frequent complication of herpes zoster . Treatment of this neuropathic pain syndrome is difficult and often disappointing . We assessed the effectiveness of a single epidural injection of steroids and local anaesthetics for prevention of postherpetic neuralgia in older patients with herpes zoster . METHODS We r and omly assigned 598 patients older than 50 years , with acute herpes zoster ( rash , to receive either st and ard therapy ( oral antivirals and analgesics ) or st and ard therapy with one additional epidural injection of 80 mg methylprednisolone acetate and 10 mg bupivacaine . The primary endpoint was the proportion of patients with zoster-associated pain 1 month after inclusion . Analyses were by intention-to-treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N32866390 . FINDINGS At 1 month , 137 ( 48 % ) patients in the epidural group reported pain compared with 164 ( 58 % ) in the control group ( relative risk [ RR ] 0.83 , 95 % CI 0.71 - 0.97 , p=0.02 ) . After 3 months these values were 58 ( 21 % ) and 63 ( 24 % ) respectively ( 0.89 , 0.65 - 1.21 , p=0.47 ) and , at 6 months , 39 ( 15 % ) and 44 ( 17 % ; 0.85 , 0.57 - 1.13 , p=0.43 ) . We detected no subgroups in which the relative risk for pain 1 month after inclusion substantially differed from the overall estimate . No patient had major adverse events related to epidural injection . INTERPRETATION A single epidural injection of steroids and local anaesthetics in the acute phase of herpes zoster has a modest effect in reducing zoster-associated pain for 1 month . This treatment is not effective for prevention of long-term postherpetic neuralgia",
"BACKGROUND The role of preoperative gabapentin in postoperative pain management is not clear , particularly in patients receiving regional blockade . Patients undergoing thoracotomy benefit from epidural analgesia but still may experience significant postoperative pain . We examined the effect of preoperative gabapentin in thoracotomy patients . METHODS Adults undergoing elective thoracotomy were enrolled in this prospect i ve , r and omized , double-blinded , placebo-controlled study , and r and omly assigned to receive 600 mg gabapentin or active placebo ( 12.5 mg diphenhydramine ) orally within 2 hours preoperatively . St and ardized management included thoracic epidural infusion , intravenous patient-controlled opioid analgesia , acetaminophen and ketorolac . Pain scores , opioid use and side effects were recorded for 48 hours . Pain was also assessed at 3 months . RESULTS One hundred twenty patients ( 63 placebo and 57 gabapentin ) were studied . Pain scores did not significantly differ at any time point ( P = 0.53 ) . Parenteral and oral opioid consumption was not significantly different between groups on postoperative day 1 or 2 ( P > 0.05 in both cases ) . The frequency of side effects such as nausea and vomiting or respiratory depression was not significantly different between groups , but gabapentin was associated with decreased frequency of pruritus requiring nalbuphine ( 14 % gabapentin vs. 43 % control group , P patients experiencing pain at 3 months post-thoracotomy was also comparable between groups ( 70 % gabapentin vs. 66 % placebo group , P = 0.72 ) . CONCLUSIONS A single preoperative oral dose of gabapentin ( 600 mg ) did not reduce pain scores or opioid consumption following elective thoracotomy , and did not confer any analgesic benefit in the setting of effective multimodal analgesia that included thoracic epidural infusion",
"Study Design . A r and omized clinical trial was conducted . Objective . To compare the effectiveness of classification-based physical therapy with that of therapy based on clinical practice guidelines for patients with acute , work-related low back pain . Summary of Background Data . Clinical practice guidelines recommend minimal intervention during the first few weeks after acute low back injury . However , studies supporting this recommendation have not attempted to identify which patients are likely to respond to particular interventions . Methods . For this study , 78 subjects with work-related low back pain of less than 3 weeks duration were r and omized to receive therapy based on a classification system that attempts to match patients to specific interventions or therapy based on the Agency for Health Care Policy and Research guidelines . The subjects were followed for 1 year . Outcomes included the impairment index , Oswestry scale , SF-36 component scores , satisfaction , medical costs , and return to work status . Results . After adjustment for baseline factors , subjects receiving classification-based therapy showed greater change on the Oswestry ( P = 0.023 ) and the SF-36 physical component ( P = 0.029 ) after 4 weeks . Patient satisfaction was greater ( P = 0.006 ) and return to full-duty work status more likely ( P = 0.017 ) after 4 weeks in the classification-based group . After 1 year , there was a trend toward reduced Oswestry scores in the classification-based group ( P = 0.063 ) . Median total medical costs for 1 year after injury were $ 1003.68 for the guideline -based group and $ 774.00 for the classification-based group ( P = 0.13 ) . Conclusions . For patients with acute , work-related low back pain , the use of a classification-based approach result ed in improved disability and return to work status after 4 weeks , as compared with therapy based on clinical practice guidelines . Further research is needed on the optimal timing and methods of intervention for patients with acute low back pain",
"Introduction In an earlier study , Gatchel et al. ( J Occup Rehabil 13:1–9 , 2003 ) demonstrated that participants at high risk for developing chronic low back pain disability ( CLBPD ) , who received a biopsychosocial early intervention treatment program , displayed significantly more symptom improvement , as well as cost savings , relative to participants receiving st and ard care . The purpose of the present study was to exp and on these results by examining whether the addition of a work-transition component would further strengthen the effectiveness of this early intervention treatment . Methods Using an existing algorithm , participants were identified as being high-risk ( HR ) or low-risk ( LR ) for developing CLBPD . HR participants were then r and omly assigned to one of three groups : early intervention ( EI ) ; early intervention with work transition ( EI/WT ) ; or st and ard care ( SC ) . Participants provided information regarding pain , disability , work status , and psychosocial functioning at baseline , periodically during treatment , and again 1 year following completion of treatment . Results At 1-year follow-up , no significant differences were found between the EI and EI/WT groups in terms of occupational status , self-reports of pain and disability , coping ability or psychosocial functioning . However , significant differences in all these outcomes were found comparing these groups to st and ard care . Conclusion The addition of a work transition component to an early intervention program for the treatment of ALBP did not significantly contribute to improved work outcomes . However , results further support the effectiveness of early intervention for high-risk ALBP patients",
"OBJECTIVE To compare the efficacy and safety of valacyclovir hydrochloride and famciclovir for the treatment of herpes zoster . DESIGN A double-blind , r and omized , controlled , multicenter clinical trial in which patients received 7 days of treatment and were followed up for 24 weeks . SETTING S Patients reported directly to specialist centers or were referred from primary care centers . PATIENTS There were 597 otherwise healthy immunocompetent out patients , aged 50 years and older , who presented within 72 hours of onset of zoster rash . INTERVENTIONS Treatment with valacyclovir hydrochloride ( 1 g 3 times daily ) or famciclovir ( 500 mg 3 times daily ) for 7 days . MAIN OUTCOME MEASURES Resolution of zoster-associated pain and postherpetic neuralgia , rash healing , and treatment safety . RESULTS Intent-to-treat analysis did not detect statistically significant differences for valacyclovir vs famciclovir on resolution of zoster-associated pain ( hazard ratio , 1 . 02 ; 95 % confidence interval , 0.84 - 1.23 ; P = .84 ) . Furthermore , no differences were evident between treatments on rash healing rates and on a range of analyses of postherpetic neuralgia . Safety profiles for valacyclovir and famciclovir were similar , with headache and nausea being the more common adverse events . CONCLUSIONS Valacyclovir treatment is comparable to famciclovir treatment in speeding the resolution of zoster-associated pain and postherpetic neuralgia . Current wholesale prices indicate that valacyclovir is the more cost-effective treatment for herpes zoster ( $ 83.90 vs $ 140.70 per course )",
"BACKGROUND Neuropathy is a common adverse effect of chemotherapy . The tricyclic antidepressant , amitriptyline , is a gold st and ard in the treatment of neuropathic pain . This double-blind , r and omized placebo-controlled trial assessed the efficacy of amitriptyline to prevent chemotherapy-induced neuropathic symptoms . PATIENTS AND METHODS Patients without previous neuropathy , who started chemotherapy with vinca alcaloids , platina derivatives or taxanes , were r and omized to receive amitriptyline ( target dose , 100 mg daily ) or placebo for the duration of their chemotherapy . Chemotherapy-induced neuropathic symptoms were evaluated with a patient diary and after every third chemotherapy cycle with clinical examination . The diary data were transformed to a neuropathy score . A total of 114 patients fulfilling the inclusion criteria were r and omly assigned to the treatment or control arm . RESULTS There was no difference in the appearance of chemotherapy-induced neuropathic symptoms between the groups . In general , the intensity of neuropathic symptoms was mild . CONCLUSION Amitriptyline does not prevent chemotherapy-induced neuropathy",
"Purpose Acute pain after open abdominal hysterectomy limits the function of patients in the postoperative period , but data regarding the analgesic efficacy of a low dose of pregabalin ( 75 or 150 mg ) have been conflicting . This study was performed to determine if a low dose of pregabalin could decrease postoperative opioid use following abdominal hysterectomy when compared with placebo . Methods American Society of Anesthesiologists I-II patients older than 18 yr and scheduled for open elective abdominal hysterectomy were recruited for participation and r and omized to one of three groups : pregabalin 75 mg ( P75 ) , pregabalin 150 mg ( P150 ) , or placebo . The study drug was administered two hours prior to surgery and 12 hr following the initial dose . Anesthetic technique and postoperative analgesia were st and ardized . Postoperative pain was managed using patient-controlled analgesia with morphine . Pain at rest and movement as well as nausea were assessed with an 11-point numeric rating scale . Results One hundred and one patients were recruited , and 89 patients completed the study . Mean ( SD ) cumulative morphine consumption at 24 hr postoperatively was 54.0 ( 26.2 ) mg for the placebo group , 53.1 ( 22.7 ) mg for the P75 group , and 44.3 ( 20.9 ) mg for the P150 group . Independent Student ’s t tests indicated no difference between the placebo group and either the P75 group ( 95 % confidence interval [ CI ] : −11.75 to 13.44 ; P = 0.8937 ) or the P150 group ( 95 % CI : −2.74 to 22.15 ; P = 0.1238 ) . Conclusions At the doses used in this study , pregabalin treatment may not be effective in reducing opioid use up to 24 hr postoperatively following abdominal hysterectomy . This trial was registered at www . Clinical Trials.gov : NCT00781131.RésuméObjectifLa douleur aiguë faisant suite à une hystérectomie par voie abdominale limite les fonctions des patients au cours de la période postopératoire , mais les données concernant l’efficacité analgésique d’une faible dose de prégabaline ( 75 ou 150 mg ) ont été contradictoires . Cette étude a été menée pour déterminer si une faible dose de prégabaline pouvait diminuer l’utilisation postopératoire des morphiniques après hystérectomie par voie abdominale , comparativement au placebo . MéthodesDes patientes , âgées de plus de 18 ans , de type I-II selon les critères de l’American Society of Anesthesiologists , et devant subir une hystérectomie programmée par voie abdominale ont été recrutées et r and omisées dans l’un des trois groupes suivants : prégabaline 75 mg ( P75 ) , prégabaline 150 mg ( P150 ) , ou placebo . Le médicament étudié a été administré deux heures avant l’intervention chirurgicale et 12 h après la dose initiale . La technique anesthésique et l’analgésie postopératoire ont été st and ardisées . La douleur postopératoire a été gérée en utilisant une analgésie par morphine contrôlée par le patient . La douleur au repos et au mouvement ainsi que les nausées ont été évaluées au moyen d’une échelle d’évaluation numérique de 11 points . RésultatsCent une patientes ont été incluses et 89 patientes ont terminé l’étude . Les consommations cumulées moyennes ( ET ) de morphine à 24 heures en postopératoire étaient de 54,0 ( 26,2 ) mg pour le groupe placebo , 53,1 ( 22,7 ) mg pour le groupe P75 et 44,3 ( 20,9 ) mg pour le groupe P150 . Des tests t de Student indépendants n’ont pas fait apparaître de différence entre le groupe placebo et soit le groupe P75 ( intervalle de confiance [ IC ] à 95 % : −11,75 à 13,44 ; p = 0,8937 ) , soit le groupe P150 ( IC à 95 % : −2,74 à 22,15 ; p = 0,1238 ) . Conclusions Aux doses utilisées dans cette étude , le traitement par prégabaline ne semble pas être efficace dans la réduction de la consommation de morphine à 24 heures postopératoires après hystérectomie par voie abdominale . Cette étude a été enregistrée sur le site www . clinical trials.gov : NCT00781131",
"Background : Treatment of herpes zoster ( HZ ) includes the use of acyclovir with or without steroids . An alternative therapy is the epidural administration of local anesthetics with or without steroids . This trial compared the efficacy of these two treatment regimens in the prevention of post‐herpetic neuralgia ( PHN ) ",
"BACKGROUND We aim ed to investigate whether the addition of non-steroidal anti-inflammatory drugs or spinal manipulative therapy , or both , would result in faster recovery for patients with acute low back pain receiving recommended first-line care . METHODS 240 patients with acute low back pain who had seen their general practitioner and had been given advice and paracetamol were r and omly allocated to one of four groups in our community-based study : diclofenac 50 mg twice daily and placebo manipulative therapy ( n=60 ) ; spinal manipulative therapy and placebo drug ( n=60 ) ; diclofenac 50 mg twice daily and spinal manipulative therapy ( n=60 ) ; or double placebo ( n=60 ) . The primary outcome was days to recovery from pain assessed by survival curves ( log-rank test ) in an intention-to-treat analysis . This trial was registered with the Australian Clinical Trials Registry , ACTRN012605000036617 . FINDINGS Neither diclofenac nor spinal manipulative therapy appreciably reduced the number of days until recovery compared with placebo drug or placebo manipulative therapy ( diclofenac hazard ratio 1.09 , 95 % CI 0.84 - 1.42 , p=0.516 ; spinal manipulative therapy hazard ratio 1.01 , 95 % CI 0.77 - 1.31 , p=0.955 ) . 237 patients ( 99 % ) either recovered or were censored 12 weeks after r and omisation . 22 patients had possible adverse reactions including gastrointestinal disturbances , dizziness , and heart palpitations . Half of these patients were in the active diclofenac group , the other half were taking placebo . One patient taking active diclofenac had a suspected hypersensitivity reaction and ceased treatment . INTERPRETATION Patients with acute low back pain receiving recommended first-line care do not recover more quickly with the addition of diclofenac or spinal manipulative therapy",
"Herpes zoster ( shingles ) develops in as many as 20 % of all persons [ 1 ] . The characteristic zoster rash is often accompanied by substantial pain , dysesthesias , and skin hypersensitivity . The unmet challenge in the management of patients with acute zoster is the alleviation of chronic pain . In many patients , pain resolves once the affected area of skin returns to normal . However , some patients continue to experience pain long after the lesions have healed ; this pain is commonly called postherpetic neuralgia . Postherpetic neuralgia is by far the most common complication of herpes zoster and is one of the most intractable pain disorders [ 2 , 3 ] . The incidence of postherpetic neuralgia increases sharply with increasing age [ 4 , 5 ] ; nearly half of patients older than 60 years have this complication [ 2 , 5 ] . Postherpetic neuralgia is also more severe and persists longer in older than in younger patients [ 3 ] . The disorder is clearly the most distressing component of the disease process for both the patient and the physician . Although for many years acyclovir has been the only oral antiviral agent approved for the treatment of patients with acute herpes zoster , its effect on postherpetic neuralgia remains controversial [ 6 - 10 ] . Famciclovir , a new antiviral agent , was approved for marketing by the Food and Drug Administration in June 1994 for the management of acute herpes zoster . Famciclovir is the well-absorbed ( 77 % bioavailable ) [ 11 ] oral form of penciclovir , with activity against varicella-zoster virus , herpes simplex virus types 1 and 2 , and Epstein-Barr virus [ 12 - 15 ] . Penciclovir is selectively activated in virus-infected cells through phosphorylation to the antiviral compound penciclovir triphosphate . Viral thymidine kinase converts penciclovir to penciclovir monophosphate , which is converted by cellular enzymes to penciclovir triphosphate [ 12 , 16 , 17 ] . Penciclovir triphosphate inhibits viral DNA polymerase , thereby halting DNA synthesis and viral replication [ 16 - 19 ] . The in vitro potencies of penciclovir and acyclovir depend on the tissue culture cell line and assay method used but are generally similar [ 14 , 15 , 20].The 50 % plaque inhibitory concentrations in human lung fibroblasts infected with varicella-zoster virus were 4.0 1.5 g/mL for penciclovir and 4.0 1.1 g/mL for acyclovir [ 14 ] . A potentially clinical ly important characteristic of penciclovir triphosphate is that it persists in virus-infected host cells longer than acyclovir triphosphate [ 19 ] . For cells infected with varicella-zoster virus , the intracellular half-life of penciclovir triphosphate is 9.1 hours ; in contrast , the half-life for acyclovir triphosphate is 0.8 hours [ 19 , 21 ] . Thus , penciclovir triphosphate has the potential to continue to inhibit viral replication even if serum concentrations are below the inhibitory level . Consistent oral bioavailability linked to a favorable intracellular half-life of penciclovir triphosphate in cells infected with varicella-zoster virus suggested that famciclovir could offer clinical ly important advantages in the management of herpes zoster over currently available therapy . These advantages include a reduced total daily dose and a reduced dosing frequency . Because persistent antiviral activity throughout each day of dosing was expected to lead to improved clinical efficacy , especially with regard to postherpetic neuralgia , we examined the effects of famciclovir on acute herpes zoster and postherpetic neuralgia . Methods Study Design In our r and omized , double-blind , placebo-controlled , multicenter trial , we compared the efficacy and safety of famciclovir , 500 mg or 750 mg , given three times daily for 7 days , with that of placebo in the treatment of patients with uncomplicated acute herpes zoster . Eligible participants were immunocompetent patients 18 years or older with clinical ly diagnosed uncomplicated herpes zoster who gave written informed consent . Exclusion criteria included zoster rash that had been present for more than 72 hours ; complications of herpes zoster ( for example , ocular or visceral involvement , disseminated herpes zoster ) ; presence of crusts at enrollment ; other serious underlying disease ( such as immune disorders or human immunodeficiency virus [ HIV ] infection ) ; or pregnancy or lactation . Patients were prohibited from receiving any concomitant antiviral or immunomodifying therapy and any topical medication that would be applied to zoster lesions during the study . Patient Assessment s Patients were instructed to return to the clinic for evaluation of lesions and pain on each of the 7 therapy days and every day for the 7 days after therapy . Patients with lesions that were fully crusted by day 7 were examined every other day during the week after therapy . After day 14 , weekly visits were required of all patients until all lesions had lost their crusts . After the lesions had healed , patients were assessed for the presence of postherpetic neuralgia ( defined as pain after healing ) at monthly intervals for an additional 5 months . These monthly pain assessment s continued for all patients , even if postherpetic neuralgia had resolved before completion of the study period . Patients attending the clinic for fewer than 80 % of required visits were deemed noncompliant . The number of papules , vesicles , ulcers , and crusts within the primary dermatome was classified as none , mild ( 50 lesions ) . A specimen for viral culture was obtained at baseline and daily thereafter while vesicles were present . Patients were asked to rate the intensity of their pain as none , mild , moderate , or severe . Definitions for mild , moderate , and severe pain were not prospect ively provided . Adverse events were assessed at each visit according to the time of onset , duration , severity , and investigator-defined relation to the study medication . Blood sample s were obtained for chemical and hematologic assessment , and urine sample s were obtained for dipstick analysis before initiation of therapy and at the last therapy visit . Statistical Analysis Efficacy end points were analyzed by st and ard survival methods . We used the Cox proportional-hazards regression model in our analyses [ 22 ] . Time-dependent covariates were modeled to evaluate the proportional hazards assumption , and a model that included the main effects of treatment was used to examine efficacy . Statistical conclusions were based on the significance of estimated hazard ratios . Hazard ratios greater than 1 indicated a faster rate of event occurrence in patients receiving famciclovir than in those receiving placebo . An estimated hazard ratio of 2 indicated that the event of interest occurred twice as rapidly in patients receiving famciclovir as it did in placebo recipients . Two comparisons were made for each end point : 500-mg famciclovir compared with placebo and 750-mg famciclovir compared with placebo . We also used Kaplan-Meier estimates of the cumulative proportion of patients achieving an event to graphically illustrate the trial results . We used the Fisher exact test ( two-tailed ) to analyze proportion data . The primary efficacy variable was the time to full crusting of the lesions . Secondary variables included duration of viral shedding ; time to resolution of vesicles , ulcers , crusts , and acute pain ; and duration of postherpetic neuralgia ( that is , the time to resolution of pain after the lesions had healed ) . Healing was defined as the first time in which a patient had no papules , vesicles , ulcers , or crusts and after which did not develop them at any later visit . Similarly , the time to the resolution of a clinical variable was the time to the complete cessation of that variable with no further occurrence at any later date . Duration of viral shedding was measured as the number of days from the first dose of the study medication to the last positive culture . The enrollment objective before the study was 400 patients ; this number was selected to ensure a target of 300 evaluable patients ( 100 per group ) . The sample provided an 80 % power to detect a significant difference from placebo , assuming a true hazard ratio of 1.5 and exponential time to full crusting ( or time to event ) . We analyzed data from both the intention-to-treat group ( patients receiving at least one dose of study medication ) and the efficacy-evaluable group ( patients complying with the protocol ) . We prospect ively defined the efficacy-evaluable group before unblinding the r and omization code . Because the results of both analyses were generally similar , we present data for the intention-to-treat group , unless otherwise specified . We also examined prospect ively defined subgroups with respect to age , duration of rash at enrollment , and severity of rash at enrollment . The safety analysis included all patients who had received at least one dose of the study medication . Each analysis included all patients who provided information for the respective end point . For example , the analysis for the time to resolution of crusts included all patients who presented with crusts during the study . Therefore , the number of patients in each analysis of the time to resolution of a condition may vary because only patients experiencing the specific condition were included in the analysis . Results Demographic Characteristics Characteristics of patients in the intention-to-treat group ( n = 419 ) , including sex , age , duration of rash , location of rash , severity of rash , and severity of pain , are shown in Table 1 . Of the 419 patients enrolled , 138 received 500 mg of famciclovir , 135 received 750 mg of famciclovir , and 146 received placebo . Approximately half of the patients were female , and the mean age was 50 years . More than half of the patients had severe rash ( > 50 lesions ) at enrollment , and more than 60 % had moderate or severe zoster pain at enrollment . Table 1 . Patient Characteristics at Study Enrollment The intention-to-treat group and the efficacy-evaluable group ( n = 323 ) had similar",
" Seventy-two patients older than 60 years of age who received a diagnosis of herpes zoster ( HZ ) were entered into a r and omized , double-blind , placebo-controlled trial of daily amitriptyline 25 mg . Treatment with either amitriptyline or placebo continued for 90 days after diagnosis . Pain prevalence at 6 months was the primary outcome . Results showed that early treatment with low-dose amitriptyline reduced pain prevalence by more than one-half ( p amitriptyline , in combination with an antiviral drug , to elderly patients with acute herpes zoster",
"BACKGROUND Epidural analgesia before limb amputation is commonly used to reduce postamputation pain . But there have been no controlled studies with large numbers of patients to prove such a pre-emptive effect . We investigated whether postamputation stump and phantom pain in the first year is reduced by preoperative epidural blockade with bupivacaine and morphine . METHODS In a r and omised , double-blind trial , 60 patients scheduled for lower-limb amputation were r and omly assigned epidural bupivacaine ( 0.25 % 4 - 7 mL/h ) and morphine ( 0.16 - 0.28 mg/h ) for 18 h before and during the operation ( 29 patients ; blockade group ) or epidural saline ( 4 - 7 mL/h ) and oral or intramuscular morphine ( 31 patients ; control group ) . All patients had general anaesthesia for the amputation and were asked about stump and phantom pain after 1 week and then after 3 , 6 , and 12 months by two independent examiners . Study endpoints were rate of stump and phantom pain , intensity of stump and phantom pain , and consumption of opioids . FINDINGS Two patients in each group were withdrawn before amputation . The groups were well matched in baseline characteristics . Median duration of preoperative saline treatment was 18.5 h ( IQR 17 - 20 ) . Median duration of preoperative epidural blockade in the blockade group was 18 h ( 15 - 20.3 ) . The combined median duration of postoperative epidural pain treatment in both groups was 166 h ( 89.3 - 308.3 ) . After 1 week , 14 ( 52 % ) patients in the blockade group and 15 ( 56 % ) in the control group had phantom pain ( 95 % CI - 30.6 to 22.7 , p = 0.9 ) . The figures for blockade versus control group were : 14 ( 82 % ) vs ten ( 50 % ; 4.0 to 60.8 , p = 0.09 ) at 3 months ; 13 ( 81 % ) vs 11 ( 55 % ; -2.7 to 55.3 , p = 0.2 ) at 6 months ; and nine ( 75 % ) vs 11 ( 69 % ; -27.0 to 39.6 , p = 1.0 ) at 12 months . Intensity of stump and phantom pain and consumption of opioids were similar in both groups at all four postoperative interviews . INTERPRETATION Perioperative epidural blockade started a median of 18 h ( 15 - 20.3 ) before the amputation and continued into the postoperative period does not prevent phantom or stump pain",
"Study Design . Prospect i ve , double-blind study , r and omized control trial . Objective . To evaluate and compare the analgesic efficacy , adverse effects , and clinical utility of gabapentin and pregabalin in postoperative pain management , long-term functional outcome , and quality of life in patients undergoing spinal surgery . Summary of Background Data . Patient outcome after lumbar discectomy for radicular low back pain is variable and the benefit is inconsistent . The most common persistent symptoms are pain , motor deficit , and decreased functional status . Methods . This study was conducted in 90 patients belonging to the 18 to 75 age group of either sex undergoing spinal surgery under general anesthesia . Group A received 300 mg of gabapentin , group B received 75 mg of pregabalin , whereas group C received placebo 1 dose 1 hour before surgery and 8 hourly for 7 days , thereafter . The outcome of postoperative static and dynamic pain and functional outcome was recorded using 3 question naires — visual analogue scale , Prolo functional and economic score , Oswestry Disability Index score from preoperative period to 3 months postoperatively . Results . Among the 3 groups , subjects receiving pregabalin showed consistently reduced static and dynamic pain intensity and also required lesser amount of rescue drug throughout the postoperative period . There was statistically significant difference ( P Prolo score and Oswestry Disability Index score at all time intervals between group B and group C. Although , significant difference in the functional outcome between group A and group B was seen at 3 months . Conclusion . Preoperative pregabalin administration is associated with less pain intensity and improved functional outcomes 3 months after lumbar discectomy followed by gabapentin and then placebo . Level of Evidence :",
"PURPOSE The aim of this study is to evaluate the neuroprotective effect of antioxidant supplementation with vitamin E in patients treated with cisplatin chemotherapy . METHODS Between April 1999 and October 2000 , forty-seven patients were r and omly assigned to either group one , which received vitamin E supplementation during cisplatin chemotherapy , or to group two , which received cisplatin chemotherapy alone . Alpha-tocopherol ( vitamin E ; 300 mg/d ) was administered orally before cisplatin chemotherapy and continued for 3 months after the suspension of treatment . For pre clinical studies , nude mice carrying the human melanoma tumor were treated with cisplatin alone or in combination with vitamin E. RESULTS Twenty-seven patients completed six cycles of cisplatin chemotherapy : 13 patients in group one and 14 patients in group two . The incidence of neurotoxicity was significantly lower in group one ( 30.7 % ) than it was in group two ( 85.7 % ; P severity of neurotoxicity , measured with a comprehensive neurotoxicity score based on clinical and neurophysiological parameters , was significantly lower in patients who were supplemented with vitamin E than in patients who were not supplemented with vitamin E ( 2 v 4.7 , P cisplatin was combined with vitamin E , no differences were observed in tumor weight inhibition , tumor growth delay , or life span as compared with treatment with cisplatin alone . CONCLUSION Supplementation of patients receiving cisplatin chemotherapy with vitamin E decreases the incidence and severity of peripheral neurotoxicity",
"e20505 Background : Neuropathic pain ( NP ) remains difficult to control for a significant proportion of patients with cancer . Chemotherapy induced peripheral neuropathy ( CIPN ) is postulated as an initial stage to the development of NP . Among breast cancer patients , taxanes , platinum agents , and vinca alkaloids are most likely to cause NP . The purpose of this study was to assess the extent to which those who experienced CIPN ( NCI toxicity criteria ≥ grade 2 sensory neuropathy ) during paclitaxel chemotherapy were at risk of developing chronic NP , controlling for disease- and treatment-related variables ( e.g. , stage of disease , location of tumor chemotherapy and other cancer therapies , dose of chemotherapy and duration of treatment ) , clinical health status ( e.g. , comorbid conditions ) , and sociodemographic characteristics ( e.g. , age , race ) . METHODS We conducted a follow-up survey of breast cancer patients who previously participated in clinical trials for paclitaxel . Patients were asked if they have ever been diagnosed by the physician or healthcare provider for NP during the survey . Clinical trial data ( NCI Toxicity , cummulative dose ) were abstract ed from a clinical data base . RESULTS Of the 430 potential respondents , 240 responded to the survey . Mean follow-up time was 9.5 years ( SD=2.1 ) . Sixty three percent of the respondents had grade 2 or greater sensory neuropathy during their previous treatment with paclitaxel . Follow-up data showed that 18 % ( 43/240 ) were subsequently diagnosed by their physician to have NP . Logistic regression analysis showed that those with CIPN during the trial were 3 times more likely to having been diagnosed with NP ( OR=3 ; 95%CI=1.2 ; 7.2 ; p included cummulative dose of paclitaxel , and comorbid conditions such as diabetes and osteoarthritis . Patients with NP reported twice as many visits to their health care provider ( p=0.028 ) ; had taken more prescription ( 50 % versus 19 % ; p=0.0001 ) for pain relative to those without NP . CONCLUSIONS We provide empirical evidence on the importance CIPN as a risk factor for NP in breast cancer patients . Prospect i ve studies with larger cohorts are needed to vali date our findings . No significant financial relationships to disclose",
"The efficacy of preemptive analgesia on postoperative pain is discussed . From experimental neurophysiological data , the present policy of preventive analgesia aims at precluding modifications of the nervous system secondary to a nervous lesion and the appearance of chronic pain , particularly of the neurogenic kind . The post-mastectomy pain syndrome ( PMPS ) falls within the realm of neurogenic pain and is still poorly understood and underestimated . This study evaluated the preemptive effect of a perioperative administration of an oral non steroid anti-inflammatory , the ibuprofen-arginine , on PMPS . Thirty patients scheduled for partial or total mastectomy with axillary dissection were prospect ively and r and omly assigned to 2 groups . The ibuprofen-arginine group ( group I ) ( n = 15 ) , received an oral administration of 400 mg of ibuprofen-arginine , 90 min before surgery , 2 h after surgery and then every 8 h in the first 32 postoperative hours . The control group ( group C ) received in doubled blind a placebo at the same time . At 6 months , we looked after pain or dysesthesia . We confirmed the diagnosis of PMPS in presence of association of diagnosis criteria s. Fourteen patients in each group have been included . Eighty-six percent of the patients ( 13 patients in group I and 11 patients in group C ) presented at 6 months dysesthesia of the upper member ipsilateral to the mastectomy and /or the operated breast , appearing either immediately or after a laps of time . Nine patients ( group I ) and 6 patients ( group C ) had PMPS . Postoperative radiotherapy and lymphoedema were statistically associated with PMPS ( p = 0.019 and p = 0.011 ) . The perioperative preventive administration of a non-steroid anti-inflammatory drug reduces neither the incidence of pain in the first post-operative months , nor the appearance of PMPS at 6 months . These results suggest that others factors than the nervous lesion may play a role in the occurrence of PMPS , as radiotherapy , lymphoedema , but also psychosocials factors",
"OBJECTIVES The purpose of this study was to evaluate the analgesic effects of perioperative gabapentin on postoperative acute and chronic pain after coronary artery bypass graft ( CABG ) surgery with median sternotomy and internal mammary artery harvesting . DESIGN A double-blind r and omized clinical study . SETTING A single-academic hospital . PARTICIPANTS Patients with ischemic heart disease who were scheduled to undergo CABG surgery . INTERVENTIONS Forty patients were allocated r and omly into 2 groups ; the gabapentin group ( n = 20 ) received 1.2 g/d of oral gabapentin before and for 2 days after surgery , and the placebo group ( n = 20 ) received a placebo capsule instead . The primary outcome was to evaluate the effects of gabapentin on acute and chronic pain after surgery . The postoperative evaluation included the assessment of pain at rest and when coughing , intravenous tramadol usage , postoperative morbidities , and side effects of gabapentin . Postoperative analgesia at 6 , 12 , 18 , 24 , 48 , and 72 hours after extubation and at discharge was evaluated with the visual analog scale . The assessment of postoperative pain at the 1- and 3-month follow-ups was performed using a numeric rating scale . MAIN RESULTS Postoperative pain scores at 1 , 2 , and 3 days were significantly lower in the gabapentin group when compared with the placebo group ( p . Pain scores at 1 and 3 months postoperatively were lower in the gabapentin group than in the placebo group ( p > 0.05 ) . Consumption of intravenous tramadol given as rescue analgesic within 24 hours after extubation in the gabapentin group was 99.0 ± 53.8 mg versus 149.4 ± 72.5 mg in the placebo group ( p side effects and time to extubation between the groups . CONCLUSIONS Gabapentin significantly reduced the intensity of pain and tramadol consumption in the early postoperative period after CABG surgery . Pain scores at 1 and 3 months after surgery were low in both groups , with no significant difference between the groups",
"BACKGROUND : Preoperative oral gabapentin has been shown to reduce postoperative pain . However , the effects of gabapentin as an adjunct to regional anesthesia is unclear and its effects on chronic pain remains unknown . In patients undergoing thyroidectomy , we investigated the effects on early and late ( at 6 mo ) postoperative pain of preoperative oral gabapentin as an adjunct to superficial cervical plexus block ( SCPB ) . METHOD : Fifty consecutive consenting patients were r and omized to receive either 1200 mg of gabapentin ( Group G ) or placebo ( Group P ) 2 h preoperatively . Preoperative anxiety was assessed on a numeric scale from 0 to 6 . A SCPB was performed after a st and ardized induction of anesthesia . The primary outcome , analgesic drug consumption , was assessed during the procedure and postoperatively in the postanesthesia care unit and after discharge to the ward . Over the first 24 h , pain levels at rest and during swallowing were measured on a numeric scale from 0 to 10 . If the pain level was more than 4/10 at rest , patients received 1 g/6 h of IV paracetamol and /or 50 mg/6 h of IV tramadol as a rescue analgesic treatment in the interval . The day before operation and 6 mo after thyroidectomy , included patients were asked to answer a neuropathic pain diagnostic question naire . RESULTS : Population characteristics , preoperative anxiety , intraoperative drug consumption , procedure duration , and postoperative care unit stay were comparable in both groups . Analgesic consumption during the first 24 postoperative hours was similar in both groups ( G : 3 [ 0–5 ] doses/24 h ; P : 3 [ 1–5 ] doses/24 h ; P = NS ) , as well as pain at rest ( G : 2,2 [ 0.2–3.7 ] ; P : 2 [ 0–6.3 ] ; P = NS ) , and during swallowing ( G : 2.8 [ 0.4–8.9 ] ; P : 3 [ 1.4–6.3 ] ; P = NS ] ) . Eight patients had a diagnostic question naire score more than 3 , 6 mo after operation versus 2 in preoperative period ( P = 0.04 ) . Such delayed neuropathic pain complaints were reported in seven patients receiving SCPB alone and only in one patient receiving both SCPB and preoperative adjunctive oral gabapentin . ( P = 0.01 ) . CONCLUSION : Oral preoperative administration of gabapentin did not modify immediate pain management in thyroidectomy patients receiving SCPB , but prevented delayed neuropathic pain at 6 mo",
"& NA ; This study tested the hypothesis that high dose systemic alfentanil administered before and during abdominal hysterectomy would pre‐empt post‐operative pain to a greater extent than administration of either low dose alfentanil or no alfentanil perioperatively . Patients ( ASA 1 or 2 ) were r and omly assigned to group 1 ( n = 15 ) , no opioid ; group 2 ( n = 15 ) , low dose alfentanil ; or group 3 ( n = 15 ) , high dose alfentanil . Anaesthesia was induced in group 1 with midazolam and thiopentone and was maintained with isoflurane and 70 % N2O in O2 . Anaesthesia was induced in group 2 with midazolam , thiopentone and i.v . alfentanil ( 30 & mgr;g kg−1 ) , and was maintained with isoflurane , 70 % N2O in O2 , and bolus doses of i.v . alfentanil ( 10–20 & mgr;g kg−1 ) every hour . Anaesthesia was induced in group 3 with midazolam and i.v . alfentanil ( 100 & mgr;g kg−1 ) , and was maintained with 70 % N2O in O2 , and an infusion of i.v . alfentanil ( 1–2 & mgr;g kg−1 min−1 ) . Blood sample s were drawn at 30 and 120 min after surgery and assayed for plasma alfentanil . Morphine consumption and VAS pain scores were consistently lowest in group 3 over the 48 h study period . A composite measure of pain and morphine consumption was significantly lower in group 3 than group 2 up to 6 h after surgery , and siificantly lower than group 1 up to 12 h. No adverse effects were observed . A 6‐month follow‐up did not reveal any significant differences among the three groups . It is concluded that intra‐operative high dose alfentanil anaesthetic pre‐empts post‐operative pain after abdominal hysterectomy , but the effects are small and of short duration . Surgical procedures carried out under general anaesthesia using st and ard ( and even high ) doses of opioids intraoperatively provide sub‐optimal protection from the injury barrage brought about by incision and subsequent noxious surgical events",
"We investigated the analgesic efficacy of mexiletine and gabapentin on acute and chronic pain associated with cancer breast surgery in 75 patients . They were r and omized to receive , in a double-blinded manner , mexiletine 600 mg/d , gabapentin 1200 mg/d , or placebo for 10 days . Anesthesia was st and ardized , and all patients had access to routine postoperative analgesics on dem and . The visual analog scale score assessed pain at rest and after movement . Three months later , all patients were interviewed to identify intensity of chronic pain and analgesic requirements . Mexiletine and gabapentin reduced codeine consumed from the second to tenth day by 50 % ( P = 0.029;P = 0.018 and P = 0.035 for mexiletine versus control and gabapentin versus control comparisons , respectively ) . Total paracetamol consumption was also reduced during the same time ( P = 0.0085;P = 0.007 and P = 0.011 for the mexiletine and gabapentin groups when compared with the control , respectively ) . Pain at rest and after movement was reduced by both drugs on the third postoperative day . Pain after movement also was reduced by gabapentin between the second and fifth postoperative day . Three months later , the incidence of chronic pain , its intensity , and need for analgesics were not affected by either treatment . However , burning pain was more frequent in the control group ( P = 0.033 )",
"STUDY DESIGN A r and omized , controlled , single-center trial with a stratified group design . OBJECTIVE To investigate the secondary prophylactic effect of the Active Back School program on minimizing recurrences of low back pain episodes . SUMMARY OF BACKGROUND DATA The results of back school interventions are controversial . Previous work often used short intervention periods and low doses of practical training . However , studies with the highest method ologic scores have shown the best results , especially when conducted in occupational setting s and coupled with a comprehensive rehabilitation program . METHODS By block r and omization , 19 men and 24 women were allocated to Active Back School , with 18 men and 20 women as control subjects . The Slumps test and number of low back pain episodes during the previous 36 months were used as stratification factors . There were no significant differences between the groups with regard to demographic factors and initially observed variables . Active Back School consisted of 20 lessons over a 13-week period . Each lesson was divided into a 20-minute theoretical part and a 40-minute exercise part . All participants were examined on enrollment , then 5 and 12 months after initiation of the program . Outcome measures were recurrence of low back pain episodes and number of days of sick leave . RESULTS The recurrence of new low back pain episodes was significantly lower ( P Active Back School group than in the control group . In the Active Back School group , seven participants took sick leave because of low back pain episodes during the first 12 months of follow-up compared with 11 among the control subjects . The number of sick leave days was significantly lower ( P Back School group than in the control group . CONCLUSION Active Back School reduced the recurrence and severity of new low back pain episodes according to results of follow-up examinations performed 5 and 12 months after enrollment",
"Abstract Objectives : To investigate the cl aim that 90 % of episodes of low back pain that present to general practice have resolved within one month . Design : Prospect i ve study of all adults consulting in general practice because of low back pain over 12 months with follow up at 1 week , 3 months , and 12 months after consultation . Setting : Two general practice s in south Manchester . Subjects : 490 subjects ( 203 men , 287 women ) aged 18 - 75 years . Main outcome measures : Proportion of patients who have ceased to consult with low back pain after 3 months ; proportion of patients who are free of pain and back related disability at 3 and 12 months . Results : Annual cumulative consultation rate among adults in the practice s was 6.4 % . Of the 463 patients who consulted with a new episode of low back pain , 275 ( 59 % ) had only a single consultation , and 150 ( 32 % ) had repeat consultations confined to the 3 months after initial consultation . However , of those interviewed at 3 and 12 months follow up , only 39/188 ( 21 % ) and 42/170 ( 25 % ) respectively had completely recovered in terms of pain and disability . Conclusions : The results are consistent with the interpretation that 90 % of patients with low back pain in primary care will have stopped consulting with symptoms within three months . However most will still be experiencing low back pain and related disability one year after consultation . Key messages It is widely believed that 90 % of episodes of low back pain seen in general practice resolve within one month In a large population based study we examined the outcome of episodes of low back pain in general practice with respect to both consultation behaviour and self reported pain and disability While 90 % of subjects consulting general practice with low back pain ceased to consult about the symptoms within three months , most still had substantial low back pain and related disability Only 25 % of the patients who consulted about low back pain had fully recovered 12 months later Since most consulters continue to have long term low back pain and disability , effective early treatment could reduce the burden of these symptoms and their social , economic , and medical",
"BACKGROUND : The treatment of postherpetic neuralgia ( PHN ) continues to be a challenge in clinical pain management . In this r and omized , controlled study , we assessed the effectiveness of repetitive paravertebral injections with local anesthetics and steroids for the prevention of PHN in patients with acute herpes zoster . METHODS : One hundred thirty-two patients with acute herpes zoster diagnosed 1–7 days after the onset of the rash were r and omly assigned to receive either st and ard therapy ( oral antivirals and analgesics ) or st and ard therapy with additional repetitive paravertebral injections of a mixture of 10 mL 0.25 % bupivacaine and 40 mg methylprednisolone acetate every 48 h for a week . Efficacy was evaluated at 1 , 3 , 6 , and 12 mo after the end of the treatments . The primary end point was the proportion of patients with zoster-associated pain and /or allodynia 1 mo after inclusion . Statistical analysis was performed based on the intent-to-treat population . RESULTS : One hundred thirteen patients completed the 1-yr follow-up . At 1 mo posttherapy , 13 % of patients in the paravertebral group reported zoster-related pain , compared with 45 % in the st and ard group ( P the incidence of PHN was still significantly lower in the paravertebral group than in the st and ard group . The quality of life improved in both groups at each follow-up time point with no significant difference between groups . CONCLUSION : Repetitive paravertebral anesthetic block in combination with steroids plus st and ard treatment with acyclovir and analgesics significantly reduced the incidence of PHN than the st and ard treatment alone",
"In a r and omized , double-blind , placebo-controlled pilot study , we examined the effect of Org 2766 - -a corticotropin ( 4 - 9 ) analogue -- on neurotoxicity in 28 patients with lymphoma who were treated with combination chemotherapy containing Vinca alkaloids ( vincristine and vinblastine ) . The patients received a total dose of 12 mg of vincristine in the case of non-Hodgkin 's lymphoma and a total dose of 16 mg of vincristine in the case of Hodgkin 's disease . Moreover , the patients with Hodgkin 's disease received a mean total dose of 84 mg of vinblastine . Subcutaneous injections of 2 mg of Org 2766 or placebo were administered to patients with non-Hodgkin 's lymphoma on days 1 and 10 of each chemotherapy course and to patients with Hodgkin 's disease on days 1 and 8 of each chemotherapy course . The first injection was always given before the administration of vincristine . Assessment of neurologic symptoms and signs and measurement of sensory thresholds ( vibration sense and temperature sense ) were performed on day 1 of the first , fourth , and sixth ( or eighth ) courses and 6 weeks after cessation of chemotherapy . Thirteen patients ( mean age , 44.7 years ) received Org 2766 and 15 patients ( mean age , 54.7 years ) received placebo . More symptoms occurred in the placebo group , but only numbness and autonomic complaints occurred significantly more often in the placebo group . Motor deficit and sensory disturbances were more severe and also occurred significantly more often in the placebo group . There was no difference with respect to reflex examination findings and sensory thresholds . ( ABSTRACT TRUNCATED AT 250 WORDS",
"The frequency , characteristics and reversibility of bortezomib‐associated peripheral neuropathy were evaluated in the phase III APEX ( Assessment of Proteasome Inhibition for Extending Remissions ) trial in patients with relapsed myeloma , and the impact of a dose‐modification guideline on peripheral neuropathy severity and reversibility was assessed . Patients received bortezomib 1·3 mg/m2 ( days 1 , 4 , 8 , 11 , eight 21‐d cycles , then days 1 , 8 , 15 , 22 , three 35‐d cycles ) ; bortezomib was held , dose‐reduced or discontinued depending on peripheral neuropathy severity , according to a protocol ‐specified dose‐modification guideline . Overall , 124/331 patients ( 37 % ) had treatment‐emergent peripheral neuropathy , including 30 ( 9 % ) with grade ≥3 ; incidence and severity were not affected by age , number/type of prior therapies , baseline glycosylated haemoglobin level , or diabetes history . Grade ≥3 incidence appeared lower versus phase II trials ( 13 % ) that did not specifically provide dose‐modification guidelines . Of patients with grade ≥2 peripheral neuropathy , 58/91 ( 64 % ) experienced improvement or resolution to baseline at a median of 110 d , including 49/72 ( 68 % ) who had dose modification versus 9/19 ( 47 % ) who did not . Efficacy did not appear adversely affected by dose modification for grade ≥2 peripheral neuropathy . Bortezomib‐associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma . Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome",
"Oxaliplatin is a promising drug for cancer therapy and the oxaliplatin/5-fluorouracil/leucovorin ( FOLFOX ) regimen has become the st and ard adjuvant treatment for colorectal cancer . However , the oxaliplatin-induced neurotoxicity still represents a clinical problem leading to a discontinuation of the therapy . Many strategies have been proposed in order to manage the neurotoxicity , but their effect on antitumoral efficacy is still unclear . In this study , we investigated the effect of reduced glutathione administration on neurotoxicity , oxaliplatin pharmacokinetics , and platinum-DNA ( Pt-DNA ) adduct formation in patients affected by colorectal cancer treated with FOLFOX4 adjuvant regimen . Twenty-seven patients were r and omized to receive GSH 1500 mg/m2 or saline solution before oxaliplatin infusion . Evaluation of neurotoxicity , pharmacokinetics of plasmatic total and ultrafiltered Pt , and determination of Pt-DNA adduct formation on white blood cells was performed during the 5th , 9th , and 12th cycles . At the end of all cycles of therapy , the patients in the GSH arm showed a statistically significant reduction of neurotoxicity ( P=0.0037 ) compared with the placebo arm . There were no significant differences in the main pharmacokinetic parameters between the two arms except a lower area under the plasma concentration – time curve and a smaller apparent steady-state volume of distribution ( Vss ) when GSH was coadministered . This difference can be explained by the natural function of GSH in the detoxification of oxaliplatin and by its ability to remove the Pt bound to plasma proteins . The determination of Pt-DNA adduct formation shows no statistically significant differences between the two arms . In conclusion , this study indicates that coadministration of GSH is an effective strategy to reduce the oxaliplatin-induced neurotoxicity without impairing neither the pharmacokinetics of oxaliplatin , nor the Pt-DNA adduct formation",
"PURPOSE Cumulative neurotoxicity is a prominent toxicity of oxaliplatin-based therapy . Intravenous calcium and magnesium have been extensively used to reduce oxaliplatin-induced neurotoxicity . This trial was design ed to definitively test whether calcium/magnesium decreases oxaliplatin-related neurotoxicity . PATIENTS AND METHODS In all , 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) were r and omly assigned to intravenous calcium/magnesium before and after oxaliplatin , a placebo before and after , or calcium/magnesium before and placebo after . The primary end point was cumulative neurotoxicity measured by the sensory scale of the European Organisation for Research and Treatment of Cancer Quality of Life Question naire-Chemotherapy-Induced Peripheral Neuropathy 20 tool . RESULTS There were no statistically significant neuropathy differences among the study arms as measured by the primary end point or additional measures of neuropathy , including clinician-determined measurement of the time to grade 2 neuropathy by using the National Cancer Institute Common Terminology Criteria for Adverse Events scale or an oxaliplatin-specific neuropathy scale . In addition , calcium/magnesium did not substantially decrease oxaliplatin-induced acute neuropathy . CONCLUSION This study does not support using calcium/magnesium to protect against oxaliplatin-induced neurotoxicity",
"& NA ; Perioperative minocycline administration for 8 days after lumbar discectomy does not improve persistent pain . & NA ; Minocycline strongly inhibits microglial activation , which contributes to central sensitization , a major mechanism underlying chronic pain development . We hypothesized that the perioperative administration of minocycline might decrease persistent pain after lumbar discectomy . We r and omly assigned 100 patients undergoing scheduled lumbar discectomy to placebo and minocycline groups . The minocycline group received 100 mg minocycline orally , twice daily , beginning the evening before surgery and continuing for 8 days . The primary outcome was the change in lower limb pain intensity at rest between baseline and 3 months . Secondary outcomes were pain intensity on movement , the incidence of persistent pain and chronic neuropathic pain , back pain intensity at rest and on movement , and changes in Neuropathic Pain Symptom Inventory , Brief Pain Inventory , and Rol and ‐Morris scores at 3 months . An intention‐to‐treat analysis was performed for patients assessed from the day before surgery to 3 months . The decrease in lower limb pain intensity was similar in the placebo and minocycline groups , both at rest −1.7 ± 1.6 vs −2.3 ± 2.4 and on movement −2.5 ± 2.1 vs −3.4 ± 2.9 . The incidence and intensity of neuropathic pain and functional scores did not differ between the minocycline and placebo groups . Exploratory analysis suggested that minocycline might be effective in a subgroup of patients with predominantly deep spontaneous pain at baseline . Perioperative minocycline administration for 8 days does not improve persistent pain after lumbar discectomy"
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BACKGROUND The physical and psychosocial benefits of participation in cardiac rehabilitation following a coronary event have well been established . Despite these benefits there is strong evidence that participation in traditional cardiac rehabilitation programs remains low . Various models of cardiac rehabilitation have been implemented including the use of brief structured interventions to enable modification of coronary risk factors . OBJECTIVES The objective of this review was to determine the effect of brief structured interventions on risk factor modification in patients with coronary heart disease . SEARCH STRATEGY A literature search was performed using the following data bases MEDLINE ( 1966 - 2006 ) , CINAHL ( 1982 - 2006 ) , EMBASE ( 1980-current ) and up to the Cochrane Controlled Trials Register ( Issue 2 , 2006 of Cochrane Library ) . In addition , the reference lists of relevant trials and conference proceedings were also scrutinised . Company representatives , experts and investigators were contacted to elicit further information . SELECTION CRITERIA All r and omised and quasi-r and omised controlled trials that compared the effects of brief structured interventions on risk factor modification in patients with coronary heart disease were considered for inclusion in the review . DATA COLLECTION AND ANALYSIS Eligibility of the trials for inclusion in the review , details of eligible trials and the method ological quality of the trials were assessed independently by two review ers . Relative risks for dichotomous data and a weighted mean difference for continuous data were calculated with 95 % confidence intervals . Where synthesis was inappropriate , trials were considered separately . MAIN RESULTS Seventeen trials involving a total of 4725 participants were included in the final review : three trials compared the effects of brief structured interventions on diet modification ; seven on smoking cessation ; and seven on multiple risk factors . Two trials involving 76 patients compared brief structured intervention versus usual care for dietary modification . Although there was a tendency for more participants in the intervention arm to lose weight at the 12-week follow up and achieve target cholesterol levels at the 6-month follow up , these results were not statistically significant . Only one small trial involving 36 patients compared brief structured intervention and extensive intervention for dietary modification and demonstrated a significant reduction in the percentage of energy obtained from fat and saturated fat intake among participants receiving extensive intervention . However , no difference in fish , fruit and vegetable intake between the groups was evident . Six trials involving 2020 patients compared brief structured intervention versus usual care for smoking cessation . There was no difference in the smoking cessation rates at the 3- and 6-week follow up , however , there was evidence of a benefit of brief structured interventions for smoking cessation at the 3- , 6- and 12-month follow up . In the only trial that and compared brief structured intervention and extensive intervention for smoking cessation in 254 participants there was no clear difference of a likelihood of smoking cessation between the two groups . In the seven trials that compared brief structured intervention and usual care for multiple risk factor modification there was evidence of a benefit of the intervention on behavioural changes such as fat intake , weight loss and consequently on reduction in the body mass index , smoking cessation and physical activity among the participants . The findings concerning the effect on blood pressure , blood glucose levels and the lipid profile , however , remain inconclusive . CONCLUSIONS There is suggestive but inconclusive evidence from the trials of a benefit in the use of brief interventions for risk factor modification in patients with coronary heart disease . This review , however , supports the concept that brief interventions for patients with coronary heart disease can have beneficial effects on risk factor modification and consequently on progression of coronary heart disease . Further trials using larger sample sizes need to be undertaken to demonstrate the benefits of brief structured intervention targeted at the modification of single or multiple risk factors
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" Seven hundred and thirty one men admitted to medical wards were interviewed to identify problem drinkers who had not received previous treatment for alcoholism and who had some social support . One hundred and sixty one met the diagnostic criteria ; 156 agreed to a follow up interview and were allocated to one of two groups . One group received a session of counselling about their drinking habits from a nurse while the other received only routine medical care . Both groups reported a reduction in alcohol consumption when interviewed 12 months later , but the counselled group had a significantly better outcome than the control group . It is concluded that systematic screening for alcohol consumption and related problems should become a routine part of medical assessment and that advice on drinking habits is effective if given before irreversible physical or psychosocial problems have developed",
"OBJECTIVE There is a pressing need for brief practical interventions that address diabetes management . Using a r and omized design , we evaluated a medical office-based intervention focused on behavioral issues relevant to dietary self-management . RESEARCH DESIGN AND METHODS There were 206 adult diabetes patients r and omized to usual care or brief intervention , which consisted of touchscreen computer-assisted assessment to provide immediate feedback on key barriers to dietary self-management , and goal setting and problem-solving counseling for patients . Follow-up components to the single session intervention included phone calls and interactive video or videotape instruction as needed . RESULTS Multivariate analyses of covariance revealed that the brief intervention produced greater improvements than usual care on a number of measures of dietary behavior ( e.g. , fewer calories from saturated fat , fewer high-fat eating habits and behaviors ) at the 3-month follow-up . There were also significant differences favoring intervention on changes in serum cholesterol levels and patient satisfaction but not on glycosylated hemoglobin . The intervention effects were relatively robust across a variety of patient characteristics , the two participating physicians , and intervention staff members . CONCLUSIONS If the long-term results are equally positive and generalize to other setting , this intervention could provide a prototype for a feasible cost-effective way to integrate patient views and behavioral management into office-based care for diabetes",
"BACKGROUND Alcohol use in older adults is common . It is associated with depression , hypertension , diabetes , drug interactions , accidents , and increased rates of emergency department visits and hospitalizations . METHODS A controlled clinical trial ( Project GOAL --Guiding Older Adult Lifestyles ) tested the efficacy of brief physician advice in reducing the alcohol use and use of health care services of older adult problem drinkers . Twenty-four community-based primary care practice s in Wisconsin ( 43 family physicians and internists ) participated in the trial . Of the 6073 patients screened , 105 men and 53 women met inclusion criteria and were r and omized into a control group ( n = 71 ) or an intervention group ( n = 87 ) . Intervention group patients received two 10- to 15-minute physician-delivered counseling sessions that included advice , education , and contracting using a scripted workbook . A total of 146 patients ( 92.4 % ) participated in the 12-month follow-up procedure . RESULTS No significant differences were found between the control and intervention groups at baseline in alcohol use , age , socioeconomic status , depression , onset of alcohol use , smoking status , activity level , or use of mood-altering drugs . The older adults who received the physician intervention demonstrated a significant reduction in 7-day alcohol use , episodes of binge drinking , and frequency of excessive drinking ( P 7-day alcohol use , 74 % reduction in mean number of binge-drinking episodes , and 62 % reduction in the percentage of older adults drinking more than 21 drinks per week in the intervention group compared with the control group . There were no significant changes in health status . Patterns of health care utilization were not extensively analyzed because of the small number of events . CONCLUSIONS This study provides the first direct evidence that brief physician advice can decrease alcohol use by older adults in community-based primary care practice",
"AIMS In a multifactorial lifestyle behaviour programme , of 2 years duration , to study the maintenance of achieved behaviour and risk factor-related changes . METHODS AND RESULTS Out of a consecutive population of 151 patients treated with percutaneous transluminal angioplasty under 65 years of age , 87 were r and omly allocated to an intervention group ( n=46 ) or to a control group ( n=41 ) . The programme started with a 4 week residential stay , which was focused on health education and the achievement of behaviour change . During the first year of follow-up , a maintenance programme included regular contacts with a nurse , while no further rehabilitative efforts were offered during the second year . One patient died ( control ) . During the second year the proportion of hospitalized patients was lower in the intervention group ( 4 % vs 20%;P lifestyle dependent behaviours : diet ( index at 0 , 12 and 24 months ) : 10.5+/-3 . 4 , 12.9+/-2.5 and 12.4+/-2.6 in the intervention group ( I ) vs 10 . 1+/-3.2 , 10.7+/-3.0 and 11.8+/-3.2 in the control group (C);P exercise sessions per week : 2.5+/-2.3 , 4.5+/-1.9 and 4.4+/-2.1 ( I ) vs 3.1+/-2.2 , 3.5+/-2.3 and 3.7+/-2.7 (C);P smoking ; 18 % , 6 % and 9 % ( I ) vs 12 % , 21 % and 18 % (C);P exercise capacity ( 0 , 12 and 24 months ) : 156+/-42 , 174+/-49 and 165+/-47 W ( I ) vs 164+/-40 , 163+/-49 and 156+/-48 watts (C);P serum cholesterol levels at 0 and 24 months : 5 . 4+/-0.8 and 5.2+/-0.9 mmol . l(-1)(I ) vs 5.4+/-1.0 and 4.9+/-0.9 mmol . l(-1)(C ) ; ns , low density lipoprotein cholesterol level : 3.6+/-0.8 and 3.4+/-0.8 mmol . l(-1)(I ) vs 3.7+/-0.9 and 3.3+/-0.7 mmol . l(-1)(C ) ; ns , triglyceride level : 2.2+/-1.6 and 1.8+/-1.3 mmol . l(-1)(I ) vs 2.2+/-1.4 and 1.6+/-0.6 mmol . l(-1)(C ) ; ns , body mass index ( 0 , 12 and 24 months ) : 27.5+/-4.5 , 27.0+/-4.3 and 27.4+/- 4.5 kg . m(-2)(I ) vs 26.8+/-2.8 , 26.9+/-2.7 and 26.9+/- 3.2 kg . m(-2)(C ) ; ns , waist/hip ratio or blood pressure . The two groups did not differ in quality of life , or psychological factors . Return to work after 12 and 24 months was 74 % and 78 % ( I ) vs 68 % and 61 % ( C ) ; ns . CONCLUSION This rehabilitation programme influenced important lifestyle behaviour and reduced some , but not all , important risk",
"Abstract Objective : To evaluate a smoking cessation intervention that can be routinely delivered to smokers admitted with cardiac problems . Design : R and omised controlled trial of usual care compared with intervention delivered on hospital wards by cardiac rehabilitation nurses . Setting : Inpatient wards in 17 hospitals in Engl and . Participants : 540 smokers admitted to hospital after myocardial infa rct ion or for cardiac bypass surgery who expressed interest in stopping smoking . Intervention : Brief verbal advice and st and ard booklet ( usual care ) . Intervention lasting 20 - 30 minutes including carbon monoxide reading , special booklet , quiz , contact with other people giving up , declaration of commitment to give up , sticker in patient 's notes ( intervention group ) . Main outcome measures : Continuous abstinence at six weeks and 12 months determined by self report and by biochemical validation at these end points . Feasibility of the intervention and delivery of its components . Results : After six weeks 151 ( 59 % ) and 159 ( 60 % ) patients remained abstinent in the control and intervention group , respectively ( P=0.84 ) . After 12 months the figures were 102 ( 41 % ) and 94 ( 37 % ) ( P=0.40 ) . Recruitment was slow , and delivery of the intervention was inconsistent , raising concerns about the feasibility of the intervention within routine care . Patients who received the declaration of commitment component were almost twice as likely to remain abstinent than those who did not receive it ( P Low dependence on tobacco and high motivation to give up were the main independent predictors of positive outcome . Patients who had had bypass surgery were over twice as likely to return to smoking as patients who had had a myocardial infa rct ion . Conclusions : Single session interventions delivered within routine care may have insufficient power to influence highly dependent smokers . What is already known on this topic Stopping smoking after a serious cardiac event is associated with a significant decrease in mortality Up to 70 % of smokers who survive cardiac surgery smoke again within a year Intensive interventions delivered by dedicated staff can help cardiac patients not to start to smoke again What this study adds An intervention delivered by cardiac rehabilitation nurses within routine care during patients ' hospital stay failed to increase the number who managed to stop smoking in the long term For busy staff with competing priorities , the 30 minute intervention was also on the borderline of practicability Patients admitted after a myocardial infa rct ion were over twice as likely to give up than those admitted for a bypass",
"This study examined the effectiveness of a nurse-managed minimal-contact smoking cessation intervention for patients hospitalized for cardiac disease . A pre-test-post-test quasi-experimental design was used . Patients who smoked prior to admission to cardiac wards of five hospitals ( n = 388 ) received the intervention , whereas smoking patients in six other hospitals were given usual care ( n = 401 ) . The intervention was initiated at the hospital and continued after discharge . The core elements were stop-smoking advice from the cardiologist , a short bedside consultation with a nurse , administration of self-help material s and aftercare by the cardiologist . Smoking cessation was assessed after 3 months by self-report . Logistic regression analysis excluding dropouts , controlling for covariates including baseline differences showed significant intervention effects ( one-tailed significance test ) on point prevalence abstinence ( OR = 2.11 ) and continuous abstinence ( OR = 1.41 ) . Intention-to-treat analysis including dropouts as smokers showed a significant effect on point prevalence abstinence ( OR 1.35 ) . We conclude that , compared to usual care , the low-intensity smoking cessation intervention for cardiac in patients was more effective in achieving smoking cessation . However , the small effects and the process evaluation suggest that improvements are needed",
"CONTEXT The Lifestyle Heart Trial demonstrated that intensive lifestyle changes may lead to regression of coronary atherosclerosis after 1 year . OBJECTIVES To determine the feasibility of patients to sustain intensive lifestyle changes for a total of 5 years and the effects of these lifestyle changes ( without lipid-lowering drugs ) on coronary heart disease . DESIGN R and omized controlled trial conducted from 1986 to 1992 using a r and omized invitational design . PATIENTS Forty-eight patients with moderate to severe coronary heart disease were r and omized to an intensive lifestyle change group or to a usual-care control group , and 35 completed the 5-year follow-up quantitative coronary arteriography . SETTING Two tertiary care university medical centers . INTERVENTION Intensive lifestyle changes ( 10 % fat whole foods vegetarian diet , aerobic exercise , stress management training , smoking cessation , group psychosocial support ) for 5 years . MAIN OUTCOME MEASURES Adherence to intensive lifestyle changes , changes in coronary artery percent diameter stenosis , and cardiac events . RESULTS Experimental group patients ( 20 [ 71 % ] of 28 patients completed 5-year follow-up ) made and maintained comprehensive lifestyle changes for 5 years , whereas control group patients ( 15 [ 75 % ] of 20 patients completed 5-year follow-up ) made more moderate changes . In the experimental group , the average percent diameter stenosis at baseline decreased 1.75 absolute percentage points after 1 year ( a 4.5 % relative improvement ) and by 3.1 absolute percentage points after 5 years ( a 7.9 % relative improvement ) . In contrast , the average percent diameter stenosis in the control group increased by 2.3 percentage points after 1 year ( a 5.4 % relative worsening ) and by 11.8 percentage points after 5 years ( a 27.7 % relative worsening ) ( P=.001 between groups . Twenty-five cardiac events occurred in 28 experimental group patients vs 45 events in 20 control group patients during the 5-year follow-up ( risk ratio for any event for the control group , 2.47 [ 95 % confidence interval , 1.48 - 4.20 ] ) . CONCLUSIONS More regression of coronary atherosclerosis occurred after 5 years than after 1 year in the experimental group . In contrast , in the control group , coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred",
"AIMS To examine the long-term impact of brief and early interventions for hazardous and harmful alcohol consumption . DESIGN A 9-month and 10-year follow-up of subjects recruited into a r and omized controlled trial of a range of alcohol-related brief interventions . SETTING General practice s , the outpatient or acute care services of a major city hospital , and a privately run health screening programmeme . PARTICIPANTS The cohort of 554 ( non-dependent ) hazardous and harmful drinkers recruited into the Australian arm of the Phase II World Health Organization collaborative project on identification and treatment of persons with harmful alcohol consumption . INTERVENTION The effectiveness of three forms of intervention , ranging from 5 to 60 minutes in duration , were compared with a no-treatment control condition . MEASUREMENTS Included drinking behaviour and biological markers of alcohol use . In addition , at 10 years subjects were asked about symptoms of diagnosable alcohol use disorders and their experience of alcohol-related psychological , social and physical harm . Mortality was also assessed . FINDINGS Results provide further evidence for the short-term effectiveness of alcohol-related brief interventions . In comparison to controls , subjects offered intervention : ( 1 ) report significantly lower consumption ; and ( 2 ) less unsafe drinking at 9-month follow-up . The intensity of intervention was not related to the amount of change in drinking behaviour . Analysis at 10 years failed to find any differences in outcomes between intervention and control groups in median consumption , mean reduction in consumption from baseline to follow-up , mortality and ICD-10 diagnoses of alcohol dependence or harmful alcohol use . CONCLUSIONS This study failed to find evidence that brief advice and counselling without regular follow-up and reinforcement can sustain significant long-term reductions in drinking behaviour at 10-year follow-up",
"PURPOSE Smoking cessation is an important goal for smokers with coronary artery disease ( CAD ) because it reduces cardiac morbidity and mortality . Effective interventions for cigarette smokers with CAD exist , but they often are considered to be intensive and expensive . Stepped-care interventions have been proposed as a promising way to allocate smoking cessation treatments in a cost-effective manner . Stepped care refers to the practice of initiating treatment with low-intensity intervention and then exposing treatment failures to successively more intense interventions . METHODS To address the efficacy of this approach , 254 cigarette smokers hospitalized with CAD were provided a brief cessation intervention . The participants then were assigned r and omly to either a more intensive stepped-care treatment ( counseling and nicotine patch therapy ) or no additional treatment . Outcomes were point-prevalent abstinence measured 3 months and 1 year after hospital discharge . RESULTS Stepped-care treatment increased smoking cessation rates from 42 % to 53 % during a 3-month follow-up period ( P = .05 ) , but showed little effect at the 1-year follow-up assessment , as evidence d by a cessation rate for the minimal intervention group of 36 % versus 39 % for the stepped-care group ( P = .36 ) . CONCLUSIONS A stepped-care approach to smoking cessation increased short-but not long-term point-prevalent abstinence in patients with CAD . For improvement of long-term effectiveness , refinement of the timing and content of stepped-care interventions needs to occur",
"BACKGROUND Disease management programs in which drugs are prescribed by dietitians or nurses have been shown to improve the coronary risk factor profile in patients with coronary heart disease . However , those disease management programs in which drugs are not prescribed by allied health professionals have not improved coronary risk factor status . The objective of the Coaching patients On Achieving Cardiovascular Health ( COACH ) study was to determine whether dietitians or nurses who did not prescribe medications could coach patients with coronary heart disease to work with their physicians to achieve the target levels for their total cholesterol ( TC ) and other risk factors . METHODS Multicenter r and omized controlled trial in which 792 patients from 6 university teaching hospitals underwent a stratified r and omization by cardiac diagnosis within each hospital : 398 were assigned to usual care plus The COACH Program and 394 to usual care alone . Patients in The COACH Program group received regular personal coaching via telephone and mailings to achieve the target levels for their particular coronary risk factors . There was one coach per hospital . The primary outcome was the change in TC ( DeltaTC ) from baseline ( in hospital ) to 6 months after r and omization . Secondary outcomes included measurement of a wide range of physical , nutritional , and psychological factors . The analysis was performed by intention to treat . RESULTS The COACH Program achieved a significantly greater DeltaTC than usual care alone : the mean DeltaTC was 21 mg/dL ( 0.54 mmol/L ) ( 95 % confidence interval [ CI ] , 16 - 25 mg/dL [ 0.42 - 0.65 mmol/L ] ) in The COACH Program vs 7 mg/dL ( 0.18 mmol/L ) ( 95 % CI , 3 - 11 mg/dL [ 0.07 - 0.29 mmol/L ] ) in the usual care group ( P reduction in TC from baseline to 6 months after r and omization was 14 mg/dL ( 0.36 mmol/L ) ( 95 % CI , 8 - 20 mg/dL [ 0.20 - 0.52 mmol/L ] ) greater in The COACH Program group than in the usual care group . Coaching produced substantial improvements in most of the other coronary risk factors and in patient quality of life . CONCLUSIONS Coaching , delivered as The COACH Program , is a highly effective strategy in reducing TC and many other coronary risk factors in patients with coronary heart disease . Coaching has potential effectiveness in the whole area of chronic disease management",
"Background —Although men hospitalized with cardiovascular disease ( CVD ) show high smoking-cessation rates , similar data for women are lacking . We tested the efficacy of smoking-cessation intervention in women hospitalized for CVD . Methods and Results —In this r and omized controlled trial conducted from 1996 to 2001 , 277 women diagnosed with CVD ( mean age 61±10 years ) were r and omly assigned within 1 of 12 San Francisco Bay Area hospitals to a usual-care group ( UG ; n=135 ) or intervention group ( IG ; n=142 ) . Baseline histories were obtained , and interviews to ascertain self-reported smoking status occurred at 6 , 12 , 24 , and 30 months after hospitalization . The UG received strong physician ’s advice , a self-help pamphlet , and a list of community re sources . The IG received strong physician ’s advice and a nurse-managed cognitive behavioral relapse-prevention intervention at bedside , with telephone contact at intervals after discharge . The groups were similar demographically and had smoked cigarettes for a median of 38 ( IG ) or 40 ( UG ) years . Time to resumption of continuous smoking was assessed by Kaplan-Meier analysis , and risk differences between groups were determined . Time smoke-free was significantly greater for the IG than the UG ( P = 0.038 ) . Point prevalence for nonsmoking at the interviews was somewhat greater for the IG than the UG ( P > 0.15 at all times ) . Conclusions —Cognitive behavioral intervention result ed in longer average times to resumption of smoking , but in these 2 groups of older women with limited social and financial re sources , long-term success rates were similar . Systematic identification of smokers and even the brief intervention afforded the UG yielded a high smoking-cessation rate over time",
"A group of 93 coronary patients recently treated with percutaneous transluminal coronary angioplasty ( PTCA ) were r and omly assigned to either an intervention or a control group . Subjects in the intervention group participated in a comprehensive behaviorally oriented program aim ed at achieving significant long-term changes in risk factor-related lifestyle behavior . Assessment s of lifestyle behaviors , psychological factors , biological risk factors , and rehabilitation as well as secondary prevention endpoints were carried out , at inclusion and after 12 months . Results showed that the intervention patients , as compared with controls , improved significantly on measures assessing smoking , exercise , and diet habits . These self-rated changes were confirmed by weight reductions and improved exercise capacity , as well as by between-group differences in sub clinical chest pain during an exercise test . However , few effects were found on the different psychological variables , as well as on morbidity or return to work",
"BACKGROUND This study evaluated the relative effects on compliance with recommended lifestyle changes of two experimental videotapes that involved different approaches for preparing coronary artery bypass graft ( CABG ) patients for the posthospital recovery period . The tapes differed in the extent to which they portrayed the recovery period as a steady , forward progression versus a series of \" ups and downs . \" METHODS Two hundred sixteen male and female CABG patients were assigned r and omly either to view one of the two videotapes before discharge from the hospital or to receive only the st and ard discharge preparation provided by the hospital . All patients completed measures of anxiety and self-efficacy at discharge , 1 month and 3 months after discharge from the hospital . Patients also completed measures of dietary fat consumption and activity level 1 and 3 months after discharge . RESULTS Relative to controls , patients who viewed either of the videotapes before hospital release reported higher self-efficacy for adhering to the recommended low-fat diet both at discharge and 1 month after surgery . Viewing either of the videotapes also result ed in significantly less dietary fat intake 1 month after hospital release compared with controls . Patients who viewed the tape that portrayed the recovery period as consisting of ups and downs also reported significantly more frequent moderate exercise at 1 month and more frequent strenuous exercise 3 months after discharge . CONCLUSIONS The experimental videotapes proved to be an effective method for increasing dietary and exercise compliance during the first 3 months after CABG",
"BACKGROUND Cardiac rehabilitation ( CR ) is widely accepted as beneficial for patients with myocardial infa rct ion ( MI ) and coronary artery bypass graft ( CABG ) . A need exists to evaluate how different formats of delivery can best meet CR service dem and s. METHODS AND RESULTS Cardiac patients ( n = 60 ) were r and omly assigned to either a st and ard 10-week ( 30 sessions ) or a 4-week ( 20 sessions ) multifactorial rehabilitation program . Patients underwent exercise testing using the Bruce protocol before , immediately after , and then 6 months after CR . Patients also completed the SF-36 quality of life question naire and the Hospital Anxiety and Depression scale at each time point . Compared with pre-CR , exercise time and metabolic equivalents attained were significantly increased , and heart rate significantly decreased both immediately ( P energy , pain , and general health were reported after CR , and in energy and emotional and social well-being at 6 months after CR . No differences were seen between the groups . CONCLUSIONS Cardiac rehabilitation after MI and CABG significantly improved exercise capacity and general health and well-being . No significant differences were detected between groups undergoing a 10-week or 4-week course . These preliminary data suggest that shortened courses of CR may be beneficial to cardiac patients and such courses may also facilitate more widespread use of CR",
"BACKGROUND The study was performed to examine the effects of giving patients with acute myocardial infa rct ion an advice and relaxation audio tape within 24 h of admission to hospital . METHODS A prospect i ve , two-group design was used with 243 subjects r and omised to receive either the advice and relaxation tape or a music tape of their choice within 24 h of sustaining a myocardial infa rct ion . Outcomes comprised anxiety , cardiac misconceptions , lifestyle change , attendance at a cardiac rehabilitation programme , and quality of life . RESULTS Although the advice and relaxation tape reduced the number of cardiac misconceptions this did not lead to any improvements in outcome , whilst in hospital or at 6 months . Both tapes were equally appreciated by the patients , 98 % of whom said that they would recommend them to other patients . CONCLUSIONS An advice and relaxation tape reduces cardiac misconceptions but does not confer any other benefits over a music tape",
"& NA ; Despite recent advances in stroke treatment and prevention , identifying effective educational interventions for “ at‐risk ” groups that will help reduce their stroke risk and improve the speed of seeking treatment remains of paramount importance . The purpose of this pilot study was to determine whether a brief educational intervention , tailored to the patient 's stage of readiness to change , could affect the initiation and achievement of stroke risk‐reducing behaviors for this at‐risk population . The study also explored potential demographic and medical confounders that could influence behavioral and knowledge goal achievement . Three groups of 20 participants , each with multiple risk factors for stroke , from a family practice clinic were r and omly assigned to a control , simple‐advice , or brief intervention group . The majority of the participants were African American with a mean age of 68 years . Selected findings showed ( a ) significant differences in the number of newly initiated stroke‐risk‐reduction behaviors and stroke knowledge among the three groups and ( b ) significant positive correlations between the action stage of readiness to change and the initiation and achievement of the new stroke‐risk‐reduction behaviors . Although results supported the usefulness of the brief intervention model to reduce modifiable stroke‐risk factors and increase stroke knowledge , the necessity of additional longitudinal research that refines the targeting of interventions for diverse racial , cultural , and age groups was acknowledged",
"STUDY OBJECTIVE To determine the effect of a nurse-managed intervention for smoking cessation in patients who have had a myocardial infa rct ion . DESIGN R and omized , with a 6-month treatment period and a 6-month follow-up . SETTING Kaiser Foundation hospitals in Redwood City , Santa Clara , Hayward , and San Jose , California . PATIENTS Sequential sample of 173 patients , 70 years of age or younger , who were smoking before hospitalization for acute myocardial infa rct ion . Eighty-six patients were r and omly assigned to the intervention and 87 to usual care ; 130 patients ( 75 % ) completed the study and were available for follow-up . INTERVENTION Nurse-managed and focused on preventing relapse to smoking , the intervention was initiated in the hospital and maintained thereafter primarily through telephone contact . Patients were given an 18-page manual that emphasized how to identify and cope with high-risk situations for smoking relapse . MEASUREMENTS AND MAIN RESULTS One year after myocardial infa rct ion , the smoking cessation rate , verified biochemically , was 71 % in the intervention group compared with 45 % in the usual care group , a 26 % difference ( 95 % CI , 9.5 % to 42.6 % ) . Assuming that all surviving patients lost to follow-up were smoking , the 12-month smoking cessation rate was 61 % in the intervention group compared with 32 % in the usual care group , a 29 % difference ( 95 % CI , 14.5 % to 43.5 % ) . Patients who either resumed smoking within 3 weeks after infa rct ion or expressed little intention of stopping in the hospital were unlikely to have stopped by 12 months . CONCLUSIONS A nurse-managed smoking cessation intervention largely conducted by telephone , initiated in the hospital , and focused on relapse prevention can significantly reduce smoking rates at 12 months in patients who have had a myocardial infa rct ion",
"R and omized clinical trials of cardiac rehabilitation following myocardial infa rct ion have typically demonstrated a lower mortality in treated patients , but with a statistically significant reduction in only one trial . To overcome the problem of not being able to detect small but clinical ly important benefits in mortality in r and omized clinical trials of exercise and risk factor rehabilitation after myocardial infa rct ion with small numbers of patients , we carried out a meta- analysis on the combined results of ten r and omized clinical trials that included 4347 patients ( control , 2145 patients ; rehabilitation , 2202 patients ) . The pooled odds ratios of 0.76 ( 95 % confidence intervals , 0.63 to 0.92 ) for all-cause death and of 0.75 ( 95 % confidence intervals , 0.62 to 0.93 ) for cardiovascular death were significantly lower in the rehabilitation group than in the control group , with no significant difference for nonfatal recurrent myocardial infa rct ion . These results suggest that , for appropriately selected patients , comprehensive cardiac rehabilitation has a beneficial effect on mortality but not on nonfatal recurrent myocardial infa rct ion",
"PURPOSE Despite demonstrated benefits of cardiac rehabilitation and risk factor reduction , only 11 % to 38 % of eligible patients with cardiovascular disease ( CVD ) participate in cardiac rehabilitation programs . Women and older adults are particularly less likely to participate in cardiac rehabilitation . In an effort to broaden access to cardiac rehabilitation , the authors developed an alternative Internet-based program that allows nurse case managers to provide risk factor management training , risk factor education , and monitoring services to patients with CVD . METHODS The evaluation consisted of a r and omized , clinical trial involving 104 patients with CVD , 53 of whom used the program as a special intervention ( SI ) for 6 months and 51 of whom received usual care ( UC ) . RESULTS The results indicate that fewer cardiovascular events occurred among the SI subjects ( 15.7 % ) than among the UC subjects ( 4.1 % ) ( P = .053 ) , result ing in a gross cost savings of $ 1418 US dollars per patient . With a projected program cost of $ 453 USD per patient , the return on investment is estimated at 213 % . More weight loss occurred in the SI group ( -3.68 pounds ) than in the UC group ( + .47 pounds ) ( P = .003 ) . The differences between the two groups in terms of blood pressure , lipid levels , depression scores , minutes of exercise , and dietary habits were not statistically significant . CONCLUSION An Internet-based case management system could be used as a cost-effective intervention for patients with CVD , either independently or in conjunction with traditional cardiac rehabilitation",
"OBJECTIVES This study assessed stages of change in fat intake , physical activity , and cigarette smoking during a r and omized controlled trial of behavioral counseling . METHODS Twenty general practice s ( primary health care centers ) were r and omized to lifestyle counseling by behavioral methods or to usual health promotion . A total of 883 patients were selected for the presence of 1 or more of the following risk factors : cigarette smoking , high cholesterol , or a combination of a high body mass index and low physical activity . Stage of change ( precontemplation , contemplation , preparation , and action/maintenance ) was assessed at baseline and after 4 and 12 months . RESULTS The odds of moving to action/maintenance for behavioral intervention vs control patients at 4 months were 2.15 ( 95 % confidence interval [ CI ] = 1.30 , 3.56 ) for fat reduction , 1.89 ( 95 % CI = 1.07 , 3.36 ) for increased physical activity , and 1.77 ( 95 % CI = 0.76 , 4.14 ) for smoking cessation . The likelihood of achieving action/maintenance was related to baseline stage for all 3 behaviors . CONCLUSIONS Brief behavioral counseling based on advice matched to stage of readiness for change may be valuable in encouraging healthy lifestyles among patients in primary care at raised risk of cardiovascular disease",
"OBJECTIVES The relative effects of simple advice and brief counseling were evaluated with heavy drinkers identified in primary care and other health setting s in eight countries . METHODS Subjects ( 1260 men , 299 women ) with no prior history of alcohol dependence were selected if they consumed alcohol with sufficient frequency or intensity to be considered at risk of alcohol-related problems . Subjects were r and omly assigned to a control group , a simple advice group , or a group receiving brief counseling . Seventy-five percent of subjects were evaluated 9 months later . RESULTS Male patients exposed to the interventions reported approximately 17 % lower average daily alcohol consumption than those in the control group . Reductions in the intensity of drinking were approximately 10 % . For women , significant reductions were observed in both the control and the intervention groups . Five minutes of simple advice were as effective as 20 minutes of brief counseling . CONCLUSIONS Brief interventions are consistently robust across health care setting s and sociocultural groups and can make a significant contribution to the secondary prevention of alcohol-related problems if they are widely used in primary care",
"Abstract Objective : To measure the effect of behaviourally oriented counselling in general practice on healthy behaviour and biological risk factors in patients at increased risk of coronary heart disease . Design : Cluster r and omised controlled trial . Participants : 883 men and women selected for the presence of one or more modifiable risk factors : regular cigarette smoking , high serum cholesterol concentration ( 6.5 - 9.0 mmol/l ) , and high body mass index ( 25 - 35 ) combined with low physical activity . Intervention : Brief behavioural counselling , on the basis of the stage of change model , carried out by practice nurses to reduce smoking and dietary fat intake and to increase regular physical activity . Main outcome measures : Question naire measures of diet , exercise , and smoking habits , and blood pressure , serum total cholesterol concentration , weight , body mass index , and smoking cessation ( with biochemical validation ) at 4 and 12 months . Results : Favourable differences were recorded in the intervention group for dietary fat intake , regular exercise , and cigarettes smoked per day at 4 and 12 months . Systolic blood pressure was reduced to a greater extent in the intervention group at 4 but not at 12 months No differences were found between groups in changes in total serum cholesterol concentration , weight , body mass index , diastolic pressure , or smoking cessation . Conclusions : Brief behavioural counselling by practice nurses led to improvements in healthy behaviour . More extended counselling to help patients sustain and build on behaviour changes may be required before differences in biological risk factors emerge",
"OBJECTIVES The National Cholesterol Education Program ( NCEP ) has enhanced public awareness of the importance of cholesterol in the development of heart disease , yet most patients with cardiovascular disease ( CVD ) do not know or achieve their low-density lipoprotein cholesterol ( LDL-C ) goals . This r and omized , controlled trial was design ed to evaluate the impact of a system that provides uniquely formatted laboratory results to patients with CVD on their changes in LDL-C levels . METHODS Eighty patients with CVD were r and omized to receive st and ard care or the intervention inclusive of a computer-generated , 11''x17 ' ' color poster depicting an individual 's LDL-C status and goals along with personalized steps to aid in goal achievement . Cholesterol profiles were obtained at baseline and 6 months after enrollment . Physicians received st and ard laboratory reports and were blinded to the r and omization . RESULTS There were no significant differences between patient groups in age , education level , race , baseline cholesterol levels , comorbidities , or percentage of patients in each group who met their NCEP goal at baseline . Patients receiving intervention tools had significant reductions in LDL-C from baseline compared with patients in the control group . Intervention patients who did not meet NCEP goals at baseline had the greatest reduction in LDL-C , with a mean change from baseline of -21.5 mg/dL ( P LDL-C levels ( -4.6 mg/dL , P=0.28 ) . At study close , 73 % of intervention patients reported that their posters remained displayed on their refrigerator . CONCLUSION This unique and personalized intervention result ed in the LDL-C lowering benefit among patients with CVD comparable to that of lipid lowering agents",
"This study evaluated the effectiveness of a brief intervention ( BI ) , a one-session motivational interview , in reducing HIV risk-taking behaviour among injecting drug users ( IDU ) not enrolled in any form of treatment for drug dependence . IDU were r and omly assigned to either BI or a non-intervention control condition ( NIC ) . One hundred and twenty-one subjects were successfully contacted for a 3-month follow-up and 88 subjects were followed up at 6 months . There were significant reductions for the sample as a whole for injecting risk-taking subscale scores on the HIV Risk-taking Behaviour Scale between pre-treatment and follow-up . There was no significant change in sexual risk-taking behaviour . There were no significant differences between groups on any measure at 3- and 6-month follow-up . There are a number of possible reasons why the sample as a whole showed significant improvements from initial to follow-up assessment s. It is possible that , having had their attention directed to their risk-taking behaviour , subjects attempted to reduce their injecting risk-taking behaviour . If this is the case and subjects in the NIC condition can be considered as having received a BI , this suggests that BIs involving a personal risk assessment are effective in reducing risk behaviours associated with injecting . However , this suggestion could only be confirmed by comparison with a non- assessment control group",
"OBJECTIVE To improve the treatment of risk factors of cardiovascular disease ( CVD ) for older patients with diabetes after a cardiac event by using a low-literacy reminder card describing these risk factors in community setting s. STUDY DESIGN A multicenter , r and omized , interventional study . METHODS Patients aged 55 years or older with diabetes hospitalized with an acute myocardial infa rct ion , congestive heart failure exacerbation , or unstable angina were eligible to enter the study . Control and experimental patients were recruited from 4 sites and were enrolled in the study before discharge from the hospital . Experimental subjects received education and a reminder card describing risk factors of CVD . They were instructed to discuss the risk factors described on the reminder card with their primary care physician on their first appointment after discharge . Control subjects did not receive any intervention but were given consent to be able to review their charts . RESULTS One hundred sixty patients completed the study , 82 in the control group and 78 in the experimental group . At the end of the study there was no difference in blood pressure control , lipid levels , and glycosylated hemoglobin levels between the control and experimental patients . Aspirin use and ACE inhibitor use were found to be significantly higher in the control group ( P = .001 and .03 , respectively ) . CONCLUSIONS Reminder cards given to patients to discuss with their primary care providers in community setting s did not improve process measures of CVD risk in patients with documented CVD and diabetes . Other approaches will be needed to improve the treatment of risk factors in these high-risk patients",
"The objective of the study was to determine the effectiveness of advice from general practitioners to heavy drinking men ( consuming 350 - 1050 grams of alcohol per week ) to reduce their alcohol consumption . One hundred and fifty-four men recruited from eight general practice s were allocated r and omly to treatment and control groups . Men in the treatment group received advice from their own general practitioner . At one year follow-up , when analyzed according to intention to treat , the treatment group had reduced their consumption by an excess of 65 grams of alcohol per week when compared with the control group ( p less than 0.05 ) . General practitioners should be recommended to screen for alcohol consumption amongst their patients and to give advice to those found to be at risk because of their drinking",
"BACKGROUND Smoking cessation after myocardial infa rct ion ( MI ) has been associated with a 50 % reduction in mortality but in-hospital smoking cessation interventions are rarely part of routine clinical practice . METHODS One hundred cigarette smokers consecutively admitted during 1996 with MI were assigned to minimal care or to a hospital-based smoking cessation program . Intervention consisted of bedside cessation counseling followed by seven telephone calls over the 6 months following discharge . Primary outcomes were abstinence rates measured at 6 months and 1 year post-discharge . RESULTS At follow-up , 43 and 34 % of participants in minimal care and 67 and 55 % of participants in intervention were abstinent at 6 and 12 months . respectively ( P Abstinence rates were calculated assuming that participants lost to attrition were smokers at follow-up . Intervention and self-efficacy were independent predictors of smoking status at follow-up . Low self-efficacy combined with no intervention result ed in a 93 % relapse rate by 1 year ( P smoking abstinence 1 year after discharge in patients post-MI . Patients with low self-efficacy are almost certain to relapse without intervention . Such smoking cessation programs should be part of the management of patients with MI",
"BACKGROUND Tobacco cessation after acute myocardial infa rct ion ( AMI ) substantially improves outcome but how effective individual programmes are needs to be established . To date , few studies have examined this factor . AIMS To assess the outcome of two smoking cessation programmes after AMI . METHODS One hundred and ninety-eight current smokers admitted to coronary care with an AMI participated in a r and omized controlled study comparing two outpatient tobacco interventions , the Stanford Heart Attack Staying Free ( SF ) programme and a Usual Care ( UC ) programme . RESULTS Log-rank analyses revealed that patients in the SF programme were retained longer ( P cotinine vali date d abstinence rates ( P cotinine vali date d tobacco cessation , representing a significant reduced relapse rate in the SF programme ( chi2 , P SF smoking cessation programme initiated in hospital can significantly reduce smoking rates at 12 months after myocardial infa rct ion . Although superior to the UC quit programme , Australian outcomes were lower than the American programme originators ' published outcomes",
"At the end of a long week in the office , you sink back into your chair , reflecting on some of the more memorable patients you cared for and counseled . Through gentle history taking , you discovered that urinary incontinence is the underlying cause of an elderly patient 's increasing social isolation . During a careful physical examination , you detected bruising on the torso of a woman with chronic headaches and began to explore the longst and ing abusive relationship between the woman and her alcoholic partner . You discontinued procainamide therapy in a 72-year-old man who had asymptomatic premature ventricular contractions after myocardial infa rct ion . To prevent bleeding from esophageal varices , you started -blocker therapy in a woman with long-st and ing cryptogenic cirrhosis and portal hypertension . In couples ' therapy , discussing the future quality of life of a middle-aged gay man with human immunodeficiency virus infection , you journeyed through emotionally intense dialogue about advance directives . You presented the risk factors for major and minor bleeding to a 39-year-old woman who was considering warfarin therapy because of recently diagnosed atrial fibrillation and valvular heart disease . You listened to , made diagnoses for , treated , advised , and comforted many patients . Yet there were some hiccoughs in your practice along the way . You stumbled while debating the pros and cons of breast cancer screening with a healthy 48-year-old woman who has been staying current with information on the Internet . You question ed the merits of a personalized walking program suggested to you by a motivated 66-year-old man with severe claudication . Explaining that you wanted to review the best current evidence on these issues , you resolved to address your uncertainties before these patients made their next office visits , in a week 's time . Sighing deeply , you acknowledge that you have little time to read . You subscribe to three journals , which you browse months after they arrive-either when your journal stack becomes precariously high or when your guilt is sufficiently motivational . You sometimes find the conclusions of individual articles conflicting or confusing . You know that some of the decisions and suggestions you made this week , specifically your decisions about stopping procainamide therapy and starting -blocker therapy and your advice about bleeding risks from anticoagulant therapy , were based on the best current research evidence [ 1 - 3 ] . On the other h and , your patients ' inquiries about breast cancer screening and exercise treatment for claudication highlight your need for a concise , current , rigorous synthesis of the best available evidence on each of these topics : in brief , a systematic review [ 4 , 5 ] . Incorporating Research Evidence into Clinical Decision Making The foregoing scenario is familiar to practitioners . In a typical week , we encounter patients with diverse problems ; exercise numerous clinical , interpersonal , and technical skills ; and make many decisions . The factors that affect these decisions and their outcomes are complex . For instance , each patient has unique sociodemographic characteristics , cultural circumstances , and personal preferences . Each physician has unique knowledge , experiences , and values . Moreover , practitioners and their patients make decisions within the context of a rapidly changing health care system that influences the availability , accessibility , and cost of diagnostic tests and therapies [ 6 ] . Timely , useful evidence from the biomedical literature should be an integral component of clinical decision making . If one treatment has been shown to be better than another , we need to know , so that we can recommend the treatment to the appropriate patients . The worldwide effort to develop new tests and treatments , and to determine their usefulness , has never been stronger , and our patients and their families expect us to be fonts of the knowledge that results from this effort [ 7 ] . Unfortunately , it is easy for current best research evidence to pass us by [ 8 ] . We may lack the time , motivation , and basic skills needed to find , critically appraise , and synthesize information , all of which we must do if we are to integrate the results of original studies into our practice . Fortunately , several potent methods are emerging that can greatly enhance our ability to interpret and apply research evidence ; foremost among them is the systematic review . This article begins a series in Annals that will examine systematic review s in detail and explore their many applications . Systematic review s represent the best chance that most practitioners will have to underst and and accurately apply the key signals arising from the robust and increasingly productive search for solutions to medical problems . A properly conducted systematic review faithfully summarizes the evidence from all relevant studies on the topic of interest , and it does so concisely and transparently . What Is a Systematic Review ? Systematic review s are scientific investigations in themselves , with pre-planned methods and an assembly of original studies as their subjects . They synthesize the results of multiple primary investigations by using strategies that limit bias and r and om error [ 9 , 10 ] . These strategies include a comprehensive search of all potentially relevant articles and the use of explicit , reproducible criteria in the selection of articles for review . Primary research design s and study characteristics are appraised , data are synthesized , and results are interpreted . When the results of primary studies are summarized but not statistically combined , the review may be called a qualitative systematic review . A quantitative systematic review , or meta- analysis , is a systematic review that uses statistical methods to combine the results of two or more studies . The term overview is sometimes used to denote a systematic review , whether quantitative or qualitative . Summaries of research that lack explicit descriptions of systematic methods are often called narrative review s. Review articles are one type of integrative publication ; practice guidelines , economic evaluations , and clinical decision analyses are others . These other types of integrative articles often incorporate the results of systematic review s. For example , practice guidelines are systematic ally developed statements intended to assist practitioners and patients with decisions about appropriate health care for specific clinical circumstances [ 11 ] . Evidence -based practice guidelines are based on systematic review s of the literature , appropriately adapted to local circumstances and values . Economic evaluations compare both the costs and the consequences of different courses of action ; the knowledge of consequences that are considered in these evaluations is often generated by systematic review s of primary studies . Decision analyses quantify both the likelihood and the valuation of the expected outcomes associated with competing alternatives . Differences between Systematic and Narrative Review s All review s , narrative and systematic alike , are retrospective , observational research studies and are therefore subject to systematic and r and om error . Accordingly , the quality of a review - and thus its worth-depends on the extent to which scientific review methods have been used to minimize error and bias . This is the key feature that distinguishes traditional narrative review s from systematic review s ( Table 1 ) . If a review is prepared according to the steps outlined in the right column of Table 1 , it is more likely to be systematic and to provide unbiased conclusions . If review methods approximate those found in the middle column of Table 1 , the article is more likely to be a narrative review , and the conclusions are less likely to be based on an unbiased summary of all relevant evidence . Table 1 . Differences between Narrative Review s and Systematic Review s Systematic review s are generated to answer specific , often narrow , clinical questions in depth . These questions can be formulated explicitly according to four variables : a specific population and setting ( such as elderly out patients ) , the condition of interest ( for example , hypertension ) , an exposure to a test or treatment ( such as pharmacologic management ) , and one or more specific outcomes ( such as cardiovascular and cerebrovascular events and mortality ) [ 12 ] . Thus , an example of a well-formulated , clinical ly relevant question is , Does pharmacologic treatment of hypertension in the elderly prevent strokes and myocardial infa rct ions or delay death ? If the question that is driving the review is not clear from the title , abstract , or introduction , or if no methods section is included , the paper is more likely to be a narrative review than a systematic review [ 13 ] . Most narrative review articles deal with a broad range of issues related to a given topic rather than addressing a particular issue in depth [ 9 ] . For example , a narrative review on diabetes ( such as that which might be found in a textbook chapter ) might include sections on the physiology and pathophysiology of carbohydrate , lipid , and protein metabolism ; the epidemiology of and prognosis associated with diabetes ; diagnostic and screening approaches ; and preventive , therapeutic , rehabilitative , and palliative interventions . Thus , narrative review s may be most useful for obtaining a broad perspective on a topic ; they are less often useful in furnishing quantitative answers to specific clinical questions . Narrative review s are appropriate for describing the history or development of a problem and its management . Narrative review s may better describe cutting-edge developments if research is scant or preliminary or if studies are very limited by flawed design or execution [ 13 ] . They may be particularly useful for discussing data in light of underlying theory and context . Narrative review s can draw analogies and can conceptually integrate two independent fields of research , such as",
"OBJECTIVE To examine the dietary habits of patients with ischemic heart disease 1 year after they received either dietary advice on using the Plate Model and how to increase intakes of fruits and vegetables in a 10-minute session ( brief counseling group , BCG ) or dietary advice primarily based on the National Cholesterol Education Program Step I diet provided in 2 individually tailored 50-minute sessions held 3 months apart ( comprehensive counseling group , CCG ) . DESIGN A r and omized study that included dietary intake evaluation on basis of 7-day weighed food records completed at 3 occasions : immediately before counseling ( week zero ) , 12 weeks after counseling , and 52 weeks after counseling . SUBJECTS BCG was composed of 15 men and 2 women and CCG was composed of 16 men and 3 women with ischemic heart disease age 70 years or younger recruited from the Department of Cardiology , Odense University Hospital , Odense , Denmark . STATISTICAL ANALYSES PERFORMED ANOVA , unpaired t tests , and multiple regression analysis , as well as nonparametric statistical analyses were carried out . RESULTS The comprehensive counseling result ed in significant improvements from week 0 to 52 in the percent of energy from fat ( 33 % to 28 % ) , saturated fat ( 12 % to 9 % ) and carbohydrate ( 51 % to 54 % ) consumed by the subjects . The corresponding values in BCG did not differ significantly ( 31 % to 32 % , 11 % to 12 % , 53 % to 52 % respectively ) . Differences from week 0 to 52 between groups were significant for fat , saturated fat , and carbohydrate intake . In CCG , median intakes of fish , fruits , and vegetables were 44 g/day , 172 g/day , and 315 g/day , respectively , at week 52 . The corresponding values in BCG were 44 g/day , 129 g/day , and 224 g/day . There was no significant difference either within or between the groups . CONCLUSION This study suggests that sustained improvements in dietary behavior require individualized and reinforced counseling in patients with ischemic heart disease . Changes in intakes of fish , fruits , and vegetables need to be specifically targeted"
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OBJECTIVE Pain is a patient-important outcome , but current reporting in r and omized controlled trials and systematic review s is often suboptimal , impeding clinical interpretation and decision making . METHODS A working group at the 2014 Outcome Measures in Rheumatology ( OMERACT 12 ) was convened to provide guidance for reporting treatment effects regarding pain for individual studies and systematic review s. RESULTS For individual trials , authors should report , in addition to mean change , the proportion of patients achieving 1 or more thresholds of improvement from baseline pain ( e.g. , ≥ 20 % , ≥ 30 % , ≥ 50 % ) , achievement of a desirable pain state ( e.g. , no worse than mild pain ) , and /or a combination of change and state . Effects on pain should be accompanied by other patient-important outcomes to facilitate interpretation . When pooling data for meta analysis , authors should consider converting all continuous measures for pain to a 100 mm visual analog scale ( VAS ) for pain and use the established , minimally important difference ( MID ) of 10 mm , and the conventionally used , appreciably important differences of 20 mm , 30 mm , and 50 mm , to facilitate interpretation . Effects ≤ 0.5 units suggest a small or very small effect . To further increase interpretability , the pooled estimate on the VAS should also be transformed to a binary outcome and expressed as a relative risk and risk difference . This transformation can be achieved by calculating the probability of experiencing a treatment effect greater than the MID and the thresholds for appreciably important differences in pain reduction in the control and intervention groups . CONCLUSION Presentation of relative effects regarding pain will facilitate interpretation of treatment effects
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[
"In the third of a series of four articles the authors show the calculation of measures of association and discuss their usefulness in clinical decision making . From the rates of death or other \" events \" in experimental and control groups in a clinical trial , we can calculate the relative risk ( RR ) of the event after the experimental treatment , expressed as a percentage of the risk without such treatment . The absolute risk reduction ( ARR ) is the difference in the risk of an event between the groups . The relative risk reduction is the percentage of the baseline risk ( the risk of an event in the control patients ) removed as a result of therapy . The odds ratio ( OR ) , which is the measure of choice in case-control studies , gives the ratio of the odds of an event in the experimental group to those in the control group . The OR and the RR provide limited information in reporting the results of prospect i ve trials because they do not reflect changes in the baseline risk . The ARR and the number needed to treat , which tells the clinician how many patients need to be treated to prevent one event , reflect both the baseline risk and the relative risk reduction . If the timing of events is important -- to determine whether treatment extends life , for example -- survival curves are used to show when events occur over time",
"The chronic electrical stimulation of a motor cortical area corresponding to a painful region of the body , by means of surgically-implanted epidural electrodes is a vali date d therapeutical strategy to control medication-resistant neurogenic pain . Repetitive transcranial magnetic stimulation ( rTMS ) permits to stimulate non-invasively and precisely the motor cortex . We applied a 20-min session of rTMS of the motor cortex at 10 Hz using a ' real ' or a ' sham ' coil in a series of 14 patients with intractable pain due to thalamic stroke or trigeminal neuropathy . We studied the effects of rTMS on pain level assessed on a 0 - 10 visual analogue scale from day 1 to day 12 following the rTMS session . A significant pain decrease was observed up to 8 days after the ' real ' rTMS session . This study shows that a transient pain relief can be induced in patients suffering from chronic neurogenic pain during about the week that follows a 20-min session of 10 Hz-rTMS applied over the motor cortex",
"Objective To vali date IV subhypnotic propofol , a γ-aminobutyric acid A ( GABA-A ) agonist , as a diagnostic test for central pain . Methods The efficacy of systemic propofol ( 0.2 mg/kg IV bolus ) was evaluated in a double-blind , placebo-controlled and crossover fashion on both spontaneous ongoing pain and allodynia in 44 patients with chronic central pain of both brain and cord origin . Results Propofol was significantly superior to the placebo ( Intralipid , Kabi Pharmacia ) in reducing the intensity of spontaneous ongoing pain for up to 1 hour after the injection : 24 of 44 patients ( 55 % ) receiving propofol showed a significant reduction in spontaneous pain , whereas only 6 patients showed this after the placebo . Propofol also significantly reduced the intensity of both mechanical and cold allodynia . In a few cases , only the evoked components were abolished but not the spontaneous pain . In general , the side effects were minimal and consisted mainly of transitory burning upon injection of both propofol and placebo and slight lightheadedness in a few cases . Conclusions Systemic propofol induces analgesic effects on all studied components of central pain and highlights the key role of GABA modulation in central pain",
"Graphic representation was used to explore to what extent the number needed to treat ( NNT ) conveys the appropriate notion of benefit for the individual patient in interventions aim ed at delaying adverse events . A sample of the Danish population ( n = 675 ) was interviewed face to face , and asked whether they would consent to a hypothetical drug that reduces the risk of heart attack . The benefit of the drug was expressed in terms of NNT and was r and omly set at 10 , 25 , 50 , 100 , 200 , and 400 . NNT does not convey information on the proportion of patients being helped by an intervention or the size of the delay of the adverse event intended to be prevented . The proportion of people consenting to the hypothetical drug was about 80 % , irrespective of NNT , and some of those who rejected the drug misinterpreted the meaning of NNT . Lay people may have difficulties in underst and ing the meaning of NNT , and clinicians may do well to use the NNT with caution until more is known about how patients comprehend it",
"Objective : To assess cortical excitability changes in patients with chronic neuropathic pain at baseline and after repetitive transcranial magnetic stimulation ( rTMS ) of the motor cortex . Methods : In 22 patients with unilateral h and pain of various neurologic origins and 22 age-matched healthy controls , we studied the following parameters of cortical excitability : motor threshold at rest , motor evoked potential amplitude ratio at two intensities , cortical silent period ( CSP ) , and intracortical inhibition ( ICI ) and intracortical facilitation . We compared these parameters between healthy subjects and patients at baseline . We also studied excitability changes in the motor cortex corresponding to the painful h and of patients after active or sham rTMS of this cortical region at 1 or 10 Hz . Results : At baseline , CSP was shortened for the both hemispheres of patients vs healthy subjects , in correlation with pain score , while ICI was reduced only for the motor cortex corresponding to the painful h and . Regarding rTMS effects , the single significant change was ICI increase in the motor cortex corresponding to the painful h and , after active 10-Hz rTMS , in correlation with pain relief . Conclusion : Chronic neuropathic pain was associated with motor cortex disinhibition , suggesting impaired GABAergic neurotransmission related to some aspects of pain or to underlying sensory or motor disturbances . The analgesic effects produced by motor cortex stimulation could result , at least partly , from the restoration of defective intracortical inhibitory processes",
"& NA ; Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies",
"Objective —To determine whether minimum clinical ly significant difference in visual analogue scale ( VAS ) pain score varies according to the severity of pain reported . Method — Prospect i ve descriptive study of adult patients in an urban emergency department ( ED ) . On presentation to the ED , patients marked the level of their pain on a 100 mm , non-hatched VAS scale . At 20 minute intervals thereafter they were asked to give a verbal categorical rating of their pain as “ a lot better ” , “ a little better ” , “ much the same ” , “ a little worse ” or “ much worse ” and to mark the level of pain on a VAS scale of the same type as used previously . It was pre-defined that patients with VAS pain scores of 30 mm or less would be categorised as having mild pain , those with scores of 70 mm or more were categorised as having severe pain and those from 31 mm to 69 mm , moderate pain . The minimal clinical ly significant difference ( MCSD ) in VAS pain score was defined as the mean difference between current and preceding scores when the subject reported “ a little worse ” or “ a little better ” pain . Results —156 patients were enrolled in the study , yielding 88 evaluable comparisons where pain was rated as “ a little better ” or “ a little worse ” . The MCSD in VAS score in the group overall was 12 mm ( 95%CI 9 mm to 15 mm ) . MCSD in VAS score for the “ mild pain ” group was 11 mm ( 95%CI 4 mm to 18 mm ) , for the “ moderate pain ” group 14 mm ( 95%CI 10 mm to 18 mm ) and for the severe pain group , 10 mm ( 95%CI 6 mm to 14 mm ) . There is no statistical difference between the MCSD in VAS score between the severity groups . Conclusions —The MCSD in VAS pain score does not differ with the severity of pain being experienced",
"OBJECTIVE To compare clinicians ' ratings of therapeutic effectiveness when different trial end points were presented as percent reductions in relative compared with absolute risk and as numbers of patients treated to avoid one adverse outcome . DESIGN Survey , with r and om allocation of two question naires . SETTING Toronto teaching hospitals . RESPONDENTS Convenience sample of 100 faculty and housestaff in internal medicine and family medicine . INTERVENTION One question naire presented results for three end points of the Helsinki Heart Study as separate drug trials using only absolute differences in events ; the other showed the same end points as relative differences . Both question naires included a fourth \" trial , \" showing person-years of treatment needed to prevent one myocardial infa rct ion . MAIN OUTCOME MEASURE The \" trials \" were each rated on an 11-point scale , from treatment \" harmful \" to \" very effective . \" RESULTS Respondents ' ratings of effectiveness varied with the end point . Controlling for end point , ratings of effectiveness by the 50 participants receiving absolute event data were lower than those by 50 participants responding to relative risk reductions ( P 77 persons were treated for 5 years to prevent one myocardial infa rct ion , mean ratings were 2.3 or 1.8 scale points lower , respectively ( both P Clinicians ' views of drug therapies are affected by the common use of relative risk reductions in both trial reports and advertisements , by end-point emphasis , and , above all , by underuse of summary measures that relate treatment burden to therapeutic yields in a clinical ly relevant manner",
"Clinical trials may lead to conflicting results . We studied how different ways of reporting results affected physicians ' recommendations . A question naire distributed to 148 general practitioners presented results of a clinical trial where a reduction of cardiac events and an increase of mortality was reported . Results were shown in four different ways -- relative risk reduction , absolute risk reduction , percentages of event-free patients , number needing to be treated to prevent an event -- as if they derived from different trials . A fifth presentation was the reduced rate of cardiac events along with the increased rate of mortality . Physicians were asked to estimate how much they would be willing to prescribe each drug . The mean agreement of physicians ' decisions was 77 (28)% for relative risk reduction , 24 (28)% for absolute risk reduction , 37 (37)% for different percentages event-free patients , 34 (34)% for number need to treat , and 23 (28)% for events reduction and mortality for increase ( p method of reporting trial results and the completeness of information in the case of controversial results affects physicians willingness to prescribe",
"BACKGROUND Uncertainty and risk are central issues in relation to health and health care services . Healthy individuals do not necessarily fall ill , despite the presence of risk factors . It has been documented that doctors , health service administrators and patients are more inclined to choose interventions against risk factors when information about the effects is presented in terms of relative risk reductions rather than absolute risk reductions . OBJECTIVES The objective of the study was to gain better insight into how GPs perceive risk of disease , and how this perception is influenced by the way the risk is presented , e.g. whether changes in risk are presented in absolute or relative terms . METHODS Question naires with clinical episodes were sent to 1500 Danish GPs . The GPs were r and omized into four groups of 375 , who all received the same case story with information about risk reduction achieved through medical treatment phrased in terms of either relative risk reduction , absolute risk reduction , number needed to treat or all of the aforementioned terms of risk reduction . The GPs were asked whether they would recommend medical treatment as primary prevention , knowing the case story and expected risk reduction . RESULTS The GPs ' attitude towards recommending medical treatment was dependent on the phrasing of risk reductions . Seventy-two per cent of doctors who received all information on risk reductions would definitely or probably recommend medication , while 91 % would recommend medication if information only about relative risk reduction was given , and 63 % would recommend medication if information was given in terms of absolute risk reduction or number needed to treat . CONCLUSION In order to advise patients in a rational way , in addition to knowledge of the patients ' preferences , doctors need to take into account all available measures of risk reductions",
"OBJECTIVE To determine the most appropriate means to assess the response to treatment in terms of pain and functional impairment in a chronic rheumatic condition ( knee osteoarthritis [ OA ] ) and an acute rheumatic condition ( rotator cuff syndrome [ RCS ] ) . METHODS Two prospect i ve studies were conducted consisting of 1,019 out patients with knee OA and 271 patients with acute RCS . The minimal clinical ly important improvement and the patient acceptable symptom state were determined for knee OA pain using a visual analog scale , and for knee OA function using the Western Ontario and McMaster Universities Osteoarthritis Index function subscale ; for acute RCS pain , a numeral rating scale was used , and the Neer function subscale was used for RCS function . RESULTS The minimal clinical ly important improvement was shown to be the change required to achieve the patient acceptable symptom state , whatever the baseline level of symptom , the outcome ( pain or function ) , or type of condition ( chronic or acute ) . This acceptable state for pain was higher for chronic ( 27.0 - 36.4 across the baseline score ) than acute ( 16.7 - 24.1 ) conditions . The level of functional impairment considered satisfactory by patients with knee OA was higher for more disabled patients ( 43.1 ) than for less disabled patients ( 20.4 ) . CONCLUSION Patients consider that they experienced an important improvement only if this improvement allowed them to achieve a state they consider satisfactory . The most appropriate means to assess the response to therapy seems to be to assess whether patients feel good ( i.e. , achieve the patient acceptable symptom state )",
"AIMS The results of clinical trials often seem to have little influence on the practice of individual doctors . This could be because trial information is presented in the style of a scientific experiment which can not often be clearly related to the context of everyday patient care . We tested the hypothesis that such framing effects would cause doctors to assess the clinical significance of treatment outcomes differently when presented as clinical trial results rather than as individual patient data . METHODS Fourteen rheumatologists independently review ed the same 50 sets of data obtained from patients with rheumatoid arthritis . The data consisted of 10 commonly used clinical and laboratory variables measured before and after a period of treatment . The same data were presented in two formats on two separate occasions . The patient data format was a collection of typed sheets attributing each set of results to an individual patient . The clinical trial format was a professionally printed and bound booklet in which each set of results was laid out as summary results of a small uncontrolled clinical trial . Doctors judged the degree of improvement or deterioration and its clinical importance for each data set for both formats . These changes were converted into units of ' Clinical Importance ' . RESULTS Although some statistically significant differences emerged in the individual doctors ' judgements between the formats none of these was of a clinical ly important size . The median of the mean trial -- patient difference between the formats for all 14 doctors was 0.035 units of clinical importance [ 95 % CI -0.244 to 0.074 ] . CONCLUSIONS This evidence does not support the hypothesis that framing effects are a major cause of the failure of clinical trials to influence clinical practice"
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BACKGROUND Carnitine , a quaternary amino acid , plays an important role in the oxidation of long chain fatty acids . Both breast milk and infant formulas contain carnitine . However , it is not routinely provided in parenteral nutrition solutions . Non supplemented parenterally fed infants have very low tissue carnitine levels . The clinical significance of this is uncertain . Carnitine deficiency may be an etiological factor in the limited ability of premature babies to utilize parenteral lipid . In vitro studies have suggested that fatty acid oxidation is impaired when the tissue carnitine levels fall below 10 % of normal . Therefore relative carnitine deficiency may impair fatty acid oxidation , thus reducing the available energy and impairing growth . OBJECTIVES The primary aim of this review is to determine whether carnitine supplementation of parenterally fed neonates will improve weight gain . The secondary aims are to determine the effect on lipid tolerance and ketogenesis . SEARCH STRATEGY Computerised search es were carried out by both review ers . Search es were made of Medline , Embase , The National Research Register ( UK ) , the Cochrane Controlled Trials Register and expert informants . The MeSH headings used were carnitine and parenteral nutrition . SELECTION CRITERIA Only r and omised trials were considered . Trials were included if they involved carnitine supplementation alone , parenterally fed newborn infants , and measured at least one outcome of interest ( weight gain , plasma fatty acids , plasma triglycerides , quantity of lipid tolerated , respiratory quotient or beta hydroxybutyrate levels ) . DATA COLLECTION AND ANALYSIS The two review ers search ed the literature separately and reached a consensus for inclusion of trials . Data were extracted and evaluated by the two review ers independently of each other . Authors were contacted if possible to clarify or provide missing data . MAIN RESULTS Fourteen studies were identified , six met the selection criteria . The results of the review are limited by the fact that the studies were generally short term and studied different outcomes . One study examined short term and long term weight gain , three reported only short term weight gain , three reported biochemical results in response to a short lipid challenge , and two reported results obtained during normal parenteral nutrition . Among infants supplemented with carnitine , there was no evidence of effect on weight gain , lipid utilization or ketogenesis . REVIEW ER 'S CONCLUSIONS We found no evidence to support the routine supplementation of parenterally fed neonates with carnitine
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"Parenterally fed preterm neonates are known to be at risk for carnitine deficiency . We studied substrate utilization in low-birth-weight infants receiving total parenteral nutrition ( TPN ) with ( A ) and without ( B ) supplementation of 48 mg carnitine.kg-1.d-1 on days 4 - 7 ( birth weights 1334 + /- 282 vs 1318 + /- 248 g , gestational age 32 + /- 2 vs 32 + /- 2 wk , A vs B , respectively ) . TPN consisted of 11 g glucose.kg-1.d-1 and 2.4 g.kg-1.d-1 of both protein and fat . Plasma carnitine concentrations at day 7 were for free carnitine 11.8 + /- 5.0 vs 164 + /- 56 mumol/L and for acyl carnitine 3.8 + /- 2.0 vs 33.9 + /- 15.4 mumol/L , respectively . Indirect calorimetry at day 7 showed a higher fat oxidation ( 0.21 , -0.31 to + 0.60 vs 1.18 , 0.70 to 1.95 g. kg-1.d-1 , respectively , P less than 0.02 , median and interquartile range ) in group B and a higher protein oxidation ( 0.37 , 0.30 - 0.43 vs 0.63 , 0.53 - 0.88 g.kg-1.d-1 , P less than 0.001 ) . The time to regain birth weight was also higher in group B ( 7 , 5.5 - 9 vs 9 , 7 - 14 d , P less than 0.05 ) . Carnitine supplementation and calorie intake were the best explanatory variables for metabolic rate ( R2 = 0.45 , P less than 0.002 ) . We conclude that carnitine supplementation of TPN in this dosage does not seem advisable",
"To investigate whether L-carnitine supplementation may correct nutritional carnitine deficiency and associated metabolic disturbances in premature infants receiving total parenteral nutrition , an intravenous fat tolerance test ( 1 gm/kg Intralipid over four hours ) was performed in 29 premature infants 6 to 10 days of age ( 15 receiving carnitine supplement 10 mg/kg . day L-carnitine IV , and 14 receiving no supplement ) . Total carnitine plasma values were normal or slightly elevated in supplemented but decreased in nonsupplemented infants . In both groups , fat infusion result ed in an increase in plasma concentrations of triglycerides , free fatty acids , D-beta-hydroxybutyrate , and short-chain and long-chain acylcarnitine , but total carnitine values did not change . After fat infusion , the free fatty acids/D-beta-hydroxybutyrate ratios were lower and the increase of acylcarnitine greater in supplemented infants of 29 to 33 weeks ' gestation than in nonsupplemented infants of the same gestational age . This study provides evidence that premature infants of less than 34 weeks ' gestation requiring total parenteral nutrition develop nutritional carnitine deficiency with impaired fatty acid oxidation and ketogenesis . Carnitine supplementation improves this metabolic disturbance",
"AIMS To evaluate the effect of L-carnitine supplementation ( 25 mg/kg/d ) on the growth and incidence of hypoglycaemia in preterm infants . METHODS A double blind , placebo controlled r and omised trial , stratified for gestational age , was conducted of 86 preterm infants between 28 and 34 gestational weeks . The median gestational ages in the carnitine group and placebo groups were 30.7 weeks ( range 28.0 to 33.6 ) and 31.4 weeks ( range 28.0 to 33.9 ) , respectively . The median birthweights were 1.557 kg ( range 0.944 to 2.275 ) and 1.645 kg ( range 0.885 to 2.545 ) , respectively . RESULTS Mean plasma free carnitine concentrations were below values for normal term infants in both groups on day 1 ( carnitine group 44.8 μmol/l , placebo group 25.5 μmol/l ) in the placebo group on day 7 ( 50.7 μmol/l ) , but in neither group on days 14 and 28 . Total , free , and acylcarnitine concentrations were significantly increased in both urine and blood in the L-carnitine group . There was no significant difference between the placebo and carnitine supplemented groups in growth rate , as assessed by weight , length , skinfold thickness and head circumference measurements , or in the incidence of episodes of hypoglycaemia . CONCLUSION The addition of carnitine as a nutritional supplement at a dose of 25mg/kg/day did not improve growth in our group of preterm infants nor protect them from episodes of hypoglycaemia",
"This study was undertaken to compare Intralipid ® with a new fat emulsion containing gamma‐linolenic acid and carnitine , named Pediatric Fat Emulsion 4501 , in neonates with regard to lipid and carnitine metabolism over a short period of total parenteral nutrition . There were 10 neonates in each group and they tolerated the total parenteral nutrition well . In spite of the gamma‐linolenic acid supplementation in the new emulsion , arachidonic acid decreased significantly in plasma lipid esters and adipose tissue in both groups after 5 d of treatment . Also , there was a decrease in plasma docosahexaenoic acid which was more pronounced in the treatment group . The relative percentage values of linoleic and linolenic acids in adipose tissue were increased , indicating that newborns have a rapid accretion of fatty acids . Plasma triglycerides were effectively cleared during the periods without fat infusion . In the group that received Pediatric Fat Emulsion 4501 the means of both free and total plasma carnitine concentrations increased significantly , whereas they tended to decrease in the Intralipid ® group",
"The effects of carnitine supplementation on fat and glucose metabolism and carnitine balance were studied in 12 preterm neonates receiving full or partial parenteral nutrition ( PN ) for 5 to 21 days . The gestational age ranged from 27 to 32 weeks and the birth weight from 790 to 2090 g. The neonates were assigned at r and om to receive either L‐carnitine 10 mg/kg ( n=6 ) or saline ( n=6 ) . In the carnitine group , increased concentrations in plasma of total and free carnitine were observed . Less than 50 % of the given dose was recovered in urine . In the placebo group no changes in the total plasma carnitine concentration were seen . In all neonates plasma triglycerides , free fatty acids , glycerol , alanine , 3‐hydroxybutyrate ( BOB ) , glucose and lactate were measured at predetermined intervals . The only significant difference between the groups was higher BOB‐concentrations in the carnitine group 2 days after the start of parenteral nutrition . Elevated BOB concentrations are an indicator of improved fatty acid oxidation in the carnitine group . In this study , only a temporary effect of the carnitine supplementation was found",
"Summary The effect of a lipid emulsion containing longchain triglycerides ( LCT ) and supplemented with L-carnitine on plasma lipids and bilirubin in premature neonates on total parenteral nutrition was compared to that of lipid emulsions containing either LCT or a mixture of LCT and medium-chain triglycerides ( MCT ) . In a double-blind r and omized study 49 premature neonates received one of the three fat emulsions , given intravenously , over 16–20 h daily for 6 days . Plasma carnitine levels increased significantly in the supplemented group only ; the addition of carnitine did not seem to affect any of the parameters studied . Mean plasma triglycerides rose by 193 and 199 % in the carnitine-supplemented and the LCT groups , respectively , and by 314 % in the MCT/LCT group . On the sixth day of the study free fatty acids were significantly higher in the MCT/LCT group than in the other two groups . Plasma phospholipids and free cholesterol increased ( p in free and total bilirubin levels despite the significant increase in plasma lipids and free fatty acids result ing from the stepwise increase in lipid load . No correlation was found between free fatty acids and free bilirubin . Since hyperbilirubinemia and hypertriglyceridemia appear to be clinical ly independent factors , the infusion of lipids should not be withheld from jaundiced infants on total parenteral nutrition"
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The use of human growth hormone to improve athletic performance has recently received worldwide attention . This practice , often called sports doping , is banned by most professional sports leagues and associations , including the International Olympic Committee , Major League Baseball , and the National Football League ( 13 ) . However , a wide range of athletes , including those from baseball ( 46 ) , cycling ( 7 , 8) , and track and field ( 5 , 9 ) , have been implicated in or have confessed to illicit growth hormone use . The Mitchell report ( 10 ) recently identified 89 Major League Baseball players who allegedly used performance-enhancing drugs , and some of these players have subsequently admitted to using growth hormone ( 11 , 12 ) . Part of the attraction of using growth hormone as a performance enhancer has been that its use is difficult to detect . The World Anti-Doping Agency , whose formation stemmed from the widely publicized doping sc and al of the 1998 Tour de France ( 13 ) , first used a blood test to detect exogenous growth hormone during the 2004 Olympic Games in Athens . However , according to the World Anti-Doping Agency , there have been no test-confirmed positive cases for growth hormone doping in professional or Olympic athletes ( 14 ) , probably because of the limited availability and implementation of this test . Although growth hormone is reportedly used to enhance athletic performance and has been called the most anabolic substance known ( 15 ) , its efficacy for this purpose is not well established . Some have suggested that growth hormone is a wonder drug ( 16 ) that results in ripped muscle ( 17 ) and provides stamina-increasing properties ( 18 ) . Exogenous growth hormone therapy in growth hormonedeficient adults ( that is , those with growth hormone deficiency due to hypothalamic or pituitary defects ) results in increased lean mass and decreased fat mass ( 19 ) , and comparable body composition changes are seen in healthy elderly adults who receive growth hormone ( 20 ) . Some experts , however , have suggested that the strength-enhancing properties of growth hormone among healthy adults have been exaggerated ( 15 ) . Serious side effects , including diabetes , hepatitis , and acute renal failure , may occur in athletes using high-dose growth hormone ( 21 ) . Furthermore , the use of growth hormone for athletic enhancement is not approved by the U.S. Food and Drug Administration , and the distribution of growth hormone for this purpose is illegal in the United States ( 22 ) . We performed a systematic review of r and omized , controlled trials to determine the effects of growth hormone therapy on athletic performance in healthy , physically fit , young adults . Our primary aim was to evaluate the effects of growth hormone on body composition , strength , basal metabolism , and exercise capacity . In addition , we sought to synthesize the evidence on adverse events associated with growth hormone in the healthy young and assess the quality of the published literature . Methods Literature Search es In consultation with 2 research librarians , we developed individual search strategies to identify potentially relevant studies from the MEDLINE , EMBASE , SPORTD iscus , and Cochrane Collaboration data bases . We sought English- language reports indexed through 11 October 2007 with keywords including growth hormone and r and omized , controlled trial ( Appendix Table 1 ) . We search ed bibliographies of retrieved articles for additional studies . Appendix Table 1 . Search Strategy Study Selection We sought r and omized , controlled trials , including crossover trials , that compared growth hormone therapy with no growth hormone therapy . We included studies that 1 ) evaluated at least 5 participants , 2 ) enrolled only community-dwelling participants , 3 ) assessed participants with a mean or median age between 13 and 45 years , and 4 ) provided data on at least 1 clinical outcome of interest . We excluded studies that 1 ) focused solely on evaluating growth hormone secretagogues , 2 ) explicitly included patients with any comorbid medical condition , or 3 ) evaluated growth hormone as treatment for a specific illness ( for example , adult growth hormone deficiency or fibromyalgia ) . Data Abstract ion One author review ed the titles and abstract s of articles identified through our search and retrieved potentially relevant studies . An endocrinologist and a physician with training in meta-analytic techniques separately review ed the retrieved studies and abstract ed data independently onto pretested abstract ion forms . We resolved abstract ion differences by repeated review and consensus . If a study did not present data necessary for analysis or mentioned results but did not present data , we requested additional data from study authors . If data were presented graphically , we used the graph-digitizing program DigitizeIt , version 1.5 ( Share It , Braunschweig , Germany ) , to abstract data from the graph ( 23 ) . If multiple studies presented findings from the same cohort , we used these data only once in our analysis . We abstract ed 4 types of data from each study : participant characteristics ( for example , age , sex , body mass index , baseline maximum oxygen uptake [ VO2max ] ) , study interventions ( for example , dose , route , frequency , and duration of growth hormone therapy ) , study quality ( for example , quality of r and omization and blinding ) ( 24 , 25 ) , and clinical outcomes . We included studies that provided data on at least 1 of the following clinical outcomes : body composition ( for example , body weight , lean body mass , fat mass ) , strength ( for example , biceps or quadriceps strength ) , basal metabolism ( for example , resting energy expenditure , basal metabolic rate , heart rate , respiratory exchange ratio , or respiratory quotient ) , exercise capacity ( for example , exercising lactate levels , exercising respiratory exchange ratio or respiratory quotient , maximum inspiratory pressure , bicycling speed , and VO2max ) , or adverse events . Because the terms lean body mass and fat-free mass are typically used interchangeably in the literature , we report fat-free mass and lean body mass data as a single category of lean body mass . Similarly , we report resting energy expenditure and basal metabolic rate as a single category of basal metabolic rate . Quantitative Data Synthesis To describe key study characteristics , we computed mean values weighted by the number of participants in the trial . To evaluate the effects of growth hormone on body composition and strength , we computed a change score for each clinical outcome for both the treatment and control groups as the value of the outcome at trial end minus the value of the outcome at trial start . We used these change scores to calculate the weighted mean difference and st and ard mean difference ( 26 ) effect sizes . The weighted mean difference is reported in the same units as the clinical outcome of interest , thereby facilitating clinical interpretation . Because our outcomes were similar for both methods , we present only the outcomes from the weighted mean difference method . For studies that did not report the variance of an outcome at trial end minus the value at trial start , we calculated it as the sum of the trial-start and trial-end variances minus twice the covariance ( 20 , 27 ) . Because trial-start data were not available for most of the studies reporting basal metabolic outcomes , we compared trial-end results between treatment and control groups for these outcomes . We combined studies by using r and om-effects models ( 2628 ) because of potential inter study heterogeneity . The considerable variability in exercise protocol s used in the included studies reporting exercise capacity outcomes made pooling these results inappropriate . Instead , we provide a narrative , qualitative assessment of exercise capacity outcomes and report their associated published P values . The variability in reporting adverse events among included studies also made a quantitative meta- analysis of these outcomes inappropriate . Instead , we calculated the proportions of adverse events among participants who received and did not receive growth hormone in studies that reported or evaluated for each adverse event . We performed sensitivity analyses and assessed inter study heterogeneity to evaluate the robustness of our results . We removed each study individually to evaluate that study 's effect on the summary estimates . We assessed publication bias by constructing funnel plots and calculated the number of unpublished studies required to statistically significantly change our results ( 28 ) . We assessed heterogeneity among study results for each of the summary effects by calculating the Q statistic ( and associated P value ) and I 2 statistic ( 26 , 2830 ) . We evaluated heterogeneity through predetermined subgroup analysis that stratified studies by duration of treatment . We performed analyses by using Stata software , version 9.1 ( Stata , College Station , Texas ) ; SPSS , version 15.0 ( SPSS , Chicago ) ; and Comprehensive Meta- Analysis , version 2 ( Biostat , Englewood , New Jersey ) . We considered P values less than 0.05 ( 2-tailed ) to indicate statistically significant differences . Role of the Funding Source The authors were supported in part or fully by the Agency for Healthcare Research and Quality , Santa Clara Valley Medical Center , the U.S. Department of Veteran Affairs , Stanford University Medical Center , Stanford University , Genentech , the National Science Foundation , and the Evidence -Based Medicine Center of Excellence of Pfizer . These funding sources had no role in the design and conduct of the study ; the collection , management , analysis , and interpretation of the data ; the preparation , review , or approval of the manuscript ; or the decision to su bmi t the manuscript for publication . Results The Figure summarizes the results of our literature search es . We review ed 7599 titles from the MEDLINE , EMBASE , SPORTD iscus , and the Cochrane Collaboration data bases . From our search , we review ed 252 abstract s in detail and retrieved 56 articles for full-text evaluation
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"The present study was design ed as a r and omized , double-blind placebo (Plc)-controlled study to determine the effect of 2 wk of growth hormone administration ( GH-adm . ) on energy expenditure ( EE ) and substrate oxidation in healthy humans . Sixteen young healthy men were divided into two groups . The study consisted of two 24-h measurements ( indirect calorimetry ) , separated by 2 wk of either Plc or GH injections ( 6 IU/day ) . At baseline , no significant differences were observed between the two groups in any of the measured anthropometric , hormonal , or metabolic parameters , neither did the parameters change over time in the Plc group . GH-adm . result ed in a 4.4 % increase in 24-h EE ( P increase in fat oxidation by 29 % ( P respiratory quotient was only observed in the postabsorptive phase after an overnight fast ( 0.84 + /- 0.1 to 0.79 + /- 0.1 , P lean body mass ( LBM ) was increased by GH-adm . only [ 62.8 + /- 2.5 kg ( baseline ) vs. 64.7 + /- 2.4 kg ( after ) , P GH-adm . increases 24-h EE , which may be partly explained by increased LBM . Furthermore , GH-adm . stimulates fat combustion , especially in the postabsorptive state",
"GH is being used by elite athletes to enhance sporting performance . To examine the hypothesis that exogenous 22-kDa recombinant human GH ( rhGH ) administration could be detected through suppression of non-22-kDa isoforms of GH , we studied seventeen aerobically trained males ( age , 26.9 + /- 1.5 yr ) r and omized to rhGH or placebo treatment ( 0.15 IU/kg/day for 1 week ) . Subjects were studied at rest and in response to exercise ( cycle-ergometry at 65 % of maximal work capacity for 20 min ) . Serum was assayed for total GH ( Pharmacia IRMA and pituitary GH ) , 22-kDa GH ( 2 different 2-site monoclonal immunoassays ) , non-22-kDa GH ( 22-kDa GH-exclusion assay ) , 20-kDa GH , and immunofunctional GH . In the study , 3 h after the last dose of rhGH , total and 22-kDa GH concentrations were elevated , reflecting exogenous 22-kDa GH . Non-22-kDa and 20-kDa GH levels were suppressed . Regression of non-22-kDa or 20-kDa GH against total or 22-kDa GH produced clear separation of treatment groups . In identical exercise studies repeated between 24 and 96 h after cessation of treatment , the magnitude of the responses of all GH isoforms was suppressed ( P rhGH in trained adult males suppressed exercise-stimulated endogenous circulating isoforms of GH for up to 4 days ; 2 ) the clearest separation of treatment groups required the simultaneous presence of high exogenous 22-kDa GH and suppressed 20-kDa or non-22-kDa GH concentrations ; and 3 ) these methods may prove useful in detecting rhGH abuse in athletes",
"In a r and omized , double-blind , placebo-controlled , cross-over study , we examined the effects of 14 days of growth hormone ( GH ) administration ( 12 IU/d subcutaneously ) on energy expenditure ( EE ) , respiratory exchange ratio ( RER ) , and thyroid function in 14 normal adults of normal weight ( eight men and six women ) . EE ( kcal/24 h ) was significantly elevated after GH administration ( 2,073 + /- 392 , [ GH ] , 1,900 + /- 310 , [ placebo ] , P = .01 ) . RER was significantly lowered during GH administration ( 0.73 + /- 0.04 v 0.78 + /- 0.06 , P = .02 ) , reflecting increased oxidation of lipids . Total triiodothyronine ( TT3 ) ( nmol/L ) and free T3 ( FT3 ) ( pmol/L ) increased significantly during GH ( TT3 : 1.73 + /- 0.06 [ GH ] , 1.48 + /- 0.08 [ placebo ] , P = .01 ; FT3 : 6.19 + /- 0.56 [ GH ] , 5.49 + /- 0.56 [ placebo ] , P = .01 ) . Concomitantly , an insignificant decrease in reverse T3 ( rT3 ) ( nmol/L ) was observed ( 0.07 + /- 0.01 [ GH ] , 0.15 + /- 0.01 [ placebo ] , P = .08 ) . GH caused a highly significant increase in T3/thyroxine ( T4 ) ( x 100 ) ratio ( 1.84 + /- 0.12 [ GH ] , 1.37 + /- 0.06 [ placebo ] ) . Serum thyrotropin ( TSH ) was not significantly changed by GH . No changes in total thyroxine ( TT4 ) ( nmol/L ) ( 98 + /- 6 [ GH ] , 111 + /- 8 [ placebo ] , P = .40 ) and free thyroxine ( FT4 ) ( pmol/L ) ( 17.4 + /- 1.3 [ GH ] , 18.6 + /- 1.1 [ placebo ] , P = .37 ) after 14 days of GH administration were observed . In conclusion , 2 weeks of GH administration increases EE and lipidoxidation . This finding may partly be mediated by an increase in peripheral T4 to T3 conversion",
"Adults with hypopituitarism receive therapy that replaces cortisol , thyroid hormone , and gonadal steroids , but growth hormone replacement has typically been reserved for children with growth hormone deficiency . However , several observations suggest that growth hormone may have an important role in maintaining bone density and body composition in adults . Bone density is reduced in patients with growth hormone deficiency that develops during childhood or adulthood [ 1 - 3 ] . In vitro , growth hormone binds to growth hormone receptors on rat osteoblast-like cells and produces a mitogenic response mediated by local synthesis and action of insulin-like growth factor 1 ( IGF-1 ) [ 4 , 5 ] . Administration of growth hormone to adults with growth hormone deficiency increases serum and urine markers of bone turnover [ 6 - 10 ] . In adults with childhood-onset growth hormone deficiency ( in whom osteopenia probably results from a failure to reach peak bone mass ) , growth hormone therapy increases bone density [ 3 , 8 , 10 , 11 ] . However , the effects of growth hormone replacement on bone density in adult-onset growth hormone deficiency are largely unknown . In addition to having an increased risk for fracture , adults with growth hormone deficiency have an excess risk for cardiovascular-related death that may be attributed to increased central fat mass [ 12 - 17 ] . Growth hormone therapy reduces body fat and increases lean mass in adults with growth hormone deficiency , primarily those in whom the deficiency developed during childhood [ 6 - 9 , 18 - 20 ] . However , previous studies of growth hormone replacement in adults have several important limitations . First , most of these studies used pharmacologic rather than physiologic doses of growth hormone . Second , most have focused on childhood-onset growth hormone deficiency . Third , effects of growth hormone on bone density in patients with adult-onset growth hormone deficiency have not been examined in a controlled study . Because of these limitations , the critical question of whether long-term growth hormone therapy is beneficial in patients with adult-onset growth hormone deficiency has not been definitively answered . We sought to determine whether long-term growth hormone replacement therapy , given at a dose adjusted according to IGF-1 levels , improves bone density , bone turnover , body composition , and several variables associated with quality of life in patients with adult-onset growth hormone deficiency . Methods Patients Thirty-two men ( median age , 51 years ; range , 24 to 62 years ) with a history of pituitary disease were recruited from the Massachusetts General Hospital Neuroendocrine Clinical Center and from surrounding communities . Growth hormone secretion profiles in 23 of these patients have been reported elsewhere [ 21 ] . All patients met the following inclusion criteria : 1 ) normal growth and development , 2 ) benign sellar neoplasm , pituitary apoplexy , or idiopathic hypopituitarism diagnosed after age 18 years , and 3 ) peak serum growth hormone levels less than 5 mg/L after receipt of two pharmacologic stimuli on separate mornings . The 13 patients younger than 50 years of age received intravenous insulin , 0.1 U/kg of body weight , and oral clonidine , 0.15 mg . The 18 patients 50 years of age or older received oral clonidine , 0.15 mg , and intravenous arginine , 30 g ; these patients were given arginine rather than insulin to avoid potential cardiovascular complications of hypoglycemia . Patients were excluded if they had a history of acromegaly or diabetes mellitus ; were taking drugs ( such as phenytoin or etidronate ) known to affect bone density ; were not receiving st and ard thyroid or adrenal hormone replacement therapy if the patient was deficient in those hormones ; or had begun receiving adrenal , gonadal , or thyroid hormone replacement therapy within 6 months before study enrollment . Growth hormone deficiency was caused by a clinical ly nonfunctioning pituitary adenoma in 12 patients , prolactinoma in 9 patients , craniopharyngioma in 9 patients , pituitary apoplexy in 4 patients , Cushing disease in 1 patient , and adult-onset idiopathic hypopituitarism in 1 patient . Twenty-one patients were deficient in adrenocorticotropin , thyroid-stimulating hormone , and gonadotropins . Five patients had two of these deficiencies , 5 patients had one , and 1 patient had none . Twenty-five patients were treated surgically ( 16 of the 25 were also treated with radiation or bromocriptine , or both ) . Five patients received bromocriptine with or without radiation therapy , and 2 were treated with hormonal replacement only . The Subcommittee on Human Studies of the Massachusetts General Hospital approved the study , and all patients gave written informed consent . Protocol Patients were r and omly assigned to receive recombinant human growth hormone ( Nutropin , Genentech , Inc. , South San Francisco , California ) at a daily dose of 10 g/kg subcutaneously or a placebo . The computerized r and omization , done by statisticians at Genentech , Inc. , stratified patients to assure balance between the groups with respect to age . Staff at Genentech , Inc. , informed the primary investigator of treatment assignment by telephone ; the study physician kept the information in a private computer data base . Only the study physician was aware of the treatment assignment . Patients were admitted to the General Clinical Research Center for measurements of bone mineral density of the lumbar spine , femoral neck , and proximal radius . Body mass index , lean body mass , and percentage of body fat were also measured . Patients had echocardiography and were tested for strength and exercise capacity . Urine was collected for 24 hours for measurement of pyridinoline , deoxypyridinoline , calcium , and creatinine excretion . Fasting blood sample s were drawn at 0900 hours for measurement of IGF-1 , glucose , insulin , lipids , and hemoglobin A1c values . Patients returned at 1 week , 1 month , and 3 months for outpatient measurement of serum IGF-1 , glucose , insulin , lipid ( at 1 and 3 months ) , and hemoglobin A1c ( at 3 months only ) values . Patients were readmitted at 6 , 12 , and 18 months so that the baseline evaluation could be repeated . Echocardiography and tests of strength and exercise capacity were repeated only at the 18-month visit . The growth hormone dose was reduced by 25 % if the patient 's serum IGF-1 level was found to be elevated at the 6- or 12-month visit ; serum IGF-1 levels were remeasured approximately 1 month after the dose was decreased . The dose was further adjusted if necessary . To maintain patient blinding , each placebo recipient was asked to reduce his dose by 25 % during the first 6 months of the study . Bone Density Bone mineral density of the lumbar spine , femoral neck , radius , and total body was determined by dual-energy x-ray absorptiometry ( Hologic QDR-2000 , Waltham , Massachusetts ) . Density of the nondominant radius was measured at the junction of the proximal two thirds and the distal one third of the radial shaft ; the coefficient of variation for this measurement is 1.5 % [ 22 ] . The bone mineral density of the lumbar spine was assessed in the anteroposterior projection in all patients and in the lateral projection in the 22 patients whose body thickness did not exceed the manufacturer 's specified limit for the lateral measurement . Because lateral measurements of bone density in the spine eliminate the contribution of the posterior vertebral elements , they estimate trabecular bone mass better than do measurements made in the anteroposterior projection [ 23 ] . In 50 persons with paired measurements , the SDs for the anteroposterior and lateral measurements were 0.010 g/cm2 and 0.013 g/cm2 , respectively ; these values did not vary with bone density . The coefficient of variation for bone density at the femoral neck was 2.1 % in 51 persons with paired measurements [ 24 ] . All scans were review ed by one physician who did not know the patients ' treatment assignment . Follow-up scans were matched to baseline scans to ensure that identical bone regions were measured . Body Composition A research dietitian determined body mass index . Lean body mass and percentage of body fat were measured by dual-energy x-ray absorptiometry ( Hologic QDR-2000 ) . According to the manufacturer , the coefficient of variation is 1.0 % for lean mass and 1.5 % for percentage of body fat . This compares favorably with the coefficients of variation of other techniques for determining body composition , such as bioelectrical impedance ( 5 % ) , 40 K counting ( 3 % ) , and deuterium oxide dilation ( 3 % ) [ 25 ] . Biochemical Assays Serum IGF-1 levels were measured by radioimmunoassay after acid-alcohol extraction ( Nichols Institute , San Juan Capistrano , California ) . The ageadjusted normal ranges for this assay were 83.3 to 378.0 mg/L for men 20 to 40 years of age and 54.0 to 328.5 mg/L for men older than 40 years of age . Interassay coefficients of variation were 5.2 % at 121.5 mg/L and 15.2 % at 84.5 mg/L. Serum osteocalcin levels were measured by immunoradiometric assay ( SmithKline Beecham , Van Nuys , California ) . The intra-assay coefficients of variation were 11.5 % for low control serum pools ( 3 to 6 mg/L ) , 11.6 % for medium pools ( 6 to 10 mg/L ) , and 10.6 % for high pools ( 25 to 35 mg/L ) . Urinary excretion of total pyridinoline and deoxypyridinoline was measured using high-performance liquid chromatography ( SmithKline Beecham ) . The intra-assay coefficients of variation for measurement of pyridinoline levels were 9.5 % at 13.8 nmol/mmol of creatinine , 9.6 % at 37.0 nmol/mmol of creatinine , and 10.7 % at 47.5 nmol/mmol of creatinine . The intra-assay coefficients of variation for measurement of deoxypyridinoline excretion were 15.8 % at 3.2 nmol/mmol of creatinine , 13.5 % at 6.7 nmol/mmol of creatinine , and 9.8 % at 10.7 nmol/mmol of creatinine . Other assays were done at the Massachusetts General Hospital as described elsewhere [ 26 ] . Echocardiography Transthoracic two-dimensional echocardiography was done while patients were in the left lateral decubitus ",
"The objective was to investigate the effect of growth hormone ( GH ) administration on circulating levels of free insulin-like growth factors ( IGFs ) in healthy adults . Eight healthy male subjects were given placebo and two doses of GH ( 3 and 6 IU/m2 per day ) for 14 days in a double-blind crossover study . Fasting blood sample s were obtained every second day . Free IGF-I and IGF-II were determined by ultrafiltration of serum . Total IGF-I and IGF-II were measured after acid-ethanol extraction . In addition , GH , insulin , IGF binding protein 1 ( IGFBP-1 ) and IGFBP-3 were measured . Serum-free and total IGF-I increased in a dose-dependent manner during the 14 days of GH administration . After 14 days , serum-free IGF-I values were 610 + /- 100 ng/l ( mean + /- SEM ) ( placebo ) , 2760 + /- 190 ng/l ( 3 IU/ m2 ) and 3720 + /- 240 ng/l ( 6 IU/m2 ) ( p = 0.0001 for 3 and 6 IU/m2 vs placebo ; p = 0.004 for 3 IU/m2 vs 6 IU/m2 ) . Total IGF-I values were 190 + /- 10 micrograms/l ( placebo ) , 525 + /- 10 ( 3 IU/m2 ) , and 655 + /- 40 micrograms/l ( 6 IU/m2 ) ( p levels of free or total IGF-II during the three study periods . Insulin-like growth factor binding protein 1 was decreased during GH administration ( p = 0.04 for placebo vs 3 IU/m2 ; p = 0.006 for placebo vs 6 IU/m2 ) . In conclusion , fasting serum free IGF-I increased dose dependently during GH administration and free IGF-I increased relatively more than total IGF-I. This may partly be due to the decrease in IGFBP-1",
"Adaptations in fat and carbohydrates metabolism after a prolonged endurance training program were examined using stable isotope tracers of glucose ( [6,6 - 2H2]glucose ) , glycerol ( [2H5]glycerol ) , and palmitate ( [2H2]palmitate ) . Active , but untrained , males exercised on a cycle for 2 h/day [ 60 % pretraining peak O2 consumption ( VO2peak ) = 44.3 + /- 2.4 ml.kg-1.min-1 ] for a total of 31 days . Three cycle tests ( 90 min at 60 % pretraining VO2peak ) were administered before training ( PRE ) and after 5 ( 5D ) and 31 ( 31D ) days of training . Exercise increased the rate of glucose production ( Ra ) and utilization ( Rd ) as well as the rate of lipolysis ( glycerol Ra ) and free fatty acid turnover ( FFARa/Rd ) . At 5D , training induced a 10 % ( P total fat oxidation because of an increase in intramuscular triglyceride oxidation ( + 63 % , P glycogen oxidation ( -16 % , P total fat oxidation during exercise increased a further 58 % ( P fat utilization during exercise at 31D showed a reduced reliance on plasma FFA oxidation ( FFA Rd ) and a greater dependence on oxidation of intramuscular triglyceride , which increased more than twofold ( P glucose Ra and Rd were reduced at all time points during exercise at 31D compared with PRE and 5D . We conclude that long-term training induces a progressive increase in fat utilization mediated by a greater oxidation of fats from intramuscular sources and a reduction in glucose oxidation . Initial changes are present as early as 5D and occur before increases in muscle maximal mitochondrial enzyme activity",
"High-dose GH administration is commonly associated with impaired insulin sensitivity ( S(I ) ) in humans . Paradoxically we have shown that low-dose GH ( 1.7 microg/kg.d ) administration enhances beta-cell function in young healthy adults . In the present double-blind , placebo-controlled , cross-over study , we explored the physiological effects of this low GH dose on glucose metabolism in 12 young healthy adults ( seven males , 19 - 29 yr ) . At pretreatment and after each 14-d treatment block , overnight metabolic profiles were assessed followed by a hyperinsulinemic euglycemic clamp , whereas fasting blood sample s were collected weekly . In subjects treated with GH first ( group A , n = 6 ) , GH treatment increased total IGF-I ( P IGF binding protein-3 ( P free IGF-I increased ( P overnight GH pulse peak amplitude decreased ( P placebo first ( group B , n = 6 ) , all biochemical parameters were unchanged after placebo treatment , whereas the changes in free and total IGF-I were similar to those of group A after GH treatment . Combined clamp data from both groups A and B ( n = 12 ) showed that 14-d GH treatment decreased overnight plasma insulin levels ( P hepatic glucose appearance ( P S(I ) ( P changes in S(I ) positively correlated with the changes in free IGF-I ( r = 0.72 , P S(I ) and suppressed endogenous peak GH release , and we hypothesize that these effects are the direct result of increased serum levels of free",
"The regulation of adipose tissue mass and energy expenditure is currently subject to intensive research , which primarily relates to the discovery of leptin . Leptin is a peptide , which is the product of the obese ( ob ) gene expressed in adipose tissue of several species icluding humans . Leptin is supposed to serve both as an index of fat mass and as a sensor of energy balance . Administration of recombinant murine leptin in ob/ob-mice , which do not produce leptin , decreases food intake and increases thermogenesis both of which result in a reduction in body weight and adipose tissue mass . The calorigenic effect of leptin presumably acts through an increase in sympathetic outflow which in turn activates the beta3 adrenergic receptor in brown adipose tissue . The regulation and action of endogenous leptin in humans are less well understood , and clinical grade recombinant human leptin is so far not available . Serum leptin correlates logarithmically with total body fat in both normal weight and obese subjects , which suggest insensitivity to leptin in obese patients . Furthermore , more rapid excursions in serum leptin have been reported following short-term changes in caloric intake and administration of insulin . Growth hormone ( GH ) exerts pronounced effects on lipid metabolism and resting energy expenditure . The lipolytic actions of GH appear to involve both increased sensitivity to the beta-adrenergic pathway , and a suppression of adipose tissue lipoprotein lipase activity . The calorigenic effects of GH have been shown not only to be secondary to changes in lean body mass . Growth hormone administration furthermore increases the peripheral conversion of thyroxine to triiodothyronine , which may contribute to the overall actions of GH on fuel and energy metabolism . So far , little is known about the effects of GH and iodothyronines on serum leptin levels in humans . We therefore measured serum leptin levels and energy expenditure before and after the administration of GH and triiodothyronine , alone and in combinaion , in a r and omized double-blind placebo-controlled study in healthy young male adults . The dose of triiodothyronine was selected to obtain serum levels comparable to those seen after GH administration",
"The case of a 36-year-old male professional bodybuilder is reported . He presented to the accident and emergency department with right upper quadrant pain . This was on the background of a 15-year history of anabolic steroid and growth hormone misuse . Examination revealed mild hepatomegaly and a r and om blood sugar of 30.2 mmol/l . There was no evidence of ketonuria or acidosis . Biochemical evidence of hepatitis was found , and the patient was in acute renal failure . He was given a sliding scale of insulin and an intravenous infusion of crystalloid . The hepatitis and hyperglycaemia settled with conservative treatment . It is believed that this is the first reported case of frank diabetes precipitated by supraphysiological recreational growth hormone misuse",
"The effects of GH on bone remodeling in healthy adults have not been systematic ally investigated . An analysis of these effects might provide insights into GH physiology and might yield data useful for the detection of GH doping in sports . The aim of this study was to evaluate the effects of GH administration on biochemical markers of bone and collagen turnover in healthy volunteers . Ninety-nine healthy volunteers of both sexes were enrolled in a multicenter , r and omized , double blind , placebo-controlled study and assigned to receive either placebo ( 40 subjects ) or recombinant human GH ( 0.1 IU/kg day in 29 subjects and 0.2 IU/kg x day in 30 subjects ) . The treatment duration was 28 days , followed by a 56-day wash-out period . The biochemical markers evaluated were the bone formation markers osteocalcin and C-terminal propeptide of type I procollagen , the resorption marker type I collagen telopeptide , and the soft tissue marker procollagen type III . All variables increased on days 21 and 28 in the two active treatment groups vs. levels in both the baseline ( P procollagen type III ( from 0.53 + /- 0.13 to 0.61 + /- 0.14 kU/L ; P osteocalcin ( from 12.2 + 2.9 to 14.6 + /- 3.6 UG/L ; P of C-terminal propeptide of type I procollagen and type I collagen telopeptide declined after day 42 and were no longer significantly above baseline on day 84 ( from 3.9 + /- 1.2 to 5.1 + /-1.5 microg/L and from 174 + /- 60 to 173 + /- 53 microg/L , respectively ) . Gender-related differences were observed in the study ; females were less responsive than males to GH administration with respect to procollagen type III and type I collagen telopeptide ( P GH administration affects the biochemical parameters of bone and collagen turnover in a dose- and gender-dependent manner . As GH-induced modifications of most markers , in particular procollagen type III and osteocalcin , persist after GH withdrawal , they may be suitable markers for detecting GH abuse",
"Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists",
"To investigate the mechanisms behind the water- and sodium-retaining effects of growth hormone ( GH ) , we studied the effect of GH on 1 ) water and sodium homeostasis , 2 ) the renin-angiotensin-aldosterone system ( RAAS ) , and 3 ) lithium clearance ( C(Li ) ) with and without concomitant prostagl and in ( PG ) synthesis inhibition with ibuprofen . GH administration for 6 days induced a significant increase in plasma renin , which was abolished by coadministration of ibuprofen ( mU x l(-1 ) x 24 h(-1 ) : control : 22.4 + /- 4.3 ; GH : 37.7 + /- 8.8 ; ibuprofen : 15.2 + /- 3.0 ; GH + ibuprofen : 19.7 + /- 2.5 ; ANOVA : P extracellular volume were seen after 6-day treatment with GH alone and in combination with ibuprofen [ liters : control , 19.57 + /- 0.92 ; GH , 20.80 + /- 1.00 ( ANOVA : P ibuprofen , 19.38 + /- 0.90 ; GH + ibuprofen , 21.63 + /- 1.37 ( ANOVA : P GH increased C(Li ) and changed the tubular h and ling of sodium and water . The absolute distal sodium reabsorption was increased , and this was only partially counterbalanced by decreased reabsorption in the proximal tubules . The data demonstrate that GH-induced activation of the RAAS can be blocked by concomitant PG synthesis inhibition and that the tubular effects of GH include increased distal nephron sodium and water reabsorption",
"GH is an agent widely used in sport to improve physical performance and has been proposed as adjunctive therapy in several clinical conditions . However , its short-term effects on the normal human heart are poorly understood . Sixty young normal volunteers ( 30 males and 30 females ) were enrolled in a multicenter , double-blind , placebo-controlled study . All subjects were r and omized to receive GH ( 0.03 or 0.06 mg/kg.d ) or placebo . A complete Doppler-echocardiographic examination was performed at baseline and after 4 wk of treatment . Low-dose GH did not significantly affect echocardiographic parameters . In contrast , high-dose GH increased left ventricular mass index by 12 % ( P of growth response was concentric , because left ventricular wall thickness but not diameter increased , leading to a 10 % increase of relative wall thickness . These structural changes were associated with functional changes , including a significant increase in cardiac index and a decrease in peripheral vascular resistance ; diastolic function was not altered . Fractional shortening and systemic blood pressure were unchanged in the two treatment groups . In conclusion , administration of GH for 4 wk at doses that simulate GH abuse in sport caused a high cardiac output state associated with concentric left ventricular remodeling",
"The role of growth hormone ( GH ) and thyroid hormone in the regulation of lipid and lipoprotein metabolism is not fully established . Furthermore , the possible linkage between the well-known GH-induced increase in peripheral thyroxine ( T4 ) to triiodothyronine ( T3 ) generation and the effects of GH on lipid and lipoprotein metabolism has not been eluci date d. In this double-blind placebo-controlled study , we compared the effects of GH and T3 administration alone and in combination on lipid and lipoprotein metabolism in a group of healthy young adults . The dose of T3 was selected to mimic the T2 increase seen during exogenous GH exposure . Eight normal male subjects ( aged 21 to 27 years ; body mass index , 21.11 to 27.17 kg/m2 ) were r and omly studied during four 10-day treatment periods with ( 1 ) daily subcutaneous placebo injections and placebo injections and placebo tablets , ( 2 ) daily subcutaneous GH injections ( 0.1 IU/kg.d ) and placebo tablets , ( 3 ) daily T3 administration ( 40 micrograms on even date s or 20 micrograms on uneven date s ) plus placebo injections , and ( 4 ) daily GH injections plus T3 administration . GH administration increased free T3 ( FT3 ) to the same level as during T3 administration . GH caused decreased levels of total cholesterol ( TC ) and low-density lipoprotein ( LDL ) cholesterol and increased levels of triglycerides ( TG ) and lipoprotein(a ) ( Lp(a ) ) , but no changes in high-density lipoprotein ( HDL ) cholesterol and apolipoprotein B ( apo B ) . T3 administration caused no alteration in these parameters , except for decreased levels of TC comparable to those seen after GH administration . Combined GH and T3 administration caused changes identical to those seen after GH administration , in addition to decreased apo B levels and a further decrease of TC levels . We conclude that GH and iodothyronines in the physiologic range exert distinct but disparate effects on lipids and lipoproteins , and do not support the hypothesis that the effects observed during GH administration are exclusively secondary to changes in peripheral T3 levels",
"The effects of recombinant human growth hormone ( rhGH ) on biochemical markers of bone turnover and bone mineral content ( BMC ) were investigated in 20 normal male volunteers ( aged 22 - 31 years ) r and omized to treatment for 7 days with either rhGH ( 0.1 IU/kg subcutaneously twice a day ) or placebo . Serum somatomedin C rose during treatment ( p less than 0.001 ) but was not significantly different from baseline at day 14 . The fasting urinary hydroxyproline/creatinine ( p less than 0.001 ) and calcium/creatinine ratios ( p less than 0.01 ) increased during treatment and remained elevated for 4 and 2 weeks , respectively . Serum bone gamma-carboxyglutamic acid-containing protein ( BGP ) increased during treatment ( p less than 0.001 ) and remained elevated for 6 months ( p less than 0.02 ) . Serum bone alkaline phosphatase ( B-AP ) , after an initial fall in the treatment period ( p less than 0.001 ) , increased slightly in the following months ( p less than 0.01 ) . In the rhGH group BMC was significantly higher than the pre study value at day 14 ( p less than 0.05 ) but was unaltered at the end of study . The simultaneous increase in markers of bone resorption and formation during rhGH treatment followed by a decline in resorption parameters within a few weeks and the prolonged effect on BGP and B-AP demonstrate that rhGH treatment stimulates osteoblasts and activates bone remodeling",
"Using double-blind , placebo-controlled procedures , the effects of methionyl-human growth hormone ( met-hGH ) on the tumor cytotoxic activity of natural killer ( NK ) cells were studied in seven healthy adults using a repeated measures experiment . Subjects were assigned at r and om to either a placebo ( bacteriostatic water ) treatment condition or a met-hGH ( 16.0 mg/wk of Protropin ) treatment condition , then crossed-over to the alternative treatment . Treatments were delivered on alternate days ( 3 d/wk ) for 6 weeks . Without bias from the met-hGH treatment , there was no evidence for GH hyposecretion as measured by the peak circulating GH response to exercise stimulation ( 14.1 + /- 3.1 ng/mL ) or insulin-like growth factor ( IGF-I ) levels ( 0.82 + /- 0.09 U/mL ) . When compared with placebo , met-hGH induced a significant overall increase in the percent specific lysis ( % SL ) of K562 tumor target cells ( placebo 22.2 + /- 1.7 v met-hGH 28.5 + /- 2.1 % SL ; P = .008 ) . NK activity was increased within the first week of treatment and this level was maintained throughout the remaining period of supplementation . There was a trend ( P = .057 ) for the met-hGH-induced percent change in NK activity ( NK% ) to be inversely related to placebo IGF-I levels ( r = -.761 ) , while there were significant positive correlations between NK% and the met-hGH-induced percent changes in IGF-I ( r = .727 ; P = .035 ) , the fat-free mass (FFM)/fat mass ( FM ) ratio derived by hydrodensitometry ( r = .792 ; P = .012 ) , and the endogenous GH response to exercise ( r = .469 ; P = .034 ) . ( ABSTRACT TRUNCATED AT 250 WORDS",
"GH administration increases energy expenditure , independent of changes in lean body mass , in healthy , obese , and GH-deficient subjects . This may be causally linked to the well known GH-induced increase in peripheral T4 to T3 generation , but experimental data are sparse . In this study we have addressed whether 1 ) the calorigenic effects of GH administration could be reproduced by oral supplementation of T3 in a dose selected to mimic the GH-induced increase in peripheral T3 levels ; and 2 ) combined GH and T3 administration have a synergistic effect on resting energy expenditure ( REE ) . Eight normal male subjects ( aged 21 - 27 yr ; body mass index , 21.11 - 27.17 kg/m2 ) were r and omly studied during four 10-day treatment periods with 1 ) daily sc placebo injections and placebo tablets , 2 ) daily sc GH injections ( 0.1 IU/kg x day ) and placebo tablets , 3 ) daily T3 administration ( 40 microg on even date s , 20 microg on uneven date s ) plus placebo injections , and 4 ) daily GH injections plus T3 administration . GH administration increased both free T3 ( FT3 ) levels [ mean + /- SE , 6.2 + /- 0.3 ( control ) vs. 7.3 + /- 0.5 ( GH ) pmol/L ; P REE [ mean + /- SE , 1959 + /- 67 ( control ) vs. 2164 + /- 55 ( GH ) Cal/24 h ; P T3 administration yielded comparable levels of FT3 ( 7.7 + /- 0.5 pmol/L ; T3 vs. GH , P = 0.37 ) , but did not increase REE ( 2015 + /- 48 Cal/24 h ; T3 vs. control , P = 0.23 ) . Combined GH and T3 administration increased REE to a level higher than that seen with T3 alone ( 2279 + /- 68 Cal/24 h ; T3 vs. GH plus T3 , P serum levels of insulin-like growth factor I and insulin were recorded with GH administration , but not with T3 alone . Resting heart rate increased to a similar degree after GH administration and T3 supplementation , respectively . Tympanic temperature remained unaltered in all four studies . The results suggest that the calorigenic effect of GH is not mediated solely through increased conversion of T4 to T3",
"Objectives To study the effects on body composition after 1 month 's administration of supraphysiological doses of growth hormone ( GH ) in healthy , active young adults with normal GH‐IGF‐I axis",
"GH is involved in the long-term regulation of peripheral vascular resistance and vascular reactivity . We determined whether GH plays a role in the acute regulation of vascular function in humans . The acute vascular effects of GH were studied in eight healthy subjects according to a double-blind , placebo-controlled design . Forearm blood flow ( FBF ) , vascular resistance , and nitric oxide ( NO ) production were monitored during a 4-h infusion of GH into the brachial artery at a rate chosen to raise local GH to stress levels ( approximately 40 ng/ml ) . During GH infusion , FBF rose 75 % ( P forearm vascular resistance decreased comparably ( P forearm release of NO ( P response of FBF to the endothelium-dependent vasodilator acetylcholine ( Ach ; P FBF reached 30.4 + /- 4.2 and 16.9 + /- 3.1 ml/dl x min in the GH and placebo studies , respectively ( P slopes of the dose-response curves also differed markedly ( 0.45 + /- 0.07 and 0.25 + /- 0.05 ml/dl x min/ microg in the GH and placebo studies , respectively ; P upward shift of the FBF response to the endothelium-independent vasodilator sodium nitroprusside ( P slope of the dose-response curve . GH infusion did not cause any appreciable increment in the venous IGF-I concentration in the test arm . In conclusion , GH acutely lowers peripheral vascular resistance and stimulates endothelial function . These effects are mediated by activation of the NO pathway and appear to be independent of",
"We measured changes in serum insulin-like growth factor-1 ( IGF-1 ) , calcitriol , parathyroid hormone ( PTH ) , thyroid hormones , insulin , and plasma glucagon in response to seven days of treatment with a pharmacological dosage of recombinant human growth hormone ( r-hGH ) ( 0.1 IU/kg sc twice daily ) or placebo in 20 normal male volunteers to evaluate whether the effect of r-hGH on biochemical bone markers could be attributed to changes in these hormones . Serum IGF-1 ( p vitamin D-binding protein ( p Total calcitriol ( p free calcitriol index ( p serum insulin ( p total ( p free triiodothyronine ( p serum PTH and plasma glucagon remained unchanged . In conclusion , pharmacological doses of r-hGH increased not only IGF-1 but also free-calcitriol index , insulin , and free T3 . The increase in these hormones may be co-responsible for some of the observed effects of r-hGH on bone turnover and calcium homeostasis",
"The effects of biosynthetic methionyl-human growth hormone ( met-hGH ) on body composition and endogenous secretion of growth hormone ( GH ) and insulin-like growth factor I ( IGF-I ) were studied in eight well-trained exercising adults between 22 and 33 yr of age . By the use of double-blind procedures , met-hGH ( 2.67 mg/0.5 ml diluent , 3 days/wk ) and bacteriostatic water ( placebo , 0.5 ml , 3 days/wk ) were administered in a repeated- measures design that counterbalanced treatment order . Duration of each treatment was 6 wk . Subjects trained with progressive resistance exercise throughout and were maintained on a high-protein diet monitored by extensive compositional analyses of daily dietary intake records . Hydrodensitometry revealed that met-hGH significantly decreased percent body fat ( % fat ) and increased fat-free weight ( FFW ) and FFW/fat weight ( FW ) , whereas the placebo treatment did not change any of these measures . Changes in FFW/FW correlated with the relative dose of met-hGH but did not correlate with either the peak GH response to L-dopa/arginine stimulation or IGF-I levels obtained after treatment with placebo . There were no differences between treatments in the dietary intakes of total kilocalories , protein , carbohydrates , and fat . Mean IGF-I levels were elevated after treatment with met-hGH compared with postplacebo levels . After treatment with met-hGH , five of seven subjects had a suppressed GH response to stimulation from either L-dopa/arginine or submaximal exercise . We conclude that supraphysiological doses of met-hGH will alter body composition in exercising adults in a relative dose-dependent manner and that such treatment may suppress endogenous release of GH in some individuals",
"The purpose of this study was to examine the effects of increased fat availability induced by growth hormone ( GH ) administration on the oxidative metabolism during exercise . Seven well-trained males ( age 25 + /- 2 years ( mean + /- S.E.M. ) ; peak oxygen consumption : 62 + /- 1 ml min(-1 ) kg(-1 ) ( completed four r and omised trials : 120 min bicycling at 55 % 4 h after receiving either 7.5 IU ( 2.5 mg ) GH or placebo ( Plc ) , and during rest after receiving either GH or Plc . In all studies a st and ardized meal was given 2 h after GH or Plc injection . GH administration result ed in an approximately 60-fold increase in serum GH concentration at rest ( P increase in serum GH was followed by an increase in circulating glycerol at rest ( 8 % , P increase in plasma glycerol was more pronounced ( GH : 716 % of baseline versus Plc : 328 % , P fat mobilization did not increase fat oxidation during exercise ( indirect calorimetry ) . In conclusion , GH administration combined with aerobic exercise increased lipolytic parameters substantially more than exercise alone , but did not further augment whole body fat oxidation",
"OBJECTIVES To determine whether six days recombinant human growth hormone ( rhGH ) in an abstinent anabolic- and rogenic steroid ( AAS ) group had any cardiovascular and biochemical effects compared with a control group . METHODS Male subjects ( n=48 ) were r and omly divided , using a single blind procedure into two groups : ( 1 ) control group ( C ) n=24 , mean+/-SD , age 32+/-11 years ; height 1.8+/-0.06 m ; ( 2 ) rhGH using group ( 0.058IUkg(-1)day(-1 ) ) ( GH ) n=24 , mean+/-SD , age 32+/-9 years ; height 1.8+/-0.07 m . Physiological responses , anthropometry , arterial pulse wave velocity ( APWV ) , blood pressure ( BP ) , heart rate ( HR ) , peak oxygen uptake ( VO(2 ) peak ) and biochemical indices were investigated . RESULTS Body mass index , fat-free mass index and VO(2 ) peak significantly increased while body fat significantly decreased within GH ( all P Insulin like growth factor-I significantly increased within GH ( P Serum sodium significantly increased ( P serum homocysteine , high sensitivity C-reactive protein , thyroid stimulating hormone and tetra-iodothyronine ( T(4 ) ) , significantly decreased within GH ( all P T(4 ) significantly decreased compared with C ( P Arterial pulse wave velocity , peak and recovery systolic and diastolic BP , significantly decreased compared with C ( P Resting HR and rate pressure product ( RPP ) significantly increased compared with C ( P rhGH may have beneficial effects on endothelial function and specific inflammatory markers of cardiovascular disease in abstinent AAS users , but may have an adverse effect on the cardiovascular system , as evidence d by the increase in resting RPP",
"The purpose of this study was to determine whether growth hormone ( GH ) administration enhances the muscle anabolism associated with heavy-resistance exercise . Sixteen men ( 21 - 34 yr ) were assigned r and omly to a resistance training plus GH group ( n = 7 ) or to a resistance training plus placebo group ( n = 9 ) . For 12 wk , both groups trained all major muscle groups in an identical fashion while receiving 40 micrograms recombinant human GH.kg-1.day-1 or placebo . Fat-free mass ( FFM ) and total body water increased ( P less than 0.05 ) in both groups but more ( P less than 0.01 ) in the GH recipients . Whole body protein synthesis rate increased more ( P less than 0.03 ) , and whole body protein balance was greater ( P = 0.01 ) in the GH-treated group , but quadriceps muscle protein synthesis rate , torso and limb circumferences , and muscle strength did not increase more in the GH-treated group . In the young men studied , resistance exercise with or without GH result ed in similar increments in muscle size , strength , and muscle protein synthesis , indicating that 1 ) the larger increase in FFM with GH treatment was probably due to an increase in lean tissue other than skeletal muscle and 2 ) resistance training supplemented with GH did not further enhance muscle anabolism and function",
"GH deficiency ( GHD ) in adulthood is accompanied by physical and psychological impairments . One hundred fifteen patients ( 67 male , 48 female ) with pronounced GHD were enrolled in a r and omized , double-blind , placebo-controlled study with objectives that included effects on body composition , cardiac structure , and function and safety of replacement therapy with recombinant human GH ( Saizen ) . Sixty patients ( 31 male , 29 female ) received GH at a dose of 0.005 - 0.010 mg/kg.d , and 55 patients ( 36 male , 19 female ) received placebo for 6 months . Assessment of body composition by dual-energy x-ray absorptiometry demonstrated a treatment difference in lean body mass increase of 2.1 kg ( between-group comparison , P fat mass of 2.8 kg ( between-group comparison , P left ventricular systolic function after GH treatment in both genders . End-systolic volume decreased by 4.3 + /- 10.5 ml ( from 35.8 + /- 17.6 ml ; between-group comparison , P = 0.035 ) and ejection fraction increased by 5.1 + /- 10.0 % ( from 55.0 + /- 11.2 % ; between-group comparison , P = 0.048 ) , approaching normalcy . Diastolic function did not change as assessed by isovolumic relaxation time , early diastolic flow , diastolic flow secondary to atrial contraction , or ratio of peak mitral early diastolic and atrial contraction velocity . GH treatment was well tolerated , with adverse events primarily related to effects on fluid balance . No apparent relationship between IGF-I levels and the occurrence or severity of adverse events was identified . In conclusion , GH replacement therapy in adults with GHD demonstrated beneficial effects on lean body mass composition that was more pronounced in males than females . In contrast , cardiac function improvement appears to benefit both genders equally",
"Sodium retention and symptoms and signs of fluid retention are commonly recorded during GH administration in both GH-deficient patients and normal subjects . Most reports have however , been casuistic or uncontrolled . In a r and omized double blind placebo-controlled cross-over study we therefore examined the effect of 14-day GH administration ( 12 IU sc at 2000 h ) on plasma volume , extracellular volume ( ECV ) , atrial natriuretic peptide ( ANP ) , arginine vasopressin , and the renin angiotensin system in eight healthy adult men . A significant GH induced increase in serum insulin growth factor I was observed . GH caused a significant increase in ECV ( L ) : 20.45 + /- 0.45 ( GH ) , 19.53 + /- 0.48 ( placebo ) ( P less than 0.01 ) , whereas plasma volume ( L ) remained unchanged 3.92 + /- 0.16 ( GH ) , 4.02 + /- 0.13 ( placebo ) . A significant decrease in plasma ANP ( pmol/L ) after GH administration was observed : 2.28 + /- 0.54 ( GH ) , 3.16 + /- 0.53 ( placebo ) P less than 0.01 . Plasma aldosterone ( pmol/L ) : 129 + /- 14 ( GH ) , 89 + /- 17 ( placebo ) , P = 0.08 , and plasma angiotensin II ( pmol/L ) levels : 18 + /- 12 ( GH ) , 14 + /- 7 ( placebo ) , P = 0.21 , were not significantly elevated . No changes in plasma arginine vasopressin occurred ( 1.86 + /- 0.05 pmol/L vs. 1.90 + /- 0.05 , P = 0.33 ) . Serum sodium and blood pressure remained unaffected . Moderate complaints , which could be ascribed to water retention , were recorded in four subjects [ periorbital edema ( n = 3 ) , acral paraesthesia ( n = 2 ) and light articular pain ( n = 1 ) ] . The symptoms were most pronounced after 2 - 3 days of treatment and diminished at the end of the period . In summary , 14 days of high dose GH administration caused a significant increase in ECV and a significant suppression of ANP",
"In a double blind , cross-over placebo-controlled trial , we studied the effects of 26 weeks of replacement therapy with recombinant human GH on body composition , metabolic parameters , and well-being in 10 patients with adult-onset GH deficiency ( GHD ) . All patients received appropriate thyroid , adrenal , and gonadal replacement therapy . The dose of recombinant human GH was 0.25 - 0.5 U/kg.week ( 0.013 - 0.026 mg/kg.day ) and was administered sc daily at bedtime . One patient was withdrawn from the study because of edema and atrial fibrillation . Body composition was estimated with three independent methods : computed tomography , bioelectric impedance , and total body potassium combined with total body water assessment s. The Comprehensive Psychological Rating Scale and the Symptom Check List-90 were used to assess any change in psychopathology . After 26 weeks of treatment , adipose tissue ( AT ) mass decreased 4.7 kg ( P Subcutaneous AT decreased by an average of 13 % , whereas visceral AT was reduced by 30 % . Muscle volume increased by 2.5 kg ( 5 % ; P body cell mass and extracellular fluid volume increased significantly by 1.6 and 3.0 kg , whereas body fat decreased by 6.1 kg . Results obtained by the bioelectric impedance technique were similar . The mean ( + /- SD ) concentrations of insulin-like growth factor-I increased from 0.26 ( 0.06 ) at baseline to 2.56 ( 1.55 ) and 2.09 ( 1.03 ) kU/L after 6 and 26 weeks of treatment . Calcium and serum phosphate , osteocalcin , and procollagen-III concentrations were significantly higher , and intact PTH concentrations were reduced after 6 and 26 weeks of treatment , respectively . Total and free T3 concentrations were significantly increased after 6 and 26 weeks of treatment , whereas free T4 concentrations were reduced at 6 weeks , but after 26 weeks , free T4 concentrations had returned to pretreatment values . Finally , after 26 weeks of treatment , there was a decrease in the Comprehensive Psychological Rating Scale score ( P body composition , fat distribution , and bone and mineral metabolism and reduces psychiatric symptoms . Finally , we conclude that the observed beneficial effects of replacement therapy with GH are of sufficient magnitude to consider treatment of GHD adults",
"The aim of GH replacement therapy in GH-deficient adults is to optimize response with minimum incidence of adverse reactions , but optimal therapy regimens are still to be established . This two-arm parallel study examined effects of two GH dose algorithms in adults with GH deficiency of adult or childhood onset . Patients on low dose ( LD ; n = 302 ) received GH at 3 microg/kg per day for 3 months increasing to 6 microg/kg per day for 3 months , and those on conventional dose ( CD ; n = 293 ) started on 6 microg/kg per day for 3 months increasing to 12 microg/kg per day for 3 months . The proportion of patients completing therapy was greater for the LD group than the CD group for the first 3 months ( 93.0 % vs. 88.1 % ; P = 0.037 ) and overall for the 6 months ( 90.7 % vs. 84.0 % ; P = 0.013 ) . Both dose groups showed significant increases in lean body mass and decreases in fat mass for all time points . Percent increase in lean body mass was less with LD than CD over the first 3 months ( 2.43 + /- 4.33 vs. 3.58 + /- 4.69 % ; P = 0.006 ) but not overall for the 6-month period ( 4.38 % + /- 5.34 % vs. 5.21 % + /- 5.99 % ; P = 0.141 ) . Percent decrease in fat mass was less with LD than CD for the first 3 months ( -2.81 % + /- 7.81 % vs. -5.53 % + /- 8.64 % ; P IGF-I SD score increased less with LD than CD for 0 to 3 and 0 to 6 months , although for IGF-binding protein-3 SD score , there was no significant difference between doses at any time . Arthralgia was the only adverse event that occurred significantly less frequently with LD than with CD . Calculated changes based on gender and onset indicated greater changes in males than females for body composition , but there was little difference in GH-related adverse events between males and females . The lower starting dose with dose titration appeared more favorable , but differences in response between genders and onset of GH deficiency need to be taken into account when setting an individual dose regimen",
"The effect of recombinant human growth hormone ( rHGH ) on cholesterol , high- and low-density lipoprotein ( HDL and LDL ) cholesterol , triglycerides ( TG ) , apolipoprotein ( apo ) B , apo A-I , and lipoprotein(a ) [ Lp(a ) ] was studied in 40 postmenopausal women treated with 0.05 , 0.1 , or 0.2 IU/kg/d rHGH or placebo for 7 days . Cholesterol , LDL cholesterol , and HDL cholesterol decreased in a dose-dependent manner ( P = .001 , P = .001 , and P = .003 , respectively ) , whereas apo B decreased insignificantly ( P = .15 ) . Apo A-I decreased significantly only among women treated with rHGH at a dose of 0.1 IU/kg/d ( P = .03 ) . When all rHGH-treated women were grouped together , Lp(a ) increased ( P = .001 ) . We also studied 20 young men treated with either 0.2 IU/kg/d rHGH or placebo . As in women , cholesterol and apo B decreased P = .005 and P = .02 , respectively ) , whereas Lp(a ) increased ( P = .05 ) . There was no detectable effect of rHGH on TG concentrations in men . As in women , there was no significant effect of 0.2 IU/kg/d rHGH on apo A-I concentrations . All lipid and lipoprotein measures reached pretreatment levels during the first week after treatment was stopped , except Lp(a ) , which remained elevated 2 weeks after rHGH cessation",
"CONTEXT Despite the fact that the use of GH as a doping agent in sports is widespread , little is known about its short-term effects . OBJECTIVE The objective was to study the effects of GH on exercise capacity . DESIGN A double-blind , placebo-controlled study was used , with a treatment period of 28 d. SETTING Subjects from general community studied ambulatory at a university hospital . PARTICIPANTS Thirty healthy active young normal volunteers ( 15 women and 15 men ) were recruited by local announcement , and all completed the study . INTERVENTION All subjects were r and omized to receive a low GH dose ( 0.033 mg/kg.d or 0.1 IU/kg.d ) , a high GH dose ( 0.067 mg/kg.d or 0.2 IU/kg.d ) , or placebo . MAIN OUTCOME MEASURES Power output and oxygen uptake on bicycle exercise were the main outcome measures . RESULTS We found no effect of the low or high dosages of GH on maximum oxygen uptake during exercise ( mean + /- se for placebo , 45.2 + /- 1.6 to 45.2 + /- 2.1 ml/kg.min ; GH low dose , 42.8 + /- 1.6 to 42.8 + /- 1.6 ml/kg.min ; GH high dose , 44.8 + /- 3.4 to 44.8 + /- 2.2 ml/kg.min ; not significant by two-way ANOVA ) . Neither was there any effect on maximum achieved power output during exercise or on blood pressure , heart rate , or the electrocardiographic ST level at rest or during exercise . GH significantly increased total body weight ( P = 0.028 ) , an effect predominantly ascribed to fluid retention ( increased extracellular water volume ) , whereas muscle mass ( as indicated by intracellular water volume ) did not change . However , changes in the latter correlated to changes in physical performance , possibly due to different training efforts . CONCLUSION Administration of supraphysiological recombinant human GH during a period of 4 wk does not improve power output or oxygen uptake",
"We studied the acute effects of a single , sc GH dose on exercise performance and metabolism during bicycling . Seven highly trained men [ age , 26 + /- 1 yr ( mean + /- SEM ) ; weight , 77 + /- 3 kg ; maximal oxygen uptake , 65 + /- 1 ml O(2).min(-1).kg(-1 ) ] performed 90 min of bicycling 4 h after receiving 7.5 IU ( 2.5 mg ) GH or placebo in a r and omized , double-blinded , cross-over design trial . A st and ardized pre-exercise meal was given 2 h before exercise . Blood was sample d at rest and during exercise and analyzed for GH , IGF-I , glucose , lactate , insulin , glycerol , and nonesterified fatty acids ( NEFA ) . In the placebo trial , all subjects completed the exercise protocol without any difficulties . In contrast , two subjects were not able to complete the exercise protocol in the GH trial , and one subject barely managed to complete the protocol . In addition , GH administration result ed in exaggerated increases in plasma lactate concentrations during exercise ( P lipolytic effect of GH and exercise , evidence d by increased plasma glycerol and serum NEFA concentrations , was 3-fold greater than the effect of exercise alone ( P whole body fat oxidation ( indirect calorimetry ) . Plasma glucose was , on average , 9 % higher during exercise after GH administration compared with placebo ( P plasma lactate and glycerol as well as serum NEFA during 90 min of subsequent bicycling at moderate to high intensity . The exaggerated increase in plasma lactate may be associated with substantially decreased exercise performance",
"Objectives Exercise is a potent physiological stimulus of GH secretion . We hypothesized that exogenous recombinant human growth hormone ( rhGH ) administration through an increase in GH and IGF‐I levels would blunt the GH response to exercise . The aim of the study was to examine and compare the impact of rhGH on the exercise‐induced GH response in healthy normal men and women",
"The aim of our hGH application study with non-competitive athletes was the investigation of selected serum parameters from different processes affected by hGH . Fifteen athletes ( age 21–33 , mean 24 ) were treated with 0.06 IU hGH/kg BW per day or placebo ( 10 hGH , 5 placebo ) respectively for 14 days . Blood sample s were taken prior to , during and until 10 weeks after treatment . The concentrations of the following markers were determined in relevant serum sample s : IGF-I , IGFBP-3 , ALS , PIIINP , PINP , osteocalcin , and leptin . The IGF-I concentration increased rapidly within the hGH treatment group and showed significantly higher levels compared to baseline even 3 days after application . The response of the IGFBP-3 to the hGH applications was lower in comparison to IGF-I. The hGH group showed an increasing IGFBP-3 compared to baseline from day 4 till day 15 . The response of PIIINP to hGH is clearly delayed compared to the IGF-I axis , but the PIIINP concentration remains on an increased level for a longer period ( from day 4 until day 21 ) . The time course and the extent of response varied strongly interindividually . PINP and osteocalcin showed only a small response to hGH applications . These parameters are characterised by a strong scattering of base values compared with the small response . In the hGH treatment group very different leptin concentrations were found at the beginning of the study , but after treatment decreasing leptin levels were observed in all cases . The determination of only one parameter will not be sufficient for detection of hGH abuse . A combination of markers by mathematical methods can be helpful to distinguish between placebo and hGH-treated athletes . By using the suggested discriminant function the data sets of hGH and placebo-treated athletes could be separated without false positive results",
"The effect of recombinant GH on strength , body composition and endocrine parameters in power athletes was investigated in a controlled study . Twenty-two healthy , non-obese males ( age 23.4 + /- 0.5 years ; ideal body weight 122 + /- 3.1 % , body fat 10.1 + /- 1.0 % ; mean + /- SEM ) were included . Prob and s were assigned in a double-blind manner to either GH treatment ( 0.09U ( kg BW)-1 day-1 sc ) or placebo for a period of six weeks . To exclude concurrent treatment with and rogenic-anabolic steroids urine specimens were tested at regular intervals for these substances . Serum was assayed for GH , IGF-I , IGF-binding proteins , insulin and thyroxine before the onset of the study and at two-weekly intervals thereafter . Maximal voluntary strength of the biceps and quadriceps muscles was measured on a strength training apparatus . Fat mass and lean body mass were derived from measurements of skinfolds at ten sites with a caliper . For final evaluation only data of those 8 and 10 subjects in the two groups who completed the study were analyzed . GH , IGF-I and IGF-binding protein were in the normal range before therapy and increased significantly in the GH-treated group . Fasting insulin concentrations increased insignificantly and thyroxine levels decreased significantly in the GH-treated prob and s. There was no effect of GH treatment on maximal strength during concentric contraction of the biceps and quadriceps muscles . Body weight and body fat were not changed significantly during treatment . We conclude that the anabolic , lipolytic effect of GH therapy in adults depends on the degree of fat mass and GH deficiency . ( ABSTRACT TRUNCATED AT 250 WORDS",
"OBJECTIVES To determine whether 6 days recombinant human growth hormone ( rhGH ) administration , in an abstinent anabolic- and rogenic steroid ( AAS ) using group had any respiratory , endurance exercise and biochemical effects compared with an abstinent AAS control group . METHODS Male subjects ( n=48 ) were r and omly divided , using a single blind procedure into two groups : ( 1 ) control group ( C ) n=24 , means+/-SD , age 32+/-11 years ; height 1.8+/-0.06 m ; ( 2 ) rhGH using group ( 0.019 mg kg(-1 ) day(-1 ) ) ( GH ) n=24 , means+/-SD , age 32+/-9 years ; height 1.8+/-0.07 m. Anthropometry , respiratory muscle function and endurance exercise were investigated . Respiratory measurements examined , were forced expiratory volume in one second , forced vital capacity , maximum inspiratory pressure and maximum expiratory pressure . Endurance exercise was assessed by measuring peak oxygen uptake ( VO(2)peak ) . Biochemical analysis included ; haemoglobin , packed cell volume , glucose , sodium , urea , creatinine , total protein , albumin , testosterone and insulin like growth factor-I ( IGF-I ) . RESULTS Forced expiratory volume in one second/forced vital capacity , maximum inspiratory pressure , maximum expiratory pressure , and IGF-I significantly increased compared with the control group ( all P Body mass index , fat free mass index , peak oxygen uptake , maximum inspiratory pressure , maximum expiratory pressure , IGF-I and serum sodium significantly increased , whilst body fat , total protein and albumin , significantly decreased within the GH group ( all P rhGH increased aerobic performance and respiratory muscle strength in former AAS users",
"Side effects that can be related to fluid retention are common during the initial phases of growth hormone ( GH ) administration . The aim of this study was to examine the changes in body fluid compartments , diurnal blood pressure and plasma renin concentration during GH administration with two different dosages in healthy adults . Eight healthy male subjects aged 24 - 32 years were examined during three 2-week study periods in a double-blind placebo controlled study . They received , in r and om order , GH ( 3 or 6 IU m-2 daily ) or placebo during 2 weeks . Bio-impedance was measured every 2nd day , and extracellular volume ( ECV ) and plasma volume ( PV ) were isotopically determined at day 6 . Blood sample s were obtained regularly . Diurnal blood pressure was recorded and 24-h urinary sample s were collected at days 0 , 6 and 14 . ECV ( l ) was increased by GH ( placebo , 19.58 + /- 0.82 ; 3 IU m-2 , 20.77 + /- 1.22 ; 6 IU m-2 , 20.65 + /- 0.94 ; p PV ( l ) was unaffected ( placebo , 3.91+/- 0.20 ; 3 IU m-2 , 4.04 + /- 0.22 ; 6 IU m-2 , 3.90 + /- 0.27 ) . Total body water ( l ) increased significantly during GH administration ( placebo , 50.8 + /- 2.6 ; 3 IU m-2 , 52.6 + /- 2.3 ; 6 IU m-2 , 53.9 + /- 1.8 , p renin ( p = 0.03 ) was observed . Mean diurnal blood pressure levels remained unchanged , whereas mean diurnal heart rate ( min-1 ) increased significantly ( placebo , 75 + /- 3.6 ; 3 IU m-2 , 79 + /- 3.2 ; 6 IU m-2 , 79 + /- 3.7 ; p elevation in total body water which may involve a stimulation of plasma renin and an increased ECV without any changes in PV or diurnal blood pressure",
"Measurements of serum insulin-like growth factor I ( IGF-I ) and related markers are routinely used in the diagnosis and treatment of GH deficiency and excess . The validity of these markers for assessment of exogenous GH exposure in healthy adults is , however , unknown . We therefore conducted a double blind , placebo-controlled GH treatment trial in 99 healthy subjects [ 49 women and 50 men ; mean + /- SE age , 25.6+/-0.6 (women)/25.7+/-0.6 yr ( men ) ] . Blood was collected weekly during a 4-week treatment period ( days 1 - 28 ) , and the subjects were subsequently followed for additional 8 weeks ( days 29 - 84 ) . The treatment arms included : I ) 0.1 IU/kg x day GH ( n = 30 ; GH 0.1 ) , II ) 0.2 IU/kg x day GH ( n = 29 ; GH 0.2 ) , and III ) placebo ( n = 40 ) . At baseline no gender-specific differences existed , except that the acid-labile subunit ( ALS ) levels were higher in females . Serum insulin-like growth factor I ( IGF-I ) levels in males receiving GH increased significantly through day 42 with no significant difference between the 2 doses . The absolute IGF-I response was significantly lower in females , and there was a clear dose-response relationship . ALS levels in males increased through day 30 ( P ALS levels were only modestly increased on day 28 compared with those in the placebo group ( P IGF-binding protein-3 ( IGFBP-3 ) levels in males increased significantly in the GH 0.1 and the GH 0.2 groups on day 30 ( P IGFBP-2 levels decreased insignificantly during GH exposure in both genders . A gender-specific upper normal range for each analyte was arbitrarily defined as 4 SD above the mean level at baseline . On the basis of IGF-I levels alone , GH exposure in the GH 0.2 group was detected in 86 % of the males and in 50 % of the females on day 21 . On day 42 GH exposure was only weakly detectable in males and was not detectable in females . We conclude that 1 ) males are significantly more responsive than females to exogenous GH ; 2 ) the increase in IGF-I is more robust compared with those in IGFBP-3 and ALS ; 3 ) IGFBP-2 changes very little during GH treatment ; and 4 ) among IGF-related substances , IGF-I is the most specific marker of supraphysiological GH exposure",
"This study examined whether six days recombinant human growth hormone ( rhGH ) affected psychological profile in an abstinent and rogenic-anabolic steroid ( AAS ) abusing group , compared with an abstinent AAS control group . Male subjects ( n = 48 ) were assigned in a r and om fashion into one of two groups : ( 1 ) : ( n=24 ) control group ( C ) ; ( 2 ) : ( n=24 ) rhGH group ( GH ) . A hospital anxiety scale ( HADS ) question naire was completed by all subjects . Physiological responses investigated included anthropometry . Biochemical markers examined included ; serum glucose , sodium , urea , lipid profile , high sensitivity C-reactive protein ( hsCRP ) , homocysteine ( HCY ) , tetra-iodothyronine ( T4 ) , thyroid stimulating ( TSH ) , luteinising ( LH ) and follicle stimulating ( FSH ) hormones , testosterone ( T ) , prolactin ( PRL ) , cortisol and insulin like growth factor-1 ( IGF-I ) . HADS question naire significantly decreased in both anxiety ( A ) and depression ( D ) symptoms within GH ( P Body mass index ( BMI ) and fat-free mass index ( FFMI ) significantly increased ( both P body fat significantly decreased within GH ( P IGF-I significantly increased within GH ( P Serum sodium significantly increased ( P serum HCY , hsCRP , TSH and T4 , significantly decreased within GH ( all P PRL significantly increased and T4 significantly decreased compared with C ( both P rhGH has beneficial effects on mental state in individuals who were previous abusers of AAS and appeared to have a beneficial effect on cardiovascular risk markers associated with adverse mental health"
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A substantial body of credible evidence has accumulated that suggest that cannabis use is an important potentially preventable risk factor for the development of psychotic illness and its worse prognosis following the onset of psychosis . Here we summarize the relevant evidence to argue that the time has come to investigate the neurobiological effects of cannabis in patients with psychotic disorders . In the first section we summarize evidence from longitudinal studies that controlled for a range of potential confounders of the association of cannabis use with increased risk of developing psychotic disorders , increased risk of hospitalization , frequent and longer hospital stays , and failure of treatment with medications for psychosis in those with established illness . Although some evidence has emerged that cannabis-using and non-using patients with psychotic disorders may have distinct patterns of neurocognitive and neurodevelopmental impairments , the biological underpinnings of the effects of cannabis remain to be fully eluci date d. In the second and third sections we undertake a systematic review of 70 studies , including over 3000 patients with psychotic disorders or at increased risk of psychotic disorder , in order to delineate potential neurobiological and neurochemical mechanisms that may underlie the effects of cannabis in psychotic disorders and suggest avenues for future research
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"Cannabidiol is a component of marijuana that does not activate cannabinoid receptors , but moderately inhibits the degradation of the endocannabinoid an and amide . We previously reported that an elevation of an and amide levels in cerebrospinal fluid inversely correlated to psychotic symptoms . Furthermore , enhanced an and amide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition . In our translational approach , we performed a double-blind , r and omized clinical trial of cannabidiol vs amisulpride , a potent antipsychotic , in acute schizophrenia to evaluate the clinical relevance of our initial findings . Either treatment was safe and led to significant clinical improvement , but cannabidiol displayed a markedly superior side-effect profile . Moreover , cannabidiol treatment was accompanied by a significant increase in serum an and amide levels , which was significantly associated with clinical improvement . The results suggest that inhibition of an and amide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia",
"AIMS To assess if cannabis use is a risk factor for future psychotic symptoms , and vice versa , in adolescents and young adults from the general population . DESIGN Cohort study . SETTING / PARTICIPANTS ' Zuid Holl and ' study , a 14-year follow-up study of 1580 initially 4 - 16-year-olds who were drawn r and omly from the Dutch general population . Because cannabis use is generally condoned in the Netherl and s , false-negative reports of cannabis use may occur less frequently than in countries with stricter drug policies , which supports the value of the present study . MEASUREMENTS Life-time cannabis use and psychotic symptoms , assessed with the Composite International Diagnostic Interview ( CIDI ) . FINDINGS Cannabis use , in individuals who did not have psychotic symptoms before they began using cannabis , predicted future psychotic symptoms ( hazard ratio = 2.81 ; 95 % confidence interval = 1.79 - 4.43 ) . However , psychotic symptoms in those who had never used cannabis before the onset of psychotic symptoms also predicted future cannabis use ( hazard ratio = 1.70 ; 95 % confidence interval = 1.13 - 2.57 ) . CONCLUSIONS The results imply either a common vulnerability with varying order of onset or a bi-directional causal relationship between cannabis use and psychosis . More research on patterns and timings of these relationships is needed to narrow down the possibilities",
"OBJECTIVE Research in both animals and humans indicates that cannabidiol ( CBD ) has antipsychotic properties . The authors assessed the safety and effectiveness of CBD in patients with schizophrenia . METHOD In an exploratory double-blind parallel-group trial , patients with schizophrenia were r and omized in a 1:1 ratio to receive CBD ( 1000 mg/day ; N=43 ) or placebo ( N=45 ) alongside their existing antipsychotic medication . Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale ( PANSS ) , the Brief Assessment of Cognition in Schizophrenia ( BACS ) , the Global Assessment of Functioning scale ( GAF ) , and the improvement and severity scales of the Clinical Global Impressions Scale ( CGI-I and CGI-S ) . RESULTS After 6 weeks of treatment , compared with the placebo group , the CBD group had lower levels of positive psychotic symptoms ( PANSS : treatment difference=-1.4 , 95 % CI=-2.5 , -0.2 ) and were more likely to have been rated as improved ( CGI-I : treatment difference=-0.5 , 95 % CI=-0.8 , -0.1 ) and as not severely unwell ( CGI-S : treatment difference=-0.3 , 95 % CI=-0.5 , 0.0 ) by the treating clinician . Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance ( BACS : treatment difference=1.31 , 95 % CI=-0.10 , 2.72 ) and in overall functioning ( GAF : treatment difference=3.0 , 95 % CI=-0.4 , 6.4 ) . CBD was well tolerated , and rates of adverse events were similar between the CBD and placebo groups . CONCLUSIONS These findings suggest that CBD has beneficial effects in patients with schizophrenia . As CBD 's effects do not appear to depend on dopamine receptor antagonism , this agent may represent a new class of treatment for the disorder",
"BACKGROUND Trajectory patterns of positive , disorganized and negative dimension symptoms during antipsychotic treatment in drug-naive patients with first-episode psychosis have yet to be examined by using naturalistic data . METHOD This pragmatic clinical trial r and omized 161 drug-naive patients with a first episode of psychosis to olanzapine , risperidone or haloperidol . Patients were assessed with the Scale for the Assessment of Negative Symptoms ( SANS ) and Positive Symptoms ( SAPS ) at baseline and at the end of weeks 1 , 2 , 3 , 4 and 6 of antipsychotic treatment . Censored normal models of response trajectories were developed with three dimensions of the SAPS-SANS scores ( positive , disorganized and negative ) in order to identify the different response trajectories . Diagnosis , cannabis use , duration of untreated psychosis ( DUP ) , smoking and antipsychotic class were examined as possible predictive variables . RESULTS Patients were classified in five groups according to the positive dimension , three groups according to the disorganized dimension and five groups according to the negative dimension . Longer DUPs and cannabis use were associated with higher scores and poorer responses in the positive dimension . Cannabis use was associated with higher scores and poorer responses in the disorganized dimension . Only schizophrenia diagnosis was associated with higher scores and poorer responses in the negative dimension . CONCLUSIONS Our results illustrate the heterogeneity of short-term response to antipsychotics in patients with a first episode of psychosis and highlight markedly different patterns of response in the positive , disorganized and negative dimensions . DUP , cannabis use and diagnosis appeared to have a prognostic value in predicting treatment response with different implication s for each dimension",
"OBJECTIVE Cannabis use disorders ( CUDs ) are highly comorbid in patients with schizophrenia and associated with poor outcome . Clozapine has been put forward as the first choice antipsychotic in this patient group . However , little is known about the mechanisms underlying the assumed superiority of clozapine . METHODS A total of 38 patients with DSM-IV schizophrenia ( 30 with and 8 without a DSM-IV CUD ) and 20 healthy comparison subjects were included between April 2009 and June 2012 . Patients were r and omized to antipsychotic treatment with clozapine or risperidone . At baseline and after 4weeks of medication , brain response to cannabis-related , positive and neutral images was measured using functional MRI . Neural correlates of cue reactivity were assessed in the following regions of interest : amygdala , ventral striatum , insula , thalamus , orbitofrontal cortex and anterior cingulate cortex . Subjective craving was assessed using self-report question naires ( OCDUS and MCQ ) . RESULTS At baseline , patients with a comorbid CUD showed higher subjective craving and greater activation in response to cannabis-related images compared to patients without a CUD and healthy controls in most regions of interest . Clozapine treated patients reported a greater reduction in craving ( F(1,28)=6.0 , p=0.04 ) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone treated patients ( T=3.94 , pFWE=0.006 ) . In addition , significant correlations were found between subjective craving and thalamus and insula activation during cannabis-related images . CONCLUSION These findings provide evidence that clozapine is superior to risperidone in decreasing subjective craving and cue reactivity for cannabis-related images probably due to a differential effect on dopaminergic neurotransmission . TRIAL REGISTRATION ' Nederl and s trial register ' ( http://www.trialregister.nl ) , nr NTR1761 , http://www.trialregister.nl/trialreg/admin/ rct view.asp?TC=1761",
"Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health . Concomitantly , adolescents are initiating cannabis use at younger ages , and more adolescents are using cannabis on a daily basis . The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users . Participants were members of the Dunedin Study , a prospect i ve study of a birth cohort of 1,037 individuals followed from birth ( 1972/1973 ) to age 38 y. Cannabis use was ascertained in interviews at ages 18 , 21 , 26 , 32 , and 38 y. Neuropsychological testing was conducted at age 13 y , before initiation of cannabis use , and again at age 38 y , after a pattern of persistent cannabis use had developed . Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning , even after controlling for years of education . Informants also reported noticing more cognitive problems for persistent cannabis users . Impairment was concentrated among adolescent-onset cannabis users , with more persistent use associated with greater decline . Further , cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users . Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents",
"Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase ( COMT Val158Met ) gene moderate the psychosis-inducing effect of cannabis . To replicate and extend this finding , a double-blind , placebo-controlled cross-over design was used in which patients with a psychotic disorder ( n=30 ) , relatives of patients with a psychotic disorder ( n=12 ) , and healthy controls ( n=32 ) were exposed to Δ-9-tetrahydrocannabinol ( Δ-9-THC , the principal component of cannabis ) or placebo , followed by cognitive assessment and assessment of current psychotic experiences . Previous expression of psychometric psychosis liability was also assessed . Models of current psychotic experiences and cognition were examined with multilevel r and om regression analyses to assess ( i ) main effects of genotype and condition , ( ii ) interactions between condition and genotype , and ( iii ) three-way interactions between condition , genotype , and psychometric psychosis liability . Carriers of the Val allele were most sensitive to Δ-9-THC-induced psychotic experiences , but this was conditional on prior evidence of psychometric psychosis liability . Δ-9-THC impacted negatively on cognitive measures . Carriers of the Val allele were also more sensitive to Δ-9-THC-induced memory and attention impairments compared to carriers of the Met allele . Experimental effects of Δ-9-THC on cognition and psychosis are moderated by COMT Val158Met genotype , but the effects may in part be conditional on the additional presence of pre-existing psychosis liability . The association between cannabis and psychosis may represent higher order gene – environment and gene – gene interactions",
"BACKGROUND Cannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear . The objective of this study was to assess prospect ively the influence of cannabis use on transition to psychosis in people at ultra-high risk ( UHR ) for the disorder . METHOD Lifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people ( 104 male , 78 female ) at UHR for psychosis . Individuals were then followed clinical ly for 2 years to determine their clinical outcomes . RESULTS Lifetime cannabis use was reported by 134 individuals ( 73.6 % ) . However , most of these individuals had stopped using cannabis before clinical presentation ( n=98 , 73.1 % ) , usually because of adverse effects . Among lifetime users , frequent use , early-onset use and continued use after presentation were all associated with an increase in transition to psychosis . Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently ( frequent early-onset use : 25 % ; infrequent or late-onset use : 5 % ; χ(2)1=10.971 , p=0.001 ) . However , within the whole sample , cannabis users were no more likely to develop psychosis than those who had never used cannabis ( cannabis use : 12.7 % ; no use : 18.8 % ; χ(2)1=1.061 , p=0.303 ) . CONCLUSIONS In people at UHR for psychosis , lifetime cannabis use was common but not related to outcome . Among cannabis users , frequent use , early-onset use and continued use after clinical presentation were associated with transition to psychosis ",
"Neurotrophins such as nerve growth factor ( NGF ) and brain-derived neurotrophic factor ( BDNF ) are important for the development and maintenance of neuron function . Neurodevelopment is thought to be impaired in schizophrenia , and vulnerable schizophrenic brains may be more sensitive to toxic influences . Thus , cannabis as a neurotoxin ( and other substances ) may be more harmful to schizophrenic brains than to non-schizophrenic brains , when used chronically . In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia . We therefore investigated whether this difference is still observed after treatment . Serum NGF measured in 114 treated schizophrenic patients ( schizophrenia alone , n=66 ; schizophrenia plus cannabis abuse , n=42 ; schizophrenia plus multiple substance abuse , n=6 ) no longer differed significantly among those groups and from the control groups ( healthy controls , n=51 ; cannabis controls , n=24 ; multiple substance controls , n=6 ) . These results were confirmed by an additional prospect i ve study in 28 patients suffering from schizophrenia ( S ) or schizophrenia with cannabis abuse ( SC ) . Previously elevated serum NGF levels in the drug-naïve state , also differing between the groups ( S : 83.44+/-265.25 pg/ml ; SC : 246.89+/-310.24 pg/ml , S versus SC : p=0.03 ) dropped to 10.72+/-14.13 pg/ml ( S ) and 34.19+/-38.96 pg/ml ( SC ) ( S versus SC , p>0.05 ) , respectively , after adequate antipsychotic treatment . We thus conclude that antipsychotic treatment leads to recovery of neural integrity , as indicated by renormalized NGF values",
"Non-technical summary Inter-individual differences in regional GABA as assessed by magnetic resonance spectroscopy ( MRS ) relate to behavioural variation in humans . However , it is not clear what the relationship is between MRS measures of the concentration of neurotransmitters in a region and synaptic activity . Transcranial magnetic stimulation ( TMS ) techniques provide physiological measures of cortical excitation or inhibition . Here , we investigated the relationship between MRS and TMS measures of glutamatergic and GABAergic activity within the same individuals . We demonstrated a relationship between MRS-assessed glutamate levels and a TMS measure of global cortical excitability , suggesting that MRS measures of glutamate do reflect glutamatergic activity . However , there was no clear relationship between MRS-assessed GABA levels and TMS measures of synaptic GABAA or GABAB activity . A relationship was found between MRS-assessed GABA and a TMS protocol with less clearly understood physiological underpinnings . We speculate that this protocol may therefore reflect extrasynaptic GABA tone",
"Ventricular enlargement and reduced prefrontal volume are consistent findings in schizophrenia . Both are present in first episode subjects and may be detectable before the onset of clinical disorder . Substance misuse is more common in people with schizophrenia and is associated with similar brain abnormalities . We employ a prospect i ve cohort study with nested case control comparison design to investigate the association between substance misuse , brain abnormality , and subsequent schizophrenia . Substance misuse history , imaging data , and clinical information were collected on 147 subjects at high risk of schizophrenia and 36 controls . Regions exhibiting a significant relationship between level of use of alcohol , cannabis or tobacco , and structure volume were identified . Multivariate regression then eluci date d the relationship between level of substance use and structure volumes while accounting for correlations between these variables and correcting for potential confounders . Finally , we established whether substance misuse was associated with later risk of schizophrenia . Increased ventricular volume was associated with alcohol and cannabis use in a dose-dependent manner . Alcohol consumption was associated with reduced frontal lobe volume . Multiple regression analyses found both alcohol and cannabis were significant predictors of these abnormalities when simultaneously entered into the statistical model . Alcohol and cannabis misuse were associated with an increased subsequent risk of schizophrenia . We provide prospect i ve evidence that use of cannabis or alcohol by people at high genetic risk of schizophrenia is associated with brain abnormalities and later risk of psychosis . A family history of schizophrenia may render the brain particularly sensitive to the risk-modifying effects of these substances",
"BACKGROUND Epidemiological findings suggest that cannabis use is a risk factor for the emergence of psychosis , and that the induction of psychotic symptoms in the context of cannabis use may be associated with a pre-existing vulnerability for psychosis . This study investigated in a non- clinical population the interaction between cannabis use and psychosis vulnerability in their effects on psychotic experiences in daily life . METHOD Subjects ( N = 79 ) with high or low levels of cannabis use were selected among a sample of 685 undergraduate university students . Experience sampling method ( ESM ) was used to collect information on substance use and psychotic experiences in daily life . Vulnerability to develop psychosis was measured using a clinical interview assessing the level of psychotic symptoms . Statistical analyses were performed using multilevel linear r and om regression models . RESULTS The acute effects of cannabis are modified by the subject 's level of vulnerability for psychosis . Subjects with high vulnerability for psychosis are more likely to report unusual perceptions as well as feelings of thought influence than subjects with low vulnerability for psychosis , and they are less likely to experience enhanced feelings of pleasure associated with cannabis . There is no evidence that use of cannabis is increased following occurrence of psychotic experiences as would be expected by the self-medication model . CONCLUSION Cannabis use interacts with psychosis vulnerability in their effects on experience of psychosis in daily life . The public health impact of the widespread use of cannabis may be considerable",
"Recent advances in the underst and ing of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis . In a 3-day , double-blind , r and omized , and counterbalanced study , the behavioral , cognitive , and endocrine effects of 0 , 2.5 , and 5 mg intravenous delta-9-tetrahydrocannabinol ( Δ-9-THC ) were characterized in 22 healthy individuals , who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder . Prospect i ve safety data at 1 , 3 , and 6 months post study was also collected . Δ-9-THC ( 1 ) produced schizophrenia-like positive and negative symptoms ; ( 2 ) altered perception ; ( 3 ) increased anxiety ; ( 4 ) produced euphoria ; ( 5 ) disrupted immediate and delayed word recall , sparing recognition recall ; ( 6 ) impaired performance on tests of distractibility , verbal fluency , and working memory ( 7 ) did not impair orientation ; ( 8) increased plasma cortisol . These data indicate that Δ-9-THC produces a broad range of transient symptoms , behaviors , and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses . These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders",
"CONTEXT Prospect i ve cohort studies have identified an association between cannabis use and later psychosis-related outcomes , but concerns remain about unmeasured confounding variables . The use of sibling pair analysis reduces the influence of unmeasured residual confounding . OBJECTIVE To explore the association between cannabis use and psychosis-related outcomes . DESIGN A sibling pair analysis nested within a prospect i ve birth cohort . SETTING Births at a Brisbane , Australia , hospital . PARTICIPANTS Three thous and eight hundred one young adults born between 1981 and 1984 as part of the Mater-University Study of Pregnancy . MAIN OUTCOME MEASURES Cannabis use and 3 psychosis-related outcomes ( nonaffective psychosis , hallucinations , and Peters et al Delusions Inventory score ) were assessed at the 21-year follow-up . Associations between duration since first cannabis use and psychosis-related outcomes were examined using logistic regression adjusted for sex , age , parental mental illness , and hallucinations at the 14-year follow-up . Within 228 sibling pairs , the association between within-pair differences in duration since first cannabis use and Peters et al Delusions Inventory score was examined with general linear modeling . The potential impact of attrition was examined . RESULTS Duration since first cannabis use was associated with all 3 psychosis-related outcomes . For those with duration since first cannabis use of 6 or more years , there was a significantly increased risk of ( 1 ) nonaffective psychosis ( adjusted odds ratio , 2.2 ; 95 % confidence interval , 1.1 - 4.5 ) , ( 2 ) being in the highest quartile of Peters et al Delusions Inventory score ( adjusted odds ratio , 4.2 ; 95 % confidence interval , 4.2 - 5.8 ) , and ( 3 ) hallucinations ( adjusted odds ratio , 2.8 ; 95 % confidence interval , 1.9 - 4.1 ) . Within sibling pairs , duration since first cannabis use and higher scores on the Peters et al Delusions Inventory remained significantly associated . CONCLUSIONS Early cannabis use is associated with psychosis-related outcomes in young adults . The use of sibling pairs reduces the likelihood that unmeasured confounding explains these findings . This study provides further support for the hypothesis that early cannabis use is a risk-modifying factor for psychosis-related outcomes in young adults",
"CONTEXT Cannabis sativa use can impair verbal learning , provoke acute psychosis , and increase the risk of schizophrenia . It is unclear where C. sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms . OBJECTIVES To investigate the effects of 2 main psychoactive constituents of C. sativa , Delta9-tetrahydrocannabinol ( Delta9-THC ) and cannabidiol , on regional brain function during verbal paired associate learning . DESIGN Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task . Each imaging session was preceded by the ingestion of Delta9-THC ( 10 mg ) , cannabidiol ( 600 mg ) , or placebo in a double-blind , r and omized , placebo-controlled , repeated- measures , within-subject design . SETTING University research center . PARTICIPANTS Fifteen healthy , native English-speaking , right-h and ed men of white race/ethnicity who had used C. sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygen level-dependent response ) , performance in a verbal learning task , and objective and subjective ratings of psychotic symptoms , anxiety , intoxication , and sedation . RESULTS Delta9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety , intoxication , and sedation , whereas no significant effect was noted on these parameters following administration of cannabidiol . Performance in the verbal learning task was not significantly modulated by either drug . Administration of Delta9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident . Delta9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs , which was directly correlated with concurrently induced psychotic symptoms . In contrast , administration of cannabidiol had no such effect . CONCLUSION The modulation of mediotemporal and ventrostriatal function by Delta9-THC may underlie the effects of C. sativa on verbal learning and psychotic symptoms , respectively",
"The aim of the presented study was to compare schizophrenia and schizoaffective patients early in the course of the disease with and without comorbid substance abuse disorder ( SUD vs. NSUD ) with regard to brain morphology . In a prospect i ve design 41 patients ( 20 SUD vs. 21 NSUD ) diagnosed as recent-onset schizophrenia or schizoaffective disorder consecutively admitted to hospital received st and ardized psychopathological evaluation ( BPRS , SANS , MADRS , CGI , GAF ) and MRI scanning with volumetric measurement of superior temporal gyrus ( STG ) , amygdala-hippocampal complex , and cingulum . Patients with SUD ( primarily cannabis ) were significantly younger , predominantly male and had a lower socioeconomic status . Despite less attentional impairment ( SANS subscore ) and elevated anxiety/depression ( BPRS subscore ) in patients with SUD compared to NSUD , no other psychopathological differences could be detected . There were no differences in the assessed temporolimbic brain morphology between the two subgroups . In conclusion , in this study substance abuse in recent-onset psychosis had no effect on brain morphology and the earlier onset of psychosis in patients with comorbid SUD could not be explained by supposed accentuated brain abnormalities in temporolimbic regions",
"Cannabis consumption is temporally associated with the development of first episode psychosis ( FEP ) . Whether or not the chronic use of this substance induces structural brain changes that may be responsible for the cognitive and psychological disturbances in this disorder is still matter of debate . To address this issue , we compared the magnetic resonance imaging (MRI)-assessed grey ( GM ) and white matter ( WM ) changes in young FEP patients between users versus non-users of cannabis . This prospect i ve study included 50 consecutive FEP subjects : 33 users ( 22.7 ± 4.1 years , 4 women ) and 17 non-users ( 23.9 ± 4.2 years , 10 women ) . Users were further divided into 15 heavy ( 23.3 ± 4.5 years , 2 women ) and 18 light users ( 22.2 ± 3.8 years , 2 women ) according to their lifetime cannabis use . Voxel-based-morphometry ( VBM ) analysis of GM and tract-based-spatial-statistics ( TBSS ) analysis of WM were performed . Age and gender were used as non-explanatory co-regressors . There were no supra-threshold differences between user and non-user groups for both GM and WM parameters . This was also the case when only heavy users were compared to non-users . Multivariate models controlling for age and gender confirmed these findings . We found no evidence for cannabis consumption related alterations in GM or WM in FEP subjects . Due to the strict correction for multiple comparisons and sample size , we can not formally exclude subtle morphometric changes associated with cannabis consumption . However , even if present , such potential alterations would be of low magnitude",
"BACKGROUND The relationship between cannabis use and cognitive functioning in patients with psychosis has yielded contradictory findings . In individuals at genetic high risk for psychosis , information is sparse . The aim of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in patients with psychosis and their unaffected siblings . METHOD We conducted a cross-sectional study in 956 patients with non-affective psychosis , 953 unaffected siblings , and 554 control subjects . Participants completed a cognitive test battery including assessment s of verbal learning , set shifting , sustained attention , processing speed , working memory , acquired knowledge , reasoning and problem solving and social cognition . Cannabis use was assessed by urinalysis and by the Composite International Diagnostic Interview . Using r and om-effect regression models the main effects of cannabis ( recency and frequency ) and the interaction with status ( patient , sibling , control ) on cognitive functioning were assessed . RESULTS Current cannabis use was associated with poorer performance on immediate verbal learning , processing speed and working memory ( Cohen 's d -0.20 to -0.33 , p performance on acquired knowledge , facial affect recognition and face identity recognition ( Cohen 's d+0.17 to + 0.33 , p status on cognitive functioning . CONCLUSIONS Lifetime cannabis-using individuals might constitute a subgroup with a higher cognitive potential . The residual effects of cannabis may impair short-term memory and processing speed",
"Summary Background Cannabis use following the onset of first-episode psychosis has been linked to both increased risk of relapse and non-adherence with antipsychotic medication . Whether poor outcome associated with cannabis use is mediated through an adverse effect of cannabis on medication adherence is unclear . Methods In a prospect i ve analysis of data acquired from four different adult inpatient and outpatient units of the South London and Maudsley Mental Health National Health Service Foundation Trust in London , UK , 245 patients were followed up for 2 years from the onset of first-episode psychosis . Cannabis use after onset of psychosis was assessed by self-reports in face-to-face follow-up interviews . Relapse data were collected from clinical notes using the WHO Life Chart Schedule . This measure was also used to assess medication adherence on the basis of both face-to-face interviews and clinical notes . Patients were included if they had a diagnosis of first-episode non-organic or affective psychosis according to ICD-10 criteria , and were aged between 18 and 65 years when referred to local psychiatric services . We used structural equation modelling analysis to estimate whether medication adherence partly mediated the effects of continued cannabis use on risk of relapse . The primary outcome variable was relapse , defined as admission to a psychiatric inpatient unit after exacerbation of symptoms within 2 years of first presentation to psychiatric services . Information on cannabis use over the first 2 years after onset of psychosis was investigated as a predictor variable for relapse . Medication adherence was assessed as a mediator variable on the basis of clinical records and self-report data . Study research ers ( TS , NP , EK , and EF ) rated the adherence . Findings 397 patients who presented with their first episode of psychosis between April 12 , 2002 , and July 26 , 2013 had a follow-up assessment until September , 2015 . Of the 397 patients approached for followed up , 133 refused to take part in this study and 19 could not be included because of missing data . 91 ( 37 % ) of 245 patients with first-episode psychosis had a relapse over the 2 years of follow-up . Continued cannabis use predicted poor outcome , including risk of relapse , number of relapses , length of relapse , and care intensity at follow-up . In controlled structural equation modelling analyses , medication adherence partly mediated the effect of continued cannabis use on outcome , including risk of relapse ( proportion mediated=26 % , βindirect effects=0·08 , 95 % CI 0·004 to 0·16 ) , number of relapses ( 36 % , βindirect effects=0·07 , 0·003 to 0·14 ) , time until relapse ( 28 % , βindirect effects=–0·26 , −0·53 to 0·001 ) and care intensity ( 20 % , βindirect effects=0·06 , 0·004 to 0·11 ) but not length of relapse ( 6 % , βindirect effects=0·03 , −0·03 to 0·09 ) . The adjusted models explained moderate amounts of variance for outcomes defined as risk of relapse ( R2=0·25 ) , number of relapses ( R2=0·21 ) , length of relapse ( R2=0·07 ) , time until relapse ( R2=0·08 ) , and care intensity index ( R2=0·15 ) . Interpretation Between 20 % and 36 % of the adverse effects of continued cannabis use on outcome in psychosis might be mediated through the effects of cannabis use on medication adherence . Interventions directed at medication adherence could partly help mitigate the harm from cannabis use in psychosis . Funding This study is funded by the National Institute of Health Research ( NIHR ) Clinician Scientist award",
"BACKGROUND This study examined the effect of Delta-9-tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) on brain activation during a motor inhibition task . METHODS Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed a Go/No-Go task following administration of either THC or CBD or placebo in a double-blind , pseudo-r and omized , placebo-controlled repeated measures within-subject design . RESULTS Relative to placebo , THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus . In contrast , CBD deactivated the left temporal cortex and insula . These effects were not related to changes in anxiety , intoxication , sedation , and psychotic symptoms . CONCLUSIONS These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition . CBD modulated function in regions not usually implicated in response inhibition",
"Importance Cannabis use after first-episode psychosis is associated with poor outcomes , but the causal nature of this association is unclear . Objective To examine the precise nature of the association between continued cannabis use after the onset of psychosis and risk of relapse of psychosis . Design , Setting , and Participants This prospect i ve cohort study followed up for at least 2 years after the onset of psychosis 220 patients who presented to psychiatric services in South London , Engl and , from April 12 , 2002 , to July 26 , 2013 , with first-episode psychosis . Longitudinal modeling ( fixed-effects analysis , cross-lagged path analysis ) was used to examine whether the association between changes in cannabis use and risk of relapse over time is the result of shared vulnerability between psychosis and cannabis use , psychosis increasing the risk of cannabis use ( reverse causation ) , or a causal effect of cannabis use on psychosis relapse . Interventions Exposure to cannabis within the first and second years after onset of psychosis . Main Outcomes and Measures The main outcome measure was relapse of psychosis , defined as subsequent hospitalization for psychosis . Effect of cannabis use status in the first year ( Ct1 ) and second year ( Ct2 ) and pattern of cannabis use continuation in the first year and second year were modeled for risk of relapse in the first year ( Rt1 ) and risk of relapse in the second year ( Rt2 ) after psychosis onset . Results A total of 220 patients with first-episode psychosis were included in the analysis ( mean [ SD ] age , 28.62 [ 8.58 ] years ; age range , 18 - 65 years ; 90 women [ 40.9 % ] and 130 men [ 59.1 % ] ) . Fixed-effects models that adjusted for time-variant ( other illicit drug use , antipsychotic medication adherence ) and time-invariant ( eg , genetic or premorbid environment ) unobserved confounders revealed that there was an increase in the odds of experiencing a relapse of psychosis during periods of cannabis use relative to periods of no use ( odds ratio , 1.13 ; 95 % CI , 1.03 - 1.24 ) . Change in the pattern of continuation significantly increased the risk ( odds ratio , 1.07 ; 95 % CI , 1.02 - 1.13 ) , suggesting a dose-dependent association . Cross-lagged analysis confirmed that this association reflected an effect of cannabis use on subsequent risk of relapse ( Ct1→Rt2 : β = 0.44 , P = .04 ) rather than an effect of relapse on subsequent cannabis use ( Rt1→Ct2 : β = -0.29 , P = .59 ) . Conclusions and Relevance These results reveal a dose-dependent association between change in cannabis use and relapse of psychosis that is unlikely to be a result of self-medication or genetic and environmental confounding",
"Cannabis use disorders ( CUDs ) are highly comorbid in patients with schizophrenia and are associated with poor outcome . Clozapine has been put forward as the first choice antipsychotic in this comorbid group . However , little is known about the mechanisms underlying the assumed superiority of clozapine . We compared the effects of clozapine and risperidone on attentional bias , subjective craving and associated regional brain activity in patients with schizophrenia and CUD . Overall , 36 patients with schizophrenia and 19 healthy controls were included . Patients were r and omised to antipsychotic treatment with clozapine or risperidone . At baseline and after 4 weeks of medication use , regional brain responses were measured during a classical Stroop and a cannabis word Stroop using functional magnetic resonance imaging . Clozapine-treated CUD patients showed a larger reduction in craving and in activation of the insula during the cannabis word Stroop , while risperidone-treated patients showed a larger decrease in activation of the right anterior cingulate cortex during the classical Stroop . A significant association was found between decreases in subjective craving and decreases in insula activation during the cannabis word Stroop . These findings strongly suggest that clozapine may be a better treatment choice in patients with schizophrenia and CUD than risperidone",
"Structural alterations of the brain in schizophrenia have been associated with genetic and environmental factors . Among the environmental factors , cannabis use has been associated with increased risk for patients with schizophrenia , but the effect of cannabis on their brain structure is unclear . We examined gray matter alterations in first episode schizophrenia patients ( FES ) with cannabis use ( FES+C ; n=15 ) compared to FES without cannabis use ( FES-C ; n=24 ) and 42 healthy controls who did not use cannabis . We conducted a voxel based morphometric analysis of a priori determined regions of interest consisting of the CB1 receptor rich brain regions . We observed a decrease in gray matter density in the right posterior cingulate cortex ( PCC ) in FES+C when compared with FES-C. The results suggest that cannabis use may be associated with altered brain structure , in particular regions rich in CB1 receptors . These findings need to be confirmed by larger , prospect i ve studies",
"Intravenous ( IV ) Δ9-tetrahydrocannabinol ( THC ) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients , but the psychotomimetic mechanism is unknown . One possibility is that THC stimulates dopamine ( DA ) release in the striatum . In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo . We also investigated whether DA release and positive psychotic symptoms were related . Eleven healthy male volunteers completed two 123I-iodobenzamide ( [123I]IBZM ) single photon emission tomography ( SPET ) sessions and received IV THC ( 2.5 mg ) or placebo in a r and omized counterbalanced order , under double-blind conditions . Analysable data were obtained from nine participants . The Positive and Negative Syndrome Scale ( PANSS ) was used to rate psychotomimetic effects . Striatal binding index values were calculated using the occipital cortex as a reference region . Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC . There were no significant differences in binding index in the cau date or putamen under THC compared to placebo conditions . Positive psychotic symptoms and DA release were unrelated . THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms . These findings do not support a central role for striatal DA in THC-elicited psychosis",
"BACKGROUND Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders . METHODS In a 3-day , double-blind , r and omized , placebo-controlled study , the behavioral , cognitive , motor , and endocrine effects of 0 mg , 2.5 mg , and 5 mg intravenous Delta-9-tetrahydrocannabinol ( Delta-9-THC ) were characterized in 13 stable , antipsychotic-treated schizophrenia patients . These data were compared with effects in healthy subjects reported elsewhere . RESULTS Delta-9-tetrahydrocannabinol transiently increased 1 ) learning and recall deficits ; 2 ) positive , negative , and general schizophrenia symptoms ; 3 ) perceptual alterations ; 4 ) akathisia , rigidity , and dyskinesia ; 5 ) deficits in vigilance ; and 6 ) plasma prolactin and cortisol . Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects . There were no serious short- or long-term adverse events associated with study participation . CONCLUSIONS Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia . These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis . Furthermore , Delta-9-THC might differentially affect schizophrenia patients relative to control subjects . Finally , the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia",
"BACKGROUND Findings are unclear as to whether cannabis use is associated with better cognitive functioning in individuals with psychosis . OBJECTIVES To eluci date the association between cannabis use , neurocognition and social cognition in first-episode psychosis ( FEP ) . METHODS Secondary data analysis was conducted on data from 133 FEP participants who had enrolled in a r and omized controlled trial of a vocational intervention . Participants completed a neurocognitive and social cognitive battery and characteristics of cannabis use were documented ( disorder , recency , frequency and dose ) . Principal axis factor analysis was used to determine the underlying structure of the cognitive batteries . Regression techniques were used to examine cognitive predictors of current cannabis use disorder ( CUD ) , and recency and frequency of cannabis use . Bivariate correlations were used to examine associations between cognition and dose of cannabis consumption . RESULTS Male gender ( p=.037 ) was the only significant predictor of having a current CUD . Better processing speed ( p=.022 ) and social cognition ( p=.039 ) , male gender ( p fewer negative symptoms ( p=.036 ) predicted recency of cannabis use . Faster processing speed ( p=.007 ) and male gender ( p=.006 ) also predicted frequency of cannabis use . No variables were significantly associated with dose of cannabis consumption . CONCLUSIONS Better social cognition and processing speed abilities predicting recency and frequency of cannabis use are consistent with cannabis users having higher cognitive abilities . A positive relationship between cannabis use and cognition may be the result of more drug taking opportunities in less cognitively impaired individuals with psychosis",
"Papers pp 1195 , 1199 The strongest evidence that cannabis use may be a risk factor for later psychosis comes from a Swedish cohort study which found that heavy cannabis use at age 18 increased the risk of later schizophrenia sixfold . 1 2 This study could not establish whether adolescent cannabis use was a consequence of pre-existing psychotic symptoms rather than a cause . We present the first prospect i ve longitudinal study of adolescent cannabis use as a risk factor for adult schizophreniform disorder , taking into account childhood psychotic symptoms3 antedating cannabis use . View this table : Association between cannabis use in adolescence and schizophrenia and depressive symptoms and disorders at age 26 ( n=759 ) , controlling for childhood psychotic symptoms and use of other drugs in adolescence The Dunedin multidisciplinary health and development study ( a study of a general population birth cohort of 1037 individuals born in Dunedin , New Zeal and , in 1972 - 3)4 has a 96 % follow up rate at age 26 . It obtained information on psychotic symptoms at age 11 and drug use at ages 15 and 18 from self reports and assessed",
"BACKGROUND Cannabis use is reported to increase the risk for psychosis , but no prospect i ve study has longitudinally examined drug use and symptoms concurrently in clinical high risk cases . METHOD We prospect ively followed for up to 2 years 32 cases who met research criteria for prodromal psychosis to examine the relationship between substance use and clinical measures . RESULTS Cases with a baseline history of cannabis use ( 41 % ) were older , but did not differ in clinical measures . Longitudinal assessment s showed these cases had significantly more perceptual disturbances and worse functioning during epochs of increased cannabis use that were unexplained by concurrent use of other drugs or medications . CONCLUSIONS These data demonstrate that cannabis use may be a risk factor for the exacerbation of subthreshold psychotic symptoms , specifically perceptual disturbances , in high risk cases",
"OBJECTIVE To prospect ively assess the relationship between cannabis use and psychotic experiences over time . METHOD In a longitudinal design , young adults aged 18 - 27years ( N=705 ) gave online information on cannabis use and completed the Community Assessment of Psychic Experiences ( CAPE ) . These measures were repeated after an interval ranging from six months to five years . RESULTS A decrease in cannabis use was associated with a decrease in total psychotic experiences ( β=-0.096 , p=0.01 ) after adjustment for a range of potential confounders . An increase in cannabis use was associated with increased positive symptoms at follow-up ( β=0.07 , p=0.02 ) , but was not significantly associated with increases in Negative and Depression symptom scores , nor with the total number of psychotic experiences . CONCLUSION In the first study to the association of change in cannabis use and psychotic experiences over time in the general population , we found an association between changes in cannabis use and changes in the frequency of psychotic experiences . While this does not prove a causal relationship between cannabis use and psychosis , our findings are consistent with studies suggesting that cessation of cannabis use may be beneficial in terms of reducing psychotic experiences ",
"Uncertainty exists whether the use of non-prescription psychoactive substances following onset of a first episode of psychosis ( FEP ) , in particular cannabis use , affects medication adherence . Data from FEP patients ( N=233 ) obtained through prospect i ve assessment s measured medication adherence and pattern of cannabis and other substance use in the first two years following onset of psychosis . Multiple logistic regression analyses were employed to compare the different substance use groups with regard to risk of medication non-adherence , while controlling for confounders . The proportion of non-adherent patients was higher in those who continued using high-potency forms of cannabis ( skunk-like ) following the onset ( 83 % ) when compared to never regular users ( 51 % ) , corresponding to an Odds Ratio ( OR ) of 5.26[95 % Confidence Interval ( CI ) 1.91 - 15.68 ] . No significant increases in risk were present in those who used cannabis more sporadically or used milder forms of cannabis ( hash-like ) . Other substances did not make an independent contribution in this model , including cigarette use ( [ OR 0.88 , 95 % CI 0.41 - 1.89 ] ) , alcohol use ( [ OR 0.66 , 95 % CI 0.27 - 1.64 ] ) or regular use of other illicit drugs ( [ OR 1.03 , 95 % CI 0.34 - 3.15 ] ) following the onset . These results suggest that continued use of high-potency cannabis following the onset of psychosis may adversely affect medication adherence"
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Background Vitamin D has been proposed to have anti‐inflammatory properties ; however , the effect of vitamin D supplementation on inflammation in type 2 diabetes has not been established . Objective The aim of this systematic review and meta‐ analysis was to examine the effect of vitamin D supplementation on inflammatory markers in patients with type 2 diabetes and to identify relevant gaps in knowledge . Data sources MEDLINE , CINAHL , Embase , and EBM Review s were search ed systematic ally from inception to January 25 , 2017 . Study selection R and omized controlled trials ( RCTs ) investigating the effects of vitamin D supplementation ( any form , route , and duration , and with any cosupplementation ) compared with placebo or usual care on inflammatory markers in patients with type 2 diabetes were selected . Data extraction Study and sample characteristics and aggregate outcome data were extracted , risk of bias was determined , and quality of evidence was assessed using the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) approach . Results Twenty‐eight RCTs were included , 20 of which had data available for pooling . In meta‐analyses of 20 RCTs ( n = 1270 participants ) , vitamin D‐supplemented groups had lower levels of C‐reactive protein ( st and ardized mean difference [ SMD ] −0.23 ; 95%CI , −0.37 to −0.09 ; P = 0.002 ) and tumor necrosis factor & agr ; ( SMD −0.49 ; 95%CI , −0.84 to −0.15 ; P = 0.005 ) , a lower erythrocyte sedimentation rate ( SMD −0.47 ; 95%CI , −0.89 to −0.05 ; P = 0.03 ) , and higher levels of leptin ( SMD 0.42 ; 95%CI , 0.04‐0.81 ; P = 0.03 ) compared with control groups . No differences were observed for adiponectin , interleukin 6 , or E‐selectin ( all P > 0.05 ) . In meta‐regression and subgroup analyses , age , sex , body mass index , duration of diabetes , baseline vitamin D status , and dose and duration of supplementation did not alter the results . Conclusions This meta‐ analysis provides level 1 evidence that vitamin D supplementation may reduce chronic low‐ grade inflammation in patients with type 2 diabetes . Systematic Review Registration PROSPERO CRD42016047755 . Available at : https://www.crd.york.ac.uk/ prospero /display_record.php?RecordID=47755 ( 9/15/2016 )
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"Objectives : To study the effect of Vitamin D3 supplementation on metabolic control in an obese type 2 diabetes Emirati population . Methods : This r and omized double-blind clinical trial was conducted with 87 vitamin D-deficient obese , type 2 diabetic participants . The vitamin D-group ( n=45 ) and the placebo group ( n=42 ) were matched for gender , age , HbA1c and 25-hydroxy vitamin D ( 25(OH ) D ) at the baseline . The study was divided into two phases of 3 months each ; in phase 1 , the vitamin D-group received 6000 IU vitamin D3/day followed by 3000 IU vitamin D3/day in phase 2 , whereas the placebo group ( n=42 ) received matching placebo . Results : After supplementation , serum 25(OH ) D peaked in the vitamin D-group in phase 1 ( 77.2±30.1 nmol/l , P=0.003 ) followed by a decrease in the phase 2 ( 61.4±18.8 nmol/l , P=0.006 ) , although this was higher compared with baseline . In the placebo group , no difference was observed in the serum 25(OH ) D levels throughout the intervention . Relative to baseline serum , parathyroid hormone decreased 24 % ( P=0.003 ) in the vitamin D-group in phase 2 , but remained unchanged in the placebo group . No significant changes were observed in blood pressure , fasting blood glucose , HbA1c , C-peptide , creatinine , phosphorous , alkaline phosphatase , lipids , C-reactive protein or thyroid stimulating hormone concentrations compared with baseline in either group . Conclusions : Six months of vitamin D3 supplementation to vitamin D-deficient obese type 2 diabetes patients in the UAE normalized the vitamin D status and reduced the incidence of eucalcemic parathyroid hormone elevation but showed no effect on the metabolic control",
"AIMS Patients with type 2 diabetes ( T2DM ) and chronic kidney disease ( CKD ) have impaired endothelial function . Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation . We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD . METHODS A double blind , r and omized , placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD . Paricalcitol 1 mcg or placebo was administered orally once daily for three months . Brachial artery flow mediated dilatation ( FMD ) , nitroglycerine mediated dilation ( NMD ) , and plasma concentrations of inflammatory cytokines , tumor necrosis factor -α and interleukin-6 , highly-sensitive C-reactive protein ; endothelial surface proteins , intercellular adhesion molecule -1 and monocyte chemo attractant protein-1 , and plasma glucose , insulin , free fatty acids , and urinary isoprostane were measured at baseline and end of three months . RESULTS 27 patients in the paricalcitol group and 28 patients in the control group completed the study , though analysis of FMD at both time points was possible in 23 patients in each group . There was no significant difference in the change in FMD , NMD or the biomarkers examined after paricalcitol or placebo treatment . CONCLUSIONS Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress . The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic , lipid and anti-hypertensive therapies",
"BACKGROUND Chronic low- grade systemic inflammation presented in Type 2 diabetes mellitus plays a major role in disease progression as well as development of micro- and macro-vascular complications of diabetes . Therefore , reducing inflammation can be beneficial in prevention of diabetes complications . OBJECTIVES To investigate the association between insulin resistance and inflammatory markers , and assessing the effects of oral Calcitriol on inflammatory cytokines in type 2 diabetic patients . METHODS In this double-blind r and omized placebo-controlled trial , 70 participants with type-2 diabetes were r and omly divided to two groups . One group received two capsules of Calcitriol ( 0.25 μg 1,25-dihydroxy cholecalciferol per each capsule ) per day . The second group received placebo tablets . At the beginning of the study , we assessed insulin resistance and its relation to inflammatory profile . Serum high sensitive C-reactive protein ( hs CRP ) , interleukin-6 and interleukin-18 were also measured at the beginning and the end of the 12-week supplementation trial . RESULTS Mean calcium , phosphorus and vitamin D concentrations in the study participants were 8.98 ± 0.79 mg/dL , 3.86 ± 0.50 mg/dL and 40.91 ± 30.9 ng/mL , respectively . IL-18 and hsCRP had significant positive associations with insulin resistance markers and negative associations with insulin sensitivity markers . At the end of the 12-week supplementation trial , no significant difference was seen in serum levels of hsCRP , IL-6 and IL-18 between the two groups , while these values were adjusted for baseline values . CONCLUSION Inflammation was associated with insulin resistance in diabetic patients . No anti-inflammatory effect of Calcitriol in terms of decreasing hsCRP , IL-6 and IL-18 detected",
"BACKGROUND & AIMS Low levels of serum 25-hydroxy vitamin D ( 25(OH)D ) are common in type 2 diabetic patients and cause several complications particularly , in postmenopausal women due to their senile and physiological conditions . This study aim ed to assess the effects of vitamin D-fortified low fat yogurt on glycemic status , anthropometric indexes , inflammation , and bone turnover in diabetic postmenopausal women . METHODS In a r and omized , placebo-controlled , double-blind parallel-group clinical trial , 59 postmenopausal women with type 2 diabetes received fortified yogurt ( FY ; 2000 IU vitamin D in 100 g/day ) or plain yogurt ( PY ) for 12 weeks . Glycemic markers , anthropometric indexes , inflammatory , and bone turnover markers were assessed at baseline and after 12 weeks . RESULTS After intervention , in FY group ( vs PY group ) , were observed : significant increase in serum 25(OH)D and decrease of PTH ( stable values in PY ) ; significant improvement in serum fasting insulin , HOMA-IR , HOMA-B , QUICKI , and no changes in serum fasting glucose and HbA1c ( significant worsening of all indexes in PY ) ; significant improvement in WC , WHR , FM , and no change in weight and BMI ( stable values in PY ) ; significant increase of omentin ( stable in PY ) and decrease of sNTX ( significant increase in PY ) . Final values of glycemic markers ( except HbA1c ) , omentin , and bone turnover markers significantly improved in FY group compared to PY group . Regarding final values of serum 25(OH)D in FY group , subjects were classified in insufficient and sufficient categories . Glycemic status improved more significantly in the insufficient rather than sufficient category ; whereas the other parameters had more amelioration in the sufficient category . CONCLUSIONS Daily consumption of 2000 IU vitamin D-fortified yogurt for 12 weeks improved glycemic markers ( except HbA1c ) , anthropometric indexes , inflammation , and bone turnover markers in postmenopausal women with type 2 diabetes . TRIAL REGISTRATION www.i rct .ir ( I RCT 2013110515294N1 )",
"Background Non-alcoholic fatty liver disease ( NAFLD ) is the most common hepatic disorder worldwide , reaching prevalence up to 90 % in obese patients with type 2 diabetes ( T2D ) , and representing an independent risk factor for cardiovascular mortality . Furthermore , the coexistence of T2D and NAFLD leads to higher incidence of diabetes ’ complications and additive detrimental liver outcomes . The existence of a close association between NAFLD and hypovitaminosis D , along with the anti-inflammatory and insulin-sensitizing properties of vitamin D , have been largely described , but vitamin D effects on hepatic fat content have never been tested in a r and omized controlled trial . We assessed the efficacy and safety of 24-week oral high-dose vitamin D supplementation in T2D patients with NAFLD . Methods This r and omized , double-blind , placebo-controlled trial was carried out at the Diabetes Centre of Sapienza University , Rome , Italy , to assess oral treatment with cholecalciferol ( 2000 IU/day ) or placebo in T2D patients with NAFLD . The primary endpoint was reduction of hepatic fat fraction ( HFF ) measured by magnetic resonance ; as hepatic outcomes , we also investigated changes in serum transaminases , CK18-M30 , N-terminal Procollagen III Propeptide ( P3NP ) levels , and Fatty Liver Index ( FLI ) . Secondary endpoints were improvement in metabolic ( fasting glycaemia , HbA1c , lipids , HOMA-IR , HOMA-β , ADIPO-IR , body fat distribution ) and cardiovascular ( ankle-brachial index , intima-media thickness , flow-mediated dilatation ) parameters from baseline to end of treatment . Results Sixty-five patients were r and omized , 26 ( cholecalciferol ) and 29 ( placebo ) subjects completed the study . 25(OH ) vitamin D significantly increased in the active treated group ( 48.15 ± 23.7 to 89.80 ± 23.6 nmol/L , P no group differences were found in HFF , transaminases , CK18-M30 , P3NP levels or FLI after 24 weeks . Vitamin D neither changed the metabolic profile nor the cardiovascular parameters . Conclusions Oral high-dose vitamin D supplementation over 24 weeks did not improve hepatic steatosis or metabolic/cardiovascular parameters in T2D patients with NAFLD . Studies with a longer intervention period are warranted for exploring the effect of long time exposure to vitamin D.Trial registration This trial was approved on July 2011 by the Ethics Committee of Policlinico Umberto I , Sapienza University of Rome , Italy , and registered at www . clinical trialsregister.eu number 2011 - 003010 - 17",
"We sought to determine if vitamin D supplementation , to target 25(OH)D concentrations of 30–40 ng/mL , improves endothelial function in Singapore ’s multi-ethnic type 2 diabetes mellitus population . We r and omised 64 type 2 diabetes mellitus patients with hypovitaminosis D to cholecalciferol 4000 International Unit/matching placebo [ baseline 25(OH)D : 20–30 ng/mL ] daily for 16 weeks with a down titration at 8 weeks if 25(OH)D > 30 ng/mL. Endothelial function was assessed by peripheral tonometry ( reactive hyperaemia index – endothelial peripheral arterial tonometry ) and vascular biomarkers : E-selectin , von-Willebr and factor and high-sensitivity C-reactive protein . We compared the change from baseline parameters in the two groups using Student ’s t-test or Kruskal – Wallis test . A log-normal multivariate regression analysis was used to adjust for relevant baseline variables . The median reactive hyperaemia index in the vitamin D group increased from 0.65 ( interquartile range : 0.42 ) to 0.73 ( interquartile range : 0.36 ) , whereas it decreased from 0.73 ( interquartile range : 0.65 ) to 0.65 ( interquartile range : 0.38 ) ( p = 0.02 ) in the placebo group . After adjustment for baseline variables , the change was not statistically significant for reactive hyperaemia index ( p = 0.07 ) and for other vascular biomarkers ( p > 0.05 ) . Targeted vitamin D supplementation for 16 weeks result ed in a small but non-significant improvement in endothelial function in a type 2 diabetes mellitus cohort",
"Background / Aims Recent epidemiological studies revealed a striking inverse relationship between vitamin D levels , glucose intolerance/insulin resistance ( IR ) , and cardiovascular disease . However , few interventional studies have evaluated the effect of vitamin D supplementation on cardiovascular risk , such as IR and arterial stiffness , in diabetes . We investigated the role of vitamin D supplementation on cardiovascular risk in type 2 diabetes patients , including metabolic parameters , IR , and arterial stiffness . Methods We enrolled patients who were taking antidiabetic medications or managed their diabetes using lifestyle changes . We excluded patients who were taking vitamin D or calcium supplements . We r and omized participants into the vitamin D group ( cholecalciferol 2,000 IU/day + calcium 200 mg/day , n = 40 ) or the placebo group ( calcium 200 mg/day , n = 41 ) . We compared their IR ( homeostasis model of assessment [HOMA]-IR ) and arterial stiffness ( brachial-ankle pulse wave velocity and radial augmentation index ) before and after 24 weeks of intervention . Results The baseline characteristics of the two groups were similar . A total of 62 participants ( placebo , 30 ; vitamin D , 32 ) completed the study protocol . At the end of the study period , the 25-hydroxyvitamin D [ 25(OH)D ] levels were significantly higher in the vitamin D group than in the placebo group ( 35.4 ± 8.5 ng/mL vs. 18.4 ± 7.3 ng/mL , p in HOMA-IR or changes in arterial stiffness ( placebo , 21 , vitamin D , 24 ) between the groups . Conclusions Our data suggest that high-dose vitamin D supplementation might be effective in terms of elevating 25(OH)D levels . However , we identified no beneficial effects on cardiovascular risk in type 2 diabetes , including IR and arterial stiffness",
"Background Diabetes and vitamin D deficiency are global epidemics . Research ers have long been exploring the role of potentially modifiable factors to manage type 2 diabetes . We conducted a systematic review of prospect i ve studies and r and omized controlled trials that involved vitamin D supplementation and specifically intended to study glycemic outcomes related to type 2 diabetes . Methods Two authors independently search ed Medline and PubMed for longitudinal studies that had assessed the effect of vitamin D supplements on glycemic control , insulin resistance and beta-cell dysfunction in patients with diabetes . Results Seventeen r and omized control trials and seven longitudinal studies with a minimum follow-up of one month were included . Results of the various short-term studies ( follow up ≤ 3 months ) suggested that vitamin D supplementation had a positive impact on glycemic control and metabolic parameters such as insulin resistance and beta cell dysfunction . However , the evidence was weak due to the low method ological quality of the studies . There was no significant effect on HbA1c , beta cell function and insulin resistance in the long-term studies ( follow up > 3 months ) . There existed heterogeneity in the methodology of the studies , inclusion criteria , mode of supplementation of vitamin D and the duration of follow up . Conclusions Current evidence based on r and omized controlled trials and longitudinal studies do not support the notion that vitamin D supplementation can improve hyperglycemia , beta cell secretion or insulin sensitivity in patients with type 2 diabetes . Large-scale trials with proper study design , optimal vitamin D supplementation and longer follow up need to be conducted",
"Abstract Aims To assess whether a single parental dose of 25-hydroxy vitamin D [ 25(OH)Vit D ] could improve glucose control and inflammation in type 2 diabetic patients ( T2D ) with ischemic heart disease ( IHD ) . Methods A r and omized , placebo-controlled , double-blind trial was performed on 95 patients ( 47—placebo and 48—vitamin D groups ) . Participants were r and omized using a r and omization table to a single dose of either vitamin D ( 300,000 IU , IM ) or a matching placebo . Fasting blood sugar ( FBS ) , glycosylated hemoglobin ( HbA1c ) , 25(OH)Vit D and high-sensitivity C-reactive protein ( hs-CRP ) were measured at baseline and at 8 weeks . Results No significant differences in baseline values were noted between groups , except in HbA1c , which was lower in the placebo group . In the supplemented group , the level of serum 25(OH)Vit D increased ( 29.6 ± 20.8 vs. 44.5 ± 19.2 ng/mL ) and those of FBS and HbA1c decreased significantly [ 186.5 ± 64.1 vs. 165.1 ± 58.5 mg/dL and 8.2 ± 2.0 % ( 66.3 ± 21.8 mmol/mol ) vs. 7.7 ± 1.8 % ( 61.7 ± 20.0 mmol/mol ) , respectively ] ( all p of outcome variables ( HbA1c , FBS , 25(OH)Vit D and hs-CRP ) from baseline between the vitamin D versus placebo group , using ANCOVA , adjusted for the baseline of each variable itself , season at study entry , age and body mass index . During trial , only HbA1c level decreased significantly [ 0.48 % ( st and ard error : 0.17 ) , p = 0.04 ] . No any adverse effect was seen . Conclusions A single parenteral dose of vitamin D in T2D patients with IHD improved glycemic control , but not inflammatory status . Clinical trial registryAustralian New Zeal and Clinical Trial Registry . Clinical trial numberACTRN12614000529640",
"Background Endothelial dysfunction has been proposed as the underlying cause of diabetic angiopathy that eventually leads to cardiovascular disease , the major cause of death in diabetes . We recently demonstrated the ameliorating effect of regular vitamin D intake on the glycemic status of patients with type 2 diabetes ( T2D ) . In this study , the effects of improvement of vitamin D status on glycemic status , lipid profile and endothelial biomarkers in T2D subjects were investigated . Methods Subjects with T2D were r and omly allocated to one of the two groups to receive either plain yogurt drink ( PYD ; containing 170 mg calcium and no vitamin D/250 mL , n1 = 50 ) or vitamin D3-fortified yogurt drink ( FYD ; containing 170 mg calcium and 500 IU/250 mL , n2 = 50 ) twice a day for 12 weeks . Anthropometric measures , glycemic status , lipid profile , body fat mass ( FM ) and endothelial biomarkers including serum endothelin-1 , E-selectin and matrix metalloproteinase (MMP)-9 were evaluated at the beginning and after the 12-week intervention period . Results The intervention result ed in a significant improvement in fasting glucose , the Quantitative Insulin Check Index ( QUICKI ) , glycated hemoglobin ( HbA1c ) , triacylglycerols , high-density lipoprotein cholesterol ( HDL-C ) , endothelin-1 , E-selectin and MMP-9 in FYD compared to PYD ( P of endothelin-1 , E-selectin and MMP-9 concentrations in FYD compared to PYD ( -0.35 ± 0.63 versus -0.03 ± 0.55 , P = 0.028 ; -3.8 ± 7.3 versus 0.95 ± 8.3 , P = 0.003 and -2.3 ± 3.7 versus 0.44 ± 7.1 ng/mL , respectively , P significant for endothelin-1 and MMP-9 ( P = 0.009 and P = 0.005 , respectively ) but disappeared for E-selectin ( P = 0.092 ) . On the contrary , after controlling for serum 25(OH)D , the differences disappeared for endothelin-1(P = 0.066 ) and MMP-9 ( P = 0.277 ) but still remained significant for E-selectin ( P = 0.011 ) . Conclusions Ameliorated vitamin D status was accompanied by improved glycemic status , lipid profile and endothelial biomarkers in T2D subjects . Our findings suggest both direct and indirect ameliorating effects of vitamin D on the endothelial biomarkers . Trial registration Clinical Trials.gov :",
"Abstract Background Recently , it has been reported that urinary angiotensinogen levels is a specific index of the intrarenal renin-angiotensin-aldosterone system ( RAAS ) status and it is significantly correlated with urinary albumin : creatinine ( Cr ) ratio in hypertensive patients . The aim of the present study was to assess the effect of activation of the Vitamin D receptor with calcitriol on albuminuria and urinary angiotensinogen as a novel biomarker of the intra-renal RAAS status in patients with diabetic nephropathy ( DN ) . Methods Ninety-eight patients with type 2 diabetes and albuminuria who were treated with RAAS inhibitors ( angiotensin-converting enzyme inhibitor ( ACE-i ) or angiotensin receptor blocker ( ARB ) ) have participated in this study . Patients were r and omized to receive either placebo ( n = 50 ) or 0.25 μg/day calcitriol ( n = 48 ) . We have examined urinary albumin : Cr ratio and urinary angiotensinogen : Cr ratio before and 24 weeks later after treatment in both group . Results The mean urinary albumin : Cr ratio and urinary angiotensinogen : Cr ratio were significantly higher in patients with DN than in normal controls ( p ) . Urinary angiotensinogen : Cr ratio was significantly , positively correlated with urinary albumin : Cr ratio in both groups ( in the placebo group ; p = 0.01 , r = 0.4236 , in calcitriol group ; p = 0.01 , r = 0.4564 ) . Conclusion These data indicated that administration of Vitamin D receptor activator in combination with RAAS inhibitors had an additional benefit in lowering albuminuria in patients with DN . More pronounced reduction of urinary albumin : Cr ratio that was positively correlated with angiotensinogen : Cr ratio in calcitriol group suggested that Vitamin D receptor activation might blunt albuminuria by reducing urinary angiotensinogen levels reflecting intra-renal RAAS status",
"Background : Diabetes mellitus ( DM ) and vitamin D deficiency are major health concerns around the world . Evidence suggests a possible role of vitamin D in improvement of insulin secretion and sensitivity . Objectives : We assessed whether vitamin D supplementation could be used in vitamin D deficient-type II diabetes to improve glucose metabolism , components of metabolic syndrome ( MetS ) and specific inflammatory biomarkers . Patients and Methods : A double blind , r and omized clinical trial was conducted in King Khalid University Hospital , Saudi Arabia to evaluate the effect of cholecalciferol supplementation on glycemic control , MetS components and specific inflammatory biomarkers including tumor necrosis factor-alpha ( TNF-α ) , Interleukin ( IL-6 ) , leptin , adiponectin and vascular cell adhesion molecule-1 ( VCAM-1 ) . Twenty-two patients with type II diabetes with insulin resistance , glycated hemoglobin ( HbA1c ) ≥ 6 ( 42 mmol/mol ) and serum 25(OH)D were r and omized using a computer program to receive either supplementation with cholecalciferol ( 5000 IU/day ) or placebo for 12 weeks . The primary outcome was change in HbA1c levels from baseline . Results : Median [ IQR ] 25(OH)D levels increased significantly in the vitamin D group as 58.1 [ 48 , 67.3 ] nmol/L ( P = 0.002 ) . There was no significant difference in the change of HbA1c between the groups ( P = 0.5 ) with a decrease of -0.1 % [ -1 , 0.5 ] in the vitamin D group and an increase of 0.15 % [ 0.1 , 0.2 ] in the placebo group . A significant improvement was observed in the homeostasis model of assessment of β-cell activity ( HOMA-%B ) ( P = 0.03 ) with vitamin D supplementation compared to baseline . Conclusions : Vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved β-cell activity in vitamin D-deficient type II diabetes with no significant changes in HbA1c or insulin sensitivity",
"Introduction The extraskeletal role of vitamin D is being increasingly recognised . This has important clinical implication s , as vitamin D deficiency has reached epidemic proportions worldwide . Vitamin D has proposed anti-inflammatory properties , yet the role of vitamin D supplementation in reducing inflammation remains largely unknown . The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation , and to identify relevant knowledge gaps in the field . Methods and analysis Medline , CINAHL , EMBASE and All EBM will be systematic ally search ed for r and omised controlled trials ( RCTs ) and systematic review s of RCTs , comparing vitamin D supplementation with placebo , usual care or other pharmacological or non-pharmacological interventions . One review er will assess articles for eligibility according to prespecified selection criteria , after which 2 independent review ers will perform data extraction and quality appraisal . Meta-analyses will be conducted where appropriate . Ethics and dissemination Formal ethical approval is not required as no primary data is collected . This systematic review will identify potential clinical implication s of vitamin D deficiency and supplementation , and will be disseminated through a peer- review ed publication and at conference meetings , to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases . PROSPERO registration number CRD42016037104",
"CONTEXT Systemic inflammation is thought to have a central role in diabetic long-term complications . OBJECTIVE The aim of this study was to investigate the effects of vitamin D either with or without extra calcium on certain inflammatory biomarkers in the subjects with type 2 diabetes ( T2D ) . DESIGN , SETTING , AND PARTICIPANTS This was a double-blind , r and omized , controlled trial conducted over 12 wk in 90 T2D subjects aged 30 - 60 yr from both sexes . INTERVENTION Subjects were r and omly allocated to one of three groups to receive two 250-ml bottles a day of plain Persian yogurt drink or doogh ( PD , containing 150 mg calcium and no detectable vitamin D(3)/250 ml ) , vitamin D-fortified doogh ( DD , containing 500 IU vitamin D(3 ) and 150 mg calcium/250 ml ) , or calcium + vitamin D(3)-fortified doogh ( CDD , containing 500 IU vitamin D(3 ) and 250 mg calcium/250 ml ) . OUTCOME MEASURES The changes in inflammatory markers were evaluated . RESULTS Compared to the baseline values , highly sensitive C-reactive protein , IL-1β , IL-6 , fibrinogen , and retinol binding protein-4 concentrations significantly decreased in both the DD and CDD groups . Although the decrement in highly sensitive C-reactive protein and fibrinogen was more in CDD compared to DD ( -4.0 ± 8.5 vs. -1.3 ± 2.8 mg/liter , and -0.40 ± 0.74 and -0.20 ± 0.52 mg/liter , respectively ) , the differences were not significant . There was a significant increase in serum adiponectin in both the DD and CDD groups ( 51.3 ± 65.3 vs. 57.1 ± 33.8 μg/liter ; P adiponectin changes in CDD were significantly higher than in PD ( P = 0.021 ) . CONCLUSIONS Daily intake of vitamin D-fortified doogh improved inflammatory markers in T2D subjects , and extra calcium conferred additional benefit only for the antiinflammatory adipokine , i.e. adiponectin",
"Background : Lower vitamin D status has been reported in diabetic patients . Serum 25-hydroxyvitamin D and adiponectin were inversely associated with type 2 diabetes and insulin resistance . Vitamin D may involve in regulation of the adiponectin levels , which is directly related to insulin sensitivity . Objectives : The aim of this study was to investigate the effect of therapeutic dose of vitamin D on serum adiponectin and insulin resistance in vitamin D-insufficient or deficient type 2 diabetic patients . Material s and Methods : This double-blind , r and omized , clinical trial was conducted on 81 type 2 diabetic patients with vitamin D level of 10 - 30 ng/mL. Intervention was 50000 IU vitamin D or placebo once a week for 8 weeks . At the beginning and end of the study , blood sample s were collected after 12 hours of fasting and serum glucose , insulin , 25-hydroxyvitamin D , and adiponectin were measured . Insulin resistance was calculated by homeostasis model assessment ( HOMA-IR ) . Results : After 8-week intervention , serum 25-hydroxyvitamin D significantly increased and reached the normal levels in patients receiving vitamin D ( P of fasting serum glucose , insulin , and HOMA-IR were significantly decreased ( P = 0.04 , 0.02 and 0.007 , respectively ) . No significant changes were observed in these levels in the placebo group . Significant differences were observed in mean changes in the above-mentioned variables between the two groups ( P = 0.01 , 0.04 and 0.006 , respectively ) . No significant changes were found in serum adiponectin in the vitamin D and placebo groups ( P = 0.83 ) . Conclusions : Therapeutic dose of vitamin D can improve vitamin D status and glycemic indicators . But it seems that an 8-week intervention period was not sufficient to reveal the possible effects of vitamin D on serum adiponectin levels",
"The aim of this study was to assess the effects of single oral bolus of 300,000 IU Vitamin D3 on serum levels and on bone and metabolic parameters in diabetic patients . This study is a Phase IV , r and omized , double-blind , placebo-controlled , monocenter clinical trial . Thirty patients , 60 years or older , with type 2 diabetes mellitus , and diabetic foot complications , were enrolled and monitored for 24 weeks : 14 were treated with Vitamin D3 and 16 with placebo . Parameters including glucose , adiponectin , leptin , osteoprotegerin ( OPG ) , 25-hydroxyvitamin D [ 25(OH)D ] , beta-CrossLaps , osteocalcin , bone-specific isoenzyme of alkaline phosphatase , tumor necrosis factor-α and parathyroid hormone were measured at screening and baseline and 12 and 24 weeks after treatment . Analysis of covariance was used to compare treatment groups . Analysis of the data detected a significant increase in 25(OH)D serum levels both at 12 and 24 weeks with respect to baseline values only in the treated patients . Significant variations with respect to baseline values were noted in OPG ( P = 0.0085 ) and in leptin ( P = 0.0442 ) levels : these were lower in the placebo group at week 24 but higher in the treated group . Vitamin D3 supplementation significantly increased serum leptin and OPG levels . Further , large-scale clinical trials are warranted to confirm these results",
"CONTEXT To the best of our knowledge , no study has examined the effects of vitamin D-calcium cosupplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient type 2 diabetics . OBJECTIVE This study was performed to assess the effects of vitamin D and calcium supplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient people with type 2 diabetes . METHODS Totally , 118 diabetic patients were enrolled in this r and omized , placebo-controlled clinical trial . After matching for age , sex , body mass index , type and dose of hypoglycemic agents , and duration of diabetes , subjects were r and omly assigned into 4 groups receiving the following : 1 ) 50000 IU/wk vitamin D + calcium placebo ; 2 ) 1000 mg/d calcium + vitamin D placebo ; 3 ) 50 000 IU/wk vitamin D + 1000 mg/d calcium ; or 4 ) vitamin D placebo + calcium placebo for 8 weeks . Blood sampling was done for the quantification of inflammatory biomarkers and adipocytokines at the study baseline and after 8 weeks of intervention . RESULTS Calcium ( changes from baseline : -75 ± 19 ng/ml , P = .01 ) and vitamin D alone ( -56 ± 19 ng/mL , P = .01 ) and joint calcium-vitamin D supplementation ( -92 ± 19 ng/mL , P = .01 ) result ed in a significant reduction in serum leptin levels compared with placebo ( -9 ± 18 ng/mL ) . This was also the case for serum IL-6 , such that calcium ( -2 ± 1 pg/mL , P and vitamin D alone ( -4 ± 1 pg/mL , P the calcium ( -3.1 ± 1.3 , P , vitamin D ( -3.1 ± 1.3 , P joint calcium-vitamin D groups ( -3.4 ± 1.3 , P reductions in serum TNF-α concentrations compared with placebo ( 0.1 ± 1.2 ) . Individuals who received joint calcium-vitamin D supplements tended to have a decrease in serum high-sensitivity C-reactive protein levels compared with placebo after controlling for baseline levels ( -1.14 ± 0.25 vs 0.02 ± 0.24 ng/mL , P = .09 ) . CONCLUSION Joint calcium-vitamin D supplementation might improve systemic inflammation through decreasing IL-6 and TNF-α concentrations in vitamin D-insufficient people with type 2 diabetes",
"BACKGROUND Suboptimal vitamin D status is associated with endothelial dysfunction and an increased risk of cardiovascular diseases but it is unclear whether vitamin D supplementation is beneficial . The aim was to investigate the effect of vitamin D supplementation on endothelial function in patients with type 2 diabetes mellitus ( DM ) . METHODS In a double-blind , placebo-controlled trial , we r and omized 100 type 2 DM patients to vitamin D supplement ( 5000 IU/day , n = 50 ) or placebo ( controls , n = 50 ) for 12 weeks . Assessment of vascular function with brachial artery flow-mediated dilatation ( FMD ) , circulating levels of endothelial progenitor cells ( EPCs ) and brachial-ankle pulse wave velocity , and metabolic parameter , high-sensitivity C-reactive protein ( hsCRP ) and oxidative stress markers were performed before and after the supplementation . RESULTS After 12 weeks , vitamin D treated patients had significant increases in serum 25-hydroxyvitamin D [ 25(OH)D ] concentration ( treatment effect 34.7 ng/mL , 95 % CI 26.4 - 42.9 , P serum ionized calcium ( treatment effect 0.037 mmol/L , 95 % CI 0.007 - 0.067 , P = 0.018 ) ; decreased serum parathyroid hormone concentration ( treatment effect -0.55 pmol/L , 95 % CI -1.08 to -0.02 , P = 0.042 ) compared to patients who received placebo . Nevertheless , vitamin D supplementation did not improve vascular function as determined by FMD , circulating EPC count or baPWV ( all P > 0.05 ) . Furthermore , hsCRP , oxidative stress markers , low- and high-density lipoprotein and glycated hemoglobin were also similar between two groups ( all P > 0.05 ) . CONCLUSION In patients with type 2 DM , 12 weeks oral supplementation of vitamin D did not significantly affect vascular function or serum biomarkers of inflammation and oxidative stress . CLINICAL TRIAL NUMBER HKCTR-867 , www.hk clinical trials.com",
"Background : Since tumor necrosis factor-α ( TNF-α ) could be one of the risk factors at the development of diabetes complications ; as well as serum leptin deficiency is related to increased susceptibility to infections in diabetic patients , they are potential indices from the preventive medicine viewpoint . This study was conducted to represent the effect of supplemental vitamin D3 on serum leptin , TNF-α and adiposity in type 2 diabetic patients . Methods : In this r and omized double-blind placebo-controlled trial , study sample was selected through type 2 diabetic patients ( n = 51 ) . A total of 26 patients were orally supplemented by vitamin D3 ( 400 IU/d ) ( vitamin D group ) and 25 patients by placebo ( placebo group ) for 14 weeks . The blood glycated hemoglobin ( HbA1c ) and the serum ionized Ca , leptin , TNF-α , and serum 25-hydroxyvitamin D ( 25[OH ] D ) were measured at the two groups in the baseline and postintervention stages . Results : It was shown that despite of theplacebo group , serum 25(OH ) D and serum leptin was significantly increased ( P = 0.001 and P = 0.002 , respectively ) , while serum TNF-α was decreased significantly ( P = 0.001 ) in vitamin D group . The remaining parameters , including body fat mass and HbA1c had no alterations between baseline and postintervention stages in vitamin D group . Conclusions : This study may advocate vitamin D supplementation among type 2 diabetic patients due to its beneficial effects on prevention of diabetes complications",
"AIM Diabetes and vitamin D deficiency are widely prevalent in India . Studies have proven correlation between low vitamin D levels and pulmonary tuberculosis ( PTB ) and low vitamin D levels and insulin resistance . We evaluated the effects of vitamin D supplementation on type 2 diabetes mellitus patients with pulmonary tuberculosis ( PTB ) . METHODS Forty-five subjects ( M : F=34:11 ) were screened . Inclusion criteria were age > 15 years , newly diagnosed PTB cases with uncontrolled diabetes , serum vitamin D The patients with vitamin D level were r and omly assigned to 2 groups . Group 1 subjects received oral cholecalceferol ( 60,000 units/week ) and calcium carbonate ( 1g/day ) along with anti tubercular treatment ( ATT ) , while group 2 subjects did not . Sputum was checked at interval of 2 weeks for 12 weeks . Primary end point was time to achieve sputum smear conversion . RESULTS Fifteen patients having vitamin D>20 ng/ml were excluded . Age of the patients was 42.9±13.2 years and serum vitamin D levels were 18.4±15.3 ng/ml . Sputum smear conversion was 6 weeks in group 1 versus 8 weeks in group 2 ( p=0.067 ) . Glycated hemoglobin levels reduced from 11.1±1.3 to 7.7±0.9 in group 1 versus 10.3±1.2 to 7.8±1.1 ( p>0.1 ) . CONCLUSION Vitamin D can serve as adjuvant treatment of tuberculosis in diabetics with vitamin D deficiency . Further studies are required to vali date this observation and define a cut off for vitamin D level to prevent immunological alterations",
"Objective . Systemic lupus erythematosus ( SLE ) is a chronic multisystem inflammatory autoimmune disease . Vitamin D has potent immunomodulatory properties that support its use in the treatment of autoimmune conditions , including SLE . We assessed vitamin D status in patients with SLE and determined alterations in inflammatory and hemostatic markers and disease activity before and after vitamin D supplementation . Methods . Patients with SLE ( n = 267 ) were r and omized 2:1 to receive either oral cholecalciferol 2000 IU/day or placebo for 12 months . Outcome measures included assessment of alterations in levels of proinflammatory cytokines and hemostatic markers , and improvement in disease activity before and after 12 months of supplementation . Disease activity was measured by the SLE Disease Activity Index . Vitamin D levels were measured by Liaison immunoassay ( normal 30–100 ng/ml ) . Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency and levels mean 25(OH)D level at baseline was 19.8 ng/ml in patients compared to 28.7 ng/ml in controls . The overall prevalence of suboptimal and deficient 25(OH)D serum levels among patients with SLE at baseline was 69 % and 39 % , respectively . Lower 25(OH)D levels correlated significantly with higher SLE disease activity . At 12 months of therapy , there was a significant improvement in levels of inflammatory and hemostatic markers as well as disease activity in the treatment group compared to the placebo group . Conclusion . Vitamin D supplementation in patients with SLE is recommended because increased vitamin D levels seem to ameliorate inflammatory and hemostatic markers and show a tendency toward subsequent clinical improvement . Clinical Trial Registry NCT01425775",
"BACKGROUND & AIMS Vitamin D supplementation has the potential to alleviate the cardiovascular damage in diabetic patients . The present study was design ed to evaluate long term impact of high doses of vitamin D on arterial properties , glucose homeostasis , adiponectin and leptin in patients with type 2 diabetes mellitus . METHODS AND RESULTS In r and omized , placebo-controlled study 47 diabetic patients were assigned into two groups : Group 1 received oral daily supplementation with vitamin D at a dose of 1000 U/day for 12 months . Group 2 received matching placebo capsules . Blood sampling for metabolic parameters , including fasting glucose , lipid profile , HbA1C , insulin , hs-CRP , 25 OH Vit D , adiponectin and leptin was performed at baseline and at the end of the study . Insulin resistance was assessed by homeostasis model assessment ( HOMA-IR ) . Central aortic augmentation index ( AI ) was evaluated using SphygmoCor . RESULTS The two groups were similar at baseline in terms of hemodynamic parameters . After 12 months , AI decreased significantly during the treatment period in patients received vitamin D ( p Glucose homeostasis parameters , leptin as well as leptin adiponectin ratio did not change in both groups . 25 OH Vit D level significantly increased ( p = 0.022 ) and circulating adiponectin marginally increased ( p = 0.065 ) during 12 month treatment period in active treatment and did not change in placebo group . CONCLUSIONS High doses of vitamin D supplementation in diabetic patients was associated with significant decrease in AI during one year treatment . This beneficial vascular effect was not associated with improvement in glucose homeostasis parameters",
"BACKGROUND Epidemiological studies suggest a higher prevalence of metabolic syndrome and its components among individuals with vitamin D deficiency . The aim of the present study was to determine whether vitamin D treatment improves glucose control and insulin sensitivity in Type 2 diabetes mellitus ( T2DM ) . METHODS Subjects with T2DM and serum 25-hydroxyvitamin D ( 25(OH)D ) concentrations were r and omized to receive 400 IU ( Group 1 ) or 1200 IU ( Group 2 ) cholecalciferol for 4 months . Fasting plasma glucose , glycosylated hemoglobin ( HbA1c ) , Quantitative Insulin Sensitivity Check Index ( QUICKI ) , serum lipid levels and serum adiponectin were measured at baseline and at 4 months . RESULTS Mean 25(OH)D levels increased in both groups ( from 17.6±1.5 to 25.5±1.8 ng/mL in Group 1 and from 15.6±1.4 to 27.4±2.4 ng/mL in Group 2 ; P≤0.001 vs baseline for each group ) . No significant differences were noted in fasting plasma glucose , HbA1c , QUICKI , serum adiponectin , and lipid levels compared with baseline within groups or between the two groups . CONCLUSIONS In the present pilot study , conventional vitamin D treatment at a level improving , but not optimizing , serum 25(OH)D did not improve glycemia , insulin sensitivity , or lipid profile . However , diabetes and lipids were relatively well controlled at baseline . Future studies should be design ed to achieve optimal concentrations of serum 25(OH)D ( at least > 32 ng/mL ) and should include subjects showing more abnormal parameters of glycemia , lipid , and insulin sensitivity at baseline",
"Background / Objectives : The aim was to examine the causal effect of vitamin D on serum adiponectin using a multiple instrument Mendelian r and omization approach . Subjects/ Methods : Serum 25-hydroxy vitamin D ( 25(OH)D ) and serum total or high molecular weight ( HMW ) adiponectin were measured in two Danish population -based studies : the Inter99 study ( 6405 adults , 30–60 years ) conducted in 1999–2001 , and the MONICA10 study ( 2656 adults , 41–71 years ) conducted in 1993–1994 . Results : In the Inter99 study , serum 25(OH)D was positively associated with total adiponectin ( the effect estimate in % per doubling of 25(OH)D was 4.78 , 95 % CI : 1.96 , 7.68 , P MONICA10 cohort , no significant association was observed between the serum concentrations of 25(OH)D and HMW adiponectin ( the effect estimate in % per doubling of 25(OH)D was −1.51 , 95 % CI : −5.80 , 2.98 , P=0.50 ) , although the instrumental variables analysis to some extent supported a positive causal association ( the effect estimate in % per doubling of 25(OH)D was 37.13 , 95 % CI : −3.67 , 95.20 , P=0.080 ) . Conclusions : The results indicate a possible causal association between serum 25(OH)D and total adiponectin . However , the association was not replicated for HMW adiponectin . Thus , further studies are needed to confirm a causal relationship"
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OBJECTIVE We aim ed to compare the efficacy of short-term ( longer-term antibiotic prophylaxis ( ≥24 hours ) in open heart surgery . BACKGROUND The optimal duration of antibiotic prophylaxis for adults undergoing cardiac surgery is unknown and guideline recommendations are inconsistent . METHODS We search ed MEDLINE , EMBASE , CINAHL , and CENTRAL for parallel-group r and omized trials comparing any antibiotic prophylaxis administered for any antibiotic prophylaxis for ≥24 hours in adult patients undergoing open heart surgery . Reference lists of selected articles , clinical practice guidelines , review articles , and congress abstract s were search ed . Study selection , data extraction and assessment of risk of bias were performed independently by 2 review ers . RESULTS Of the 1338 citations identified by our search strategy , 12 studies involving 7893 patients were selected . Compared with short-term antibiotic prophylaxis , longer-term antibiotic prophylaxis reduced the risk of sternal surgical site infection ( SSI ) by 38 % ( risk ratio 1.38 , 95 % confidence interval ( CI ) 1.13 - 1.69 , P = 0.002 ) and deep sternal SSI by 68 % ( risk ratio 1.68 , 95 % CI 1.12 - 2.53 , P = 0.01 ) . There were no statistically significant differences in mortality , infections overall and adverse events . Eleven of the trials were at high risk for bias due to limitations in study design . CONCLUSIONS Perioperative antibiotic prophylaxis of ≥24 hours may be more efficacious in preventing sternal SSIs in patients undergoing cardiac surgery compared to shorter regimens . The findings however are limited by the heterogeneity of antibiotic regimens used and the risk of bias in the published studies
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"The efficiency of a single two gram bolus of Ceftriaxone for cardiac operations was evaluated versus a classical , multiple dose , antibiotic prophylaxis using Cefam and ole . The results were quite similar in both groups , with a very low infection rate . We conclude that a single bolus prophylaxis using a broad spectrum antibiotic is as efficient as an ordinary , multiple dose technique",
"BACKGROUND Despite evidence supporting short antibiotic prophylaxis ( ABP ) , it is still common practice to continue ABP for more than 48 hours after coronary artery bypass graft ( CABG ) surgery . METHODS AND RESULTS To compare the effect of short ( prolonged ( > 48 hours ) ABP on surgical site infections ( SSIs ) and acquired antimicrobial resistance , we conducted an observational 4-year cohort study at a tertiary-care center . An experienced infection control nurse performed prospect i ve surveillance of 2641 patients undergoing CABG surgery . The main exposure was the duration of ABP , and main outcomes were the adjusted rate of SSI and the isolation of cephalosporin-resistant enterobacteriaceae and vancomycin-resistant enterococci ( acquired antibiotic resistance ) . Adjustment for confounding was performed by multivariable modeling . A total of 231 SSIs ( 8.7 % ) occurred after a median of 16 days , including 93 chest-wound infections ( 3.5 % ) and 13 deep-organ-space infections ( 0 . 5 % ) . After 1502 procedures using short ABP , 131 SSIs were recorded , compared with 100 SSIs after 1139 operations with prolonged ABP ( crude OR , 1.0 ; CI , 0.8 to 1.3 ) . After adjustment for possible confounding , prolonged ABP was not associated with a decreased risk of SSI ( adjusted OR , 1.2 ; CI , 0.8 to 1.6 ) and was correlated with an increased risk of acquired antibiotic resistance ( adjusted OR , 1.6 ; CI , 1.1 to 2.6 ) . CONCLUSIONS Our findings confirm that continuing ABP beyond 48 hours after CABG surgery is still widespread ; however , this practice is ineffective in reducing SSI , increases antimicrobial resistance , and should therefore be avoided",
"The efficacy of antibiotic prophylaxis in cardiac surgery was compared between 97 patients receiving a single 2 g dosage of ceftriaxone and 103 receiving 500 mg of vancomycin i.v . every 6 h for 48 h. The overall infection rate was 13.4 % in the ceftriaxone and 10.7 % in the vancomycin group . Four ( 4 % ) wound infections , including one mediastinitis , occurred in the ceftriaxone group and five ( 5 % ) in the vancomycin group , with no statistically significant difference . The findings of this study support the adequacy of a simple single dose of ceftriaxone prophylaxis in cardiac surgery , at least in hospitals with low incidence of vancomycin-resistant staphylococcal infections",
"In a prospect i ve study of cephalothin prophylaxis for patients who underwent aortocoronary bypass an unacceptably high rate ( 44 % ) of Staphylococcus aureus sternotomy infections occurred in a placebo-treated group . In two other groups of patients , one group given cephalothin intraoperatively and the other given the antibiotic both intra- and postoperatively , such infections occurred with similar frequency ( 2.6 % and 2.1 % respectively ) . This study demonstrates the need for antistaphylococcal agents during aortocoronary bypass operation . No advantage is derived by extending this therapy beyond the operative period",
"HYPOTHESIS Surgical site infections ( SSIs ) are a major contributor to patient injury , mortality , and health care costs . Despite evidence of effectiveness of antimicrobials to prevent SSIs , previous studies have demonstrated inappropriate timing , selection , and excess duration of administration of antimicrobial prophylaxis . We herein describe the use of antimicrobial prophylaxis for Medicare patients undergoing major surgery . DESIGN National retrospective cohort study with medical record review . SETTING Two thous and nine hundred sixty-five acute-care US hospitals . PATIENTS A systematic r and om sample of 34,133 Medicare in patients undergoing coronary artery bypass grafting ; other open-chest cardiac surgery ( excluding transplantation ) ; vascular surgery , including aneurysm repair , thromboendarterectomy , and vein bypass operations ; general abdominal colorectal surgery ; hip and knee total joint arthroplasty ( excluding revision surgery ) ; and abdominal and vaginal hysterectomy from January 1 through November 30 , 2001 . MAIN OUTCOME MEASURES The proportion of patients who had parenteral antimicrobial prophylaxis initiated within 1 hour before the surgical incision ; the proportion of patients who were given a prophylactic antimicrobial agent that was consistent with currently published guidelines ; and the proportion of patients whose antimicrobial prophylaxis was discontinued within 24 hours after surgery . RESULTS An antimicrobial dose was administered to 55.7 % ( 95 % confidence interval [ CI ] , 54.8%-56.6 % ) of patients within 1 hour before incision . Antimicrobial agents consistent with published guidelines were administered to 92.6 % ( 95 % CI , 92.3%-92.8 % ) of the patients . Antimicrobial prophylaxis was discontinued within 24 hours of surgery end time for only 40.7 % ( 95 % CI , 40.2%-41.2 % ) of patients . CONCLUSION Substantial opportunities exist to improve the use of prophylactic antimicrobials for patients undergoing major surgery",
"One hundred four patients undergoing elective open heart surgery were enrolled in a prospect i ve , double-blind trial comparing prophylaxis against infection using a single 1 g dose of ceftriaxone and seven doses of cefazolin . Patients in both groups had similar risk factors for infection . The likelihood of achieving a tissue concentration in excess of the minimal inhibitory concentration for Staph . aureus was significantly greater with ceftriaxone in atrial appendage ( p less than 0.001 ) , muscle ( p less than 0.01 ) , and bone ( p less than 0.01 ) than with cefazolin . The serum half-life of ceftriaxone was approximately 15.7 hours . All 49 serum sample s obtained 18 to 24 hours after delivery of ceftriaxone and 26 of 33 sample s obtained 40 to 48 hours after delivery had drug concentrations in excess of 3.1 micrograms/ml , the mean minimal inhibitory concentration for isolates of Staph . aureus . Early and late infectious complications were infrequent and occurred at similar rates in both groups . Neither drug was associated with significant toxicity . A single 1 g dose of ceftriaxone was as effective and safe as multiple doses of cefazolin and demonstrated superior tissue penetration",
"OBJECTIVE Cephalosporins , especially cefazolin , are widely used in the prevention of postoperative wound infections after cardiac operations . As more and more Staphylococcus aureus and Staphylococcus epidermidis strains are becoming resistant to cephalosporins and other antibiotics , alternative agents , such as glycopeptides , are often used as prophylaxis . We performed a multicenter double-blind r and omized controlled trial comparing teicoplanin , a glycopeptide antibiotic , with cefazolin . METHODS A total of 3027 adult patients undergoing elective coronary artery bypass grafting , valve operations , or both were r and omized to a single dose of teicoplanin ( 15 mg/kg ) or a 2-day course of cefazolin ( 2 g initial dose , followed by 1 g every 8 hours for 6 more doses ) . Patients were followed up for a total of 6 months postoperatively . The primary objective was to compare , between groups , the incidence of surgical infections up to 30 days postoperatively . Secondary objectives were incidence of other infections , other complications , and death . RESULTS A total of 3027 patients were r and omized to receive either teicoplanin ( n = 1518 ) or cefazolin ( n = 1509 ) . Thirty days postoperatively , there was a trend to more deep sternotomy wound infections in the teicoplanin group ( 31 vs 18 , P = . 087 ) , which became significant by 6 months ( 36 vs 19 , P = .032 ) . One hundred percent of the gram-positive strains infecting patients were susceptible to teicoplanin , whereas 8.3 % were resistant to cefazolin . Pneumonia and urinary tract infections were more common in the teicoplanin group . Deep wound infections of the leg were more common in the cefazolin group . CONCLUSIONS Cefazolin was more effective prophylaxis than teicoplanin against postoperative wound infections after elective cardiac operations . Infection rates were low with either treatment",
"To assess the efficacy of single-dose antibiotic prophylaxis in coronary artery bypass grafting , 1,016 consecutive patients were prospect ively r and omized to receive either a single dose or a three-day course of cefuroxime . Nine patients ( 0.9 % ) died within seven days ; no death was caused by infection . For various reasons 163 other patients were not evaluable . Therefore , 844 patients were evaluated . Patients in group A ( n=419 ) received 20 mg/kg cefuroxime intravenously at induction of anaesthesia ; group B ( n=425 ) received the same dose followed by 750 mg t.i.d . for three consecutive days . Both groups were comparable regarding all risk factors . The efficacy of the prophylactic regimens was evaluated by comparison of occurrence of wound infection in both groups . No significant differences in wound infection were observed between the two treatment groups : sternal site infection in the single-dose prophylaxis group was 14 % versus 13 % in the three-day course group ; donor site infection occurred in 38 % versus 39 % . It is concluded that in coronary artery bypass grafting a single dose of cefuroxime is as effective as a three-day course in the prevention of wound infection",
"Objective To investigate possible differences in prophylaxis with ceftriaxone compared with other antimicrobial agents for surgical-site infections and remote infections such as respiratory tract infections ( RTIs ) and urinary tract infections ( UTIs ) . Methods The efficacy of ceftriaxone was compared with that of other antibiotics in the perioperative prophylaxis of local ( surgical wound ) and remote ( RTIs and UTIs ) infections in a meta- analysis of r and omised controlled trials published between 1984 and 2003 . The analysis was based on a 2 × 2 contingency table with classification by treatment and number of infections obtained from individual studies . Results Evaluations were performed on 48 studies , for a total of 17 565 patients . Overall , 406 patients ( 4.8 % ) in the ceftriaxone group and 525 ( 6.3 % ) in the comparator group developed a surgical-site infection ( log odds ratio [ OR ] −0.30 [ CI −0.50 to −0.13 ] ; p were observed in 292 ( 6.01 % ) patients in the ceftriaxone group and in 369 ( 7.6 % ) patients in the comparator group , ( log OR −0.30 [ CI −0.55 to −0.09 ] ; p = 0.0013 ) . UTIs were reported for 2.2 % of the ceftriaxone prophylaxis patients compared with 3.74 % of the comparator group patients ( log OR −0.54 [ CI −1.18 to −0.16 ] ; p developed a surgical site infection in the ceftriaxone and comparator groups , respectively ( log OR −0.22 [ CI −0.51 to 0.01 ] ; p = 0.0476 ) . RTIs were prevented for all but 1.57 % of patients in the ceftriaxone group and 2.62 % of patients in the comparator group ( p = 0.01 ) in clean surgery , and for 9.54 % of the ceftriaxone group versus 11.6 % of the comparator group ( p = 0.01 ) in clean-contaminated surgery . While results observed in clean surgery did not show statistically significant superiority of ceftriaxone in preventing UTI insurgence ( log OR −0.21 [ CI 0.0–0.65 ] ; p = 0.7702 ) , this was clearly shown in the clean-contaminated surgery . In fact , 4.47 % of patients in the ceftriaxone group versus 7.52 % of patients in the comparator group developed a UTI ( log OR −0.56 [ CI −1.25 to −0.16 ] ; p events were observed in a similar proportion in the ceftriaxone prophylaxis and the comparator groups ( 0.35 % and 0.23 % , respectively ) . Duration of prophylaxis did not influence outcome of infection . Conclusions The meta- analysis showed that ceftriaxone is statistically superior to other antibiotics in preventing both local and remote postoperative infections ",
"This clinical trial , which was composed of 1,031 adults undergoing cardiac operations , compared the efficacy of a single dose of 1 g of ceftriaxone with a 48-our regimen consisting of flucloxacillin and gentamicin . There was no significant difference ( p = 0.89 ) in the overall incidence of major infections : 30 of 515 patients ( 5.8 % ; 95 % confidence interval , 5.4 % to 6.2 % ) taking ceftriaxone and 29 of 516 patients ( 5.6 % ; 95 % confidence interval , 5.2 % to 6.0 % ) taking flucloxacillin and gentamicin . Subgroup analyses , with a lower statistical power , failed to show a significant difference between patients who received ceftriaxone and those who received flucloxacillin/gentamicin : major sternal wound infections arose in 2.7 % of the patients taking ceftriaxone versus 1.6 % in those on the 48-hour regimen ( p = 0.20 ) and major limb wound infections arose in 4.2 % and 5.4 % , respectively ( p = 0.44 ) . Single-dose prophylaxis was associated with fewer intravenous administrations ( 864 doses versus 9,570 doses ) and cost less ( A$ 17,248 versus A$ 78,510 ) . Although the regimen that included gentamicin was associated with the greatest biochemical impairment of renal function , the overall toxicity for both groups was low . We conclude that a single dose of ceftriaxone provided cost-efficient prophylaxis for adults undergoing cardiac operations when compared with a 48-hour regimen of gentamicin and flucloxacillin . The general principle revealed by our data is that the short-term administration of an appropriate antibiotic regimen represents optimal prophylaxis for patients undergoing cardiac procedures",
"OBJECTIVE In a prospect i ve , r and omized study , postoperatively prolonged antibiotic prophylaxis is evaluated in a high-risk group of patients undergoing cardiac operations . These patients had postoperative low cardiac output necessitating inotropic support and intraaortic balloon pumping . METHODS Between January 1991 and 1994 , 53 patients were enrolled in the study ( 42 men , mean age 65 years ) . All patients received the usual perioperative ( 24 hours ) cefazolin prophylaxis . In the study group ( n = 28 ) a prolonged regimen of prophylaxis with ticarcillin/clavulanate was performed for 2 days and vancomycin was added in a low dose until removal of the intraaortic balloon pump . The control group ( n = 25 ) did not receive a prolonged regimen of prophylaxis . Follow-up ended at hospital discharge . RESULTS Early mortality was 7 of 28 patients ( 25 % ) in the prophylaxis group and 8 of 25 patients ( 32 % ) in the control group ( p = 0.397 ) . Defined infections ( pneumonia , n = 22 ; sepsis , n = 8 ; deep sternal wound infection , n = 2 ) occurred in 50 % of the study group and 68 % of the control group ( p = 0.265 ) . In all patients with septicemia , only coagulase-negative staphylococci could be isolated from the bloodstream ( 5 patients in the prophylaxis group vs 3 in the control group ) . Infectious parameters were controlled daily and did not differ significantly between groups . A total of 1158 bacteriologic tests were performed ( blood cultures , n = 389 ; intravascular catheters , n = 208 ; bronchial aspirates , n = 411 ; intraaortic balloon pumps , n = 42 ; wound secretions , n = 108 ) showing bacterial growth in 322 ( 28 % ) without a significant difference between the groups . In the prophylaxis group , 13 intravascular catheters and intraaortic balloon pumps showed bacterial growth versus 11 in the control group . No side effects were seen . CONCLUSIONS In a high-risk group of patients undergoing cardiac operations , infectious outcome could not be effectively influenced by an additional and prolonged postoperative prophylaxis regimen with low-dose vancomycin and ticarcillin/clavulanate . Low-dose vancomycin did not reduce the rate of infections or colonizations of intravascular catheters with gram-positive organisms",
"The most serious infection after coronary artery bypass grafting ( CABG ) is mediastinitis following deep sternal wound infection . Antibiotic prophylaxis for at least 48 hours has been recommended . In this trial 551 consecutive patients were r and omized to receive ceftriaxone in a single dose or cefuroxime thrice daily until the end of the second postoperative day . The overall infection rate was 7.7 % in the ceftriaxone and 8.3 % in the cefuroxime group , and the incidence of deep sternal infection was 2.9 % in both groups . Significant risk factors for such infection were chronic respiratory disease ( p diabetes ( p harmful effects on the colonic flora in either group . Acquisition and delivery costs for the prophylactic agents were three times higher in the cefuroxime than in the ceftriaxone group . Both antibiotics are concluded to be equally safe and effective . Single-dose ceftriaxone prophylaxis is as effective as cefuroxime given for 48 hours postoperatively . Single-dose ceftriaxone is also simple to use",
"BACKGROUND The first version of The Society of Thoracic Surgeons National Adult Cardiac Surgery Data base ( STS NCD ) was developed nearly 2 decades ago . Since its inception , the number of participants has grown dramatically , patient acuity has increased , and overall outcomes have consistently improved . To adjust for these and other changes , all STS risk models have undergone periodic revisions . This report provides a detailed description of the 2008 STS risk model for coronary artery bypass grafting surgery ( CABG ) . METHODS The study population consisted of 774,881 isolated CABG procedures performed on adult patients aged 20 to 100 years between January 1 , 2002 , and December 31 , 2006 , at 819 STS NCD participating centers . This cohort was r and omly divided into a 60 % training ( development ) sample and a 40 % test ( validation ) sample . The development sample was used to identify predictor variables and estimate model coefficients . The validation sample was used to assess model calibration and discrimination . Model outcomes included operative mortality , renal failure , stroke , reoperation for any cause , prolonged ventilation , deep sternal wound infection , composite major morbidity or mortality , prolonged length of stay ( > 14 days ) , and short length of stay ( c-index for the mortality model was 0.812 , and the c-indices for other endpoints ranged from 0.653 for reoperation to 0.793 for renal failure in the validation sample . Plots of observed versus predicted event rates revealed acceptable calibration in the overall population and in numerous subgroups . When patients were grouped into categories of predicted risk , the absolute difference between the observed and expected event rates was less than 1.5 % for each endpoint . The final model intercept and coefficients are provided . CONCLUSIONS New STS risk models have been developed for CABG mortality and eight other endpoints . Detailed descriptions of model development and testing are provided , together with the final algorithm . Overall model performance is excellent",
"OBJECTIVE Use of single-dose antibiotic prophylaxis is associated with reduced antibiotic resistance , lower costs , and fewer problems with drug toxicity and superinfections . We tested the hypothesis that single doses of cefazolin are as effective as a 24-hour regimen of cefazolin in preventing surgical site infections in adults undergoing cardiac procedures . METHODS This r and om , prospect i ve , clinical study included 838 adult patients undergoing elective coronary artery bypass grafting , valve operations , or both . These patients were r and omly given a single dose of cefazolin ( 2 g ) or a 24-hour treatment ( 2-g initial dose , followed by 1 g every 8 hours ) . Investigators blinded to the drug regimen diagnosed wound infections according to Centers for Disease Control and Prevention criteria . Patient clinical and demographic characteristics were noted , with follow-up for 12 postoperative months . The primary objective was to compare the incidence of surgical infections between groups up to 12 months postoperatively . RESULTS A total of 419 patients received single-dose cefazolin , and another 419 received the 24-hour treatment . Surgical site infection occurred in 35 ( 8.3 % ) patients receiving single doses and 15 ( 3.6 % ) patients administered the 24-hour treatment ( P = .004 ) . We identified no differences between groups for mortality or duration of hospitalization ( preoperative hospitalization , intensive care unit stay , and hospitalization after surgical intervention ) . The microorganisms isolated showed a similar distribution in both groups . The germs isolated were gram-positive cocci in 86 % of the surgical site infections . CONCLUSIONS Single-dose cefazolin used as antibiotic prophylaxis in cardiac surgery is associated with a higher surgical site infection rate than the 24-hour , multiple-dose cefazolin regimen"
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BACKGROUND The main objectives in treating mania are to control dangerous behaviour , reduce suicide , produce appropriate acute sedation and shorten the episode of mood disturbance . Among different drugs , haloperidol has for many years been used in treating psychotic patients , but it has a troublesome side effect profile . OBJECTIVES To assess the effects of haloperidol for the treatment of mania in comparison with placebo or other active drugs , either as monotherapy or add-on treatment . SEARCH STRATEGY We search ed the Cochrane Collaboration Depression , Anxiety and Neurosis Controlled Trials Register ( 11 October 2005 ) , the Cochrane Central Register of Controlled Trials ( The Cochrane Library Issue 3 , 2005 ) , MEDLINE ( 1966 - 2003 ) , EMBASE ( 1980 - 2003 ) , CINAHL ( 1982 - 2003 ) , PsycINFO ( 1872 - 2003 ) and reference lists . We also contacted experts , triallists and pharmaceutical companies in the field . SELECTION CRITERIA R and omised trials comparing haloperidol with placebo or other active treatment in the treatment of acute manic or mixed episodes in patients with bipolar disorder or schizoaffective disorder . DATA COLLECTION AND ANALYSIS Two authors independently assessed trial quality and extracted data . We contacted study authors for additional information . We collected adverse effects information from the trials . MAIN RESULTS Fifteen trials involving 2022 people were included . Compared to placebo , haloperidol was more effective at reducing manic symptoms , both as monotherapy ( Weighted Mean Difference ( WMD ) -5.85 , 95 % Confidence Interval ( CI ) -7.69 to -4.00 ) and as adjunctive treatment to lithium or valproate ( WMD -5.20 , 95 % CI -9.26 to -1.14 ) . There was a statistically significant difference , with haloperidol being less effective than aripiprazole ( Relative Risk ( RR ) 1.45 , 95 % CI 1.22 to 1.73 ) . No significant differences between haloperidol and risperidone , olanzapine , carbamazepine or valproate were found . Compared with placebo , a statistically significant difference in favour of haloperidol in failure to complete treatment ( RR 0.74 , 95 % Cl 0.57 to 0.96 ) was reported . Haloperidol was associated with less weight gain than olanzapine ( RR : 0.28 , 95 % CI 0.12 to 0.67 ) , but with a higher incidence of tremor ( RR : 3.01 , 95 % CI 1.55 to 5.84 ) and other movement disorders . AUTHORS ' CONCLUSIONS There is some evidence that haloperidol is an effective treatment for acute mania . From the limited data available , there was no difference in overall efficacy of treatment between haloperidol and olanzapine or risperidone . Some evidence suggests that haloperidol could be less effective than aripiprazole . Referring to tolerability , when considering the poor evidence comparing drugs , clinicians and patients should consider different side effect profiles as an important issue to inform their choice
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"BACKGROUND The effectiveness of antipsychotic monotherapy in schizoaffective disorder is limited , and further constrained by safety concerns . AIMS We aim ed to compare the efficacy , tolerability and safety profile of the new pharmaceutical , olanzapine , with haloperidol . METHOD Data were assessed from 300 DSM-III-R schizoaffective subjects from a larger double-blind prospect i ve international study . Subjects were r and omly allocated to six weeks of olanzapine ( 5 - 20 mg ) or haloperidol ( 5 - 20 mg ) treatment ; responders were followed for up to one year of double-blind , long-term maintenance therapy . RESULTS Olanzapine-treated patients achieved a statistically significant greater improvement than haloperidol treated patients on overall measures of efficacy , including clinical response . Significantly fewer olanzapine patients left the study early , and fewer adverse events were observed among those receiving olanzapine . During maintenance , olanzapine-treated patients continued to experience additional improvement , with fewer EPS but more weight gain than those on haloperidol . CONCLUSIONS Olanzapine demonstrated substantial advantages over the conventional antipsychotic haloperidol in the management of schizoaffective disorder",
"Zuclopenthixol acetate — a new injectable formulation with a duration of action of 2–3 days — was compared with conventional intramuscular and oral formulations of haloperidol and zuclopenthixol in the initial treatment of acutely disturbed , psychotic patients . The patients were stratified into 3 diagnostic categories : acute psychoses ( 48 patients ) , mania ( 22 patients ) , and exacerbation of chronic psychoses ( 73 patients ) . The patients were rated on the Brief Psychiatric Rating Scale ( BPRS ) , the Bech‐Rafaelsen Mania Rating Scale ( brmas ) ( only manic patients ) and globally on the Clinical Global Impression ( CGI ) . The study was an open , r and omized multicentre trial with a 6‐day treatment period . The zuclopenthixol acetate patients received 1–4 doses , the haloperidol patients 1–26 and the zuclopenthixol patients 1–22 doses . The assessment s on the CGI showed that all 3 treatments caused a clear reduction of the severity of illness scores in all 3 diagnostic categories , with no differences between treatments . The ratings of the acute and chronic psychotic patients on the BPRS also showed significant reductions in scores with no differences between treatments . All 3 treatments caused a rapid remission of symptoms on the BRMAS . Haloperidol induced hypokinesia in significantly more patients than zuclopenthixol acetate after 24 h. Later there were no significant differences between treatments . Zuclopenthixol acetate fulfils many desires for an amended neuroleptic formulation for the initial treatment of acutely disturbed psychotic patients",
"Previous investigations of the treatment of mania have result ed in uncertainty about the efficacy of lithium versus a neuroleptic . In addition there have been reports of toxicity with a haloperidol -- lithium combination . In order to determine the comparative efficacy of lithium vs haloperidol vs a combination of haloperidol -- lithium , we studied 21 severely ill manic patients who all met rigorous criteria for bipolar illness and who required in hospital treatment . Subjects were r and omly assigned to 3 groups : ( A ) Lithium plus placebo ( B ) Placebo plus haloperidol and ( C ) Lithium plus haloperidol . The study was conducted in double blind fashion for 3 weeks with the dosages of the medications varied according to clinical response or untoward effects . Subjects on haloperidol and placebo or the haloperidol -- lithium combination were significantly improved after 7 days in comparison to the lithium-treated group . Groups B and C did not differ from each other , either in degree of improvement or in side effects . Inspite of the relatively small sample size the results suggest ( 1 ) that haloperidol is superior to lithium for treating severely ill acute mania and ( 2 ) that while a haloperidol -- lithium combination does not result in a significant increase in side effects , it is not superior to haloperidol alone",
"In this study , the authors examined the relationship between steady-state haloperidol blood levels and clinical response in patients with acute psychotic mania . Fifty-four in patients with acute mania were r and omly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg/day . Each subject also received a concomitant medication : lorazepam 4 mg/day , lithium , or placebo . The relationship between steady-state haloperidol blood levels and clinical improvement was studied using analysis of covariance . There was wide interindividual variation in the haloperidol blood level – dose ratio . Haloperidol blood levels ( log-transformed ) were found to significantly correlate with clinical response in acute mania . Low-dose haloperidol with concomitant lithium may produce an optimal response in acute mania . Haloperidol blood levels may be clinical ly useful in identifying patients who are nonresponsive because of low drug levels and , hence , in enhancing optimal haloperidol dosing for acute mania with psychosis",
"Lithium carbonate , haloperidol , and chlorpromazine hydrochloride were compared in a double-blind controlled study with severely ill hospitalized manics . Lithium carbonate and haloperidol produced a highly significant improvement of manic symptoms without sedation . Although producing considerable sedation , chlorpromazine did little to alter the underlying mania qualitatively . Qualitative differences between lithium carbonate and haloperidol indicate that , while haloperidol has a more dramatically rapid impact on behavior-motor activity , lithium carbonate acted more evenly on the entire manic picture , with total normalization realized during active treatment . The majority of lithium carbonate-treated patients met discharge criteria at study termination , but not the patients receiving either neuroleptic drug . The rating scales are not sensitive enough to monitor manic psychopathology ; this accounts for the lack of statistically significant differences among drug groups at treatment termination , despite the widely disparate discharge rates",
"BACKGROUND This r and omized controlled trial compares the efficacy and safety of olanzapine vs haloperidol , as well as the quality of life of patients taking these drugs , in patients with bipolar mania . METHODS The design consisted of 2 successive , 6-week , double-blind periods and compared flexible dosing of olanzapine ( 5 - 20 mg/d , n = 234 ) with haloperidol ( 3 - 15 mg/d , n = 219 ) . RESULTS Rates of remission ( Young-Mania Rating Scale score of 21-item Hamilton Rating Scale for Depression score of olanzapine- and haloperidol-treated patients ( 52.1 % vs 46.1 % , respectively ; P = .15 ) . For the subgroup of patients whose index episode did not include psychotic features , rates of remission were significantly greater for the olanzapine group compared with the haloperidol group ( 56.7 % vs 41.6 % , P = .04 ) . Relapse into an affective episode ( mania and /or depression ) occurred in 13.1 % and 14.8 % of olanzapine- and haloperidol-treated patients , respectively ( P = .56 ) . Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques ( P = .04 ) , and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms , as indicated by several measures . Weight gain was significantly greater in the olanzapine group compared with the haloperidol group ( 2.82 vs 0.02 kg , P quality of life on several dimensions compared with the haloperidol group . CONCLUSIONS These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania . However , haloperidol carries a higher rate of extrapyramidal symptoms , whereas olanzapine is associated with weight gain",
"This double-blind clinical trial studied 16 acutely agitated psychotic patients with manic or manic-like symptoms who needed rapid tranquilization and were therefore on maintenance treatment . They were r and omized to receive intramuscular preparations of clonazepam ( 1 to 2 mg ) or haloperidol ( 5 to 10 mg ) at 0 , 0.5 , and 1.0 hours . Both medications produced significant reduction of manic symptoms within two hours of initial treatment ; however , haloperidol produced beneficial results more rapidly than clonazepam . All patients completed the study , with the exception of one haloperidol-treated patient who developed severe parkinsonism . It was concluded that I.M. clonazepam is an effective , safe , but slower-acting alternative to I.M. haloperidol in the treatment of agitated psychiatric patients in need of rapid tranquilization",
"After 2 days of drug-free observation , 20 newly admitted psychotic patients received 20 - 35 mg of haloperidol intravenously and 20 patients received 30 - 40 mg of diazepam intravenously . Posttreatment ratings at 4 and 24 hours with the Brief Psychiatric Rating Scale and the Clinical Global Impressions revealed significant improvement in both groups but no significant differences between the two treatments",
"BACKGROUND Bipolar affective disorder ( BPAD ) has considerable implication s for personal and social functioning . However a tendency to be over-represented in high socio-economic classes has been reported in earlier studies , suggesting that social disadvantage accompanying the illness is not severe . In addition , an association between affective disorders in general and increased residential mobility has been suggested , but it is unclear if such an association exists with BPAD . OBJECTIVES ( 1 ) To investigate the suggestion made in previous studies that patients with bipolar disorder are advantaged socially . ( 2 ) To test the hypothesis that patients with bipolar disorder show greater residential mobility compared with other patients with psychiatric disorders . METHODS Ninety patients with DSM IV diagnosis of bipolar disorder admitted to the acute in-patient unit of a public-financed district psychiatric service in Dublin were compared with a control group of 91 r and omly selected patients with other psychiatric diagnoses , excluding schizophrenia . Socio-economic , educational and employment ratings were compared , and also duration of illness , frequency of admission and residential mobility . The data were collected retrospectively from case notes and through semistructured interviews with patients or their relatives . The bipolar group was compared with the control group and to the unipolar depression subgroup . RESULTS The bipolar and control groups were found to have similar demographic and socio-economic features , although the bipolar group had more years of education compared with the whole control group but not when compared with the unipolar depression group . The bipolar group showed longer duration of psychiatric disorder , more frequent hospital admissions and more frequent residential moves since the onset of the illness . CONCLUSION Bipolar patients requiring in-patient care in this service experience severe disruption to their lives over prolonged periods",
"The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied . Sixty-two patients ( 29 depressed type ; 33 bipolar type ) entered a three-site , r and omized , double-blind , 6-week trial of risperidone ( up to 10 mg/day ) or haloperidol ( up to 20 mg/day ) . Trained raters assessed baseline , weekly , and end-of- study levels of psychopathology with the Positive and Negative Syndrome Scale ( PANSS ) , the 24-item Hamilton Rating Scale for Depression ( HAM-D-24 ) and the Clinician-Administered Rating Scale for Mania ( CARS-M ) . The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms . In addition , there was no difference in worsening of mania between the two agents in either subgroup ( i.e. , depressed or bipolar subgroups ) . For the total PANSS , risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol . For the total CARS-M scale , risperidone and haloperidol produced mean change scores of 5 and 8 points , respectively , and for the CARS-M Mania subscale , 3 and 7 points , respectively . Additionally , risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D , compared with an 8-point decrease with haloperidol . In those patients who had more severe depressive symptoms ( i.e. , HAM-D baseline score > 20 ) , risperidone produced at least a 50 % mean improvement in 12 ( 75 % ) of 16 patients in comparison to 8 ( 38 % ) of 21 patients receiving haloperidol . Haloperidol produced significantly more extrapyramidal side effects and result ed in more dropouts caused by any side effect . There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder . Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol . In those subjects with higher baseline HAM-D scores ( i.e. , > 20 ) , risperidone produced a greater improvement in depressive symptoms than haloperidol",
"The aim of this study is to evaluate the activity of flupentixol oral high concentration and to define the profile of the drug according to the administered dose . The trial includes 40 acute patients ( 21 schizophrenics , 13 manic patients and 6 other psychotics ) . The study was open , but the patients were treated at r and om either by haloperidol or by flupentixol . Both substances showed a strong antipsychotic and antimanic effect . The differences according to the administered doses were : a quicker onset of action for flupentixol in schizophrenic patients ; a more pronounced activity of flupentixol in the same patients , as far as anxiety , depressive tendencies and defect symptoms are concerned . Extrapyramidal side effects are the most common ones amongst the two drugs",
"BACKGROUND Uncontrolled evidence suggests that divalproex administered via the oral loading strategy of 20 mg/kg/day may produce clinical ly significant antimanic response within 3 days of treatment in some patients . We conducted a prospect i ve study to compare the antimanic response of divalproex oral loading with that of haloperidol in the initial treatment of acute psychotic mania . METHOD After a 36 consecutive hospitalized patients with bipolar disorder , manic or mixed phase and with psychotic features , were r and omly assigned to receive either divalproex 20 mg/kg/day or haloperidol 0.2 mg/kg/day for 6 full days , without other psychotropic agents except lorazepam up to 4 mg/day for management of agitation . Serum valproate concentrations were measured after 1 day of treatment . Response was measured daily by a blind rater using the Young Mania Rating Scale and the Scale for Assessment of Positive Symptoms . RESULTS Divalproex oral loading and haloperidol were equally effective in acutely reducing manic and psychotic symptoms . The greatest rate of improvement for both drug regimens occurred over the first 3 full days of treatment . Side effects were infrequent and minor for both treatments , except for extrapyramidal side effects which were significantly more common with haloperidol . CONCLUSION Divalproex oral loading may produce rapid onset of antimanic and antipsychotic response comparable to that of haloperidol and with minimal side effects in the initial treatment of acute psychotic mania in a subset of bipolar patients",
"BACKGROUND Relations between pretreatment symptom ratings and ECT outcome were examined in acute manic patients admitted at a state psychiatric center who were nonresponsive to medication . METHOD One or 2 days after undergoing pretreatment clinical ratings , patients were r and omly assigned to intensive pharmacotherapy , right unilateral ECT , left unilateral ECT , or bilateral ECT . Patients who failed to respond to any of the first three treatment conditions were assigned to crossover bilateral ECT . Patients who failed to respond to a primary treatment condition other than bilateral ECT but refused crossover bilateral ECT and those in whom ECT was terminated due to an organic brain syndrome were not considered for this study . No psychotropic drugs were prescribed for 4 - 7 days before , or during , the course of ECT . Of the 24 patients who entered the study , 18 patients completed the protocol . Based on independent clinical assessment s by two research psychiatrists , a favorable treatment response was defined as a complete recovery from manic episode that was sustained for 1 week during which no psychotropic medications were prescribed . RESULTS ECT nonresponders were significantly more angry , irritable , and suspicious than ECT responders . Severity of mania and depression ratings at baseline were not related to ECT response . CONCLUSION Symptoms associated with poor response to ECT may overlap with those that have been reported to predict nonresponse to treatment with lithium . Our evidence also may support the view that differential symptom patterns may predict treatment outcomes to ECT and carbamazepine , respectively , in manic patients who do not respond to treatment with lithium or neuroleptics ",
" This study was carried out on 38 chronic refractory psychotic patients who received partial multimodal treatment with individually adapted doses of Haldol . The study was based on : --Howard 's experiences : more than half of his chronic psychotic patients were able to leave the State Hospital because of the multimodal treatment with high individualized doses of Haldol ; -Paquay and Tanghe 's experiences : one-fourth to more than one-half of their chronic refractory patients showed remarkable improvement with a partial multimodal treatment . This study shows that improvement is obtained in more than 2 out of 3 cases , thus proving that the best results are obtained when an adequate selection of the patients is made . As side-effects , above all , the extrapyramidal symptoms are possible . However , their frequency and intensity are not higher than those provoked by other incisive neuroleptics or conventional doses of Haldol . Special attention should be given to any pseudodepression or neurovegetative reactions . The individualization of the doses should be carefully done",
"BACKGROUND We compared three doses of a neuroleptic as a treatment for mania . METHOD Forty-seven newly admitted in- patients with mania were r and omised to receive 10 , 30 , or 80 mg a day of oral haloperidol , under double-blind conditions for up to six weeks . All subjects received prophylactic benztropine . RESULTS Repeated- measures analysis of variance and survival analysis showed no difference in outcome by the different doses . Excluding drop-outs ( 38 % ) , most of whom left the study during the first two weeks , 72 % of the subjects responded . Side-effects were minimal ; there were no differences among the three doses . Non-responders received more adjunctive lorazepam than responders . CONCLUSIONS The limited data suggest that more than 10 mg a day of haloperidol offers no advantage in mania",
"In a r and omized , double-blind trial , patients with acute bipolar mania received 1 - 6 mg/day of risperidone , 2 - 12 mg/day of haloperidol , or placebo for 3 weeks , followed by double-blind risperidone or haloperidol for 9 weeks . Of 438 patients , 154 were r and omized to risperidone , 144 to haloperidol , and 140 to placebo . The mean+/-S.D. modal doses were 4.2+/-1.7 mg/day of risperidone and 8.0+/-3.6 mg/day of haloperidol during the initial 3-week phase and 4.1+/-1.8 and 7.4+/-3.7 mg/day during the 12-week period . At week 3 , mean Young Mania Rating Scale ( YMRS ) score reductions from baseline were significantly greater in patients receiving risperidone than placebo ( p risperidone and haloperidol on this efficacy measure were not significant . Further reductions in YMRS scores were seen in patients receiving risperidone or haloperidol during the subsequent 9 weeks . No unexpected adverse events were reported . Extrapyramidal disorder and hyperkinesias , the most commonly reported adverse events with antipsychotic use , occurred less frequently with risperidone than haloperidol . We conclude that risperidone monotherapy was an effective and well-tolerated treatment for bipolar mania and that efficacy was maintained over the long term",
"Hospitalized manic patients were withdrawn from psychoactive medications for 2 weeks after which they were r and omized to double-blind treatment with carbamazepine plus lithium [ CBZ-Li ] or haloperidol plus lithium [ HAL-Li ] with benztropine . Unit dosages of Li 300 mg , CBZ 200 mg and HAL 2 mg were titrated to therapeutic plasma levels and maintained for 8 weeks . No rescue medications were permitted after 3 weeks . St and ard ratings of psychopathology and side effects were accomplished weekly . Sixty patients entered the study but only 33 remained for r and omization after drug washout . By 8 weeks both groups were improved from baseline without statistically reliable differences between them . However HAL-Li patients had more extrapyramidal side effects that were major reasons for dropout , whereas CBZ-Li patients were more often noncompliant and initially required more rescue medications . We conclude that either combination treatment can be beneficial but CBZ-Li has the advantage because of fewer neurologic side effects",
"In a double-blind comparative clinical study , both thiothixene and haloperidol were found to be effective agents for rapid tranquilization of manic and schizophrenic patients . While no statistically significant difference in any of the psychopathological areas which may create a psychiatric emergency was found , results of this study provide further substantiation of the notion that thiothixene has favorable effects on anergia",
"In a double-blind , between-patient clinical trial carbamazepine ( CBZ ) ( n = 8) was compared to haloperidol ( HP ) ( n = 9 ) in patients presenting with mania ( DSM III ) . Seven patients on HP and 2 on CBZ failed to complete 4 weeks treatment . In 4 of the HP group this was because of extrapyramidal side-effects ( EPS ) . Two patients on CBZ and 2 on HP were withdrawn because of lack of efficacy . Statistically significant clinical improvement was seen in both groups within the first 2 weeks of treatment with HP acting more quickly . In addition to EPS which occurred in HP patients , drowsiness was experienced in 4 on CBZ and 3 on HP , and gastrointestinal symptoms in 3 on CBZ . No serious haematological changes , nor abnormalities in clinical chemistry occurred in either group . We conclude that CBZ appears to be a potentially useful drug in the treatment of acute mania",
"INTRODUCTION Pretreatment plasma homovanillic acid ( HVA ) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic , bipolar manic , and mixed groups of psychotic patients . Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment . METHOD Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder , manic with psychotic features were entered into this double-blind study and were r and omly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study . Subjects also received one of the following concomitant medications : st and ard lithium , lorazepam 4 mg/day , or placebo . RESULTS The primary multiple regression analysis , including all subjects on both haloperidol doses , yielded a significant main effect for pretreatment plasma HVA ( n=31 , F=5.7 , P=0.025 ) , indicating that higher pretreatment plasma HVA was predictive of better clinical response . In addition , the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response ( F=12.59 , P=0.0015 ) . When the two haloperidol doses were analyzed separately , we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group ( n=18 , F=11.73 , P=0.0038 ) and was unrelated to clinical response to the high haloperidol 25 mg/day group . LIMITATIONS The sample size was small . Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam . DISCUSSION These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics . Patients with high plasma HVA levels would be good c and i date s for low-dose treatment because they are more likely to improve on such a dose , while patients with low plasma HVA levels might warrant more rapid dosage escalation",
"The effects of haloperidol , risperidone , and thioridazine on the pharmacokinetics and side-effect profile of quetiapine were investigated in 36 patients with schizophrenia , schizoaffective disorder , or bipolar disorder in a single-center , two-period , multiple-dose , open-label , r and omized trial . Over a one-to two-week period , quetiapine doses were escalated to 300 mg twice daily ( bid ) . Patients were then treated for at least 7 days at the target quetiapine dose and subsequently entered into the combination therapy period , receiving haloperidol ( 7.5 mg , bid ) , risperidone ( 3 mg , bid ) , or thioridazine ( 200 mg , bid ) for 8.5 days ( after 3 days of dose escalation ) . Key assessment s included the pharmacokinetics of quetiapine at steady state ( area under the curve within a dosing interval [ AUCtSS ] , maximum [ CmaxSS ] , and minimum [ CminSS ] observed plasma concentrations , and oral clearance [ Cl/f ] ) , as well as the UKU Side Effect Rating Scale scores and safety evaluations . Neither risperidone nor haloperidol had significant effects on quetiapine pharmacokinetics . However , thioridazine produced statistically significant changes , decreasing the least squares means values of the AUCtSS , CmaxSS , and CminSS by 40 % , 47 % , and 31 % , respectively , and increasing Cl/f by 68 % . Increases in the following adverse events were noted during coadministration : somnolence ( risperidone ) , insomnia and dry mouth ( all three coadministered therapies ) , and dizziness ( thioridazine ) . UKU side effect items that became worse in ≥ 25 % of patients during each coadministration period included sedation and increased sleep duration . Results of laboratory tests , electrocardiograms , and vital sign measurements revealed few clinical ly important changes . Clinical stability can be maintained with good tolerability during the transition from quetiapine monotherapy to periods of coadministration with haloperidol , risperidone , or thioridazine . Coadministration of either haloperidol or risperidone did not have any important effects on the steady-state pharmacokinetics of quetiapine . Thioridazine significantly increased the oral clearance of quetiapine . Increased doses of quetiapine may be necessary to control psychotic symptoms when thioridazine is coadministered with quetiapine",
" Three doses of haloperidol , 10 mg/day , 30 mg/day , and 80 mg/day , were compared in 47 newly admitted manic patients . There was no difference in outcome within 6 weeks among the three doses . Four blood levels of plasma and red blood cell ( RBC ) haloperidol and reduced haloperidol showed no linear or curvilinear relationships to clinical response",
"We aim ed to compare clinical outcomes , health-related quality of life ( HRQOL ) and work status associated with olanzapine and haloperidol treatment in patients with bipolar disorder . This double-blind , r and omized controlled trial , comparing flexible dosing of olanzapine ( 5–20 mg/day , n = 234 ) to haloperidol ( 3–15 mg/day , n = 219 ) , consisted of a 6-week acute phase , followed by a 6-week continuation phase . Symptomatic remission rates were similar for olanzapine- and haloperidol-treated patients at weeks 6 and 12 . At week 6 , significant changes in five dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey ( SF-36 ) [ general health ( P = 0.010 ) , physical functioning ( P 0.001 ) , role limitations due to physical problems ( P , social functioning ( P and vitality ( P ] and the SF-36 physical components summary score were found in favour of olanzapine compared to haloperidol . At week 12 , olanzapine treatment maintained the significantly favourable HRQOL changes . At the end of week 12 , patients on olanzapine showed significantly greater improvement than haloperidol in work activities impairment and household activities impairment scores on the Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation ( SLICE/LIFE ) activities impairment scores . Subgroup analyses revealed that olanzapine treatment significantly increased a proportion of employed patients and their weekly paid working hours . In conclusion , compared to haloperidol , olanzapine treatment was comparably effective in the remission of bipolar mania and significantly improved HRQOL and work status in patients with bipolar I disorder",
"BACKGROUND Behavioural and psychological symptoms ( BPSD ) are common during the course of dementia and present severe problems to patients and their caregivers . OBJECTIVES To assess the therapeutic efficacy and safety of haloperidol and risperidone in treating BPSD in Chinese dementia patients . METHODS A 12-week double-blind r and omised comparison of haloperidol and risperidone treatments was conducted in 58 patients with DSM-IV diagnosis of dementia of Alzheimer 's type or vascular dementia . They were r and omly assigned to receive flexible doses ( 0.5 to 2 mg/day ) of haloperidol or risperidone . Clinical response was evaluated using the Cohen-Mansfield Agitation Inventory ( CMAI ) , the Behavioral Pathology in Alzheimer 's Disease Rating Scale ( BEHAVE-AD ) , Simpson-Angus Scale , Functional Assessment Staging and Cantonese version of the Mini-Mental State Examination . RESULTS The mean doses at the last week were 0.90 mg/day of haloperidol and 0.85 mg/day of risperidone . Both haloperidol and risperidone significantly reduced the severity of BPSD ( scores on CMAI and BEHAVE-AD ) , with no significant between-group differences . Haloperidol-treated patients showed a worsening on Simpson-Angus scale while there was no significant change in this measure in risperidone-treated patients . CONCLUSIONS Low-dose haloperidol and risperidone were well tolerated and associated with reductions in the severity and frequency of behavioural symptoms in subjects with dementia . Risperidone may have a more favourable risk-benefit profile in view of its lower propensity to induce extrapyramidal symptoms",
"Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania . Forty-five in patients with DSM-IV mania were studied in a 28-day r and omized , controlled , double-blind trial of either 6 mg daily of risperidone , 10 mg daily of haloperidol , or 800 to 1200 mg daily of lithium . The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 ( Brief Psychiatric rating scale : lithium 9.1 , haloperidol 4.9 , risperidone 6.5 , F = 1.01 , df = 2 , p = 0.37 ; Mania rating scale : lithium 15.7 , haloperidol 10.2 , risperidone 12.4 , F = 1.07 , df = 2 , p = = 0.35 [ analysis of variance ] ) . The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement . This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania . The extrapyramidal side effects of risperidone and haloperidol were not significantly different",
"OBJECTIVE The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania . METHOD This 3-week r and omized , double-blind , placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer ( lithium or divalproex ) and placebo , risperidone , or haloperidol . The primary efficacy measure was the Young Mania Rating Scale . Other assessment s used the Brief Psychiatric Rating Scale , the Clinical Global Impression scale , and safety measures . RESULTS The trial was discontinued by 25 ( 49 % ) of the 51 placebo group patients , 18 ( 35 % ) of the 52 risperidone group patients , and 28 ( 53 % ) of the 53 haloperidol group patients . Mean modal doses were 3.8 mg/day ( SD=1.8 ) of risperidone and 6.2 mg/day ( SD=2.9 ) of haloperidol . Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group , compared with the placebo group . Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline . Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients . Antiparkinsonian medications were received by 8 % , 17 % , and 38 % of patients in the placebo , risperidone , and haloperidol groups , respectively . CONCLUSIONS Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone , and as efficacious as haloperidol plus a mood stabilizer , for the rapid control of manic symptoms and was well tolerated"
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BACKGROUND Multiple sclerosis is a disease of the central nervous system characterized by demyelination of the nerve sheaths which can result in varying levels of disability . Disease occurrence and progression are considered by some to be associated with low serum levels of vitamin D. Studies investigating vitamin D supplementation in MS patients have illustrated a noticeable improvement in the course of the disease . OBJECTIVES To evaluate the safety and effectiveness of vitamin D in the management of multiple sclerosis . SEARCH STRATEGY We search ed the Cochrane Multiple Sclerosis Group Trials Register comprising references identified from comprehensive electronic data base search es and h and search es of relevant journals and abstract books of conferences . SELECTION CRITERIA R and omised and quasi-r and omised controlled trials comparing vitamin D with placebo or any other treatment for the management of multiple sclerosis . DATA COLLECTION AND ANALYSIS Two review authors selected trials for inclusion , assessed the risk of bias and extracted data independently . Disagreements were resolved by consensus . Trialists were contacted for clarification of study details . MAIN RESULTS We included a single trial ( 49 participants ) conducted over 52 weeks , which treated 25 patients with escalating doses of vitamin D compared with control ( 24 ) . The trial provided some evidence of the potential benefit of the intervention on several outcomes i.e. the annualised relapse rate ; EDSS scores ; suppression of T-cell proliferation and illustrated a measure of comparative safety in the relative absence of any adverse events or of high serum calcium levels over the study period . This was a low powered trial with a potential high risk of bias which may ultimately impose limits on the applicability of the available evidence to the MS population as a whole . AUTHORS ' CONCLUSIONS The current level of evidence for the effectiveness of vitamin D supplementation in the management of people with MS is based on a single RCT with potential high risk of bias , which does not at present allow confident decision-making about the use of Vitamin D in MS . Therefore , until further high quality evidence is available , clinicians may wish to consider relevant MS guidelines on vitamin D supplementation when making decisions about the care of people with multiple sclerosis . Adequately powered , multi-centred RCTs with a focus on clinical as well as immunological and MRI outcomes that are meaningful to people with MS , and are able to provide insight into the benefits of Vitamin D in people with MS , are still required
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"AIM To evaluate the efficacy and safety of an annual intramuscular injection of cholecalciferol for vitamin D deficiency . DESIGN Prospect i ve open-label study . PARTICIPANTS Five men and 45 women ( mean age 66.3 years ) with vitamin D deficiency who were given a single therapeutic intramuscular injection of 600 000 IU ( 15 mg ) cholecalciferol ( vitamin D(3 ) ) . OUTCOME MEASURES Serum levels of calcium , creatinine , 25-hydroxyvitamin D(3 ) ( 25OHD(3 ) ) and parathyroid hormone , as well as early morning 2-hour urine calcium/creatinine excretion index . Specimens were collected at baseline and after 4 and 12 months of therapy . Data are reported as mean + /- 1 SD . RESULTS Vitamin D deficiency was severe ( Twenty-four participants ( 48 % ) had secondary hyperparathyroidism . Following intramuscular cholecalciferol injection , serum 25OHD(3 ) levels normalised in all participants and remained above 50 nmol/L throughout the study . Serum 25OHD(3 ) levels were significantly higher at 4 months ( 114 + /- 35 nmol/L ) , and 12 months ( 73 + /- 13 nmol/L ) compared with baseline ( 32 + /- 8 nmol/L ) ( P serum parathyroid hormone levels at 4 months ( 6 + /- 3 pmol/L ) and at 12 months ( 5.2 + /- 3 pmol/L ) , with a 30 % decrease at 12 months from baseline ( 7.4 + /- 4 pmol/L ) ( P Primary hyperparathyroidism was unmasked in one participant at 4 months and mild hypercalcaemia ( serum calcium , Serum creatinine levels remained normal in all participants throughout the study , while increases in 2-hour urine calcium/creatinine excretion index were seen in 10 participants ( 20 % ) at 12 months , three of whom had had elevated values at baseline . CONCLUSIONS Once-yearly intramuscular cholecalciferol injection ( 600 000 IU ) is effective therapy for vitamin D deficiency . While this therapy appears to be safe , the potential for developing hypercalciuria needs to be examined in a large r and omised controlled trial",
" A group of young patients having multiple sclerosis was treated with dietary supplements containing calcium , magnesium and vitamin D for a period of one to two years . The experimental design employed self-pairing : the response of each patient was compared with his/her own case history as control . The number of exacerbations observed during the program was less than one half the number expected from case histories . No side effects were apparent . The dietary regimen may offer a new means of controlling the exacerbation rate in MS , at least for younger patients . The results tend to support a theory of MS which states that calcium and magnesium are important in the development , structure and stability of myelin",
"Multiple sclerosis ( MS ) is a possible cause of secondary osteoporosis . In this phase II trial we assessed whether a weekly dose of 20,000 IU vitamin D3 prevents bone loss in ambulatory persons with MS age 18–50 years . Clinical Trials.gov ID NCT00785473 . All patients managed at the University Hospital of North Norway who fulfilled the main inclusion criteria were invited to participate in this double-blinded trial . Participants were r and omised to receive 20,000 IU vitamin D3 or placebo once a week and 500 mg calcium daily for 96 weeks . The primary outcome was the effect of the intervention on percentage change in bone mineral density ( BMD ) at the hip , the spine , and the ultradistal radius over the study period . Of 71 participants r and omised , 68 completed . Mean serum 25-hydroxyvitamin D [ 25(OH)D ] levels in the intervention group increased from 55 nmol/L at baseline to 123 nmol/L at week 96 . After 96 weeks , percentage change in BMD did not differ between groups at any site . BMD decreased at the hip , by 1.4 % in the placebo group ( 95 % CI −2.3 to −0.4 , SD 2.7 , p = 0.006 ) and by 0.7 % in the treatment group ( −1.6 to 0.2 , 2.7 , p = 0.118 ) , difference 0.7 % ( −1.9 to 0.7 , p = 0.332 ) . Findings were not altered by adjustment for sex or serum 25(OH)D. Supplementation with 20,000 IU vitamin D3 a week did not prevent bone loss in this small population . Larger studies are warranted to assess the effect of vitamin D on bone health in persons with MS",
"CONTEXT Epidemiological and experimental evidence suggests that high levels of vitamin D , a potent immunomodulator , may decrease the risk of multiple sclerosis . There are no prospect i ve studies addressing this hypothesis . OBJECTIVE To examine whether levels of 25-hydroxyvitamin D are associated with risk of multiple sclerosis . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , nested case-control study among more than 7 million US military personnel who have serum sample s stored in the Department of Defense Serum Repository . Multiple sclerosis cases were identified through Army and Navy physical disability data bases for 1992 through 2004 , and diagnoses were confirmed by medical record review . Each case ( n = 257 ) was matched to 2 controls by age , sex , race/ethnicity , and date s of blood collection . Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum sample s collected before the date of initial multiple sclerosis symptoms . MAIN OUTCOME MEASURES Odds ratios of multiple sclerosis associated with continuous or categorical levels ( quantiles or a priori-defined categories ) of serum 25-hydroxyvitamin D within each racial/ethnic group . RESULTS Among whites ( 148 cases , 296 controls ) , the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D ( odds ratio [ OR ] for a 50-nmol/L increase in 25-hydroxyvitamin D , 0.59 ; 95 % confidence interval , 0.36 - 0.97 ) . In categorical analyses using the lowest quintile ( 25-hydroxyvitamin D levels higher than 99.1 nmol/L , was significantly different from 1.00 ( OR , 0.38 ; 95 % confidence interval , 0.19 - 0.75 ; P = .006 ) . The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years . Among blacks and Hispanics ( 109 cases , 218 controls ) , who had lower 25-hydroxyvitamin D levels than whites , no significant associations between vitamin D and multiple sclerosis risk were found . CONCLUSION The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis",
"Background : Epidemiological and ecological studies suggest links between vitamin D deficiency and increased multiple sclerosis ( MS ) prevalence . Objective : To evaluate the safety and tolerability of oral calcitriol therapy in an open label pilot study . Methods : 15 ambulatory patients with relapsing – remitting MS and at least one clinical relapse within the previous 12 months received oral calcitriol ( target dose : 2.5 μg/d ) for 48 weeks . Dietary calcium was restricted to 800 mg/d . Patients were monitored using frequent clinical and laboratory examinations , the exp and ed disability status scale ( EDSS ) , and brain magnetic resonance imaging ( MRI ) . Results : Two patients withdrew because of symptomatic hypercalcaemia ( serum calcium > 3.35 mmol/l in each case ) result ing from persistent dietary indiscretion . Two diet compliant patients required temporary dose adjustments for mild asymptomatic hypercalcaemia . Diet compliant patients experienced mild adverse effects . The on- study exacerbation rate ( 27 % ) was less than baseline . Four patients experienced five clinical relapses but only one patient worsened by > 1 EDSS point . Brain MRI revealed enhancing lesions in five patients at baseline ( 33 % ) and in four ( 29 % ) at both 24 and 48 weeks . Conclusions : Oral calcitriol is safe and well tolerated for up to one year by diet compliant relapsing – remitting MS patients . Further study of vitamin D related mechanisms is warranted in MS",
"Objective : Low vitamin D status has been associated with multiple sclerosis ( MS ) prevalence and risk , but the therapeutic potential of vitamin D in established MS has not been explored . Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical , immunologic , and clinical outcomes in patients with MS prospect ively . Methods : An open-label r and omized prospect i ve controlled 52-week trial matched patients with MS for demographic and disease characteristics , with r and omization to treatment or control groups . Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [ 25(OH)D ] rapidly and assess tolerability , followed by 10,000 IU/day ( 12 weeks ) , and further downtitrated to 0 IU/day . Calcium ( 1,200 mg/day ) was given throughout the trial . Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups . Secondary endpoints included 25(OH)D and other biochemical measures , immunologic biomarkers , relapse events , and Exp and ed Disability Status Scale ( EDSS ) score . Results : Forty-nine patients ( 25 treatment , 24 control ) were enrolled [ mean age 40.5 years , EDSS 1.34 , and 25(OH)D 78 nmol/L ] . All calcium-related measures within and between groups were normal . Despite a mean peak 25(OH)D of 413nmol/L , no significant adverse events occurred . Although there may have been confounding variables in clinical outcomes , treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls . Conclusions : High-dose vitamin D ( ∼10,000 IU/day ) in multiple sclerosis is safe , with evidence of immunomodulatory effects . Classification of evidence : This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation . The trial , however , lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures ( relapses and Exp and ed Disability Status Scale scores ) , providing only Class level IV evidence for these outcomes",
"Recent studies have shown that related genetic influences on bone mineral density ( BMD ) and bone turnover are related to allelic variations in the vitamin D receptor ( VDR ) gene . Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption . In addition , VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus ( IDDM ) and multiple sclerosis ( MS ) . In the gene encoding the VDR , we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence . The subjects were 131 female Japanese patients with Graves ' disease and 150 female controls . The distribution of genotype frequencies differs between Graves ' disease and controls ( chi2 = 5.99 , degrees of freedom = 2 , p = 0.0386 ) . We found overexpression of F allele ( 69 % vs. 61 % , p = 0.0472 ) and homozygote FF ( 48 % vs. 33 % , p = 0.0118 ) in Graves ' disease patients compared with controls . We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves ' disease in remission . Although generally , no significant association was seen between age-adjusted BMD and genotype , patients in remission for fewer than 5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes ( z = 1.14 ff vs. z = -0.43 Ff , p serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes ( 78 + /- 12 vs. 59 + /- 10 , p serum concentrations of osteocalcin , urinary hydroxyproline , or urinary deoxypyridinoline . Our results indicate , for the first time , an association between Graves ' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves ' disease in patients in remission",
"Summary We studied the effect of alphacalcidol ( 1-α-hydroxycholecalciferol ) on bone metabolism in patients who were placed on glucocorticoid therapy . We selected 41 women ( age : 32–52 yrs ) who were recently diagnosed with systemic lupus erythematodes , multiple sclerosis , rheumatoid arthritis or asthma bronchiale . Patients did not have other disease or take drugs known to influence bone metabolism . Patients were r and omly enrolled into two groups and were given 5–25 mg prednisone daily . After 4 weeks , group A ( n=21 ) received 0.5–1.0μg ( mean=0.54±0.03μg ) alphacalcidol and group B ( control ; n=20 ) was given 500 mg calcium daily for three years . There were no significant differences in age and steroid doses between groups . Serum calcium ( Ca ) , osteocalcin ( OC ) , collagen I C-terminal propeptide ( PICP ) , parathyroid hormone ( PTH ) , and urinary calcium and deoxypyridinoline crosslink excretion ( DPD ) were measured before corticosteroid administration , and before alphacalcidol or calcium treatment as well as 6 weeks , 6 months , and 1 , 2 , and 3 years later . Bone mineral density ( BMD ) was examined before treatment and 6 months , 1 , 2 , and 3 years later by DEXA and SPA . OC and PICP decreased significantly after 4 weeks on steroid in both groups and increased in group A but not in group B after 6 weeks of treatment with alphacalcidol and remained unchanged for 3 years . Serum PTH increased in both groups after 4 weeks of glucocorticoid treatment and was reduced in group A , but not in group B , after 6 weeks on alphacalcidol . Serum Ca , urinary Ca , and DPD did not change significantly in either group during the study period . Lumbar spine and femoral neck BMD were significantly reduced in group B after 6 months and 1 year , respectively , and continued to decrease during the study , while no significant change in group A was observed . BMD of the radius did not change in either group for 2 years but there was a significant reduction by the third year in group B. Based on these results , alphacalcidol treatment appears to be effective in preventing glucocorticoid-induced bone loss in these patients by reducing secondary hyperparathyroidism and stimulating bone formation",
"Objective To determine the relative efficacy of amantadine , pemoline , and placebo in treatment of multiple sclerosis (MS)-related fatigue . Background Fatigue is a complication of MS . Both pemoline and amantadine have been used to treat MS fatigue , but their relative efficacy is not known . Methods Amantadine , pemoline , and placebo were compared in a r and omized , double-blind , placebo-controlled study using a parallel-group design . Ninety-three ambulatory MS patients completed the study . Primary outcome measures were the fatigue seventy scale ( FSS ) ; the MS-specific fatigue scale ( MS-FS ) ; and subjective response determined by verbal self-report . Secondary outcome measures consisted of assessment s of sleep , depression , and vitality . Repeated- measures analysis of variance with planned post-hoc contrasts and Fisher 's exact test were used to compare treatment response . Results Amantadine-treated patients showed a significantly greater reduction in fatigue , as measured by the MS-FS , than did patients treated with placebo ( p = 0.04 ) . By verbal report at the end of the study , 79 % of patients treated with amantadine versus 52 % treated with placebo and 32 % treated with pemoline preferred drug therapy compared with no treatment ( p = 0.03 ) . No significant differences in any primary outcome measures were noted between pemoline and placebo . Neither amantadine nor pemoline affected sleep or depression relative to placebo . Conclusion Amantadine was significantly better than placebo in treating fatigue in MS patients , whereas pemoline was not . The benefit of amantadine was not due to changes in sleep , depression , or neurologic disability",
" Multiple sclerosis ( MS ) patients were r and omized , in a double blind design , and placed into either a vitamin D supplemented group or a placebo control group . As expected , serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation ( 17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months ) . Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later . Placebo treatment had no effect on serum TGF-beta 1 levels . Tumor necrosis factor (TNF)-alpha , interferon (IFN)-gamma , and interleukin (IL)-13 were not different following vitamin D supplementation . IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance . Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1",
"The effects of acute pharmacologic steroid treatment on skeletal and mineral metabolism were assessed in 56 multiple sclerosis patients who were to receive 1 g intravenous methylprednisolone for 10 days , followed by a 4 day intravenous and 28 day oral glucocorticoid taper . Serum and urine sample s were obtained at baseline and then within 3 days , 1 , 2 , and 3 weeks after beginning steroids . A subset of patients ( n = 11 ) had sampling throughout the 6 weeks of steroid administration and up to 8 weeks afterward . All mean basal biochemistries were normal except 25(OH)D , which was in the \" insufficient \" range ( 25 - 50 nM ) at 10 nM. During and after steroid administration , there were no changes in ionized calcium , 25(OH)D , urinary hydroxyproline , or pyridinoline . There was an increase in 1,25(OH)2D and a decrease in serum phosphorus , accompanied by an increase in urinary phosphate clearance , within 3 days of administration ( p Serum osteocalcin ( BGP ) decreased to below assay sensitivity limits within 3 days of steroid administration ( p PTH(1 - 84 ) increased to a peak at week 2 ( p peak and the serum phosphorus nadir . Tartrate-resistant acid phosphatase , urinary calcium , and urinary cyclic AMP all increased above baseline ( p steroid administration , serum sample s were obtained at the same four times on both the day before and the day after the first intravenous methylprednisolone dose in a r and omly chosen subset of patients ( n = 9 ) . ( ABSTRACT TRUNCATED AT 250 WORDS",
"Multiple sclerosis ( MS ) is an inflammatory disease in which the myelin sheaths around the axons of the central nervous system are damaged . The damage leads to demyelination and scarring as well as a broad spectrum of signs and symptoms . The epidemiological data suggest a possible influence of vitamin D as an immunomodulatory agent on multiple sclerosis susceptibility as well as on clinical course of the disease . We investigated the effects of short-term vitamin D3 therapy on Iranian patients with MS . In a prospect i ve r and omized controlled trial study , 62 MS patients received 300,000 IU/month vitamin D3 or placebo as intramuscular injection for 6 months . Our results showed no significant difference between the treatment and the control groups in the exp and ed disability status scale scores and number of gadolinium-enhancing lesions during the 6-month treatment period . After 6 months , the levels of cell proliferation in the vitamin D treatment group were significantly lower than the control group . Also , the levels of transforming growth factor-beta and interleukin-10 in the vitamin D treatment group were significantly higher than the control group . This result suggests that vitamin D therapy may help prevent the development of MS and could be a useful addition to the therapy",
"OBJECTIVE To develop a self-administered rating scale for quantifying quality of life ( QoL ) in multiple sclerosis ( MS ) patients . METHODS The RAYS scale items were derived from a source of 600 questions composed by our Centre 's experts from commonly used instruments that assess physical , psychological , and social-familial dimensions . Prior to finalization of the RAYS QoL , c and i date items were administered to 15 health rehabilitation professionals . Clarity , importance , relevance and specificity were grade d for each item by every professional independently . Items chosen for the final version were grade d as good or excellent on all these aspects . The Medical Outcome Study Short Form-36 ( SF-36 ) was used to compare health appraisal with the RAYS scale . RESULTS Each of the three subscales of the RAYS covers a different dimension ( physical , psychological , and social-familial ) and each includes 15 self-report items scored from 1 ( best ) to 4 ( worse ) , focusing on the preceding week . Validation was achieved through administration of the scale to 50 r and omly selected MS patients and to 50 age , sex- , education- and family status-matched healthy controls . All RAYS dimensions among MS patients reached a Cronbach 's coefficient alpha > 0.8 . Mean values for all dimensions were greater in patients than in controls ( P social functioning subscales . CONCLUSION The RAYS scale demonstrated high internal consistency and significant discriminative value , and is thus a suitable disease-specific tool for measuring QoL in MS",
"Multiple sclerosis ( MS ) is a consequence of genetic and environmental factors . Geographic , genetic , and biological evidence suggests that an important immunopathogenic factor might be the insufficiency of vitamin D. The aim of our study was to investigate the immunomodulatory effect of alfacalcidol , a vitamin D analogue , on cytokine levels in RRMS patients in relapse . We investigated 15 patients suffering from RRMS relapse ( an RRMS group ) and two control groups : one control group of healthy subjects ( n=10 ) and a NIND group , consisting of patients with non-inflammatory neurological diseases ( n=10 ) . All of the MS patients were treated with 5 microgr/day of oral alfacalcidol for a period of five days . The serum cytokine levels of TNF-alpha , IL-10 , IL-4 , and IL-12 were measured in all the MS patients one day prior to and one day after therapy , and in all the control subjects ( ELISA , Quantikine human immunoassay , R&D Systems , UK ) . Our results showed significantly lower IL-4 and IL-12 levels in the RRMS patients group compared to the N group and the NIND group ( p TNF-alpha and IL-10 levels were found between the groups , and there was no influence of alfacalcidol on these cytokines in RRMS patients . High doses of oral alfacalcidol induced significant increases in IL-4 and IL-12 levels in RRMS patients ( p IL-4 and IL-12 levels compared to the N group and the NIND group . Alfacalcidol therapy in RRMS patients did not provoke any side effects . Vitamin D and its analogues , such as alfacalcidol , act as immunomodulatory agents , with potential therapeutic effects for patients with multiple sclerosis",
"Susceptibility to Graves ' disease ( GD ) , which is determined by environmental and genetic factors , is conferred by genes in the human leukocyte antigen ( HLA ) and genes unlinked to HLA , including the CTLA-4 gene . We recently described the association of GD with the vitamin D receptor ( VDR ) exon 2 initiation codon ( VDR-FOK : I ) polymorphism . An association of some VDR genotypes with osteoporosis , primary hyperparathyroidism , and some autoimmune diseases , such as insulin-dependent diabetes mellitus and multiple sclerosis , has been reported . We investigated the distribution of VDR gene polymorphism in 180 Japanese patients with GD ( 48 males and 132 females ) and 195 controls ( 67 males and 128 females ) . A VDR allelic polymorphism was assessed by BSM : I endonuclease restriction after specific PCR amplification . Genotypic polymorphism was clearly defined as BB ( no restriction site on both alleles ) , bb ( restriction site on both alleles ) , or Bb ( heterozygous ) . The distribution of genotype frequencies differed between patients with GD and controls ( chi(2 ) = 7.53 ; 2 degrees of freedom ; P : = 0.023 ) . The relative risk conferred by at least 1 B allele ( BB or Bb ) was 1.5 . We also found an association between VDR-APA : I polymorphism and GD . No relation was detected between this polymorphism and the VDR-FOK : I polymorphism in the patients . The present results support the association of the VDR gene with GD in Japanese by showing that the VDR gene could be a non-HLA-linked gene predisposing an individual to GD . The role of the VDR gene polymorphism should be further studied in other population s , and the distribution of other polymorphisms , such as the polyadenylase polymorphism further down the VDR 3'-untranslated region , should be studied in terms of GD susceptibility",
"Background : A protective effect of vitamin D on risk of multiple sclerosis ( MS ) has been proposed , but no prospect i ve studies have addressed this hypothesis . Methods : Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women : the Nurses ’ Health Study ( NHS ; 92,253 women followed from 1980 to 2000 ) and Nurses ’ Health Study II ( NHS II ; 95,310 women followed from 1991 to 2001 ) . Diet was assessed at baseline and up date d every 4 years thereafter . During the follow-up , 173 cases of MS with onset of symptoms after baseline were confirmed . Results : The pooled age-adjusted relative risk ( RR ) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 ( 95 % CI = 0.40 to 1.12 ; p for trend = 0.03 ) . Intake of vitamin D from supplements was also inversely associated with risk of MS ; the RR comparing women with intake of ≥400 IU/day with women with no supplemental vitamin D intake was 0.59 ( 95 % CI = 0.38 to 0.91 ; p for trend = 0.006 ) . No association was found between vitamin D from food and MS incidence . Conclusion : These results support a protective effect of vitamin D intake on risk of developing MS ",
"Recent studies have demonstrated the immunomodulatory properties of vitamin D , and vitamin D deficiency may be a risk factor for the development of MS . The risk of developing MS has , in fact , been associated with rising latitudes , past exposure to sun and serum vitamin D status . Serum 25-hydroxyvitamin D [ 25(OH)D ] levels have also been associated with relapses and disability progression . The identification of risk factors , such as vitamin D deficiency , in MS may provide an opportunity to improve current treatment strategies , through combination therapy with established MS treatments . Accordingly , vitamin D may play a role in MS therapy . Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects , reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions . However , large r and omized clinical trials of vitamin D supplementation in patients with MS are lacking . SOLAR ( Supplementation of VigantOL ( ® ) oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif ( ® ) treatment ) is a 96-week , three-arm , multicenter , double-blind , r and omized , placebo-controlled , Phase II trial ( NCT01285401 ) . SOLAR will evaluate the efficacy of vitamin D(3 ) as add-on therapy to subcutaneous interferon beta-1a in patients with RRMS . Recruitment began in February 2011 and is aim ed to take place over 1 calendar year due to the potential influence of seasonal differences in 25(OH)D levels",
"CONTEXT The active metabolite of vitamin D , 1,25-dihydroxyvitamin D [ 1,25(OH)(2)D ] , is a potent modulator of immune cells in vitro . OBJECTIVE Our objective was to determine whether the sun-dependent nutrient , cholecalciferol , can alter disease-associated cellular immune abnormalities in patients with multiple sclerosis ( MS ) . DESIGN This was an open-label , 12-month , r and omized controlled trial . SETTING Patients with MS were recruited from the MS Clinic at St. Michael 's Hospital , Toronto . PATIENTS Forty-nine patients were matched ( for age , sex , disease duration , disease-modifying drug , and disability ) and enrolled ( treated n = 25 ; control n = 24 ) . Four patients were lost to follow-up ( n = 2 from each group ) . INTERVENTION Treated patients received increasing doses of cholecalciferol ( 4,000 - 40,000 IU/d ) plus calcium ( 1200 mg/d ) , followed by equilibration to a moderate , physiological intake ( 10,000 IU/d ) . Control patients did not receive supplements . MAIN OUTCOME MEASURES At enrollment and at 12 months , peripheral blood mononuclear cell ( P BMC ) proliferative responses to disease-associated , MS-relevant , and control antigens were measured , along with selected serum biochemical markers . RESULTS At 12 months , mean serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations were 83 ± 35 nmol/liter and 179 ± 76 nmol/liter in control and treated participants , respectively ( paired t , P Serum 1,25(OH)(2)D did not differ between baseline and 1 yr . In treated patients , 12-month P BMC proliferative responses to neuron antigens myelin basic protein and exon-2 were suppressed ( P = 0.002 ) . In controls , there were no significant changes in disease-associated P BMC responsiveness . There were no significant differences between groups in levels of selected biomarkers . INTERPRETATION MS-associated , abnormal T cell reactivities were suppressed in vivo by cholecalciferol at serum 25(OH)D concentrations higher than 100 nmol/liter"
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Attention-deficit/hyperactivity disorder ( ADHD ) is a complex and heterogeneous disorder , affecting individuals across the life cycle . Although its etiology is not yet completely understood , genetics plays a substantial role . Pharmacological treatment is considered effective and safe for children and adults , but there is considerable inter-individual variability among patients regarding response to medication , required doses , and adverse events . We present here a systematic review of the literature on ADHD pharmacogenetics to provide a critical discussion of the existent findings , new approaches , limitations , and recommendations for future research . Our main findings are : first , the number of studies continues to grow , making ADHD one of the mental health areas with more pharmacogenetic studies . Second , there has been a focus shift on ADHD pharmacogenetic studies in the last years . There is an increasing number of studies assessing gene-gene and gene-environment interactions , using genome-wide association approaches , neuroimaging , and assessing pharmacokinetic properties . Third and most importantly , the heterogeneity in method ological strategies employed by different studies remains impressive . The question whether pharmacogenetics studies of ADHD will improve clinical management by shifting from trial- and -error approach to a pharmacological regimen that takes into account the individual variability remains unanswered . © 2014 Wiley Periodicals ,
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"OBJECTIVE The aim of this study was to examine whether demographic or pretreatment clinical and social characteristics influenced the response to methylpheni date ( MPH ) in the Preschoolers with ADHD Treatment Study ( PATS ) . METHODS Exploratory moderator analyses were conducted on the efficacy data from the PATS 5-week , double-blind , placebo-controlled six-site titration trial . Children ( N = 165 , age 3 - 5.5 years ) were r and omized to 1 week each of four MPH doses ( 1.25 , 2.5 , 5 , and 7.5 mg ) and placebo administered three times per day ( t.i.d . ) . We assessed the fixed effects on the average slope in the regression outcome on moderators , weight-adjusted dose , and the moderator-by-dose interaction using SAS PROC GENMOD . RESULTS A significant interaction effect was found for a number of co-morbid disorders diagnosed in the preschoolers at baseline ( p = 0.005 ) . Preschoolers with three or more co-morbid disorders did not respond to MPH ( Cohen 's d at 7.5 mg dose relative to placebo = -0.37 ) compared to a significant response in the preschoolers with 0 , 1 , or 2 co-morbid disorders ( Cohen 's d = 0.89 , 1.00 , and 0.56 , respectively ) . Preschoolers with more co-morbidity were found to have more family adversity . No significant interaction effect was found with the other variables . CONCLUSIONS In preschoolers with ADHD , the presence of no or one co-morbid disorder ( primarily oppositional defiant disorder ) predicted a large treatment response at the same level as has been found in school-aged children , and two co-morbid disorders predicted moderate treatment response ; whereas the presence of three or more co-morbid disorders predicted no treatment response to MPH",
"We sought to test the hypothesis that the variable number of t and em repeat ( VNTR ) polymorphism in the 3′-untranslated region ( 3′-UTR ) of the SLC6A3 gene modulates behavior in children with ADHD and /or behavioral response to methylpheni date ( MPH ) . One hundred and fifty-nine children with AHDH ( 6–12 years ) were assessed with regard to the Conners ’ Global Index for parents ( CGI-Parents ) and teachers ( CGI-Teachers ) and the response of these behaviors to MPH ( 0.5 mg/kg/day ) using a 2-week prospect i ve within-subject ( crossover ) trial . Based on CGI-Parents , the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3′-UTR VNTR polymorphism of SLC6A3 , as indicated by a significant ( p=0.017 ) genotype by treatment two-way interaction . Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele . No genotype or genotype by treatment interaction was observed for CGI-Teachers . These findings support a role for the DAT gene 3′-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD . They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH",
"Little is known about the effect of clinical characteristics , parental psychopathology , family functioning , and environmental stressors in the response to methylpheni date in children with attention-deficit/hyperactivity disorder ( ADHD ) followed up in a naturalistic setting . Data from cultures outside the United States are extremely scarce . This is a longitudinal study using a nonr and om assignment , quasi-experimental design . One hundred twenty-five children with ADHD were treated with methylpheni date according to st and ard clinical procedures , and followed up for 6 months . The severity of ADHD symptoms was assessed by the Swanson , Nolan , and Pelham rating scale . In the final multivariate model , ADHD combined subtype ( P levels of maternal ADHD symptoms were also associated with worse prognosis ( P undesired pregnancy was associated with poorer response to methylpheni date in the final comprehensive model ( P = 0.02 ) . Our study provides evidence for the involvement of clinical characteristics , maternal psychopathology , and environmental stressors in the response to methylpheni date . Clinicians may consider adjuvant strategies when negative predictors are present to increase the chances of success with methylpheni date treatment",
"BACKGROUND Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood . The mechanism of action of methylpheni date , the most common treatment for attention deficit hyperactivity disorder , is unclear . In vitro , the affinity of methylpheni date for the norepinephrine transporter ( NET ) is higher than that for the dopamine transporter ( DAT ) . The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylpheni date in vivo in humans . METHODS We used (S , S)-[¹¹C ] methylreboxetine ( [¹¹C]MRB ) to determine the effective dose 50 ( ED₅₀ ) of methylpheni date for NET . In a within-subject design , healthy subjects ( n = 11 ) received oral , single-blind placebo and 2.5 , 10 , and 40 mg of methylpheni date 75 min before [¹¹C]MRB injection . Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph . The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable ( BP(ND ) ) in the thalamus and other NET-rich regions . RESULTS BP(ND ) was reduced by methylpheni date in a dose-dependent manner in thalamus and other NET-rich regions . The global ED₅₀ was estimated to be .14 mg/kg ; therefore , the average clinical maintenance dose of methylpheni date ( .35-.55 mg/kg ) produces 70 % to 80 % occupancy of NET . CONCLUSIONS For the first time in humans , we demonstrate that oral methylpheni date significantly occupies NET at clinical ly relevant doses . The ED₅₀ is lower than that for DAT ( .25 mg/kg ) , suggesting the potential relevance of NET inhibition in the therapeutic effects of methylpheni date in attention-deficit/hyperactivity disorder",
"OBJECTIVE OROS methylpheni date HCL ( MPH ) is a recently developed long-acting stimulant medication used to treat attention-deficit/hyperactivity disorder ( ADHD ) . This study was conducted to examine dosage effects on ADHD symptoms and stimulant side effects and to explore potential moderating effects of ADHD subtype . METHODS Children with ADHD combined type ( ADHD-CT ) or predominantly inattentive type ( ADHD-PI ; n = 47 ) , ages 5 to 16 years , underwent a placebo-controlled , crossover trial using forced titration with weekly switches at 3 dosage levels . Parent and teacher ratings of ADHD symptoms were used to evaluate efficacy . In addition , vital signs and st and ardized measures of stimulant side effects were obtained weekly . RESULTS Parent ratings were more sensitive to treatment effects than teacher ratings . ADHD symptoms and Clinical Global Impressions Severity Index ratings at each dose condition differed significantly from placebo and baseline ratings , which did not differ from one another . For those with ADHD-CT , there was a clear linear dose-response relationship , with clinical ly significant reductions in ADHD Rating Scale-IV scores occurring in two thirds to three fourths of the subjects during either 36- or 54-mg dose conditions . Children with ADHD-PI , conversely , were more likely to respond optimally to lower doses and derived less benefit from higher doses , with 60 % displaying significant improvement on the ADHD Rating Scale-IV at 36 mg or lower . Mild stimulant side effects were reported during placebo and at all dosage levels . With the exception of insomnia and decreased appetite , which were more common at higher doses , parent report of side effects was not related to dose . In addition , younger and smaller children were more likely to display sleep difficulties and decreased appetite at the higher dose levels Although pulse rate increased slightly with increasing dose , there were no dose effects on blood pressure . CONCLUSIONS In children with ADHD-CT , the most common subtype of ADHD , increasing doses of stimulant medication were associated with increased improvement of inattention and hyperactivity symptoms . In children with ADHD-PI , symptom improvement occurred at lower doses and less benefit was derived from higher doses . In both ADHD subtypes , higher doses were associated with parent ratings of increased insomnia and decreased appetite",
"CONTEXT As genes associated with common disorders are increasingly identified , we need to progress from observing associations to identifying risk pathways . The high-activity COMT genotype , in the presence of attention-deficit/hyperactivity disorder ( ADHD ) , has previously been shown to be associated with extreme antisocial behavior . The same genotype has also been implicated in affecting cognitive function in healthy individuals . Impaired cognitive function might therefore lie on the risk pathway from genotype to clinical outcome . OBJECTIVES To replicate the association between COMT genotype and antisocial behavior in ADHD and to then test whether ( 1 ) impaired executive control or ( 2 ) impaired social underst and ing act as intermediate phenotypes for this association and lie on the risk pathway between COMT genotype and antisocial behavior . DESIGN Prospect i ve epidemiological cohort sample . SETTING The Avon Longitudinal Study of Parents and Children . PARTICIPANTS Four thous and three hundred sixty-five children with data on COMT Val¹⁵⁸Met genotype , ADHD symptoms and diagnoses , and measures of social cognition/underst and ing and executive control . MAIN OUTCOME MEASURES Antisocial behavior at age 7.5 years assessed using DSM-IV conduct disorder symptoms . RESULTS We replicated the association of the high-activity COMT genotype , in the presence of ADHD , with extreme antisocial behavior ( odds ratio , 2.82 ; 95 % confidence interval , 2.02 - 3.94 ; P with both executive control and impaired social underst and ing . The strength of the association between genotype and antisocial behavior was unchanged by including executive control in the model but dropped when impaired social underst and ing was included ( odds ratio , 1.87 ; 95 % confidence interval , 1.26 - 2.76 ; P = .002 ) . CONCLUSIONS The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social underst and ing . Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior . The findings demonstrate the importance of testing links between genotype , intermediate phenotype , and clinical outcome in the same sample to identify potential risk pathways",
"OBJECTIVE Atomoxetine is an investigational , nonstimulant pharmacotherapy being studied as potential treatment for attention-deficit/hyperactivity disorder ( ADHD ) . It is thought to act via blockade of the presynaptic norepinephrine transporter in the brain . We assessed the efficacy of 3 doses of atomoxetine compared with placebo in children and adolescents with ADHD . METHODS A total of 297 children and adolescents who were 8 to 18 years of age and had ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders , 4th edition , were r and omized to placebo or atomoxetine dosed on a weight-adjusted basis at 0.5 mg/kg/day , 1.2 mg/kg/day , or 1.8 mg/kg/day for an 8-week period . ADHD symptoms , affective symptoms , and social and family functioning were assessed using parent and investigator rating scales . RESULTS Approximately 71 % of children enrolled were male , approximately 67 % met criteria for mixed subtype ( both inattentive and hyperactive/impulsive symptoms ) , and the only common psychiatric comorbidity was oppositional defiant disorder ( approximately 38 % of the sample ) . At baseline , symptom severity was rated as moderate to severe for most children . At endpoint , atomoxetine 1.2 mg/kg/day and 1.8 mg/kg/day were consistently associated with superior outcomes in ADHD symptoms compared with placebo and were not different from each other . The dose of 0.5 mg/kg/day was associated with intermediate efficacy between placebo and the 2 higher doses , suggesting a grade d dose-response . Social and family functioning also were improved in the atomoxetine groups compared with placebo with statistically significant improvements in measures of children 's ability to meet psychosocial role expectations and parental impact . Discontinuations as a result of adverse events were children and adolescents aged 8 to 18 , atomoxetine was superior to placebo in reducing ADHD symptoms and in improving social and family functioning symptoms . Atomoxetine was associated with a grade d dose-response , and 1.2 mg/kg/day seems to be as effective as 1.8 mg/kg/day and is likely to be the appropriate initial target dose for most patients . Treatment with atomoxetine was safe and well tolerated",
"CONTEXT Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder ( ADHD ) , with varying methods , small sample s , cross-sectional design s , and without accounting for stimulant drug exposure . OBJECTIVE To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls . DESIGN , SETTING , AND PARTICIPANTS Case-control study conducted from 1991 - 2001 at the National Institute of Mental Health , Bethesda , Md , of 152 children and adolescents with ADHD ( age range , 5 - 18 years ) and 139 age- and sex-matched controls ( age range , 4.5 - 19 years ) recruited from the local community , who contributed 544 anatomic magnetic resonance images . MAIN OUTCOME MEASURES Using completely automated methods , initial volumes and prospect i ve age-related changes of total cerebrum , cerebellum , gray and white matter for the 4 major lobes , and cau date nucleus of the brain were compared in patients and controls . RESULTS On initial scan , patients with ADHD had significantly smaller brain volumes in all regions , even after adjustment for significant covariates . This global difference was reflected in smaller total cerebral volumes ( -3.2 % , adjusted F(1,280 ) = 8.30 , P = .004 ) and in significantly smaller cerebellar volumes ( -3.5 % , adjusted F(1,280 ) = 12.29 , P = .001 ) . Compared with controls , previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes ( overall F(2,288 ) = 6.65 ; all pairwise comparisons Bonferroni corrected , -5.8 % ; P = .002 ) and cerebellar volumes ( -6.2 % , F ( 2,288 ) = 8.97 , P total white matter volumes ( F(2,288 ) = 11.65 ) compared with controls ( -10.7 % , P Volumetric abnormalities persisted with age in total and regional cerebral measures ( P = .002 ) and in the cerebellum ( P = .003 ) . Cau date nucleus volumes were initially abnormal for patients with ADHD ( P = .05 ) , but diagnostic differences disappeared as cau date volumes decreased for patients and controls during adolescence . Results were comparable for male and female patients on all measures . Frontal and temporal gray matter , cau date , and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample ( Pearson coefficients between -0.16 and -0.26 ; all P values were Developmental trajectories for all structures , except cau date , remain roughly parallel for patients and controls during childhood and adolescence , suggesting that genetic and /or early environmental influences on brain development in ADHD are fixed , nonprogressive , and unrelated to stimulant treatment",
"A polymorphism in the dopamine transporter gene ( DAT1 ) has been previously associated with ADHD and methylpheni date has been hypothesized to block the dopamine transporter . The goal of this study was to examine whether a 40‐bp variable number of t and em repeats ( VNTR ) of DAT1 moderate response and adverse effects associated with methylpheni date treatment of adults with ADHD . Subjects were 106 adults with ADHD enrolled in 6‐week r and omized placebo‐controlled parallel design trials of methylpheni date ( OROS and immediate release preparations ) . There was no evidence of an association between DAT1 VNTR and response to methylpheni date ( F(2,100 ) = 0.04 , P = 0.9 ) . Similarly , there was no pattern of statistically significant association with DAT1 VNTR and cardiovascular or spontaneously reported adverse effects . We failed to identify an association with DAT1 and the response or tolerability of methylpheni date in adults with ADHD . © 2006 Wiley‐Liss ,",
"Research on psychostimulants , analysis of animal models and genetic association studies all suggest that the brain-derived neurotrophic factor gene ( BDNF ) may be a good c and i date for pharmacogenetic studies of attention deficit hyperactivity disorder ( ADHD ) . Yet to date there have been no pharmacogenetic studies of BDNF in ADHD . A total of 102 drug-naive ADHD children ( 8.7±2.1 yr ) were treated with osmotic release oral system-methylpheni date ( OROS-MPH ) for 12 wk , and four kinds of response criteria were applied , based first , on a combined threshold of the ADHD Rating Scale - IV ( ARS ) and the Clinical Global Impression - Improvement scale ( CGI-I ) ; second , on scores of 1 or 2 vs. 3 - 7 on the CGI - Severity scale ; third , on a > 50 % reduction in ARS scores ; and fourth , on satisfaction of all of the aforementioned criteria . The Val⁶⁶Met polymorphism of BDNF and six single nucleotide polymorphisms from the SLC6A2 , ADRA2A and NTF-3 genes were tested for association with each criterion . Relative to other genotypes , homozygosity for the Val allele of the BDNF Val⁶⁶Met polymorphism was associated with a greater relative frequency of good response under all four response criteria ( after controlling for baseline ARS score , age , gender , final dose ( mg/kg ) of OROS-MPH at 12 wk , and level of academic functioning ) . This association was significant at the uncorrected level for the first and third response criteria ( p=0.013 and p=0.018 , respectively ) and significant at a Bonferroni-corrected level for the second and fourth response criteria ( p=0.0002 , p=0.0003 , respectively ) . Our findings support an association between homozygosity for the Val allele of BDNF and better response to OROS-MPH in Korean ADHD children as assessed by four different response criteria",
"Abstract Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder ( ADHD ) , including increased response time variability , which has been proposed as a leading endophenotype for ADHD . The aim of this study was to examine the relationship between polymorphisms in the & agr;-2A-adrenergic receptor ( ADRA2A ) and norepinephrine transporter ( SLC6A2 ) genes and attentional performance in ADHD children before and after pharmacological treatment . One hundred one medication-naive ADHD children were included . All subjects were administered methylpheni date (MPH)–OROS for 12 weeks . The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks . Additive regression analyses controlling for ADHD symptom severity , age , sex , IQ , and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment . Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained ( P = 2.0 × 10−3 ) and auditory selective attention ( P = 1.0 × 10−3 ) tasks . Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task ( P = 2.0 × 10−3 ) . After medication , increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task ( P = 1.0 × 10−3).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD . Our results add to a growing body of evidence , suggesting that response time variability is a viable endophenotype for ADHD and suggesting its utility as a surrogate end point for measuring stimulant response in pharmacogenetic studies",
"Atomoxetine , a selective inhibitor of the norepinephrine transporter , exerts its therapeutic effect for attention-deficit hyperactivity disorder ( ADHD ) by increasing the concentration of synaptic norepinephrine . The objective of this study was to evaluate the association of the genetic variants of multiple genes of the noradrenergic neurotransmitter system with atomoxetine response . One hundred and eleven ADHD children and adolescents were enrolled in a prospect i ve , open-label study of atomoxetine for 8–12 weeks . The dose was titrated to 1.2–1.4 mg/kg per day and maintained for at least 4 weeks . The primary efficacy measure was the investigator-rated ADHD Rating Scale-IV . Two categorical evaluations of treatment effects ( defined as response and remission ) were used . Twelve SNPs in SLC6A2 , ADRA2A , and ADRA1A were genotyped to analyze their association with response or remission status . rs3785143 in SLC6A2 was associated with responder status ( nominal P = 0.0048 ; corrected by multiple test , P = 0.0416 ; OR 2.66 , 95 % confidence interval ( CI ) 1.35–5.26 ) . rs2279805 of SLC6A2 was nominally significantly associated with the remission status . ( P = 0.0221 , OR 2.32 , 95 % CI 1.13–4.75 , multiple test P = 0.2130 ) . The GG haplotype of rs1800544 and rs553668 in ADRA2A achieved nominal significance for association with non-remission ( P = 0.0219 , OR 2.82 , 95 % CI 1.16–6.85 , multiple test , P = 0.2076 ) . The results of this study suggest that DNA variants of both SLC6A2 and ADRA2A in the adrenergic neurotransmitter system might alter the response to atomoxetine , though further replication study in larger sample for validation of these findings is still needed",
"The response of 23 children with attention deficit disorder ( ADD ) with hyperactivity ( + H ) and 17 children with ADD without hyperactivity ( -H ) to three doses of methylpheni date ( 5 , 10 , and 15 mg twice a day ) was evaluated in a triple-blind , placebo-controlled cross-over design using parent and teacher ratings of behavior , laboratory tests of ADD symptoms , and behavioral observations during academic performance . Results indicated that the children with ADD+H were rated as having more pervasive behavioral problems at home and more pervasive and severe conduct problems at school than the children with ADD-H. Laboratory tests found the children with ADD+H to be impaired in behavioral inhibition and vigilance whereas children with ADD-H were more impaired in the consistent retrieval of verbally learned material Drug effects were noted on the parent and teacher ratings and on most laboratory measures , with all three doses typically producing significant changes but rarely differing among themselves in effectiveness . The groups were not found to differ significantly on any measures in their response to methylpheni date . However , more children with ADD-H were clinical ly judged as having either no clinical response ( 24 % ) or responding best to the low dose ( 35 % ) of medication . In contrast , most ADD+H ( 95 % ) children were judged to be positive responders and most were recommended to receive the moderate to high dose ( 71 % )",
"CONTEXT Pre clinical studies have demonstrated the relevance of adrenergic alpha2A receptor on the attentional process and the mechanism of action of methylpheni date hydrochloride . Several molecular genetic investigations suggest a role for the adrenergic alpha2A receptor gene ( ADRA2A ) in attention-deficit/hyperactivity disorder ( ADHD ) , especially in the inattentive dimension . However , the effect of ADRA2A in the response to methylpheni date in humans has not been previously investigated , to our knowledge . OBJECTIVE To evaluate the association between the ADRA2A -1291 C > G polymorphism and the clinical response to methylpheni date treatment in children and adolescents with ADHD . DESIGN A pharmacogenomic study was undertaken between November 1 , 2002 , and May 1 , 2004 , using a nonr and om assignment , quasi-experimental design . SETTING An ADHD outpatient program at a university hospital in Brazil . Patients One hundred six patients consecutively diagnosed as having ADHD were genotyped for the ADRA2A -1291 C > G polymorphism and were included in the analyses . Intervention Short-acting methylpheni date administered in increasing dosages until no further clinical improvement was detected or until limited adverse effects occurred . MAIN OUTCOME MEASURES The primary outcome measure was the parent-rated inattentive subscale of the Swanson , Nolan , and Pelham Scale version IV . Secondary outcome measures included the Barkley Side Effect Rating Scale and the parent-rated hyperactivity-impulsivity subscale of the Swanson , Nolan , and Pelham Scale version IV . Scales were applied by child psychiatrists blinded to genotype at baseline and at 1 and 3 months of treatment . RESULTS A significant interaction effect between the presence of the G allele and treatment with methylpheni date over time on inattentive scores was detected during the 3 months of treatment ( n = 106 ; F(2,198 ) = 4.30 ; P = .02 ) . CONCLUSIONS We documented the effect of the G allele at the ADRA2A -1291 C > G polymorphism on the improvement of inattentive symptoms with methylpheni date treatment in children and adolescents with ADHD . Our findings provide clinical evidence for the involvement of the noradrenergic system in the modulation of methylpheni date action",
"Stimulant medications , such as methylpheni date ( MPH ) , are the most commonly used , effective treatment for ADHD . MPH acts primarily by inhibiting the dopamine transporter ( DAT ) , a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals . We sought to evaluate the relationship between DAT1 3′-untranslated region ( 3′-UTR ) variable number t and em repeats ( VNTR ) genotypes and dose response to MPH . Children with ADHD ( n=47 ) , ages 5–16 years ( mean=9.02 years ) , underwent a 4-week , double-blinded , crossover trial with forced weekly dosage changes . Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS ® MPH . Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms , impairment , and stimulant side effects each week . Children who were homozygous for the less common , 9-repeat DAT1 3′-UTR genotype displayed a distinct dose – response curve from that of the other genotype groups , with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg . Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype , and to determine if this group responds differentially to alternative treatments",
"Although genetic factors are known to be important in addiction , no c and i date genes have yet been consistently linked to drug use or abuse . Brain‐derived neurotrophic factor ( BDNF ) , which has been implicated in the behavioral response to psychomotor stimulants and potentiates neurotransmitters that are strongly linked to addiction , is a logical c and i date gene to study . Using a drug challenge approach , we tested for association between BDNF G196A ( val66met ) genotype and subjective responses to amphetamine ( AMPH ) . Healthy volunteers participated in a double blind , crossover design in which they received placebo , 10 mg , and 20 mg oral d‐amphetamine in r and om order . Subjective and physical responses to ingestion of AMPH were measured at 30‐min intervals after drug ingestion . Each subject was genotyped for the BDNF G196A polymorphism and grouped and analyzed accordingly . The effects of AMPH on ratings of arousal , energy , and heart rate were compared in subjects with the val/val genotype ( N = 67 ) and the subjects with either the val/met or met/met genotypes ( N = 32 ) . AMPH produced less pronounced self‐ratings of arousal and energy , yet higher increases in heart rate , in the val/met and met/met compared to the val/val group . These results suggest that BDNF is related to the subjective and physical response to low doses of AMPH . © 2006 Wiley‐Liss ,",
"Few studies on pharmacogenetics of Attention‐Deficit/Hyperactivity Disorder ( ADHD ) have been conducted . Most of them evaluated dopaminergic genes result ing in positive and negative findings . We assessed effects of polymorphisms in c and i date dopaminergic ( DRD4 , DAT1 ) and serotonergic genes ( HTR1B , HTR2A , and 5‐HTT ) on the response to treatment in 111 patients for whom methylpheni date ( MPH ) was prescribed . Outcome measures ( Swanson , Nolan , and Pelham scale — version IV , Children Global Assessment Scale , Barkley 's Stimulants Side Effects Rating Scale ) were assessed at baseline and 1 month after the intervention . No significant association was detected between polymorphisms assessed and both response and side effects to MPH . Prospect i ve multi‐site controlled studies with larger sample sizes are needed in order to disentangle the role of c and i date genes in response to ADHD treatment . © 2006 Wiley‐Liss ,",
"Summary An association between ADRA2A −1291 C > G polymorphism and response to methylpheni date in inattentive symptoms was previously suggested in children with ADHD . No investigation specifically assessed this association in ADHD – inattentive type ( ADHD-I ) . In this naturalistic pharmacogenetic study , 59 subjects with ADHD-I from a non-referred sample were treated with short-acting methylpheni date and genotyped for ADRA2A −1291 C > G polymorphism . The primary outcome measure was the inattentive subscale of the SNAP-IV applied by a child psychiatrist blinded to genotype at baseline and first month of treatment . Children and adolescents with the G allele showed significantly lower inattentive scores with MPH treatment at the first month of treatment than subjects without the G allele ( n = 59 ; F = 6.14 ; p = 0.016 ) . We extended to ADHD-I previous findings suggesting the influence of the G allele at the ADRA2A −1291 C > G polymorphism on the improvement of inattentive symptoms with methylpheni date in children with all ADHD subtypes",
"OBJECTIVE We conducted a genome-wide association study of blood pressure in an open-label study of the methylpheni date transdermal system ( MTS ) for the treatment of attention-deficit/hyperactivity disorder ( ADHD ) . METHOD Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0 . Multivariate association analyses were conducted using the software package PLINK . After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD . RESULTS We observed no genome-wide statistically significant findings , but a SNP in a K(+)-dependent Na(+)/Ca(2 + ) exchanger expressed in vascular smooth muscle ( SLC24A3 ) was included in our top associations at p in blood pressure observed with methylpheni date pharmacotherapy in children with ADHD",
"Rationale The cardiovascular effects of psychostimulant drugs ( methylpheni date , amphetamine , cocaine ) have been mostly associated with their noradrenergic effects . However , there is some evidence that dopaminergic effects are involved in the cardiovascular actions of these drugs . Here , we evaluated this association in humans . Methods Positron emission tomography ( PET ) and [11C]raclopride , a dopamine ( DA ) D2 receptor radiolig and that competes with endogenous DA for occupancy of the D2 receptors , were used to measure changes in brain DA after different doses of intravenous methylpheni date in 14 healthy subjects . Cardiovascular ( heart rate and blood pressure ) and catecholamine ( plasma epinephrine and norepineprhine ) responses were determined in parallel to assess their relationships to methylpheni date -induced changes in brain DA . Results Methylpheni date administration significantly increased heart rate , systolic and diastolic blood pressures and epinephrine concentration in plasma . The increases in blood pressure were significantly correlated with methylpheni date -induced increases of DA in striatum ( r>0.78 , P plasma epinephrine levels ( r>0.82 , P methylpheni date -induced DA increases in striatum were correlated with increases of epinephrine in plasma ( r=0.85 , P methylpheni date did not increase DA had no change in blood pressure or in plasma epinephrine concentration . Discussion These results are consistent with the hypothesis that methylpheni date -induced increases in blood pressure are in part due to its central dopaminergic effects . They also suggest that methylpheni date 's pressor effects may be in part mediated by DA-induced increases in peripheral epinephrine",
"Several studies have evaluated the association between individual polymorphisms and response to methylpheni date ( MPH ) in subjects with attention‐deficit/hyperactivity disorder ( ADHD ) . There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field . Although data collection from multiple international sites would allow large sample sizes , this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies . To examine these issues , we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis : ( a ) we evaluated the role of method ological aspects in the variability of ADHD symptom improvement between studies using meta‐regression analysis ; ( b ) we assessed the role of individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets . At the study level , from five evaluated factors , only the design of the study ( open studies vs. r and omized controlled trials ) was significantly associated with heterogeneity of results ( P = 0.001 ) . At the individual level , age ( P comorbid oppositional defiant disorder ( P change of ADHD scores with treatment in the final multivariate model . Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising , since fixed variables , such as the site where the study was conducted , were not related to results . Nevertheless , stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed . © 2008 Wiley‐Liss ,",
"OBJECTIVE Clinicians have difficulty applying drug research findings to clinical practice , because research protocol s use methods different from those used in daily office practice setting s. METHOD To design a medication protocol for a multisite clinical trial involving 576 children with attention-deficit hyperactivity disorder ( ADHD ) while maintaining relevance to clinical practice , investigators from the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder ( MTA study ) developed novel medication strategies . These were design ed to work either in a monomodal or multimodal format and to ensure st and ard approaches are used across diverse sites . Each child r and omized to medication ( projected N = 288 ) is individually titrated to his or her \" best \" methylpheni date dose and has individual ADHD symptoms monitored . Decision rules were developed to guide \" best dose \" selection , dose changes , medication changes , the management of side effects , and integration with psychosocial treatments . CONCLUSIONS The MTA study uses a controlled method to st and ardize the identification of each child 's \" best \" methylpheni date dose in a national , multisite cooperative treatment program . Although the titration protocol is complex , the study 's individual dosing approach and algorithms for openly managing ADHD children 's medication over time will be of interest to clinicians in office practice",
"Objectives Osmotic-release oral system (OROS)-methylpheni date ( MPH ) is a safe and well-tolerated drug . Some patients can not continue this regimen with adverse drug reactions ( ADRs ) . As drug efflux transporters of the central nervous system , ABCB1 plays an important role in the clearance of psychotropic drugs and their metabolites from brain tissues . We hypothesized that genetic variations in the ABCB1 gene may affect ADRs to OROS-MPH . Methods We analyzed ADRs of OROS-MPH in 134 children and adolescents with attention-deficit hyperactivity disorder who completed a 4-week trial of OROS-MPH . The ADRs of OROS-MPH were evaluated by administering the Barkley Stimulant Side Effects Rating Scale . Results Our study proved that MPH is a substrate for ABCB1 by using membrane vesicle assay . We analyzed the influence of ABCB1 polymorphisms on ADRs to OROS-MPH . From the association study between ABCB1 polymorphisms and ADRs of OROS-MPH , c.2677G > T ( p . Ala893Ser , rs2032582 ) showed a strong association with OROS-MPH – related ADRs ( P = 0.008 ; odds ratio , 5.72 ) . Furthermore , logistic regression analysis indicated that the TT genotype at the ABCB1 2677 locus is an independent determinant of ADRs attributed to OROS-MPH . In a functional study , the 893Ser variant markedly reduced MPH transport across the cell membrane . Conclusions This is the first study to demonstrate that the TT genotype at position 2677 in the ABCB1 gene is associated with ADRs to OROS-MPH ",
"OBJECTIVE Because of significant individual variability in attention-deficit/hyperactivity disorder ( ADHD ) medication response , there is increasing interest in identifying genetic predictors of treatment effects . This study examined the role of four catecholamine-related c and i date genes in moderating methylpheni date ( MPH ) dose-response . METHOD Eighty-nine stimulant-naive children with ADHD 7 to 11 years old participated in a r and omized , double-blind , crossover trial of long-acting MPH . Parents and teachers assessed each child 's response on placebo and three MPH dosage levels using the V and erbilt ADHD rating scales . Children were genotyped for polymorphisms in the 3 ' untranslated region of dopamine transporter ( DAT ) , exon 3 on dopamine receptor D(4 ) ( DRD4 ) , codon 158 on catechol-O-methyltransferase , and the adrenergic α(2A)-receptor promoter . Linear mixed models evaluated gene , dose ( milligrams per kilogram per day ) , and gene-by-dose effects on inattentive and hyperactive-impulsive domain outcomes . RESULTS The most statistically significant gene-by-dose interactions were observed on hyperactive-impulsive symptoms for DRD4 and DAT polymorphisms , with participants lacking the DAT 10-repeat allele showing greater improvements in symptoms with increasing dose compared with 10-repeat carriers ( p = .008 ) and those lacking the DRD4 4-repeat allele showing less improvement across MPH doses compared with 4-repeat carriers ( p = 0.02 ) . CONCLUSIONS This study suggests that DAT and DRD4 polymorphisms may be associated with individual variability in MPH dose-response , although further research in larger sample s is required to confirm these findings and their clinical utility . CLINICAL TRIAL REGISTRATION INFORMATION Response Variability in Children with Attention-Deficit/Hyperactivity Disorder ( ADHD ) ; http://www . clinical trials.gov ; NCT01238822",
"PURPOSE Attention-deficit/hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) are highly comorbid and may share a genetic vulnerability . Methylpheni date ( MPH ) , a dopamine transporter ( DAT ) blocker , is an effective drug for most ADHD patients . Although dopamine D4 receptor ( DRD4 ) and dopamine transporter ( DAT1 ) genes have a role in both disorders , little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs . The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs . METHODS Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [ Tc(99 m ) ] TRODAT-1 at baseline and after three weeks on MPH . Cau date and putamen DAT binding potential was calculated . Comparisons on DAT changes were made according to the subjects ' genotype . RESULTS The combination of both DRD4 7-repeat allele ( 7R ) and homozygosity for the DAT1 10-repeat allele ( 10/10 ) was significantly associated with a reduced DAT change after MPH treatment in right and left cau date and putamen , even adjusting the results for potential confounders ( P ≤ 0.02 ; R² from 0.50 to 0.56 ) . CONCLUSIONS In patients with ADHD/SUDs , combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy . This might be important for clinical trials , in terms of better underst and ing individual variability in treatment response"
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BACKGROUND This is an up date d version of the original Cochrane review published in 2005 on selective serotonin reuptake inhibitors ( SSRIs ) for preventing migraine and tension-type headache . The original review has been split in two parts and this review now only regards migraine prevention . Another up date d review is under development to cover tension-type headache . Migraine is a common disorder . The chronic forms are associated with disability and have a high economic impact . In view of discoveries about the role of serotonin and other neurotransmitters in pain mechanisms , selective serotonin reuptake inhibitors ( SSRIs ) and serotonin-norepinephrine reuptake inhibitors ( SNRIs ) have been evaluated for the prevention of migraine . OBJECTIVES To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic migraine in adults . SEARCH METHODS For the original review , we search ed MEDLINE ( 1966 to January 2004 ) , EMBASE ( 1994 to May 2003 ) , the Cochrane Central Register of Controlled Trials ( CENTRAL 2003 , Issue 4 ) , and Headache Quarterly ( 1990 to 2003 ) . For this up date , we applied a revised search strategy to reflect the broader type of intervention ( SSRIs and SNRIs ) . We search ed CENTRAL ( 2014 , Issue 10 ) , MEDLINE ( 1946 to November 2014 ) , EMBASE ( 1980 to November 2014 ) , and PsycINFO ( 1987 to November 2014 ) . We also checked the reference lists of retrieved articles and search ed trial registries for ongoing trials . SELECTION CRITERIA We included r and omised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older of either sex with migraine . DATA COLLECTION AND ANALYSIS Two authors independently extracted data ( migraine frequency , index , intensity , and duration ; use of symptomatic/analgesic medication ; days off work ; quality of life ; mood improvement ; cost-effectiveness ; and adverse events ) and assessed the risk of bias of trials . The primary outcome of this up date d review is migraine frequency . MAIN RESULTS The original review included eight studies on migraine . Overall , we now include 11 studies on five SSRIs and one SNRI with a total of 585 participants . Six studies were placebo-controlled , four compared a SSRI or SNRI to amitriptyline , and one was a head-to-head comparison ( escitalopram versus venlafaxine ) . Most studies had method ological or reporting shortcomings ( or both ) : all studies were at unclear risk of selection and reporting bias . Follow-up rarely extended beyond three months . The lack of adequate power of most of the studies is also a major concern . Few studies explored the effect of SSRIs or SNRIs on migraine frequency , the primary endpoint . Two studies with unclear reporting compared SSRIs and SNRIs to placebo , suggesting a lack of evidence for a difference . Two studies compared SSRIs or SNRIs versus amitriptyline and found no evidence for a difference in terms of migraine frequency ( st and ardised mean difference ( SMD ) 0.04 , 95 % confidence interval ( CI ) -0.72 to 0.80 ; I(2 ) = 72 % ) , or other secondary outcomes such as migraine intensity and duration .SSRIs or SNRIs were generally more tolerable than tricyclics . However , the two groups did not differ in terms of the number of participants who withdrew due to adverse advents or for other reasons ( one study , odds ratio ( OR ) 0.39 , 95 % CI 0.10 to 1.50 and OR 0.42 , 95 % CI 0.13 to 1.34).We did not find studies comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants ( e.g. antiepileptics and anti-hypertensives ) . AUTHORS ' CONCLUSIONS Since the last version of this review , the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine as preventive drugs for migraine . There is no evidence to consider SSRIs or venlafaxine as more effective than placebo or amitriptyline in reducing migraine frequency , intensity , and duration over two to three months of treatment . No reliable information is available at longer-term follow-up . Our conclusion is that the use of SSRIs and SNRIs for migraine prophylaxis is not supported by evidence
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"Conclusions In this double-blind , r and omized study extended-release venlafaxine 150 mg/day found to be effective in chronic migraine . Our study showed a clear effect that was in subgroup of subjects with medication overuse . In addition , in this study , the low number of adverse events showed venlafaxine to be well tolerated . Future controlled trials expended lon ger with larger sample size , should also support the effectiveness and safety of venlafaxine in patients suffering from chronic migraine . No conflict of interest",
"Current treatment of migraine either abortive or prophylactic is often unsatisfactory . Prophylactic treatment of severe migraine may reduce attack frequency , and current therapy centers on beta-blockers , serotonin ( 5-HT ) reuptake blockers and 5-HT2 receptor antagonists . The author compared the efficacy and safety of amitriptyline and fluvoxamine among migraine patients ( 24F , 8 M vs. 23F , 9 M ) in a double blind study . The efficacy of amitriptyline has already been established by earlier clinical studies . The other investigated drug , fluvoxamine , has a more selective 5-HT reuptake blocking property than amitriptyline . In this study , amitriptyline significantly reduced the number of headache attacks , but it caused severe drowsiness in many migraineurs . The fluvoxamine also favorably influenced on the number of headache attacks and caused only slight side effects . These findings suggest , that fluvoxamine may be an alternative drug in migraine prophylaxis , however , further studies should be performed with more subjects",
"UNLABELLED Selective serotonin reuptake inhibitors have recently been used in the treatment of migraine . OBJECTIVE We studied the safety and efficacy of fluoxetine in the prevention of migraine . PATIENTS Between February 1997 and December 1997 , we examined 52 patients ( 33 women ) at the Headache Diagnosis and Therapy Service of the Second University of Naples . Ages ranged from 18 to 65 years , and all patients suffered from migraine without aura according to IHS 1988 criteria . The sample was divided into two groups : group A included 32 patients ( 19 women ; mean age , 36.8 years [ SD 12.4 ] ) who received fluoxetine at a dosage of 20 mg per day ; group B included 20 patients ( 14 women ; mean age , 38.8 years [ SD 15.6 ] ) who received placebo . METHODS Our study was a single-center , r and omized , double-blind , parallel study of fluoxetine for the prophylactic control of migraine and consisted of two phases : 30 days of pharmacological wash out and 6 months of therapy with monthly follow-up . Patients were r and omly assigned to two groups : A , fluoxetine or B , placebo . At the first visit , patients provided a detailed history and underwent neurological evaluation and a Zung test for depression . No pathological values were revealed . In order to monitor symptomatology , all patients received a form for the calculation of the total pain index at monthly follow-up . RESULTS A comparison of the total pain index between basal values ( calculated during the period of wash out ) and monthly follow-up ( calculated monthly during the period of 6 months of the therapy ) showed significant reduction ( P fluoxetine in the treatment of migraine",
" In patients with migraine with or without aura the prophylactic effect of amitriptyline ( AMT ) and venlafaxine ( VLF ) was compared in a r and omized double-blind crossover study . Intolerable side effects result ed in drop out of five patients on AMT ( due to hypersomnia , difficulty in concentration and orthostatic hypotension ) and one patient on VLF ( because of nausea and vomiting ) . Following the run-in period the patients ( n = 52 ) were r and omly treated with one of the study medications for 12 weeks . After a wash-out period lasting 4 weeks the patients were treated with the other drug for further 12 weeks . Both drugs had significant beneficial effect on pain parameters . Total number of side effects of VLF was low when compared with the side effect profile of AMT . In conclusion , it is suggested that VLF may be considered for the prophylaxis of migraine because of its low and /or tolerable side effect properties",
"Background and Objectives .—Antidepressants are often used to treat chronic daily headache disorders such as transformed migraine , in part because of the high prevalence of associated mood disorder . We conducted this study to evaluate the efficacy and tolerability of combined treatment with amitriptyline and fluoxetine compared with amitriptyline alone for chronic daily headache due to transformed migraine",
"OBJECTIVE To evaluate the efficacy and safety of venlafaxine in the prophylaxis of migraine . BACKGROUND The efficacy of venlafaxine , which is selectively effective on the serotonergic and noradrenergic mechanisms , on various headaches and chronic pain syndromes has been demonstrated . To our knowledge , this is the first placebo-controlled , double-blind , r and omized study of two different doses of venlafaxine for migraine treatment . METHODS In this prospect i ve study , 60 migraine patients without aura were r and omly assigned to venlafaxine XR 75 mg , venlafaxine XR 150 mg , or placebo . The frequency of headache attacks , the severity and the duration of attacks , and analgesic use were monitored every 2 weeks for 2 months . Adverse events and patient satisfaction were also evaluated during these visits . At the end of the 2 months , global efficacy and tolerance were investigated . RESULTS A significant difference was observed between the venlafaxine 150 mg and placebo groups in the number of headache attacks ( P= .006 ) . According to patient satisfaction comparisons , the active drug groups were significantly different when compared with placebo ( P= .001 at visit 2 and visit 6 ) . When the global efficacy was considered , 80 % of patients in the 75-mg group and 88.2 % of the patients in the 150-mg group evaluated treatment benefits as either good or very good . CONCLUSIONS Venlafaxine was more effective than placebo and is safe and well tolerated as migraine prophylaxis",
"SYNOPSIS",
" Many patients with severe migraine remain refractory to the current treatment regimens or can not tolerate the side effects . Since current research implicates serotonin dysregulation in migraine pathogenesis , we investigated in a double blind , placebo controlled study the prophylactic effect of the serotonergic drug fluoxetine . Sixteen subjects were r and omly assigned to 8 week fluoxetine treatment and 16 to the placebo group ; nine subjects in each group completed the study . Migraine headache scores were obtained for two weeks prior to commencement of treatment , and then for each successive two week period . Zung depression scores were obtained before and after completion of the study . Fluoxetine caused significant reduction in headache scores starting with weeks 3 - 4 of treatment ; there was no significant change with placebo . Depression scores did not differ between groups before treatment , and did not significantly change with either treatment . Fluoxetine appears to be a safe and effective drug for migraine prophylaxis , and deserves further therapeutic trials with larger groups for longer periods of time",
" The prophylactic effect in migraine of femoxetine , a 5‐HT‐uptake inhibitor , was compared to that of placebo in a double‐blind group‐comparative study . A total of 59 patients , referred to the department from general practitioners , was stratified according to age , sex , duration , and frequency of attacks and then allocated at r and om to treatment with either femoxetine or placebo . Each patient was treated for 12 weeks with 200 mg in the first week and 300 in the remaining weeks . Ten patients on femoxetine and four patients on placebo failed to complete the study",
"There is evidence that some antidepressant drugs are beneficial in the prophylaxis of migraine . Previous reports have shown that migraine patients may respond to various antidepressant agents used for prophylactic therapy . The main purpose of this study was to compare the efficacy of antidepressants from 2 different groups ( venlafaxine vs escitalopram ) on people who had migraine headache without depression or anxiety . In this prospect i ve study , we evaluated the headache diaries of 93 patients who were being treated with venlafaxine ( n = 35 ) and escitalopram ( n = 58 ) . At the end of the 3-month period , patients were reassessed , and those with marked differences in attack frequency , duration , intensity ( with visual analog scales ) , lost work-day equivalent index , and migraine disability assessment question naire were compared . There was a clear reduction in headache frequency ( P severity ( P venlafaxine group . In addition , there was a significant improvement in daily work performance during headaches ( P escitalopram group , monthly headache frequency ( P duration ( P intensity ( P venlafaxine . After the third month of venlafaxine and escitalopram treatment , most of the patients ( 82.8 % vs 96.5 % ) were seen to have moved to the minimal or infrequent migraine disability assessment group . According to our findings , venlafaxine and escitalopram are both effective in the prophylaxis of migraine headache without depression and anxiety . This effect was independent of mood disorder . Escitalopram should be the first choice because of its fewer side effects , but venlafaxine may be used if escitalopram is found to be insufficient",
"SYNOPSIS",
"The objective of this study was to assess the efficacy of sertraline in migraine prophylaxis . Other selective serotonin reuptake inhibitors have been studied for migraine prophylaxis , but this is the first report with sertraline . Twenty-seven subjects were enrolled and baseline assessment of migraine frequency and severity were measured over a 4-week period . Subjects were then r and omized to receive placebo or sertraline in a double-blind fashion with headache frequency and severity measured over an 8-week period . Subjects completed a daily diary reporting the occurrence , severity , and degree of impairment associated with migraine . The headache index , a composite measure of migraine frequency and severity , scores did not significantly improve between assessment s at baseline ( 20.8 + /- 14.88 ) , 8 weeks ( 17.6 + /- 12.27 ) , and 12 weeks ( 16.7 + /- 6.38 ) in the treatment group ( n=6 ) ( P=0.956 ) . This finding is compared to other studies with the serotonin selective reuptake inhibitors , fluoxetine , fluvoxamine , and paroxetine . The authors believe that the selective serotonin reuptake inhibitors are not as effective as conventional migraine prophylaxis medications such as beta-blockers , tricyclic antidepressants , or divalproex sodium , but that in patients with comorbid depression who have failed conventional therapy selective serotonin reuptake inhibitors may be effective",
"OBJECTIVES The primary objective of this guideline is to assist the practitioner in choosing an appropriate prophylactic medication for an individual with migraine , based on current evidence in the medical literature and expert consensus . This guideline is focused on patients with episodic migraine ( headache on ≤ 14 days a month ) . METHODS Through a comprehensive search strategy , r and omized , double blind , controlled trials of drug treatments for migraine prophylaxis and relevant Cochrane review s were identified . Studies were grade d according to criteria developed by the US Preventive Services Task Force . Recommendations were grade d according to the principles of the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) Working Group . In addition , a general literature review and expert consensus were used for aspects of prophylactic therapy for which r and omized controlled trials are not available . RESULTS Prophylactic drug choice should be based on evidence for efficacy , side-effect profile , migraine clinical features , and co-existing disorders . Based on our review , 11 prophylactic drugs received a strong recommendation for use ( topiramate , propranolol , nadolol , metoprolol , amitriptyline , gabapentin , c and esartan , butterbur , riboflavin , coenzyme Q10 , and magnesium citrate ) and 6 received a weak recommendation ( divalproex sodium , flunarizine , pizotifen , venlafaxine , verapamil , and lisinopril ) . Quality of evidence for different medications varied from high to low . Prophylactic treatment strategies were developed to assist the practitioner in selecting a prophylactic drug for specific clinical situations . These strategies included : first time strategies for patients who have not had prophylaxis before ( a beta-blocker and a tricyclic strategy ) , low side effect strategies ( including both drug and herbal/vitamin/mineral strategies ) , a strategy for patients with high body mass index , strategies for patients with co-existent hypertension or with co-existent depression and /or anxiety , and additional monotherapy drug strategies for patients who have failed previous prophylactic trials . Further strategies included a refractory migraine strategy and strategies for prophylaxis during pregnancy and lactation . CONCLUSIONS There is good evidence from r and omized controlled trials for use of a number of different prophylactic medications in patients with migraine . Medication choice for an individual patient requires careful consideration of patient clinical features",
"ABSTRACT — In a r and omized general practice study , the prophylactice effect of femoxetive ( a 5HT uptake inhibitor ) was compared with placebo in migraine patients . Treatment , with separate r and omization schedules in each practice , was allocated to 65 patients . Each patient was treated for 16 weeks with 200 mg increasing during the first nine days to 600 mg daily . No effect of femoxetine could be demonstrated in attack frequency and headache index . Separate analysis of maximum reduction in serotonin concentration during treatment revealed no difference in efficacy when compared with placebo . This supports earlier studies that femoxetine generally exerts no prophylactic effect on migraine , and the hypothesis that platelet 5HT might be of major importance in the pathogenesis of migraine is not supported",
"S-fluoxetine is the long-acting enantiomer of the racemic antidepressant serotonin reuptake inhibitor . Sixty-five patients needing migraine prophylaxis were recruited into a phase II , double-blind , placebo-controlled trial . After a 1-month placebo run-in , 53 patients met entry criteria with regard to attack frequency and were r and omized , 27 to S-fluoxetine and 26 to matching placebo . Three failed to start treatment and mere were 17 early discontinuations , 9 from S-fluoxetine , 8 from placebo , at similar times and for similar reasons . The primary efficacy variable was attack frequency and analysis compared decline-from-baseline in the two groups . This was earlier and greater ( 1.7 attacks/28 days , or 52 % ) on active therapy than on placebo ( 1.1 attacks/28 days , or 27 % ) , and statistically significant in month 2 ( F=4.93 ; p=0.033 ) and month 4 ( F=4.55 ; p=0.041 ) . As secondary measures of efficacy , migraine-days per month and Patient 's Global Impression of Disease Severity coherently reflected the changes in attack frequency . Mean attack severity and acute medication use ( doses per attack ) were unaltered by either treatment . There were no serious adverse events . Withdrawals for adverse events were four from each group but none was considered causally related . The finding of greater efficacy of S-fluoxetine than of placebo should be interpreted conservatively , since the analysis in the final month was made on only half of the entered patients . It supports progression to phase III evaluation , which was the purpose of the study",
"objectiue This article estimates lost work days and lost work day equivalents in a population sample of migraineurs , differentiating work loss due to headache episodes that met criteria for migraine from migrainous headaches not meeting full criteria and nonmigrainous headaches . Methods A r and om digit dialing survey of 5,071 adults identified 800 subjects with migraine headaches . By clinical examination , a sub sample of 225 met migraine diagnostic criteria ; 174 of these patients completed at least 11 weeks of daily diaries . This report concerns the subgroup of 122 individuals with regular paid employment . Subjects completed a daily diary over a 3-month period to assess the occurrence of headaches and International Headache Society ( IHS ) criteria for each headache occurrence . We report estimates of lost work days and lost work day equivalents by type of headache . Results Participants reported headaches on 8.1 work days , of which 2.2 headache days met criteria for migraine ( IHS 1.1 , 1.2 ) , and an additional 2.1 headache days were migrainous without meeting full migraine criteria ( IHS 1.7 ) . On average , migraineurs missed 1.1 days of work due to headache in 3 months , of which 0.7 lost work days were due to migraine and 0.3 were due to migrainous headaches . When at work with headache , work effectiveness was reduced 41 % for migraine headaches , 28 % for migrainous headaches , and 24 % for other headaches . Over 3 months , migraineurs experienced an average of 3.0 lost work day equivalents , of which 1.4 were due to migraine and an additional 0.7 were due to migrainous headaches . The most disabled 20 % of the participants accounted for 77 % of the lost work days ; 40 % of subjects accounted for 75 % of the lost work day equivalents . Conclusions Employed migraine sufferers experienced considerable work loss and reduced work performance due to headache . The most severely affected migraineurs accounted for most of the reduced work performance . Targeting the most severely affected persons may be necessary to reduce work loss among migraineurs substantially . NEUROLOGY",
"The prophylactic effect of the 5-HT uptake inhibitor femoxetine was compared with propranolol ( Frekven R ) in a double-blind crossover trial of 6 months duration . Forty-nine patients commenced the trial . Twelve patients withdrew because of drug failure or failure to attend checkups ( 6 ) , side effects ( 4 ) or other non-drug related causes ( 2 ) . In the 37 patients who completed the trial there was no significant difference between propranolol 160 mg and femoxetine 400 mg with respect to the number of headache days or the number of migraine attacks during the last 2 months of each treatment , Propranolol , however , was superior to femoxetine when the headache index was used ( P less than 0.05 ) . The study has shown that partial depletion of thrombocyte 5-HT by a 5-HT uptake inhibitor does not lead to a marked improvement in all patients contrary to what might be expected from the 5-HT hypothesis of migraine . Nevertheless , due to the infrequent subjective side effects associated with femoxetine treatment it may be a valuable prophylactic drug to a subgroup of migraine patients",
"Antidepressants are used to treat chronic daily headache disorders such as migraine and chronic tension-type headache ( TTH ) , which are often associated with depression and anxiety . Here , we studied the efficacy and tolerability of amitriptyline and citalopram , given alone or in combination , in patients with ‘ triple ’ comorbidity of depression , TTH , and migraine . Eighty-eight patients were enrolled in the study and r and omly divided into two groups . The first group received amitriptyline and the second citalopram for 16 weeks . Patients were assessed at weeks 0 , 4 , 8 , and 16 . The two drugs were equally efficacious in relieving depressive symptoms , although amitriptyline was more efficacious than citalopram in reducing migraine and TTH attacks . Patients who did not respond to monotherapy ( improvement in depression , migraine and TTH without producing major side effects such as those commonly related to the ‘ serotonergic ’ syndrome . The results indicate that a combined therapy with amitriptyline and citalopram may be particularly beneficial for patients with TTH , migraine and comorbid depression that do not respond to monotherapy "
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OBJECTIVE To assess the existing evidence of associations between assisted conception and cerebral palsy ( CP ) , autism spectrum disorders ( ASD ) , and developmental delay . DATA SOURCES Forty-one studies identified in a systematic al PubMed and Excerpta Medica Data base ( EMBASE ) search for articles published from January 1 , 1996 , to April 1 , 2008 . STUDY SELECTION Studies written in English comparing children born after assisted conception with children born after natural conception assessing CP , ASD , and developmental delay , based on original data with a follow-up of 1 year or more . Main Exposures In vitro fertilization ( IVF ) with or without intracytoplasmic sperm injection or ovulation induction with or without subsequent intrauterine insemination . MAIN OUTCOME MEASURES Cerebral palsy , ASD , and developmental delay . RESULTS Nine CP studies showed that children born after IVF had an increased risk of CP associated with preterm delivery . In our meta- analysis including 19 462 children exposed to IVF , we estimated a crude odds ratio of 2.18 ( 95 % confidence interval , 1.71 - 2.77 ) . Eight ASD studies and 30 studies on developmental delay showed inconsistent results . No studies assessed the risk of CP , ASD , or developmental delay in children born after ovulation induction exclusively . CONCLUSIONS Method ological problems were revealed in the identified studies , and the gaps in our knowledge about the long-term outcomes of children born after assisted conception are considerable , including a lack of information on the long-term consequences of ovulation induction . Possible associations with ASD and developmental delay need assessment in larger studies . Studies on assisted conception and CP from countries outside of Sc and inavia are needed , including detailed information on time to pregnancy , underlying cause of infertility , and type of IVF treatment
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"BACKGROUND As a continuation of two large-scale , multicentre studies on the development of 5-year-old ICSI children , we present results of the follow-up study undertaken on the cognitive and motor development of 8-year-old ICSI children . METHODS Developmental outcomes of 151 8-year-old singletons born through ICSI after 32 weeks of gestation were compared with those of 153 singletons of the same age born after spontaneous conception ( SC ) . Part of this population was seen in a cohort at the age 5 years . Outcome measures include Wechsler Intelligence Scale for Children-Revised ( WISC-R ) and Movement Assessment Battery for Children ( ABC ) . RESULTS Regarding intellectual functioning , ICSI children tend to obtain significantly higher total ( P than SC children , nevertheless remaining in similar ranges . These effects are small ( Cohen 's d maternal educational level stayed in the regression as a factor accounting for some of the variance in total IQ between the groups . In terms of motor development , no significant differences were found between ICSI and SC children regarding overall motor skills , manual , balance and ball skills . CONCLUSION In this follow-up study , ICSI and SC children show a comparable cognitive and motor development until the age of 8 years",
"Research suggests that heredity and early fetal development play a causal role in autism . This case-control study explored the association between perinatal factors , parental psychiatric history , socioeconomic status , and risk of autism . The study was nested within a cohort of all children born in Denmark after 1972 and at risk of being diagnosed with autism until December 1999 . Prospect ively recorded data were obtained from nationwide registries in Denmark . Cases totaled 698 children with a diagnosis of autism ; each case was individually matched by gender , birth year , and age to 25 controls . Analyses by conditional logistic regression produced risk ratios and 95 % confidence intervals . Adjusted analyses showed that the risk of autism was associated with breech presentation ( risk ratio ( RR ) = 1.63 , 95 % confidence interval ( CI ) : 1.18 , 2.26 ) , low Apgar score at 5 minutes ( RR = 1.89 , 95 % CI : 1.10 , 3.27 ) , gestational age at birth 35 weeks ( RR = 2.45 , 95 % CI : 1.55 , 3.86 ) , and parental psychiatric history ( schizophrenia-like psychosis : RR = 3.44 , 95 % CI : 1.48 , 7.95 ; affective disorder : RR = 2.91 , 95 % CI : 1.65 , 5.14 ) . Analyses showed no statistically significant association between risk of autism and weight for gestational age , parity , number of antenatal visits , parental age , or socioeconomic status . Results suggest that prenatal environmental factors and parental psychopathology are associated with the risk of autism . These factors seem to act independently",
"Abstract Objective To compare neurological sequelae in twins born after assisted conception with singletons after assisted conception and naturally conceived twins and to assess neurological sequelae in children conceived after in vitro fertilisation ( IVF ) compared with intracytoplasmic sperm injection ( ICSI ) . Design Controlled , national register based , cohort study . Participants Twins ( n = 3393 ) and singletons ( n = 5130 ) conceived by using assisted reproductive technologies and naturally conceived twins ( n = 10 239 ) born in Denmark between 1995 and 2000 . The children 's age at time of follow up was 2 - 7 years . Data sources Children were identified by cross linkage of the national medical birth registry and the national registry for in vitro fertilisation . Neurological and psychiatric diagnoses were retrieved from the national patients ' registry and the Danish psychiatric central registry . Main outcome measures Neurological sequelae , defined as cerebral palsy , mental retardation , severe mental developmental disturbances , and retarded psychomotor development . Further we made separate analyses on the specific cerebral palsy diagnosis . Results The crude prevalence rates per 1000 of neurological sequelae in twins and singletons after assisted conception and in naturally conceived twins were 8.8 , 8.2 , and 9.6 , and of cerebral palsy 3.2 , 2.5 , and 4.0 , respectively . In twins after assisted conception compared with control twins , the odds ratios of neurological sequelae and specifically of cerebral palsy , adjusted for child sex and year of birth , were 0.9 ( 95 % confidence interval 0.6 to 1.4 ) and 0.8 ( 0.4 to 1.6 ) , respectively . The corresponding odds ratios for twins after assisted conception compared with singletons after assisted conception were 1.1 ( 0.7 to 1.7 ) for neurological sequelae and 1.3 ( 0.6 to 2.9 ) for cerebral palsy . The odds ratio of neurological sequelae in children conceived by ICSI was 0.9 ( 0.5 to 1.7 ) ν children conceived by IVF . Conclusions Twins from assisted conception have a similar risk of neurological sequelae as their naturally conceived peers and singletons from assisted conception . Children born after ICSI have the same risk of neurological sequelae as children born after IVF",
"BACKGROUND The primary objective of this study was to investigate whether subfertility explains poor perinatal outcome after assisted conception . A secondary objective was to test the hypothesis that ovarian hyperstimulation rather than the IVF procedure may influence the perinatal outcome . METHODS Using data from a Dutch population -based historical cohort of women treated for subfertility , we compared perinatal outcome of singletons conceived after controlled ovarian hyperstimulation ( COHS ) and IVF ( IVF + COHS ; n = 2239 ) with perinatal outcome in subfertile women who conceived spontaneously ( subfertile controls ; n = 6343 ) and in women who only received COHS ( COHS only ; n = 84 ) . Furthermore , we compared perinatal outcome of singletons conceived after the transfer of thawed embryos with ( Stim + Cryo ; n = 66 ) and without COHS ( Stim - Cryo ; n = 73 ) . RESULTS The odds ratios ( ORs ) for very low birthweight ( low birthweight ( 1500 - 2500 g ) were 2.8 [ 95 % confidence interval ( 95 % CI ) 1.9 - 3.9 ] and 1.6 ( 95 % CI 1.2 - 1.8 ) in the IVF + COHS group compared with the subfertile control group . The ORs for very preterm birth ( preterm birth ( 32 - 37 weeks ) were 2.0 ( 95 % CI 1.4 - 2.9 ) and 1.5 ( 95 % CI 1.3 - 1.8 ) , respectively . Adjustment for confounders did not material ly change these risk estimates . The difference in risk between the COHS-only group and the subfertile group was significant only for very low birthweight ( OR 3.5 ; 95 % CI 1.1 - 11.4 ) , but the association became weaker after adjustment for maternal age and primiparity ( OR 3.1 ; 95 % CI 1.0 - 10.4 ) . No significant difference in birthweight and preterm delivery was found between the group of children conceived after ovarian stimulation/ovulation induction and ( Stim + Cryo ) and the group of children conceived after embryo transfer of thawed embryos in a spontaneous cycle without ovarian stimulation/ovulation induction ( Stim - Cryo ) . CONCLUSIONS The poor perinatal outcome in this data base could not be explained by subfertility and suggests that other factors may be important in the known association between assisted conception and poor perinatal outcome ",
"BACKGROUND To examine the long-term child outcome after IVF until the age of 3 years in Northern Finl and , we conducted a population -based cohort study . METHODS First , a cohort of 299 IVF children born in 1990 - 1995 was compared with a cohort of 558 controls representing the general population in terms of a multiple birth rate of 1.2 % , r and omly chosen from the Finnish Medical Birth Register ( FMBR ) and matched for sex , year of birth , area of residence , parity , maternal age and social class ( full sample analyses ) . Second , IVF singletons ( n = 150 ) were compared with singleton controls ( n = 280 ) . Third , a plurality matched control cohort ( n = 100 ) for IVF twins ( n = 100 ) was r and omly chosen , matched as above , from the FMBR and analysed separately . Infant mortality rate was compared with the national rate from the FMBR . RESULTS Infant mortality in the IVF group was > 2-fold higher compared to the national rate in the general population . The risk ( OR , 95 % CI ) of low weight and height , below the lowest quartile , at 1 year of age ( 1.6 , 1.1 - 2.2 ; 1.6 , 1.1 - 2.4 ) and 2 years of age ( 1.5 , 1.1 - 2.4 ; 1.7 , 1.2 - 2.5 ) was significantly higher in the IVF group when compared with the general population control group . No statistically significant differences were found in the psychomotor development between the cohorts . Cumulative incidence of different diseases up to 3 years of age was significantly higher among IVF children in the full sample and singleton analyses ( OR , 95 % CI : 2.3 , 1.7 - 3.2 ; 2.1 , 1.3 - 3.3 respectively ) especially regarding respiratory diseases ( 3.5 , 1.9 - 6.5 ; 3.1 , 1.0 - 9.4 ) and diarrhoea ( 3.7 , 2.2 - 6.2 ; 5.7 , 2.6 - 12.7 ) , but not in twin comparisons . CONCLUSIONS The growth of IVF children was behind that of control children during the first 3 years of life , but their psychomotor development was similar . Their postnatal health was worse , probably reflecting the problems in the neonatal period",
"BACKGROUND Autism is considered to have a genetic basis , although exposure to certain stimuli in the prenatal period has been implicated to be causal in some cases . Some investigations have shown an association with obstetric complications but findings have been inconsistent owing to differences in sampling and methods . OBJECTIVE To examine the association of obstetric factors with autism spectrum disorders for a cohort of children , using obstetric data contained in a statutory data base collected at the time of birth . DESIGN Subjects born in Western Australia between 1980 and 1995 and diagnosed with an autism spectrum disorder by 1999 were included as cases ( n = 465 ) . Siblings of the cases ( n = 481 ) and a r and om population -based control group ( n = 1313 ) were compared with the cases on obstetric information contained in the Maternal and Child Health Research Data base of Western Australia . RESULTS Compared with control subjects , cases had significantly older parents and were more likely to be firstborn . Case mothers had greater frequencies of threatened abortion , epidural caudal anesthesia use , labor induction , and a labor duration of less than 1 hour . Cases were more likely to have experienced fetal distress , been delivered by an elective or emergency cesarean section , and had an Apgar score of less than 6 at 1 minute . Cases with a diagnosis of autism had more complications than those with pervasive developmental disorder not otherwise specified or Asperger syndrome . Nonaffected siblings of cases were more similar to cases than control subjects in their profile of complications . CONCLUSIONS Autism is unlikely to be caused by a single obstetric factor . The increased prevalence of obstetric complications among autism cases is most likely due to the underlying genetic factors or an interaction of these factors with the environment",
"Background . Etiologic hypotheses in infantile autism suggest a strong genetic component , as well as possible environmental risks linked to early fetal development . We evaluated the association of maternal , pregnancy , delivery , and infant characteristics and risk of infantile autism . Methods . We conducted a case-control study nested within a population -based cohort ( all Swedish children born in 1974–1993 ) . We used prospect ively recorded data from the Swedish Birth Register , which were individually linked to the Swedish Inpatient Register . Cases were 408 children ( 321 boys and 87 girls ) discharged with a main diagnosis of infantile autism from any hospital in Sweden before 10 years of age in the period 1987–1994 , plus 2,040 matched controls . Conditional logistic regression was used to calculate odds ratios ( ORs ) and 95 % confidence intervals ( CIs ) . Results . The risk of autism was associated with daily smoking in early pregnancy ( OR = 1.4 ; CI = 1.1–1.8 ) , maternal birth outside Europe and North America ( OR = 3.0 ; CI = 1.7–5.2 ) , cesarean delivery ( OR = 1.6 ; CI = 1.1–2.3 ) , being small for gestational age ( SGA ; OR = 2.1 ; CI = 1.1–3.9 ) , a 5-minute Apgar score below 7 ( OR = 3.2 , CI = 1.2–8.2 ) , and congenital malformations ( OR = 1.8 , CI = 1.1–3.1 ) . No association was found between autism and head circumference , maternal diabetes , being a twin , or season of birth . Conclusions . Our findings suggest that intrauterine and neonatal factors related to deviant intrauterine growth or fetal distress are important in the pathogenesis of autism",
"OBJECTIVE . The purpose of this study was to use nationwide registries to examine the health of children up to 4 years of age who were born as a result of in vitro fertilization . METHODS . Children born after in vitro fertilization ( N = 4559 ) from 1996 to 1999 were monitored until 2003 . Two control groups were selected from the Finnish Medical Birth Register as follows : all other children ( excluding children born after ovulation induction ) from the same period ( N = 190398 , for study of perinatal health and hospitalizations ) and a r and om sample of those children ( n = 26877 , for study of health-related benefits ) . Mortality rates and odds ratios for perinatal outcomes , hospitalizations , health-related benefits , and long-term medication use were calculated . RESULTS . Although the health of most in vitro fertilization children was good , such children had more health problems than other children . A total of 35.7 % of in vitro fertilization children and 2.2 % of control children were multiple births , and the health of multiple births was worse than that of singletons . Perinatal outcomes of in vitro fertilization children were worse and hospital episodes were more common than among control children . Risks for cerebral palsy and psychological and developmental disorders were increased . Among in vitro fertilization singletons , worse results for perinatal outcomes and hospitalizations , but no increased risk for specific diseases , were found . The health of in vitro fertilization multiple births was comparable to the health of control multiple births . CONCLUSIONS . Reducing the number of transferred embryos would improve the health of in vitro fertilization children . Additional studies are needed to explain the poorer health of in vitro fertilization singletons , as well as follow-up studies to examine the health of in vitro fertilization children from 4 years onward",
"OBJECTIVE To assess the somatic , psychomotor , and intellectual development of children conceived through intracytoplasmic single sperm injection ( ICSI ) over the whole preschool period . DESIGN Prospect i ve , controlled , cohort study . SETTING Fertility clinic in Brussels , Belgium . PATIENT(S ) Sixty-six ICSI-conceived children prospect ively compared with 52 IVF-conceived and 59 spontaneously conceived children . All children were full-term singletons . INTERVENTION(S ) Home visits by a trained psychologist . St and ardized interviews . Assessment s using the revised Brunet-Lézine scale and the revised Wechsler preschool and primary scale of intelligence . MAIN OUTCOME MEASURE(S ) Physical growth and general health . Formal developmental and intellectual assessment s. RESULT ( S ) Children conceived by ICSI were healthy : no significant differences appeared in the incidence of combined congenital malformations ( 11.3 % ) , health problems ( 44.1 % ) , surgical interventions ( 18.6 % ) , and hospitalizations ( 6.8 % ) , nor for the developmental assessment s ( mean developmental quotient at 9 months : 93.9 ; at 18 months : 102.0 ) . For the intellectual assessment s , the between-group differences disappeared when adjusted for levels of parental education ( mean intelligence quotient at 3 years : 97.0 ; at 5 years : 103.3 ) . CONCLUSION ( S ) This pilot study shows that throughout the preschool period , ICSI-conceived children have psychomotor and intellectual development similar to that of IVF-conceived and spontaneously conceived children . These conclusions need to be confirmed by multicenter studies",
"BACKGROUND Intracytoplasmic sperm injection ( ICSI ) was introduced as a new form of in-vitro fertilisation ( IVF ) in 1993 and is now accepted as the treatment of choice for severe male infertility in many centres around the world . However , there is little information about the long-term outcome of children conceived by ICSI . We aim ed to find out the medical and developmental outcome of children conceived by ICSI at age 1 year . METHODS In this prospect i ve study , we compared the medical and developmental outcome at 1 year of 89 children conceived by ICSI with 84 children conceived by routine IVF , and with 80 children conceived naturally . Formal developmental assessment was done with Bayley Scales of Infant Development ( 2nd edition ) from which a mental development index ( MDI ) was derived . FINDINGS There was no significant difference in the incidence of major congenital malformations or major health problems in the first year of life . However , the mean Bayley MDI was significantly lower for the children conceived by ICSI than for the children conceived by routine IVF or naturally ( 95.9 [ SD 10.7 ] , 101.8 [ 8.5 ] , and 102.5 [ 7.6 ] , respectively , p ICSI experienced mildly or significantly delayed development ( MDI ICSI are healthy and develop normally , there is an increased risk of mild delays in development at 1 year when compared with children conceived by routine IVF or conceived naturally . These findings support the need for ongoing developmental follow-up of children conceived by ICSI to see whether they are at increased risk of intellectual impairment or learning difficulties at school age"
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