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TITLE: Telemonitoring in heart failure patients treated by cardiac resynchronisation therapy with defibrillator (CRT-D): the TELECART Study.ABSTRACT: Telemonitoring (TM) is a safe and efficient monitoring system for internal cardioverter defibrillator device (ICD) recipients. TM has been used to track info on the clinical status of heart failure patients treated by ICD and/or cardiac resynchronisation therapy defibrillator (CRT-D). The aim of this study was to investigate the impact of TM on clinical outcomes in a population of CRT-D patients with heart failure.In a multicentre, randomised study, patients with chronic heart failure, New York Heart Association (NYHA) functional class II or III, left bundle branch block, severe left ventricle ejection fraction reduction (LVEF < 35%) have been identified and screened.One hundred and ninety-one patients have been randomised to receive either a CRT-D with TM or a CRT-D with traditional ambulatory monitoring (control group) and completed the 12-month study follow-up. Primary endpoints were all cause death, cardiac death and hospital admission for heart failure. Secondary endpoints were atrial fibrillation, sustained episodes, non-sustained and self terminated ventricular tachyarrhythmia, sustained ventricular tachycardia, and ventricular fibrillation, ICD shocks and percentage of CRT-D responder patients. Univariate analysis identified the following factors predicting hospitalisation: TM, age, chronic kidney disease, hypercholesterolaemia, LVEF and NYHA class. At multivariate analysis, TM was the only factor predicting heart failure hospitalisation (hazard ratio 0.6, 0.42-0.79, 95% CI, p = 0.002), without affecting overall mortality and cardiac deaths events.Taken together, our data indicate the importance of TM in predicting heart failure hospitalisation in patients treated with CRT-D.

TITLE: Association Between Sitagliptin Use and Heart Failure Hospitalization and Related Outcomes in Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized Clinical Trial.ABSTRACT: Previous trial results have suggested that dipeptidyl peptidase 4 inhibitor (DPP4i) use might increase heart failure (HF) risk in type 2 diabetes mellitus (T2DM). The DPP4i sitagliptin has been shown to be noninferior to placebo with regard to primary and secondary composite atherosclerotic cardiovascular (CV) outcomes in the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS).To assess the association of sitagliptin use with hospitalization for HF (hHF) and related outcomes.TECOS was a randomized, double-blind, placebo-controlled study evaluating the CV safety of sitagliptin vs placebo, each added to usual antihyperglycemic therapy and CV care among patients with T2DM and prevalent atherosclerotic vascular disease. The median follow-up was 2.9 years. The setting was 673 sites in 38 countries. Participants included 14 671 patients with T2DM and atherosclerotic vascular disease. The study dates were December 2008 through March 2015.Patients were randomized to sitagliptin vs placebo added to standard care.Prespecified secondary analyses compared the effect on hHF, hHF or CV death, and hHF or all-cause death composite outcomes overall and in prespecified subgroups. Supportive analyses included total hHF events (first plus recurrent) and post-hHF death. Meta-analyses evaluated DPP4i effects on hHF and on hHF or CV death.Of 14 671 patients, 7332 were randomized to sitagliptin and 7339 to placebo. Hospitalization for HF occurred in 3.1% (n = 228) and 3.1% (n = 229) of the sitagliptin and placebo groups, respectively (unadjusted hazard ratio, 1.00; 95% CI, 0.83-1.19). There was also no difference in total hHF events between the sitagliptin (n = 345) and placebo (n = 347) groups (unadjusted hazard ratio, 1.00; 95% CI, 0.80-1.25). Post-hHF all-cause death was similar in the sitagliptin and placebo groups (29.8% vs 28.8%, respectively), as was CV death (22.4% vs 23.1%, respectively). No heterogeneity for the effect of sitagliptin on hHF was observed in subgroup analyses across 21 factors (P > .10 for all interactions). Meta-analysis of the hHF results from the 3 reported DPP4i CV outcomes trials revealed moderate heterogeneity (I2 = 44.9, P = .16).Sitagliptin use does not affect the risk for hHF in T2DM, both overall and among high-risk patient subgroups.clinicaltrials.gov Identifier: NCT00790205.

TITLE: Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.ABSTRACT: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years.Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed.The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age.Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

TITLE: Correlation between gastric residual volumes and markers of gastric emptying: A post hoc analysis of a randomized clinical trial.ABSTRACT: The correlation between gastric residual volumes (GRVs) and markers of gastric emptying (GE) in critically ill patients is unclear. This particularly applies to critically ill surgical patients, as they are underrepresented in previous studies.We conducted a post hoc analysis of a multicenter trial that investigated the effectiveness of a promotility drug. Pharmacokinetic markers of GE (3-O-methylglucose [3-OMG] and acetaminophen) were correlated with GRV measurements. High GRV was defined as one episode of >400 ml or two consecutive episodes of >250 ml, and delayed GE was defined as <20th percentile of the pharmacokinetic GE marker that had the strongest correlation with GE.Of 77 patients, 8 (10.4%) had high GRV, and 15 (19.5%) had delayed GE. The 3-OMG concentration at 60 min had the strongest correlation with GRV (ρ = -0.631), and high GRV had low sensitivity (46.7%) but high specificity (98.4%) in discriminating delayed GE. The positive (87.5%) and negative (88.4%) predictive values were similar. Compared with medical patients, surgical patients (n = 14, 18.2%), had a significantly higher incidence of high GRV (29% vs 6%, P = .032) and a trend toward delayed GE (36% vs 16%, P = .132).GRV reflects GE, and high GRV is an acceptable surrogate marker of delayed GE. From our preliminary observation, surgical patients may have a higher risk of high GRV and delayed GE. In summary, GRV should be monitored to determine whether complex investigations or therapeutic interventions are warranted.

TITLE: Tolvaptan in hospitalized cancer patients with hyponatremia: a double-blind, randomized, placebo-controlled clinical trial on efficacy and safety.ABSTRACT: The rate of hyponatremia is higher in hospitalized cancer patients than in hospitalized patients without cancer and is associated with poor clinical outcomes. The availability of V2 receptor antagonists has been a major breakthrough in the management of hyponatremia, but its efficacy and safety in treating hyponatremia in patients with cancer is not known.Adult patients with cancer who were admitted to The University of Texas MD Anderson Cancer Center with nonhypovolemic hyponatremia (125-130 mmol/L) were randomized to receive either tolvaptan or placebo in a double-blind, placebo-controlled, adaptive, randomized trial. Both groups received the standard of care for hyponatremia, except that patients were allowed to drink to thirst.A preplanned Data Safety Monitoring Board analysis of 30 of 48 randomized patients who completed the study revealed that the primary endpoint of hyponatremia correction was met by 16 of 17 patients who received tolvaptan and by 1 of 13 patients who received placebo (94% vs 8%; P < .001), which met the study stopping rule for superiority. The secondary endpoints between the tolvaptan and placebo groups (mean ± standard deviation) for length of stay (21 ± 15 days vs 26 ± 15 days, respectively) and change in the Mini-Mental State Examination score (-0.35 ± 1.66 vs 0.31 ± 2.42, respectively) were not significantly different. No overcorrection of serum sodium (>12 mmol/L per day) was noted in the tolvaptan group, and the main adverse events noted were dry mouth, polydipsia, and polyuria, leading to 13% study withdrawal.Although tolvaptan was effective for correcting hyponatremia in patients with cancer, studies with a larger sample size will be required to confirm the current findings, including the outcomes of secondary endpoints.

TITLE: Ingestion of a high-molecular-weight hydrothermally modified waxy maize starch alters metabolic responses to prolonged exercise in trained cyclists.ABSTRACT: We examined whether the ingestion of a hydrothermally modified starch (HMS) would alter metabolic and hormonal responses to prolonged cycling compared with maltodextrin (MAL).Nine male cyclists (30 ± 2 y, 79.2 ± 2.1 kg, 4.7 ± 0.1 L of O(2)/min, 7.5 ± 1.3 y training) fasted 10 h before cycling for 150 min at 70% peak oxygen consumption and completing a cycling-to-exhaustion trial at 100% peak oxygen consumption. Participants ingested 1g/kg of HMS or MAL 30 min before and within 10 min of completing the bout. Blood samples were provided every 15 min before, during, and 90 min after exercise. Expired gases were collected every 30 min during exercise. In a crossover, randomized, and double-blind fashion, identical testing was completed 1 wk later.Primary findings from this study were that 1) increases in serum glucose were greater during MAL (peak 9.5 mM) versus HMS (peak 7.4 mM, P ≤ 0.01), 2) insulin levels were significantly lower during HMS (peak 2.5 μIU/mL) versus MAL (peak 20.3 μIU/mL, P < 0.001), and 3) HMS was associated with greater fat breakdown as indicated by the increased serum non-esterified fatty acids (P < 0.01) and glycerol levels (P < 0.05).Ingestion of a low-glycemic HMS before prolonged cycling exercise blunted the initial spike in serum glucose and insulin and increased the breakdown in fat compared with MAL.

TITLE: Laparoscopic versus open gastric resections for primary gastrointestinal stromal tumors (GISTs): a size-matched comparison.ABSTRACT: Laparoscopic resection of gastric GISTs appears technically feasible and associated with favorable outcomes. Tumor size however frequently plays a role in surgical approach with larger tumors tending toward laparotomy, raising concern that favorable outcomes reported for the laparoscopic approach may reflect this selection bias.From a prospectively collected sarcoma database, 155 primary gastric GIST resections were identified (1998-2009); 40 patients underwent successful laparoscopic resection for non-GE junction GIST and were randomly matched (1:1) by tumor size (±2.0 cm) to patients with open resection. Clinical and pathologic variables and surgical outcomes were associated with surgery type using conditional logistic regression analyses.The two surgical approaches were comparable for clinical and pathologic variables. Median operating room (OR) time was similar, although median length of stay postsurgery was lower in the laparoscopic versus open group (4 vs. 7 days, P = 0.002), as was estimated blood loss (EBL) (25 vs. 100 ml, P = 0.006). There was no operative mortality, and 30-day morbidity was similar. Oncologic outcomes were also similar with no positive microscopic margins, and 1 recurrence in each group with a median follow-up of 34 months. There were 13 conversions overall, 5 secondary to tumor location at the GE junction or lesser curve.When matched for tumor size, laparoscopic resection of primary gastric GISTs ≤8 cm results in shorter hospital stays with similar OR time while maintaining sound oncologic outcomes compared with open resection.

TITLE: Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial.ABSTRACT: Disturbance in the metabolism of tryptophan and tryptophan-derived compounds (e.g., melatonin) may have a role in the pathogenesis of delirium.To evaluate the efficacy of low dose exogenous melatonin in decreasing delirium.A randomized, double-blinded, placebo-controlled study.An Internal Medicine service in a tertiary care centre in London, Ontario, Canada.145 individuals aged 65 years or over admitted through the emergency department to a medical unit in a tertiary care hospital.Patients were randomized to receive either 0.5 mg of melatonin or placebo every night for 14 days or until discharge.The primary outcome was the occurrence of delirium as determined by Confusion Assessment Method (CAM) criteria.Of a total of 145 individuals (mean age (standard deviation): 84.5 (6.1) years) 72 were randomly assigned to the melatonin group and 73 to the placebo group. Melatonin was associated with a lower risk of delirium (12.0% vs. 31.0%, p = 0.014), with an odds ratio (OR), adjusted for dementia and co-morbidities of 0.19 (95% confidence intervals (CI): 0.06-0.62). Results were not different when patients with prevalent delirium were excluded.An intention to treat analysis was not possible due to loss to follow-up.Exogenous low dose melatonin administered nightly to elderly patients admitted to acute care may represent a potential protective agent against delirium.

TITLE: Rosuvastatin for primary prevention in patients with European systematic coronary risk evaluation risk ≥ 5% or Framingham risk >20%: post hoc analyses of the JUPITER trial requested by European health authorities.ABSTRACT: On the basis of the JUPITER trial, European health authorities recently approved the use of rosuvastatin to reduce first major cardiovascular events among 'high' global risk primary prevention patients defined either by Framingham risk score >20% or European systematic coronary risk evaluation (SCORE) ≥5%. However, as these are post hoc analyses, data describing these subgroups have not previously been available to the clinical community.We randomized 17 802 apparently healthy men aged ≥50 and women ≥60 with low-density lipoprotein cholesterol (LDL-C) <3.4 mmol/L, who were at an increased vascular risk due to elevated levels of C-reactive protein measured with a high-sensitivity (hs) assay to rosuvastatin 20 mg daily or placebo. Patients with high global cardiovascular risk at baseline were identified by 10-year Framingham risk score >20% or SCORE risk ≥5%. During 1.8-year median follow-up (maximum 5 years) of patients with Framingham risk >20%, the rate of myocardial infarction/stroke/cardiovascular death was 9.4 and 18.2 per 1000 person-years in rosuvastatin and placebo-allocated patients, respectively [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.27-0.93, P = 0.028]. Among patients with SCORE risk ≥5%, the corresponding rates were 6.9 and 12.0 using a model extrapolating risk for age ≥65 years (HR: 0.57, 95% CI: 0.43-0.78, P = 0.0003) and rates were 5.9 and 12.7 when risk for age was capped at 65 years (HR: 0.47, 95% CI: 0.32-0.68, P < 0.0001).In primary prevention patients with elevated hs C-reactive protein who have high global cardiovascular risk (10-year Framingham risk score >20% or SCORE risk ≥5%), but LDL-C levels not requiring pharmacologic treatment, rosuvastatin 20 mg significantly reduced major cardiovascular events.

TITLE: Safety and efficacy of gas-forced infusion (air pump) in coaxial phacoemulsification.ABSTRACT: To evaluate the safety and efficacy of gas-forced infusion (air pump) in uncomplicated coaxial phacoemulsification.Dr. Agarwal's Eye Hospital, Chennai, India.Comparative case series.Specular microscopy and optical coherence tomography were used to analyze the endothelium, central macular thickness (CMT), and peripapillary retinal nerve fiber layer (RNFL) thickness before and approximately 1, 7, 30, and 90 days after coaxial phacoemulsification with (infusion group) or without (control group) gas-forced infusion. Surgical time, surge, phaco energy, irrigation fluid volume, surgical ease, complications, and visual gain in the 2 groups were compared.The mean endothelial cell loss was lower in the infusion group than in the control group (6.98% ± 8.46% [SD] versus 10.54% ± 11.24%; P = .045) and the irrigation/aspiration time significantly shorter (54 ± 39 seconds versus 105 ± 84 seconds; P = .0001). The surgery was rated as easier with gas-forced infusion (scale 1 to 10: mean 8.3 ± 2.1 versus 6.6 ± 1.6; P = .00002). However, the amount of irrigating fluid volume was higher in the infusion group (117 ± 37 mL versus 94 ± 41 mL; P = .003). No surge occurred in the infusion group; it occurred a mean of 3.00 ± 4.16 times in the control group (P<.0001). The rate of visual gain, CMT, peripapillary RNFL thickness, phaco time, and amount of phaco energy were comparable in the 2 groups.Gas-forced infusion was safe and effective in controlling surge and increased the safety, ease, and speed of coaxial phacoemulsification.

TITLE: Suicidality is associated with medication access problems in publicly insured psychiatric patients.ABSTRACT: Beginning January 1, 2006, the Medicare Part D prescription drug benefit shifted drug coverage from Medicaid to the new Medicare Part D program for patients who were eligible for both Medicare and Medicaid benefits ("dual-eligibles"). These patients were randomly assigned to a private Part D plan and came under specific formulary and utilization management procedures of the plan in which they were enrolled.To examine the relationship between physician-reported medication switches, discontinuations, and other access problems and suicidal ideation or behavior among "dual-eligible" psychiatric patients.Data were collected in 3 cross-sectional cycles in 2006 (January-April, May-August, and September-December) as part of the National Study of Medicaid and Medicare Psychopharmacologic Treatment Access and Continuity using through-the-mail, practice-based survey research methods. Data from the third cycle, representing all events since January 1, 2006, were used for these analyses. A national sample of psychiatrists randomly selected from the AMA Masterfile provided clinically detailed data on 1 systematically selected, dual-eligible psychiatric patient (N = 908). Propensity score analyses adjusted for patient sociodemographics, treatment setting, diagnoses, and psychiatric symptom severity.Patients who experienced medication switches, discontinuations, and other access problems had 3 times the rate of suicidal ideation or behavior compared with patients with no access problems (22.0% vs 7.4%, P < .0001). Mean odds ratios and excess probabilities were highest for patients who were clinically stable but were required to switch medications (31.8%; mean OR = 4.87, mean P = 8.92(-5), excess probability = 0.21). Patients who experienced discontinuations (26.4%; mean OR = 2.13, mean P = 2.12(-2), excess probability = 0.12), other access problems (18.7%; mean OR = 3.01, mean P = 1.03(-5), excess probability = 0.15), and multiple access problems (22.3%; mean OR = 2.88, mean P = 4.10(-5), excess probability = 0.14) also had significantly increased suicidal ideation or behavior.Increased occurrences of suicidal ideation or behavior appear to be associated with disruptions in patient medication access and continuity. Clinicians need to be aware of the possibility of increased suicidality when, for administrative reasons, a clinically stable patient's medication regimen is altered. Dual-eligible psychiatric patients represent a highly vulnerable group with a substantial burden of illness; these findings underscore the need to provide special protections for this population.

TITLE: Hemodiafiltration with endogenous reinfusion with and without acetate-free dialysis solutions: effect on ESA requirement.ABSTRACT: Hemofiltrate reinfusion (HFR) is a form of hemodiafiltration (HDF) in which replacement fluid is constituted by ultrafiltrate from the patient 'regenerated' through a cartridge containing hydrophobic styrene resin. Bicarbonate-based dialysis solutions (DS) used in routine hemodialysis and HDF contain small quantities of acetate (3-5 mM) as a stabilizing agent, one of the major causes of intradialytic hypotension. Acetate-free (AF) DS have recently been made available, substituting acetate with hydrochloric acid. The impact of AF DS during HFR on Hb levels and erythropoietic-stimulating agent (ESA) requirement in chronic dialysis patients was assessed.After obtaining informed consent, 30 uremic patients treated by standard bicarbonate dialysis (BHD, DS with acetate) were randomized to treatment in 3-month cycles: first AF HFR, followed by HFR with acetate, and again AF HFR. At the beginning and end of each period, Hb and ESA requirements were evaluated.A significant increase in the Hb level was observed throughout all periods of HFR versus BHD (from 11.1 to 11.86 g/dl; p = 0.04), with a significant decrease of ESA requirements from 29,500 to 25,033 IU/month (p = 0.04).Regardless of the presence or absence of acetate in DS, HFR per se allows a significant lowering of ESA dosage versus BHD, while at the same time increasing Hb levels. Taking for granted the clinical impact produced, HFR seems to provide a relevant decrease in end-stage renal disease patient costs.

TITLE: Pasireotide for postoperative pancreatic fistula.ABSTRACT: Postoperative pancreatic fistula is a major contributor to complications and death associated with pancreatic resection. Pasireotide, a somatostatin analogue that has a longer half-life than octreotide and a broader binding profile, decreases pancreatic exocrine secretions and may prevent postoperative pancreatic fistula.We conducted a single-center, randomized, double-blind trial of perioperative subcutaneous pasireotide in patients undergoing either pancreaticoduodenectomy or distal pancreatectomy. We randomly assigned 300 patients to receive 900 μg of subcutaneous pasireotide (152 patients) or placebo (148 patients) twice daily beginning preoperatively on the morning of the operation and continuing for 7 days (14 doses). Randomization was stratified according to the type of resection and whether the pancreatic duct was dilated at the site of transection. The primary end point was the development of pancreatic fistula, leak, or abscess of grade 3 or higher (i.e., requiring drainage).The primary end point occurred in 45 of the 300 patients (15%). The rate of grade 3 or higher postoperative pancreatic fistula, leak, or abscess was significantly lower among patients who received pasireotide than among patients who received placebo (9% vs. 21%; relative risk, 0.44; 95% confidence interval [CI], 0.24 to 0.78; P=0.006). This finding was consistent among 220 patients who underwent pancreaticoduodenectomy (10% vs. 21%; relative risk, 0.49; 95% CI, 0.25 to 0.95) and 80 patients who underwent distal pancreatectomy (7% vs. 23%; relative risk, 0.32; 95% CI, 0.10 to 0.99), as well as among 136 patients with a dilated pancreatic duct (2% vs. 15%; relative risk, 0.11; 95% CI, 0.02 to 0.60) and 164 patients with a nondilated pancreatic duct (15% vs. 27%; relative risk, 0.55; 95% CI, 0.29 to 1.01).Perioperative treatment with pasireotide decreased the rate of clinically significant postoperative pancreatic fistula, leak, or abscess. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00994110.).

TITLE: Exaggerated blood pressure variability in patients with pneumoconiosis: a pilot study.ABSTRACT: Chronic hypoxia is a risk factor for cardiovascular disease, but its association with blood pressure (BP) remains unclear. We performed this study to clarify the hypothesis that chronic hypoxia is associated with abnormal BP variability in patients with pneumoconiosis.We recruited 19 patients with pneumoconiosis and 30 age- and BP level-matched control subjects. We used simultaneous pulse oximetry and ambulatory BP monitoring for all subjects. We evaluated their BP levels and variability by determining the SD and coefficient of variation (CV) of the BP data. The dipper pattern was defined as nocturnal BP fall ≥10%; the nondipper pattern was defined as nocturnal BP fall ≥0% but <10%; the riser pattern was defined as nocturnal BP fall <0%. Pearson and Spearman correlation coefficients were used to calculate the correlations between parameters.In patients with pneumoconiosis, the daytime systolic BP (SBP) level was lower, the CV in 24-hour SBP (P < 0.05) and diastolic BP (P < 0.001) were higher than that in control subjects. And although not statistically significant (P = 0.13), the odds ratio of riser pattern was 3.73 in patients with pneumoconiosis, and their nighttime pulse rate was significantly higher (P < 0.05) than that in control subjects. The median daytime pulse oximetry oxygen saturation was inversely associated with mean (r = -0.30; P < 0.01) and SD (r = -0.38; P < 0.001) in daytime SBP. The median nighttime pulse oximetry oxygen saturation was inversely associated (r = -0.55; P < 0.001) and the mean nighttime pulse rate was associated (r = 0.51; P < 0.001) with CV in nighttime SBP. Partial pressure of oxygen was inversely associated with CV in daytime SBP (r = -0.24; P < 0.05).Exaggerated BP variability was seen in patients with pneumoconiosis, and the measures of hypoxia were associated with large fluctuations in ambulatory BP. Chronic and intermittent hypoxia could be the contributing factors of these findings.Clinical Trial Number UMIN000000894 (University Hospital Medical Information Network Clinical Trials Registry website).

TITLE: Efficacy and safety of percutaneous nephrolithotomy (PCNL): a prospective and randomized study comparing regional epidural anesthesia with general anesthesia.ABSTRACT: To compare the efficacy and safety of regional epidural anesthesia and general anesthesia in patients who underwent PCNL.Fifty patients submitted to percutaneous nephrolithotomy (PCNL) were randomized into two groups: Group I (N = 26) received general anesthesia and Group II (N = 24) received regional epidural anesthesia. Demographic and operative data including age, BMI, stone position, stone size, postoperative pain, amount of postoperative analgesic usage, length of hospital stay, patient satisfaction, preoperative and postoperative hemoglobin and hematocrit, adverse effects and surgical complications were compared between both groups.Average pain score at 1 hour. was 6.88 in group I and 3.12 in group II (p < 0.001), at 4 hours. 5.07 in group I and 3.42 in group II (p = 0.025). Less morphine was required in the regional epidural anesthesia group compared to the general anesthesia group. Higher satisfaction was found in the regional epidural group. 6 (23.07 %) patients in Group I and 1 patient (4.19 %) in Group II had postoperative nausea and vomiting, respectively (p = 0.05). Pain score at 12 hours, 24 hours, 48 hours, 72 hours, preoperative and postoperative hemoglobin and hematocrit, length of hospital stay, and adverse effects were no different between the two groups.Regional epidural anesthesia is an alternative technique for PCNL which achieves more patient satisfaction, less early postoperative pain and less adverse effects from medication with the same efficacy and safety compared to general anesthesia.

TITLE: Cognitive therapy versus fluvoxamine as a second-step treatment in obsessive-compulsive disorder nonresponsive to first-step behavior therapy.ABSTRACT: To compare the effectiveness of second-step treatment with cognitive therapy (CT) versus fluvoxamine in patients with obsessive-compulsive disorder (OCD) who are nonresponsive to exposure in vivo with response prevention (ERP).A 12-week randomized controlled trial at an outpatient clinic in the Netherlands comparing CT with fluvoxamine in OCD. Of 118 subjects with OCD treated with 12 weeks of ERP, 48 appeared to be nonresponders (Y-BOCS improvement score of less than one third). These nonresponders were randomized to CT (n = 22) or fluvoxamine (n = 26). The main outcome measure was the Y-BOCS severity scale. Statistical analyses were conducted in the intention-to-treat sample (n = 45) on an 'as randomized basis' and in the per-protocol sample (n = 30). Due to selective dropout in the fluvoxamine group, two additional sensitivity analyses were performed.Complete data could be obtained from 45 subjects (94%) after 12 weeks. Fifty percent of the patients refused fluvoxamine after randomization compared to 13% who refused CT [χ(2)(1) = 7.10; p = 0.01]. CT as a second-step treatment did not appear to be effective in this sample of nonresponders. Fluvoxamine was significantly superior to CT in the intention-to-treat sample, in the per-protocol sample and in the two separately defined samples in which the sensitivity analyses were performed.OCD patients who are nonresponsive to ERP may benefit more from a switch to treatment with an antidepressant instead of switching to CT. In clinical practice, it may be important to motivate this subgroup of patients to undergo psychopharmacological treatment, as this may improve their outcome considerably.

TITLE: Vitamin E serum levels and controlled supplementation and risk of amyotrophic lateral sclerosis.ABSTRACT: There are no observational studies or controlled trials of amyotrophic lateral sclerosis (ALS) and circulating α-tocopherol (vitamin E) for prevention of ALS. This study addresses that gap. The study population comprised 29,127 Finnish male smokers, aged 50-69 years, who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, which is both a prospective cohort and a randomized, double-blind, placebo-controlled trial of α-tocopherol (50 mg/day) and β-carotene (20 mg/day). Serum α-tocopherol and β-carotene was assayed at baseline (1985 - 1988). Follow-up (median 16.7 years) continued through 2004. ALS cases were identified through the national Hospital Discharge Register with diagnostic verification by hospital records and death certificates. During 407,260 person-years of follow-up, 50 men were identified with ALS. For males with serum α-tocopherol concentration above the median (≥ 11.6 mg/l), the age-adjusted relative risk (RR) compared to α-tocopherol below the median, was 0.56 (95% confidence interval 0.32 - 0.99), p = 0.046. The RR among α-tocopherol supplement recipients was 0.75 (95% CI 0.32 - 1.79), p = 0.52. Neither serum β-carotene level nor β-carotene supplementation was associated with ALS. In conclusion, the results are consistent with a hypothesized protective effect of α-tocopherol on ALS risk. However, pooled analyses of cohorts with serum and controlled trials are needed to clarify the role of α-tocopherol in ALS risk.

TITLE: Outpatient Foley catheter versus inpatient prostaglandin E2 gel for induction of labour: a randomised trial.ABSTRACT: Induction of labour (IOL) is one of the commonest obstetric interventions, with significant impact on both the individual woman and health service delivery. Outpatient IOL is an attractive option to reduce these impacts. To date there is little data comparing outpatient and inpatient IOL methods, and potential safety concerns (hyperstimulation) if prostaglandins, the standard inpatient IOL medications, are used in the outpatient setting. The purpose of this study was to assess feasibility, clinical effectiveness and patient acceptability of outpatient Foley catheter (OPC) vs. inpatient vaginal PGE2 (IP) for induction of labour (IOL) at term.Women with an unfavourable cervix requiring IOL at term (N=101) were randomised to outpatient care using Foley catheter (OPC, n=50) or inpatient care using vaginal PGE2 (IP, n=51). OPC group had Foley catheter inserted and were discharged overnight following a reassuring cardiotocograph. IP group received 2 mg/1 mg vaginal PGE2 if nulliparous or 1 mg/1 mg if multiparous. Main outcome measures were inpatient stay (prior to birth, in Birthing Unit, total), mode of birth, induction to delivery interval, adverse reactions and patient satisfaction.OPC group had shorter hospital stay prior to birth (21.3 vs. 32.4 hrs, p< .001), IP were more likely to achieve vaginal birth within 12 hours of presenting to Birthing Unit (53% vs. 28%, p= .01). Vaginal birth rates (66% OPC Vs. 71% IP), total induction to delivery time (33.5 hrs vs. 31.3 hrs) and total inpatient times (96 hrs OPC Vs. 105 hrs IP) were similar. OPC group felt less pain (significant discomfort 26% Vs 58%, p=.003), and had more sleep (5.8 Vs 3.4 hours, p< .001), during cervical preparation, but were more likely to require oxytocin IOL (88 Vs 59%, p=.001).OPC was feasible and acceptable for IOL of women with an unfavourable cervix at term compared to IP, however did not show a statistically significant reduction in total inpatient stay and was associated with increased oxytocin IOL.Australian New Zealand Clinical Trials Registry, ACTRN:12609000420246.

TITLE: Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized clinical trial.ABSTRACT: Bioidentical compounded hormone therapy is popular among patients, but providers do not have pharmacokinetic information or dosing guidelines for these preparations. Our objective was to compare the pharmacokinetics of the commonly used compounded preparations with conventional hormonal preparations that are considered bioequivalent in practice.We conducted a randomized, blinded, four-arm 16-day clinical trial of forty postmenopausal women assigned to one of three doses of a compounded estrogen cream (Bi-est (80:20); 2.0, 2.5, or 3.0 mg)+compounded oral progesterone 100 mg, or to a conventional estradiol patch (Vivelle-Dot™ 0.05 mg)+Prometrium™ 100mg. Serum levels of estrone, estradiol, estriol, and progesterone were obtained at multiple time intervals during the first 24-h, and at steady-state.Results were analyzable for 37/40 women. Study medications were well tolerated. The AUC at 24h and at steady-state for estrogens remained consistently lower for all doses of Bi-est tested relative to the patch. The difference was statistically significant for Bi-est 2.0mg (AUC-estradiol=181 vs. 956; p<0.001) and 2.5mg (AUC-estradiol=286 vs. 917; p<0.001). Estriol levels remained low in all study arms. Serum progesterone levels were comparable in conventional vs. compounded groups.This pharmacokinetic trial showed that the currently used doses of compounded hormones yield lower levels of estrogen compared to the standard-dose estradiol patch. To find comparable doses, further studies are needed. This successfully conducted randomized controlled study attests to the feasibility of using a similar design in the setting of a larger clinical trial.

TITLE: Reduced hepatotoxicity by total glucosides of paeony in combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis.ABSTRACT: Combination use of methotrexate (MTX) and leflunomide (LEF) has been proved effective in the treatment of active rheumatoid arthritis (RA). However, previous trials have documented that both are associated with increased incidence of liver toxicity. As active compounds extracted from the roots of the traditional Chinese herb Paeonia lactiflora Pall, total glucosides of paeony (TGP) have been shown to have anti-inflammatory, hepatoprotective and immuno-regulatory activities, without evident toxicity or side effects. In this 24-week, open label, randomized multicenter clinical trial, we investigated the efficacy of TGP and the protective effect on hepatotoxicity in the combination treatment with LEF and MTX for patients with active RA. A total of 204 patients with active RA (DAS28>3.2) recruited from 3 regional referral centers were enrolled and received MTX and LEF combination therapy (MTX 10 mg/week plus LEF 20 mg/day) with or without TGP for up to 24 weeks by randomization. Hepatotoxicity was defined as an increase of at least 1.5-fold the upper limits of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Significantly less frequent hepatotoxicity was observed in patients with TGP than those without (9.5% vs 34.8%, p < 0.001) at 12 weeks. The proportion of patients whose ALT or AST levels were > 1.5 to ≤2 times and >2 to ≤3 times the ULN were lower in TGP group than the control (1.9% vs 10.1%, 2.9% vs 12.4%, p < 0.05 respectively). More patients in the TGP group achieved a European League Against Rheumatism (EULAR) good response or moderate response at 12 weeks, although there is no statistical significance. Similar results were observed at 24 weeks. Our preliminary study demonstrates the hepatoprotective and additive role of TGP in combination with MTX and LEF in the treatment of active RA.

TITLE: Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine.ABSTRACT: Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo.Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up.Nine English old-age psychiatry services.A pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+.clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer.(1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily.MAIN OUTCOME MEASURES METHODSCSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed.Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine).Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112).Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group.This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.

TITLE: Clinical, angiographic, and intravascular ultrasound results of the VestSaync II trial.ABSTRACT: We sought to assess the long term efficacy of the novel VESTAsync™ Eluting Stent (VES) combining a Cro-Co platform with a nanothin-microporous hydroxyapatite surface coating impregnated with a polymer-free low-dose of Sirolimus (55 μg).The Vestasync II trial was a randomized (2:1), double-blinded, multicenter comparison of the VES to its platform, the Gen X stent, with microporous hydroxyapatite surface coating without sirolimus. Patients were eligible if they presented de novo lesions in native coronary arteries with 3.0-3.5 mm diameter and ≤ 14 mm in length. Primary endpoint was 8-month in-stent late loss and % of stent obstruction. Lifelong aspirin and 6-month clopidogrel were prescribed to all patients.Seventy-five patients were enrolled (VES = 50 pts). Baseline characteristics included mean age of 58 years and 29% of diabetics. Reference vessel diameter and lesion length were 2.8 ± 0.4 mm and 13.0 ± 2.0 mm, respectively. In-stent late loss (0.39 ± 0.20 vs. 0.74 ± 0.52, P = 0.03) and % of neointima hyperplasia (9.3 ± 6.6% vs. 17.6 ± 9.4%, P = 0.0016) were significantly reduced in the VES cohort. Up to 1 year, there was a single case of myocardial infarction and one target lesion revascularization (TLR) (2%) in the VES group while in the control cohort there were one TLR (4%) and one cardiac death (4%).The VestSync II trial is a proof-of-concept study and demonstrates the sustained efficacy of this novel polymer-free sirolimus drug-eluting stents. A larger trial, with more complex lesions, clinical endpoints and longer FU period is warranted. © 2013 Wiley Periodicals, Inc.

TITLE: Body weight, plasma insulin, and coronary events with gemfibrozil in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT).ABSTRACT: The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that gemfibrozil significantly reduced major coronary events in men with known coronary heart disease (CHD). To better understand why therapy was especially effective with obesity, diabetes, and hyperinsulinemia, changes in body weight and plasma insulin were determined after 1 year of gemfibrozil or placebo therapy and related to changes in lipids and CHD events.With gemfibrozil significantly more subjects lost weight (51.7% versus 38.6%, P<0.0001) and significantly fewer subjects gained weight (42.5% versus 54.0%, P<0.0001) than with placebo. Both a greater loss and smaller gain in weight with gemfibrozil were age-related and significant in subjects > or =66 years (median age), but not in younger subjects. Weight change was paralleled by changes in insulin. With gemfibrozil, CHD events were significantly reduced with weight loss (hazard ratio [HR], 0.61; 95% CI, 0.44-0.84; P=0.002) and, particularly, with diabetes or hyperinsulinemia (HR, 0.53; 95% CI, 0.34-0.83; P=0.006). In contrast, CHD events were not significantly reduced without weight loss (HR, 0.83; 95% CI, 0.62-1.12; P=0.22).In VA-HIT, gemfibrozil resulted in weight loss associated with reductions in insulin. With weight loss gemfibrozil produced a significant reduction in CHD events that did not occur in the absence of weight loss.

TITLE: Sexual function in nondepressed women using escitalopram for vasomotor symptoms: a randomized controlled trial.ABSTRACT: To evaluate sexual function in midlife women using selective serotonin reuptake inhibitors for vasomotor symptoms. Selective serotonin reuptake inhibitors effectively treat vasomotor symptoms but adversely affect sexual function in depressed populations. Information on sexual function in nondepressed midlife women using selective serotonin reuptake inhibitors for vasomotor symptoms is lacking; any treatments that might impair function are of concern.This was a randomized controlled trial comparing 8 weeks of escitalopram with placebo in women ages 40-62 years with 28 or more bothersome vasomotor symptoms per week. Change in Female Sexual Function Index composite score (ranges from 2 [not sexually active, no desire] to 36) and six sexual domains (desire, arousal, lubrication, orgasm, satisfaction, pain) and the Female Sexual Distress Scale, and a single-question of sexually-related personal distress from the Female Sexual Distress Scale, were compared between groups.Among all women, median composite baseline Female Sexual Function Index score was 18.1 (interquartile range 2.4-26.5, n=200) and among sexually active women was 22.8 (interquartile range 17.4-27.0, n=75) in the escitalopram group and 23.6 (interquartile range 14.9-31.0, n=70) in the placebo group. Treatment with escitalopram did not affect composite Female Sexual Function Index score at follow-up compared with placebo (P=.18 all women; P=.47 sexually active at baseline). Composite mean Female Sexual Function Index change from baseline to week 8 was 0.1 (95% confidence interval [CI] -1.5 to 1.7) for escitalopram and 2.0 (95% CI 0.2-3.8) for placebo. The Female Sexual Distress Scale results did not differ between groups (P=.73) nor did adverse reports of sexual function. At week 8, among those women sexually active at baseline, there was a small difference between groups in Female Sexual Function Index domain mean score change in lubrication (P=.02) and a marginal nonsignificant difference in orgasm (P=.07).Escitalopram, when used in the treatment of vasomotor symptoms, did not worsen overall sexual function among nondepressed midlife women.

TITLE: Association Between Peritoneal Glucose Exposure and Peritonitis in Peritoneal Dialysis Patients: The balANZ Trial.ABSTRACT: Glucose is the primary osmotic medium used in most peritoneal dialysis (PD) solutions, and exposure to glucose has been shown to exert detrimental effects both locally, at the peritoneal membrane, and systemically. Moreover, high dialysate glucose exposure may predispose patients to an increased risk of peritonitis, perhaps as a result of impaired host defences, vascular disease, and damage to the peritoneal membrane.In this post-hoc analysis of a multicenter, multinational, open-label randomized controlled trial of neutral pH, low-glucose degradation product (GDP) versus conventional PD solutions (ANZ trial), the relationship between peritonitis rates of low (< 123.1 g/day) versus high (≥ 123.1 g/day) dialysate glucose exposure was evaluated in 177 incident PD patients over a 2-year study period.Peritonitis rates were 0.44 episodes per patient-year in the low-glucose exposure group and 0.31 episodes per patient-year in the high-glucose exposure group, (incidence rate ratio [IRR] 0.69, = 0.09). There was no significant association between dialysate glucose exposure and peritonitis-free survival on univariable analysis (high glucose exposure hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.40 - 1.08) or on multivariable analysis (adjusted HR 0.64, 95% CI 0.39 - 1.05). Moreover, there was no relationship between peritoneal glucose exposure and type of organism causing peritonitis. Physician-rated severity of first peritonitis episodes was similar between groups, as was rate and duration of hospital admission.Overall, this study did not identify an association between peritoneal dialysate glucose exposure and peritonitis occurrence, severity, hospitalization, or outcomes. A further large-scale, prospective, randomized controlled trial evaluating patient-level outcomes is merited.

TITLE: Effects of progressive resistance training in individuals with type 2 diabetic polyneuropathy: a randomised assessor-blinded controlled trial.ABSTRACT: The aim of this study was to evaluate the effects of progressive resistance training (PRT) on muscle strength, intraepidermal nerve fibre density (IENFD) and motor function in individuals with type 2 diabetic polyneuropathy (DPN) and to compare potential adaptations to those of individuals with type 2 diabetes without DPN and healthy controls.This was an assessor-blinded trial conducted at the Neurology department, Aarhus University Hospital. Adults with type 2 diabetes, with and without DPN and healthy control participants were randomised to either supervised PRT or non-PRT for 12 weeks. Allocation was concealed by a central office unrelated to the study. The co-primary outcomes were muscle strength in terms of the peak torque of the knee and ankle extensors and flexors, and IENFD. Secondary outcome measures included the 6 min walk test (6MWT), five-time sit-to-stand test (FTSST) and postural stability index obtained by static posturography.A total of 109 individuals were enrolled in three groups (type 2 diabetes with DPN [n = 42], type 2 diabetes without DPN [n = 32] and healthy control [n = 35]). PRT resulted in muscle strength gains of the knee extensors and flexors in all three groups using comparative analysis (DPN group, PRT 10.3 ± 9.6 Nm vs non-PRT -0.4 ± 8.2 Nm; non-DPN group, PRT 7.5 ± 5.8 Nm vs non-PRT 0.6 ± 8.8 Nm; healthy control group, PRT 6.3 ± 9.0 Nm vs non-PRT -0.4 ± 8.4 Nm; p<0.05, respectively). Following PRT the DPN group improved the 6MWT (PRT 34.6 ± 40.9 m vs non-PRT 2.7 ± 19.6 m; p=0.001) and the FTSST (PRT -1.5 ± 2.2 s vs non-PRT 1.5 ± 4.6 s; p=0.02). There was no change in IENFD following PRT in any of the groups.PRT improved muscle strength of the knee extensors and flexors and motor function in individuals with type 2 diabetic polyneuropathy at levels comparable with those seen in individuals with diabetes without DPN and healthy control individuals, while no effects were observed in IENFD.ClinicalTrials.gov NCT03252132 FUNDING: Research reported in this paper is part of the International Diabetic Neuropathy Consortium (IDNC) research programme, supported by a Novo Nordisk Foundation Challenge Program grant (grant no. NNF14OC0011633) and Aarhus University.

TITLE: Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans.ABSTRACT: Use of β-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation β-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5-20 mg/day) or metoprolol succinate (100-300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 ± 2.6/81.7 ± 1.8 vs. 131.6 ± 2.7/80.8 ± 1.5 mmHg and 63 ± 2 vs. 64 ± 2 beats/min) compared with baseline (142.1 ± 2.0/88.7 ± 1.4 mmHg and 75 ± 2 beats/min, respectively, both P < 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P < 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.

TITLE: Long-Term Follow-Up of the Intergroup Exemestane Study.ABSTRACT: Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

TITLE: Ethnic differences in prevalence and barriers of HBV screening and vaccination among Asian Americans.ABSTRACT: Our study identifies the prevalence of HBV virus (HBV) screening and vaccination among Asian Americans, and ethnic differences for factors associated with screening and vaccination behaviors. In 2009-2010 we recruited 877 Korean, Chinese, and Vietnamese Americans 18 years of age and above through several community organizations, churches and local ethnic businesses in Maryland for a health education intervention and a self-administered survey. Prevalence of HBV screening, screening result and vaccinations were compared by each ethnic group. We used logistic regression analysis to understand how sociodemographics, familial factors, patient-, provider-, and resource-related barriers are associated with screening and vaccination behaviors, using the total sample and separate analysis for each ethnic group. Forty-seven percent of participants reported that they had received HBV screening and 38% had received vaccinations. Among the three groups, the Chinese participants had the highest screening prevalence, but lowest self-reported infection rate; Vietnamese has the lowest screening and vaccination prevalence. In multivariate analysis, having better knowledge of HBV, and family and physician recommendations was significantly associated with screening and vaccination behaviors. Immigrants who had lived in the US for more than a quarter of their lifetime were less likely to report ever having been screened (OR = 0.39, 95% CI: 0.28-0.55) or vaccinated (OR = 0.62, 95% CI: 0.44-0.88). In ethnic-specific analysis, having a regular physician (OR = 4.46, 95% CI: 1.62-12.25) and doctor's recommendation (OR = 2.11, 95% CI: 1.05-4.22) are significantly associated with Korean's vaccination behaviors. Health insurance was associated with vaccination behaviors only among Vietnamese (OR = 2.66, 95% CI: 1.21–5.83), but not among others.

TITLE: A partially hydrolyzed formula with synbiotics supports adequate growth and is well tolerated in healthy, Chinese term infants: A double-blind, randomized controlled trial.ABSTRACT: The aim of this study was to evaluate growth and gastrointestinal tolerance in infants fed a partially hydrolyzed protein formula (pHF) with a synbiotic mixture of short-chain galacto-oligosaccharides and long-chain fructooligosaccharides (scGOS/lcFOS; 9:1) and Bifidobacterium breve M-16V (test formula) compared with an intact protein infant formula (IF) with scGOS/lcFOS (control formula).This randomized, double-blind, controlled, multicenter trial enrolled healthy, fully formula-fed Chinese infants (≤44 d) who received either the test (n = 112) or control formula (n = 112) until 17 wk of age. Fully breastfed infants served as a reference (n = 60). Anthropometrics, gastrointestinal symptoms, and adverse events were assessed monthly. Primary outcome was weight gain in grams per day from baseline to 17 wk of age.Equivalence in daily weight gain (primary outcome) was demonstrated between the test and control groups (estimated mean difference [SE]: -0.36 [0.93] g/d, 90% confidence interval [CI], -1.90 to 1.18) as well as between each IF group and the breastfed reference group (test: 0.02 [1.05] g/d, 90% CI, -1.71 to 1.75; control: 0.36 [1.04] g/d, 90% CI, -1.35 to 2.08). There were no clinically relevant differences in gastrointestinal tolerance or adverse events between the formula groups.A pHF with synbiotics supports adequate growth and is well tolerated in healthy, term-born Chinese infants. Additionally, infant growth and gastrointestinal tolerance measures of both IF groups were comparable to the breastfed group and can be considered suitable and well tolerated for use.

TITLE: Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial.ABSTRACT: Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer.In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566.In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months [95% CI 3·9-9·8]) and placebo (5·1 months [3·6-7·3]) group (hazard ratio [HR] 0·74 [95% CI 0·52-1·06]; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months [95% CI 3·7-9·8] vs placebo 5·1 months [2·6-10·4]; HR 0·73 [95% CI 0·42-1·28]; p=0·268) or absence (5·8 months [3·6-11·1] vs 3·6 months [2·8-7·3]; HR 0·72 [0·42-1·23]; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months [95% CI 3·8-8·3] vs 10·0 months [3·6-13·0]; HR 1·07 [95% CI 0·53-2·18]; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group.Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing.F Hoffmann-La Roche.

TITLE: Cytochrome 2C19 polymorphism and response to adjunctive cilostazol versus high maintenance-dose clopidogrel in patients undergoing percutaneous coronary intervention.ABSTRACT: Among patients treated with clopidogrel, carriers of the cytochrome P450 (CYP) 2C19 loss-of-function allele have shown increased platelet reactivity and higher rates of ischemic events. Although adjunctive cilostazol to dual antiplatelet therapy (or "triple antiplatelet therapy") intensifies platelet inhibition, it remains unknown whether triple antiplatelet therapy after percutaneous coronary intervention can achieve adequate platelet inhibition in patients with the CYP2C19 mutant allele.CYP2C19 genotyping for *1, *2, and *3 was performed in 134 high-risk patients undergoing elective percutaneous coronary intervention. After measurement of preprocedural platelet reactivity, patients were randomly assigned to receive either adjunctive cilostazol 100 mg twice daily (triple group; n=69) or high maintenance-dose (MD) clopidogrel of 150 mg daily (high-MD group; n=65). Using light transmittance aggregometry and the VerifyNow P2Y(12) assay, platelet reactivity was assessed before the index procedure and at 30-day follow-up. The primary end point was absolute change in maximal platelet aggregation (ΔAgg(max)) according to CYP2C19 genotyping. High posttreatment platelet reactivity was defined as 5 μmol/L ADP-induced maximal platelet aggregation >50%. In noncarriers of the CYP2C19*2/*3 mutant allele, ΔAgg(max) values after 5 and 20 μmol/L ADP stimuli did not differ significantly between the triple (n=22) versus the high-MD group (n=22) (23.6±21.6% versus 16.6±15.4%, P=0.224 and 26.4±22.2% versus 18.6±14.9%, P=0.174, respectively). Absolute changes in late platelet aggregation and P2Y(12) reaction unit were not different between the groups. The rate of high posttreatment platelet reactivity at 30-day follow-up also was comparable between the triple versus the high-MD group (4.5% versus 13.6%, P=0.607). In carriers of at least 1 CYP2C19*2/*3 mutant allele, the triple group (n=47) showed greater values of ΔAgg(max) after addition of 5 μmol/L (25.8±16.8% versus 11.1±19.8%, P<0.001) and 20 μmol/L ADP (26.3±16.0% versus 11.5±16.3%, P<0.001) compared with the high-MD group (n=43). Likewise, absolute changes in late platelet aggregation and P2Y(12) reaction unit were consistently greater in the triple versus the high-MD group. Fewer patients in the triple group met the criteria of high posttreatment platelet reactivity at 30-day follow-up compared with the high-MD group (6.4% versus 37.2%, P<0.001).Among high-risk patients undergoing elective percutaneous coronary intervention, adjunctive cilostazol can achieve consistently intensified platelet inhibition and reduce the risk of high posttreatment platelet reactivity irrespective of CYP2C19 genotyping.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01012193.

TITLE: Glomerular filtration rate reserve is reduced during mild passive heat stress in healthy young adults.ABSTRACT: We tested the hypothesis that, compared with normothermia, the increase in glomerular filtration rate (GFR) after an oral protein load (defined as the GFR reserve) is attenuated during moderate passive heat stress in young healthy adults. Sixteen participants (5 women; 26 ± 2 yr) completed two experimental visits, heat stress or a normothermic time-control, assigned in a block-randomized crossover design. During the heat stress trial, core temperature was increased by 0.6°C in the first hour before commencing a 2-min cold pressor test (CPT) to assess renal vasoconstrictor responses. One-hour post-CPT, subjects ingested a whey protein shake (1.2 g of protein/kg body wt), and measurements were taken pre-, 75, and 150 min postprotein. Segmental artery vascular resistance was calculated as the quotient of Doppler ultrasound-derived segmental artery blood velocity and mean arterial pressure and provided an estimate of renal vascular tone. GFR was estimated from creatinine clearance. The increase in segmental artery vascular resistance during the CPT was attenuated during heat stress (end CPT: 5.6 ± 0.9 vs. 4.7 ± 1.1 mmHg/cm/s, = 0.024). However, the reduction in segmental artery vascular resistance in response to an oral protein load did not differ between heat stress (at 150 min: 1.9 ± 0.4 mmHg/cm/s) and normothermia (at 150 min: 1.8 ± 0.5 mmHg/cm/s; = 0.979). The peak increase in creatinine clearance postprotein, independent of time, was attenuated during heat stress (+26 ± 19 vs. +16 ± 20 mL/min, = 0.013, = 13). GFR reserve is diminished by mild passive heat stress. Moreover, renal vasoconstrictor responses are attenuated by mild passive heat stress, but renal vasodilator responses are maintained.

TITLE: Assessing race and ethnicity differences in outcomes based on GDMT and target NT-proBNP in patients with heart failure with reduced ejection fraction: An analysis of the GUIDE-IT study.ABSTRACT: The GUIDE-IT trial was, a multicenter, randomized, parallel group, unblinded study that randomized patients to having heart failure therapy titrated to achieve an NT-proBNP <1000 pg/mL or to usual clinical care.We performed pre-specified subgroup analysis to look for the race and ethnicity-based differences in clinical outcomes of patients who were able to achieve GDMT or target NT-proBNP concentration of ≤1000 pg/mL at 90 days of follow-up. There were 894 patients enrolled in GUIDE-IT study. Of these, 733 participants had available data on 90-day guideline directed triple therapy and 616 on NT-proBNP. 35% of the patients were Black and 6% were Hispanic. Black patients were younger, had more comorbidities, lower EF, and higher NYHA class compared with non-Black. Adjusting for 90-day NT-proBNP and important baseline covariates, Black patients were at a higher risk than non-Black patients for HF hospitalization [HR, 2.19; 95% CI, 1.51-3.17; p < 0.0001], but at a similar risk for mortality [HR, 0.85.; 95% CI, 0.44-1.66; p = 0.64]. Similar results were seen adjusting for 90-day GDMT [HF hospitalization: Black vs non-Black, HR: 1.97; 1.41-2.77, P < 0.0001; mortality: HR: 0.70; 0.39-1.26, p = 0.23]. There were no significant differences between Hispanic and non-Hispanic patients with respect to heart failure hospitalization, cardiovascular or all-cause mortality. Over the study period, Black and Hispanic patients experienced smaller changes in physical function and quality of life as measured by the Kansas City Cardiomyopathy Questionnaire overall score.Compared to non-Black patients, Black patients in GUIDE-IT study had a higher risk of heart failure hospitalization, but a comparable risk of mortality, despite improved use of GDMT and achievement of similar biomarker targets.

TITLE: Early cryoprecipitate transfusion versus standard care in severe postpartum haemorrhage: a pilot cluster-randomised trial.ABSTRACT: There is a lack of evidence evaluating cryoprecipitate transfusion in severe postpartum haemorrhage. We performed a pilot cluster-randomised controlled trial to evaluate the feasibility of a trial on early cryoprecipitate delivery in severe postpartum haemorrhage. Pregnant women (>24 weeks gestation), actively bleeding within 24 h of delivery and who required at least one unit of red blood cells were eligible. Women declining transfusion in advance or with inherited clotting deficiencies were not eligible. Four UK hospitals were randomly allocated to deliver either the intervention (administration of two pools of cryoprecipitate within 90 min of first red blood cell unit requested plus standard care), or the control group treatment (standard care, where cryoprecipitate is administered later or not at all). The primary outcome was the proportion of women who received early cryoprecipitate (intervention) vs. standard care (control). Secondary outcomes included consent rates, acceptability of the intervention, safety outcomes and preliminary clinical outcome data to inform a definitive trial. Between March 2019 and January 2020, 199 participants were recruited; 19 refused consent, leaving 180 for analysis (110 in the intervention and 70 in the control group). Adherence to assigned treatment was 32% (95%CI 23-41%) in the intervention group vs. 81% (95%CI 70-90%) in the control group. The proportion of women receiving cryoprecipitate at any time-point was higher in the intervention (60%) vs. control (31%) groups; the former had fewer red blood cell transfusions at 24 h (mean difference -0.6 units, 95%CI -1.2 to 0); overall surgical procedures (odds ratio 0.6, 95%CI 0.3-1.1); and intensive care admissions (odds ratio 0.4, 95%CI 0.1-1.1). There was no increase in serious adverse or thrombotic events in the intervention group. Staff interviews showed that lack of awareness and uncertainty about study responsibilities contributed to lower adherence in the intervention group. We conclude that a full-scale trial may be feasible, provided that protocol revisions are put in place to establish clear lines of communication for ordering early cryoprecipitate in order to improve adherence. Preliminary clinical outcomes associated with cryoprecipitate administration are encouraging and merit further investigation.

TITLE: Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study.ABSTRACT: Targeted inhibition of the PD-L1-PD-1 pathway might be further amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE trial, we aimed to assess the preliminary efficacy and safety of tiragolumab plus atezolizumab (anti-PD-L1) therapy as first-line treatment for non-small-cell lung cancer (NSCLC).CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako, Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with measurable disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe, Asia, and the USA. Patients were randomly assigned (1:1), via an interactive voice or web-based response system, to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3 weeks. Investigators and patients were masked to treatment assignment. The co-primary endpoints were investigator-assessed objective response rate and progression-free survival as per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population, analysed after approximately 80 progression-free survival events had been observed in the primary population. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is ongoing.Patients were enrolled between Aug 10, 2018, and March 20, 2019. At data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients assessed for eligibility were randomly assigned to receive tiragolumab plus atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary analysis, after a median follow-up of 5·9 months (4·6-7·6, in the intention-to-treat population, 21 patients (31·3% [95% CI 19·5-43·2]) in the tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7-25·7]) in the placebo plus atezolizumab group had an objective response (p=0·031). Median progression-free survival was 5·4 months (95% CI 4·2-not estimable) in the tiragolumab plus atezolizumab group versus 3·6 months (2·7-4·4) in the placebo plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37-0·90], p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%) patients receiving placebo plus atezolizumab had serious treatment-related adverse events. The most frequently reported grade 3 or worse treatment-related adverse event was lipase increase (in six [9%] patients in the tiragolumab plus atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab plus atezolizumab group.Tiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC.F Hoffmann-La Roche and Genentech.

TITLE: Weight management and determinants of weight change in patients with coronary artery disease.ABSTRACT: To study the effects of a comprehensive secondary prevention programme on weight loss and to identify determinants of weight change in patients with coronary artery disease (CAD).We performed a secondary analysis focusing on the subgroup of overweight CAD patients (BMI ≥27 kg/m) in the Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists-2 (RESPONSE-2) multicentre randomised trial. We evaluated weight change from baseline to 12-month follow-up; multivariable logistic regression with backward elimination was used to identify determinants of weight change.Intervention patients (n=280) lost significantly more weight than control patients (n=257) (-2.4±7.1 kg vs -0.2±4.6 kg; p<0.001). Individual weight change varied widely, with weight gain (≥1.0 kg) occurring in 36% of interventions versus 41% controls (p=0.21). In the intervention group, weight loss of ≥5% was associated with higher age (OR 2.94), lower educational level (OR 1.91), non-smoking status (OR 2.92), motivation to start with weight loss directly after the baseline visit (OR 2.31) and weight loss programme participation (OR 3.33), whereas weight gain (≥1 kg) was associated with smoking cessation ≤6 months before or during hospitalisation (OR 3.21), non-Caucasian ethnicity (OR 2.77), smoking at baseline (OR 2.70), lower age (<65 years) (OR 1.47) and weight loss programme participation (OR 0.59).The comprehensive secondary prevention programme was, on average, effective in achieving weight loss. However, wide variation was observed. As weight gain was observed in over one in three participants in both groups, prevention of weight gain may be as important as attempts to lose weight.NTR3937.

TITLE: Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome.ABSTRACT: Interindividual variation in the ability of aspirin to inhibit platelet cyclooxygenase-1 (COX-1) could account for some on-treatment cardiovascular events. Here, we sought to determine whether there are clinical phenotypes that are associated with a suboptimal pharmacological effect of aspirin. In a prospective, 2-week study, we evaluated the effect of aspirin (81 mg) on platelet COX-1 in 135 patients with stable coronary artery disease by measuring serum thromboxane B(2) (sTxB(2)) as an indicator of inhibition of platelet COX-1. A nested randomized study compared enteric-coated with immediate-release formulations of aspirin. We found that sTxB(2) was systematically higher among the 83 patients with metabolic syndrome than among the 52 patients without (median: 4.0 versus 3.02 ng/mL; P=0.013). Twelve patients (14%) with metabolic syndrome, but none without metabolic syndrome, had sTxB(2) levels consistent with inadequate inhibition of COX (sTxB(2) ≥13 ng/mL). In linear regression models, metabolic syndrome (but none of its individual components) significantly associated with higher levels of log-transformed sTxB(2) (P=0.006). Higher levels of sTxB(2) associated with greater residual platelet function measured by aggregometry-based methods. Among the randomized subset, sTxB(2) levels were systematically higher among patients receiving enteric-coated aspirin. Last, urinary 11-dehydro thromboxane B(2) did not correlate with sTxB(2), suggesting that the former should not be used to quantitate aspirin's pharmacological effect on platelets. In conclusion, metabolic syndrome, which places patients at high risk for thrombotic cardiovascular events, strongly and uniquely associates with less effective inhibition of platelet COX-1 by aspirin.

TITLE: Effects of probiotics supplementation on the hormone and body mass index in perimenopausal and postmenopausal women using the standardized diet. A 5-week double-blind, placebo-controlled, and randomized clinical study.ABSTRACT: The results of pioneering studies indicate that probiotics can alleviate menopausal symptoms (including cardiometabolic dysfunctions) and improve the quality of life of perimenopausal/postmenopausal women. However, the results of randomized control trials are scarce to evaluate whether the administration of probiotics could affect the balance of sex hormones during the menopause period.In this randomized, double-blind, and placebo-controlled study, 48 perimenopausal and postmenopausal women received multispecies probiotic Sanprobi Barrier in a dose of 2.5 × 109 (CFU) for five weeks. Dietary guidelines were introduced in both groups simultaneously (~1800 kcal/per day, whole grain, no-wheat meals). The study aimed to assess the variations in follicle-stimulating hormone (FSH), estradiol (E2), cortisol (as the hypothalamic-pituitary-ovarian axis hormone), and the body mass during the intervention.At the endpoint, FSH level has increased significantly concerning the baseline after the probiotic intake (31.91 vs. 42.00 mIU/ml; p < 0.009). Also, in the placebo group, a strong trend to elevate FSH was observed (22.31 vs. 41.99 mIU/ml; p = 0.055). Body mass has crucially decreased in reference to the baseline in both groups (PRO: 27.90 vs. 26.30 kg/m2, p<0.001; PBO: 25.90 to 24.60 kg/m2, p<0.001).Probiotics affect FSH levels in perimenopausal women while simultaneously representing a non-invasive strategy to impact hormonal homeostasis. They could potentially have an impact on cardiometabolic health.

TITLE: Efficacy of Preoperative Oral Midodrine in Preventing Hypotension After Spinal Anesthesia in Young Adults: A Randomized Controlled Trial.ABSTRACT: Midodrine was effectively used for prophylaxis against hypotensive syndromes such as postural hypotension and intradialytic hypotension, and during the recovery phase of septic shock. In our study, we aimed to assess the efficacy of prophylactic administration of midodrine tablets before spinal anesthesia in reducing the occurrence of hypotension.This randomized placebo-controlled study embraced 67 patients aged 18 to 40 years undergoing elective knee surgery under spinal anesthesia. Patients were randomized to midodrine group (given 10-mg tablets of midodrine) or placebo group (given placebo tablets), and tablets were administered 1 hour before spinal anesthesia (intrathecal injection of 12.5-mg 0.5% hyperbaric bupivacaine and 15-μg fentanyl). The primary outcome was the occurrence of hypotension, defined as a systolic blood pressure <90 mm Hg or <80% of baseline. Secondary outcomes were hemodynamic characteristics (mean arterial pressure [MAP] and heart rate [HR]) after spinal anesthesia, ephedrine dose, and occurrence of complications including bradycardia, vasovagal attacks, reactive hypertension nausea, vomiting, and shivering.The number of patients who became hypotensive after spinal anesthesia was 5 (14.7%) in midodrine group versus 14 (42.4%) in the placebo group; relative risk (95% confidence interval) was 0.35 (0.14-0.85) ( P = .021). The median (interquartile range) total dose of ephedrine was significantly lower in midodrine group 0 (0-10) mg than in placebo group (0 (0-15) mg; the Hodges-Lehmann median difference (95% confidence interval) was 0 (0-5) mg ( P = .015). For MAP data, the group × time interaction was significant ( P = .038), and the MAP was significantly lower in the placebo group than in the midodrine group after intrathecal injection at 2 minutes ( P = .047), 10 minutes ( P = .045), 15 minutes ( P < .001), 20 minutes ( P = .007), 30 minutes ( P =.013), 45 minutes ( P = .029), 60 minutes ( P = .029), and at the end of surgery ( P < .001). For HR data, the group × time interaction was nonsignificant ( P = .807), and the difference in means (95% confidence interval) between groups collapsing over time was -1.4 (-3.1 to 0.2) beats/min ( P = .096). There was no significant difference between the 2 groups regarding the occurrence of complications.Prophylactic administration of 10-mg midodrine tablets before spinal anesthesia is an effective method in the prevention of hypotension in young adult patients undergoing elective orthopedic knee surgery.

TITLE: A web-based self-care program to promote healthy lifestyles and control blood pressure in patients with primary hypertension: A randomized controlled trial.ABSTRACT: Hypertension is a major risk factor for cardiovascular diseases, which contributes to the worldwide mortality rate. Successful blood pressure control requires adherence to medications and lifestyle modifications. However, motivating patients with primary hypertension to change and sustain behaviors long-term is challenging. A web-based self-care program centered on self-efficacy theory could provide feedback for effective control of blood pressure.To examine the effect of a web-based self-care program for patients with primary hypertension on cardiovascular risk-factors (pulse pressure and lipids), self-efficacy, and self-care behaviors (medication adherence and lifestyle).A two-armed randomized controlled trial with 3-month and 6-month follow-ups.A total of 222 patients with primary hypertension were recruited between February 2017 and August 2018 at a cardiology clinic of a medical center in Taipei, Taiwan.Eligible patients were randomized by permuted block randomization into the intervention group (n = 111) and control group (n = 111). Patients in the intervention group received a 6-month web-based self-care program, based on the theory of self-efficacy, while patients in the control group received usual care. Baseline and outcome measures (3 and 6 months) included self-efficacy, evaluated with the Chinese version of the 6-item Self-Efficacy for Managing Chronic Diseases (SEMC6), self-care, using subscales of the Hypertension Self-Care Activity Level Effects Scale (H-SCALE) for lifestyle and medication adherence, and blood pressure and serum lipid data, collected through web-based self-reports and chart review. Generalized estimating equations evaluated the effects of the intervention.At baseline, the control group had higher scores on the SEMC6, and lower cholesterol (HDL) compared with the intervention group (t = -2.70, p < 0.05; and t = 1.76, p < 0.05, respectively). Pulse pressure decreased significantly (β = -20.30, 95% CI -23.76, -16.83), and serum triglycerides and low-density lipoprotein cholesterol levels were significantly lower compared with controls at 6 months (all p < 0.001). At 6 months, the intervention group had significantly higher mean scores for the SEMC6 compared with the control group (β = 21.84, 95% confidence interval [CI] 19.25, 24.42) and H-SCALE subscale for medication adherence, diet, weight management, and physical activity compared with controls at 6 months (all, p < 0.001).The greatest benefit of this program was allowing participants to immediately consult with the researchers about self-care issues via the website. Lifestyles vary from person to person; therefore, the individuality of each participant was considered when providing feedback. We provided devising interventions for participants that would increase their confidence in self-care for hypertension and ultimately achieve home blood pressure control. We encourage incorporating this program into standard clinical care for patients with hypertension.

TITLE: Use of area under the curve to evaluate the effects of antimalarial drugs on malaria-associated anemia after treatment.ABSTRACT: To evaluate the effects of antimalarial drugs on Plasmodium falciparum malaria-associated anemia, we use the area under the curve (AUC) of anemia levels after treatment as an approach to combine their duration and magnitude. The method involves numeric estimation, by trapezoidal rule, of AUC from a plot of deficit in hematocrit levels from 30% (the lower threshold of normal) versus time in anemic children. Using the method, we evaluated, in randomized trials, the effects of artesunate-mefloquine versus mefloquine alone and artemether-lumefantrine versus amodiaquine-artesunate on the time course of recovery from malaria-associated anemia in 109 children. Anemia resolution times were similar (10.9 ± 6.2 [standard deviation] versus 13.3 ± 8.9 days, P = 0.2), but mean AUC was significantly lower in artesunate-mefloquine- compared with mefloquine-treated children (35.5 ± 7.1 [standard error of mean] versus 49.8 ± 11.3 %·h, P = 0.02) indicating larger exposure to anemia in mefloquine-treated children. In artemether-lumefantrine- and amodiaquine-artesunate-treated children, both anemia resolution times (8.6 ± 5.3 [standard deviation] versus 8.6 ± 4.8 days, P = 0.98) and mean AUC (57.1 ± 12.9 [standard error of mean] versus 46.3 ± 8.7 %·h, P = 0.74) were similar. Estimation of AUC appears more robust than estimation of anemia resolution time in evaluating antimalarial drug effects and can be used in both observational studies and clinical trials assessing the effects of therapies on malaria-associated anemia.

TITLE: Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy.ABSTRACT: To examine the safety and efficacy of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone.Treatment-naive patients or those receiving metformin, sulfonylurea, or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone. They were then randomized, along with patients previously receiving pioglitazone ≥30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10 mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA(1c) change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24. Primary analysis was based on ANCOVA model using last observation carried forward; all remaining analyses used repeated-measures analysis.At week 24, the mean reduction from baseline in HbA(1c) was -0.42% for placebo versus -0.82 and -0.97% for dapagliflozin 5 and 10 mg groups, respectively (P = 0.0007 and P < 0.0001 versus placebo). Patients receiving pioglitazone alone had greater weight gain (3 kg) than those receiving dapagliflozin plus pioglitazone (0.7-1.4 kg) at week 48. Through 48 weeks: hypoglycemia was rare; more events suggestive of genital infection were reported with dapagliflozin (8.6-9.2%) than placebo (2.9%); events suggestive of urinary tract infection showed no clear drug effect (5.0-8.5% for dapagliflozin and 7.9% for placebo); dapagliflozin plus pioglitazone groups had less edema (2.1-4.3%) compared with placebo plus pioglitazone (6.5%); and congestive heart failure and fractures were rare.In patients with type 2 diabetes inadequately controlled on pioglitazone, the addition of dapagliflozin further reduced HbA(1c) levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk.

TITLE: Effect of amlodipine + candesartan on cardiovascular events in hypertensive patients with coronary artery disease (from The Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease [HIJ-CREATE] Study).ABSTRACT: Combination therapy with calcium channel blockers and angiotensin II receptor blockers is recommended as one of the effective therapies for hypertension. However, it remains unclear whether this combination reduces major adverse cardiovascular events (MACEs) in patients with hypertension with coronary artery disease (CAD). The purpose of the present study was to examine the effects of amlodipine plus candesartan on MACEs in patients with hypertension with CAD. The study population was drawn from The Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE), which was a multicenter, prospective, randomized controlled trial including 2,049 patients with hypertension with angiographically documented CAD. Subgroup analysis was performed in patients treated with amlodipine at baseline (n = 388). The median follow-up period was 4.3 years. Treatment using amlodipine plus candesartan reduced the risk for MACEs by 39% (p = 0.015) compared to that using amlodipine without angiotensin II receptor blockers. Among the individual events constituting MACEs, the incidence of unstable angina pectoris requiring hospitalization was significantly lower, by 52% (p = 0.007). In conclusion, amlodipine plus candesartan demonstrated a more favorable effect on reducing cardiovascular events in patients with hypertension with CAD compared to amlodipine-based therapy without candesartan.

TITLE: The alteration of aspart insulin pharmacodynamics when mixed with detemir insulin.ABSTRACT: Mixing rapid acting insulin analogs with detemir insulin to minimize daily injections has been adopted as a common regimen, especially for some children with type 1 diabetes, despite the manufacturing company's caution against mixing these analogs in the same syringe. The effect of this practice on the pharmacodynamics (PD) of rapid-acting insulin has not been widely studied. This crossover, randomized study was undertaken to determine whether mixing aspart with detemir insulin has an adverse effect on the early glucodynamic action of rapid-acting insulin analog in humans.Eight adolescents with type 1 diabetes (age 17.3 ± 0.6 years and A1C 7.3 ± 0.3%) had two euglycemic glucose clamps during which 0.2 units/kg aspart and 0.4 units/kg detemir insulin were injected either as a separate or single mixed injection in random order.Mixing the two insulins diminished the peak and overall early aspart insulin action with significantly lower maximum glucose infusion rate (GIR(max) separate 6.1 ± 0.7 mg/kg/min vs. mix 4.5 ± 0.5 mg/kg/min; P = 0.03) values and the area under curve for GIR during the first 3 h of the insulin action study (separate 757 ± 105 mg/kg vs. mix 491 ± 66 mg/kg; P = 0.04).These data demonstrate that mixing aspart with detemir insulin markedly lowers the early PD action of aspart and prolongs its time-action profile as compared with the separate injection of these analogs. These changes in insulin PD should be weighed against the added convenience of mixing when considering such unlicensed use of these insulins in youth with type 1 diabetes.

TITLE: Laparoscopic versus open approach for aortobifemoral bypass for severe aorto-iliac occlusive disease--a multicentre randomised controlled trial.ABSTRACT: To investigate differences between open and laparoscopic aortobifemoral bypass surgery for aorto-iliac occlusive disease on postoperative morbidity and mortality.A multicentre randomised controlled trial.Between January 2007 and November 2009, 28 patients with severe aorto-iliac occlusive disease (TASC II C or D) were randomised between laparoscopic and open approach at one community hospital and one university hospital (TASC = Trans-Atlantic Inter-Society Consensus on the Management of Peripheral Arterial Disease).The operation time was longer for the laparoscopic approach (mean 4 h 19 min (2 h 00 min to 6 h 20 min) vs. 3 h 30 min (1 h 42 min to 5 h 11 min); p = 0.101)). Nevertheless, postoperative recovery and in-hospital stay were significantly shorter after laparoscopic surgery. Also oral intake could be restarted earlier (mean 20 h 34 min (6 h 00 min to 26 h 55 min) vs. 43 h 43 min (19 h 40 min to 77 h 30 min); p = 0.00014)) as well as postoperative mobilisation (walking) (mean 46 h 15 min (16 h 07 min to 112 h 40 min) vs. mean 94 h 14 min (66 h 10 min to 127 h 23 min); p = 0.00016)). Length of hospitalisation was shorter (mean 5.5 days (2.5-15) vs. mean 13.0 days (7-45); p = 0.0095)). Visual pain scores and visual discomfort scores were both lower after laparoscopic surgery. Also return to normal daily activities was achieved earlier. There were no major complications in both groups.Laparoscopic aortobifemoral bypass surgery for aorto-iliac occlusive disease is a safe procedure with a significant decrease in postoperative morbidity and in-hospital stay and earlier recovery.

TITLE: Early statin treatment prior to primary PCI for acute myocardial infarction: REPERATOR, a randomized placebo-controlled pilot trial.ABSTRACT: The aim of this pilot study was to determine whether early atorvastatin treatment will reduce left ventricle (LV) remodeling, infarct size, and improve microvascular perfusion.In animal studies, early statin therapy reduces reperfusion injury after a percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).Forty-two consecutive patients (82% male, mean age 61.2 ± 9.8) who underwent a primary PCI for a first ST-elevated AMI were randomized for pretreatment with atorvastatin 80 mg (n = 20) or placebo (n = 22) and continued with the same dosage daily for 1 week. All patients received atorvastatin 80 mg once daily 7 days after primary PCI. The LV function and infarct size were measured by magnetic resonance imaging within 1 day, at 1 week, and 3 months follow up. The primary endpoint was the end-systolic volume index (ESVI) at 3 months. Secondary endpoints were global LV function measurements, myocardial infarct size, biochemical cardiac markers, TIMI flow, and ST-T elevation resolution.ESVI 3 months after AMI was 25.1 mL/m(2) in the atorvastatin arm and 25.0 mL/m(2) in the placebo arm (P = 0.74). The differences in change from baseline to 3 months follow up in global LV function and myocardial infarct size did not differ between both treatment arms. Furthermore, biochemical markers, TIMI flow, and ST-T elevation resolution did not differ between atorvastatin and placebo arm.In this pilot study, pretreatment with atorvastatin in an acute myocardial infarction does not result in an improved cardiac function, microvascular perfusion, or decreased myocardial infarct size.

TITLE: The powerful pre-treatment effect: placebo responses in restless legs syndrome trials.ABSTRACT: To investigate whether dopaminergic pre-treatment alters placebo and dopamine agonist responses in restless legs syndrome (RLS).Two large, multi-centre trials (SP790 and SP792; registration numbers NCT00136045 and NCT00135993) on the efficacy of rotigotine in RLS reported supplemental International RLS (IRLS) sum score data for pre-treated and drug-naïve patients, allowing for the estimation of the regression slope of the clinical response (change in the IRLS sum score) on baseline IRLS sum score.In both trials, patients pre-treated with dopaminergic medications tended to have blunted responses after placebo administration compared with drug-naïve patients. In the SP790 study, the pre-treated group had a negative slope (i.e. the response observed after placebo administration decreased as the baseline IRLS sum score increased), whereas the slope was positive in drug-naïve patients (slope, -0.43 vs. 0.28; P = 0.027). In the SP792 study, the two slopes were parallel (P = 0.84), but the magnitude of the response after placebo administration was smaller in the pre-treated group (6.31 vs. 10.49; P = 0.0089). Pre-treatment had no significant effect on rotigotine-group responses in either of the two studies.In RLS trials, dopaminergic pre-treatment tends to increase the apparent effect of new dopaminergic drugs by decreasing the placebo effect in the placebo arm without substantially modifying the placebo effect in the active treatment arm. This observation highlights that placebo-controlled trials are not necessarily placebo-effect controlled trials.

TITLE: Red meat consumption and risk of heart failure in male physicians.ABSTRACT: Heart failure (HF) remains a major public health issue. Red meat and dietary heme iron have been associated with an increased risk of coronary heart disease and hypertension, two major risk factors for HF. However, it is not known whether red meat intake influences the risk of HF. We therefore examined the association between red meat consumption and incident HF.We prospectively studied 21,120 apparently healthy men (mean age 54.6 y) from the Physicians' Health Study (1982-2008). Red meat was assessed by an abbreviated food questionnaire and incident HF was ascertained through annual follow-up questionnaires. We used Cox proportional hazard models to estimate hazard ratios. In a multivariable model, there was a positive and graded relation between red meat consumption and HF [hazard ratio (95% CI) of 1.0 (reference), 1.02 (0.85-1.22), 1.08 (0.90-1.30), 1.17 (0.97-1.41), and 1.24 (1.03-1.48) from the lowest to the highest quintile of red meat, respectively (p for trend 0.007)]. This association was observed for HF with (p for trend 0.035) and without (p for trend 0.038) antecedent myocardial infarction.Our data suggest that higher intake of red meat is associated with an increased risk of HF.

TITLE: Long-term effects of pioglitazone on carotid atherosclerosis in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity.ABSTRACT: No previous studies have evaluated the long-term anti-atherosclerotic effects of pioglitazone in Asian patients with type 2 diabetes. Therefore, the present study investigated the protective effects of pioglitazone on the progression of carotid intima-media thickness (IMT), an established surrogate marker of cardiovascular events in Japanese type 2 diabetic patients without a recent history of cardiovascular morbidity.This 2.5-4-year, randomized, open-label, blinded endpoint study was conducted in 6 centers across Japan. Patients received pioglitazone with or without other oral glucose-lowering drugs (excluding another thiazolidinedione) (n=89) or oral glucose-lowering drugs, excluding thiazolidinediones (n=97). Treatment was adjusted to achieve HbA(1c) <6.5%. The primary endpoints of the study were the absolute changes from the baseline to final visit in max- and mean-IMT in the average of bilateral common carotid arteries.Pioglitazone induced carotid IMT regression compared to baseline measurements (from 1.060 ± 0.2368 to 0.992 ± 0.1921 mm; p=0.0042 in max-IMT and from 0.839 ± 0.1873 to 0.780 ± 0.1571 mm; p=0.0019 in mean-IMT). Although the between-group difference did not reach statistical significance, the regression of carotid IMT values was greater in the pioglitazone-treatment group than in the non-pioglitazone group, (max-IMT: -0.069 ± 0.2199 mm vs -0.031 ± 0.2327 mm, respectively; p=NS, mean-IMT: -0.058 ± 0.1718 mm vs -0.043 ± 0.1644 mm, respectively; p=NS).Pioglitazone induced and maintained the long-term regression of carotid IMT in Japanese type 2 diabetic patients. This suggests that pioglitazone may inhibit the progression of atherosclerosis in this patient group. Further studies are required to verify these findings.

TITLE: Quality of life in hormone receptor-positive HER-2+ metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib.ABSTRACT: A phase III trial compared lapatinib plus letrozole (L + Let) with letrozole plus placebo (Let) as first-line therapy for hormone receptor (HR)(+) metastatic breast cancer (MBC) patients. The primary endpoint of progression-free survival (PFS) in patients whose tumors were human epidermal growth factor receptor (HER)-2(+) was significantly longer for L + Let than for Let (8.2 months versus 3 months; p = .019). This analysis focuses on quality of life (QOL) in the HER-2(+) population.QOL was assessed at screening, every 12 weeks, and at withdrawal using the Functional Assessment of Cancer Therapy-Breast (FACT-B). Changes from baseline were analyzed and the proportions of patients achieving minimally important differences in QOL scores were compared. Additional exploratory analyses evaluated how QOL changes reflected tumor progression status.Among the 1,286 patients randomized, 219 had HER-2(+) tumors. Baseline QOL scores were comparable in the two arms. Mean changes in QOL scores were generally stable over time for patients who stayed on study. The average change from baseline on the FACT-B total score in both arms was positive at all scheduled visits through week 48. There was no significant difference between the two treatment arms in the percentage of QOL responders.The addition of lapatinib to letrozole led to a significantly longer PFS interval while maintaining QOL during treatment, when compared with letrozole alone, thus confirming the clinical benefit of the combination therapy in the HR(+) HER-2(+) MBC patient population. This all oral regimen provides an effective option in this patient population, delaying the need for chemotherapy and its accompanying side effects.

TITLE: Comparison of Vie Scope® and Macintosh laryngoscopes for intubation during resuscitation by paramedics wearing personal protective equipment.ABSTRACT: Endotracheal intubation (ETI) is still the gold standard of airway management, but in cases of sudden cardiac arrest in patients with suspected SARS-CoV-2 infection, ETI is associated with risks for both the patient and the medical personnel. We hypothesized that the Vie Scope® is more useful for endotracheal intubation of suspected or confirmed COVID-19 cardiac arrest patients than the conventional laryngoscope with Macintosh blade when operators are wearing personal protective equipment (PPE).Study was designed as a prospective, multicenter, randomized clinical trial performed by Emergency Medical Services in Poland. Patients with suspected or confirmed COVID-19 diagnosis who needed cardiopulmonary resuscitation in prehospital setting were included. Patients under 18 years old or with criteria predictive of impossible intubation under direct laryngoscopy, were excluded. Patients were randomly allocated 1:1 to Vie Scope® versus direct laryngoscopy with a Macintosh blade. Study groups were compared on success of intubation attempts, time to intubation, glottis visualization and number of optimization maneuvers.We enrolled 90 out-of-hospital cardiac arrest (OHCA) patients, aged 43-92 years. Compared to the VieScope® laryngoscope, use of the Macintosh laryngoscope required longer times for tracheal intubation with an estimated mean difference of -48 s (95%CI confidence interval [CI], -60.23, -35.77; p < 0.001). Moreover VieScope® improved first attempt success rate, 93.3% vs. 51.1% respectively (odds ratio [OR] = 13.39; 95%CI: 3.62, 49.58; p < 0.001).The use of the Vie Scope® laryngoscope in OHCA patients improved the first attempt success rate, and reduced intubation time compared to Macintosh laryngoscope in paramedics wearing PPE for against aerosol generating procedures.ClinicalTrials registration number NCT04365608.

TITLE: Pansomatostatin Agonist Pasireotide Long-Acting Release for Patients with Autosomal Dominant Polycystic Kidney or Liver Disease with Severe Liver Involvement: A Randomized Clinical Trial.ABSTRACT: We assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy.Individuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life.Of 48 subjects randomized, 41 completed total liver volume measurements (=29 pasireotide long-acting release and =12 placebo). From baseline, there were -99±189 ml/m absolute and -3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo (<0.001 for both). Total kidney volumes decreased by -12±34 ml/m and -1%±4% in pasireotide long-acting release compared with 21±21 ml/m and 4%±5% increase in the placebo group (=0.05 for both). Changes in eGFR were similar between groups. Among the =48 randomized, adverse events included hyperglycemia (26 of 33 [79%] in pasireotide long-acting release versus four of 15 [27%] in the placebo group; <0.001), and among the 47 without diabetes at baseline, 19 of 32 (59%) in the pasireotide long-acting release group versus one of 15 (7%) in the placebo group developed diabetes (=0.001).Another somatostatin analog, pasireotide long-acting release, slowed progressive increase in both total liver volume/total kidney volume growth rates without affecting GFR decline. Participants experienced higher frequency of adverse events (hyperglycemia and diabetes).Pasireotide LAR in Severe Polycystic Liver Disease, NCT01670110 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_08_28_CJN13661119.mp3.

TITLE: Comparative study of cisplatin-based definitive concurrent chemoradiotherapy with S-1 versus paclitaxel for unresectable locally advanced esophageal squamous cell carcinoma.ABSTRACT: This study compared the efficiency and safety of definitive concurrent chemoradiotherapy (CCRT) using Paclitaxel plus Cisplatin (TP) versus S-1 plus Cisplatin (CS) in unresectable locally advanced esophageal squamous cell carcinoma (LAESCC). Between January 2009 and December 2013, 203 LAESCC patients were retrospectively reviewed. We performed a propensity score matching analysis; 41 patients treated with the CS regimen were matched 1:1 to patients who received the TP regimen. Patient- and disease-related characteristics were well-balanced between the two groups. The CS group showed significantly better treatment compliance (90.2% vs. 70.7%, P = 0.026) and less hospital stay (48 days vs 49 days, P = 0.025) over the TP group during the CCRT course. The complete response rate was comparable between the two groups (51.2% vs. 48.8%, P = 0.825). The 1- and 3-year overall survival (OS) rates in the TP group were 63.4% and 32.4% compared to 62.8% and 32.1% in the CS group, respectively (P = 0.796). The 1- and 3-year progression-free survival (PFS) rates in the TP group were 51.2% and 24.9%, compared to 53.6% and 18.9% in the CS group, respectively (P = 0.630). The incidence of severe and total neutropenia in the TP group was significantly higher compared to the CS group (P = 0.011 and 0.046, respectively). Multivariate analysis revealed that T stage and the complete response rate were strong prognostic factors associated with OS and PFS. In conclusion, both treatment regimens yielded satisfactory survival outcomes, but the CS regimen could significantly improve treatment compliance, reduce hematological toxicities and lengths of hospital stay. Future prospective studies in large cohorts are highly warranted to confirm the findings in our report.

TITLE: Pseudophakic cystoid macular edema prevention and risk factors; prospective study with adjunctive once daily topical nepafenac 0.3% versus placebo.ABSTRACT: Define the effectiveness of a topical non-steroidal anti-inflammatory drug (NSAID) added to topical steroid use after uncomplicated phacoemulsification for the prevention of pseudophakic cystoid macular edema (PCME) using a prospective, randomized, double-masked, placebo-controlled clinical study.Eyes (1000) were randomized to placebo (497) or nepafenac 0.3% (503) used once daily, post-operatively for 5 weeks at two ophthalmology clinics. Diagnosis of PCME was made by clinical, ocular coherence tomography (OCT), and with fluorescein angiography confirmation. Correlation of PCME to NSAID use and the presence of pre-operative risk factors for PCME were assessed including, contralateral PCME, diabetic retinopathy, retinal vein occlusion, macular hole, epiretinal membrane, macular degeneration, retinal detachment repair, and prostaglandin use.PCME was the most common complication associated with routine cataract surgery (4.2% with PCME risk factors, 2.0% with risk factors excluded). Topical nepafenac 0.3% significantly reduces the incidence of PCME compared to placebo when used after routine cataract surgery (p = .0001). When patients with pre-operative risk factors are excluded, the incidence of PCME between treatment and placebo groups is equivalent (p = 0.31). PCME relative risk (RR) was most significant in contralateral PCME (RR 19.5), diabetic retinopathy (RR 13.1), retinal vein occlusion (RR 12.9), macular hole (RR 7.7), and epiretinal membrane (RR 5.7). Prostaglandin use and previous retinal detachment were not shown to increase risk.Pseudophakic cystoid macular edema is common after phacoemulsification cataract surgery. Topical nepafenac 0.3% reduces PCME in patients with pre-operative risk factors for PCME compared to placebo but shows no benefit in patients without pre-operative risk factors.NIH ClincalTrials.gov retrospectively registered January 15, 2017, NCT03025945 .

TITLE: Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial.ABSTRACT: To evaluate the effect of simultaneous zinc and vitamin A supplementation on diarrhoea and acute lower respiratory infections in children.Randomised double blind placebo controlled trial.Urban slums of Dhaka, Bangladesh.800 children aged 12-35 months were randomly assigned to one of four intervention groups: 20 mg zinc once daily for 14 days; 200 000 IU vitamin A, single dose on day 14; both zinc and vitamin A; placebo. The children were followed up once a week for six months, and morbidity information was collected.The incidence and prevalence of diarrhoea were lower in the zinc and vitamin A groups than in the placebo group. Zinc and vitamin A interaction had a rate ratio (95% confidence interval) of 0.79 (0.66 to 0.94) for the prevalence of persistent diarrhoea and 0.80 (0.67 to 0.95) for dysentery. Incidence (1.62; 1.16 to 2.25) and prevalence (2.07; 1.76 to 2.44) of acute lower respiratory infection were significantly higher in the zinc group than in the placebo group. The interaction term had rate ratios of 0.75 (0.46 to 1.20) for incidence and 0.58 (0.46 to 0.73) for prevalence of acute lower respiratory infection.Combined zinc and vitamin A synergistically reduced the prevalence of persistent diarrhoea and dysentery. Zinc was associated with a significant increase in acute lower respiratory infection, but this adverse effect was reduced by the interaction between zinc and vitamin A.

TITLE: Follow-up Schedule for Patients With Sentinel Node-negative Cutaneous Melanoma (The MELFO Study): An International Phase III Randomized Clinical Trial.ABSTRACT: The MELFO (MELanoma FOllow-up) study is an international phase III randomized controlled trial comparing an experimental low-intensity schedule against current national guidelines.Evidence-based guidelines for the follow-up of sentinel node-negative melanoma patients are lacking.Overall, 388 adult patients diagnosed with sentinel node-negative primary melanoma patients were randomized in cancer centers in the Netherlands and United Kingdom between 2006 and 2016. The conventional schedule group (control: n=196) was reviewed as per current national guidelines. The experimental schedule group (n=192) was reviewed in a reduced-frequency schedule. Quality of life was the primary outcome measurement. Detection rates and survival outcomes were recorded. Patient satisfaction rates and compliance with allocated schedules were compared.At 5 years, both arms expressed high satisfaction with their regimens (>97%). This study found no significant group effect on any patient-reported outcome measure scores between the follow-up protocols. In total, 75/388 (19.4%) patients recurred, with no difference in incidence found between the 2 arms (hazard ratio=0.87, 95% confidence interval: 0.54-1.39, P =0.57). Self-examination was the method of detection for 25 experimental patients and 32 control patients (75.8% vs. 76.2%; P =0.41). This study found no difference in any survival outcomes between the 2 study arms (disease-free survival: hazard ratio=1.00, 95% confidence interval: 0.49-2.07, P =0.99).A reduced-intensity, American Joint Committee on Cancer (AJCC) stage-adjusted follow-up schedule for sentinel node-negative melanoma patients is a safe strategy, and patient self-examination is effective for recurrence detection with no evidence of diagnostic delay. Patients' acceptance is very high.

TITLE: Effects of vatinoxan in dogs premedicated with medetomidine and butorphanol followed by sevoflurane anaesthesia: a randomized clinical study.ABSTRACT: To investigate effects of vatinoxan in dogs, when administered as intravenous (IV) premedication with medetomidine and butorphanol before anaesthesia for surgical castration.A randomized, controlled, blinded, clinical trial.A total of 28 client-owned dogs.Dogs were premedicated with medetomidine (0.125 mg m) and butorphanol (0.2 mg kg) (group MB; n = 14), or medetomidine (0.25 mg m), butorphanol (0.2 mg kg) and vatinoxan (5 mg m) (group MB-VATI; n = 14). Anaesthesia was induced 15 minutes later with propofol and maintained with sevoflurane in oxygen (targeting 1.3%). Before surgical incision, lidocaine (2 mg kg) was injected intratesticularly. At the end of the procedure, meloxicam (0.2 mg kg) was administered IV. The level of sedation, the qualities of induction, intubation and recovery, and Glasgow Composite Pain Scale short form (GCPS-SF) were assessed. Heart rate (HR), respiratory rate (f), mean arterial pressure (MAP), end-tidal concentration of sevoflurane (Fe'Sevo) and carbon dioxide (Pe'CO) were recorded. Blood samples were collected at 10 and 30 minutes after premedication for plasma medetomidine and butorphanol concentrations.At the beginning of surgery, HR was 61 ± 16 and 93 ± 23 beats minute (p = 0.001), and MAP was 78 ± 7 and 56 ± 7 mmHg (p = 0.001) in MB and MB-VATI groups, respectively. No differences were detected in f, Pe'CO, Fe'Sevo, the level of sedation, the qualities of induction, intubation and recovery, or in GCPS-SF. Plasma medetomidine concentrations were higher in group MB-VATI than in MB at 10 minutes (p = 0.002) and 30 minutes (p = 0.0001). Plasma butorphanol concentrations were not different between groups.In group MB, HR was significantly lower than in group MB-VATI. Hypotension detected in group MB-VATI during sevoflurane anaesthesia was clinically the most significant difference between groups.

TITLE: Interactive Inpatient Asthma Education: A Randomized Controlled Trial.ABSTRACT: Inpatient asthma education interventions provide benefit compared with usual care, but evaluation of the most effective educational model is needed. We compared the impact of interactive versus didactic inpatient pediatric asthma education on subsequent emergency department (ED) visits and hospitalizations.Children (aged 2‒16) with asthma admitted to a tertiary care children's hospital with an asthma exacerbation between October 2016 and June 2017 were randomly assigned to interactive or didactic (control) asthma education. The primary outcome was asthma ED visits at 6 and 12 months; secondary outcomes included hospitalizations (6 and 12 months), inhaler technique, asthma knowledge, symptoms, quality of life, and parental management skills at baseline, discharge, and/or 12 months.One hundred forty participants (69 interactive, 71 control) completed the study. There were no differences in ED visits at 6 or 12 months. Compared to controls, the interactive group had fewer hospitalizations (10.1% vs 22.5%; P = .04) at 6 months. Inhaler technique in the interactive group improved at discharge (mean change 4.07 [95% confidence interval (CI): 3.21-4.94]) and remained increased at 12 months (P = .03). Patient-reported asthma symptoms and quality of life were similar in both groups at baseline (19.9 vs 20.62, best possible score 8) and significantly improved in the interactive group at 12 months (least square mean change, 3.52 vs -1.75; P < .01).There were no differences in ED visits; however, the interactive education reduced asthma hospitalizations over a 6-month period. These findings demonstrate that educational delivery methods can play a role in improving clinical outcomes for asthma.

TITLE: Efficacy of 4.0 mg versus 0.4 mg Folic Acid Supplementation on the Reproductive Outcomes: A Randomized Controlled Trial.ABSTRACT: Folic acid (FA) supplementation prevents neural tube defects (NTDs), but the effects on other reproductive outcomes are unclear. While common recommendation is 0.4 mg/day in addition to regular nutrition, the most appropriate dose of FA is still under debate. We investigated the effects of a higher dose of periconception FA on reducing adverse reproductive outcomes. In this multicenter double-blind randomized controlled trial (RCT), 1060 women (aged 18-44 years and planning a pregnancy) were randomly assigned to receive 4.0 mg or 0.4 mg of FA daily. The primary outcome was the occurrence of congenital malformations (CMs). A composite outcome including one or more adverse pregnancy outcomes was also evaluated. A total of 431 women had a natural conception within 1 year. The primary outcome occurred in 8/227 (3.5%) women receiving 4.0 mg FA and 9/204 (4.4%) women receiving 0.4 mg FA (RR 0.80; 95%CI 0.31 to 2.03). The composite outcome occurred in 43/227 (18.9%) women receiving 4.0 mg FA and 75/204 (36.8%) women receiving 0.4 mg FA (RR 0.51; 95%CI 0.40 to 0.68). FA 4.0 mg supplementation was not associated with different occurrence of CMs, compared to FA 0.4 mg supplementation. However, FA 4.0 mg supplementation was associated with lower occurrence of other adverse pregnancy outcomes.

TITLE: Incidence and predictors of surgical site infection in women who are obese and give birth by elective caesarean section: A secondary analysis.ABSTRACT: Surgical site infection (SSI) after a caesarean section is of concern (CS) is of concern to both clinicians and women themselves.The aim of this study is to identify the cumulative incidence and predictors of SSI in women who are obese and give birth by elective CS.The method used was planned secondary analysis of data from women with a pre-pregnancy body mass index (BMI) ≥30 kg/m giving birth by elective CS in a multicentre randomised controlled trial of a prophylactic closed-incision negative pressure wound therapy dressing. Data were collected from medical records, direct observations of the surgical site and self-reported signs and symptoms from October 2015 to December 2019. The Centers for Disease Control and Prevention definition was used to identify SSI. Women were followed up once in hospital just before discharge and then weekly for four weeks after discharge. Blinded outcome assessors determined SSI. After the cumulative incidence of SSI was calculated, multiple variable logistic regression models were used to identify independent risk factors for SSI.SSI incidence in 1459 women was 8.4% (122/1459). Multiple variable-adjusted odds ratios (OR) for SSI were BMI ≥40 kg/m (OR 1.55, 95% confidence interval (CI) 1.30-1.86) as compared to BMI 30-34.9 0 kg/m , ≥2 previous pregnancies (OR 1.38, 95% CI 1.00-1.80) as compared to no previous pregnancies and pre-CS vaginal cleansing (OR 0.55, 95% CI 0.33-0.99).Our findings may inform preoperative counselling and shared decision-making regarding planned elective CS for women with pre-pregnancy BMI ≥30 kg/m .

TITLE: Peanuts or an Isocaloric Lower Fat, Higher Carbohydrate Nighttime Snack Have Similar Effects on Fasting Glucose in Adults with Elevated Fasting Glucose Concentrations: a 6-Week Randomized Crossover Trial.ABSTRACT: The glycemic effects of peanuts are not well studied and no trials have been conducted in adults with elevated fasting plasma glucose (FPG). Furthermore, intake of peanuts as a nighttime snack, an eating occasion affecting FPG, has not been examined.The aim was to determine the effect of consuming 28 g/d of peanuts as a nighttime snack for 6 wk on glycemic control and cardiovascular disease risk factors, compared with an isocaloric lower fat, higher carbohydrate (LFHC) snack (whole grain crackers and low-fat cheese), in adults with elevated FPG.In a randomized crossover trial, 50 adults (FPG 100 ± 8 mg/dL) consumed dry roasted, unsalted peanuts [164 kcal; 11% energy (E) carbohydrate, 17% E protein, and 73% E fat] or a LFHC snack (164 kcal; 54% E carbohydrate, 17% E protein, and 33% E fat) in the evening (after dinner and before bedtime) for 6 wk with a 4-wk washout period. Primary (FPG) and secondary end points [Healthy Eating Index-2015 (HEI-2015), weight, insulin, fructosamine, lipids/lipoproteins, central and peripheral blood pressure, and pulse wave velocity] were evaluated at the beginning and end of each condition. Linear mixed models were used for data analysis.FPG was not different between the peanut and LFHC conditions (end point mean difference: -0.6 mg/dL; 95% CI: -2.7, 1.6; P = 0.67). There were no between-condition effects for secondary cardiometabolic endpoints. The HEI-2015 score was not different between the conditions (3.6 points; P = 0.19), although the seafood/plant protein (2.0 points; P < 0.01) and added sugar (0.8 points; P = 0.04) components were improved following peanut intake. The whole grain component was lower with peanuts compared with LFHC (-2.6 points; P < 0.01).In adults with elevated FPG, peanuts as a nighttime snack (28 g/d) did not affect FPG compared with an isocaloric LFHC snack after 6 wk.This trial was registered at clinicaltrials.gov as NCT03654651.

TITLE: Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.ABSTRACT: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear.We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed.Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

TITLE: Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma.ABSTRACT: A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma.The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma.In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period.Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P <.001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo.The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.

TITLE: Efficacy and Safety of Intensive Versus Nonintensive Supplemental Insulin With a Basal-Bolus Insulin Regimen in Hospitalized Patients With Type 2 Diabetes: A Randomized Clinical Study.ABSTRACT: Administration of supplemental sliding scale insulin for correction of hyperglycemia in non-intensive care unit (ICU) patients with type 2 diabetes is frequently used with basal-bolus insulin regimens. In this noninferiority randomized controlled trial we tested whether glycemic control is similar with and without aggressive sliding scale insulin treatment before meals and bedtime in patients treated with basal-bolus insulin regimens.Patients with type 2 diabetes with admission blood glucose (BG) 140-400 mg/dL treated with basal-bolus insulin were randomized to intensive (correction for BG >140 mg/dL, n = 108) or to nonintensive (correction for BG >260 mg/dL, n = 107) administration of rapid-acting sliding scale insulin before meals and bedtime. The groups received the same amount of sliding scale insulin for BG >260 mg/dL. Primary outcome was difference in mean daily BG levels between the groups during hospitalization.Mean daily BG in the nonintensive group was noninferior to BG in the intensive group with equivalence margin of 18 mg/dL (intensive 172 ± 38 mg/dL vs. nonintensive 173 ± 43 mg/dL, P = 0.001 for noninferiority). There were no differences in the proportion of target BG readings of 70-180 mg/dL, <70 or <54 mg/dL (hypoglycemia), or >350 mg/dL (severe hyperglycemia) or total, basal, or prandial insulin doses. Significantly fewer subjects received sliding scale insulin in the nonintensive (n = 36 [34%]) compared with the intensive (n = 98 [91%] [P < 0.0001]) group with no differences in sliding scale insulin doses between the groups among those who received sliding scale insulin (intensive 7 ± 4 units/day vs. nonintensive 8 ± 4 units/day, P = 0.34).Among non-ICU patients with type 2 diabetes on optimal basal-bolus insulin regimen with moderate hyperglycemia (BG <260 mg/dL), a less intensive sliding scale insulin treatment did not significantly affect glycemic control.

TITLE: Effects of luseogliflozin on estimated plasma volume in patients with heart failure with preserved ejection fraction.ABSTRACT: Sodium glucose co-transporter 2 inhibitors have diuretic effects in both patients with glycosuria and with natriuresis. We sought to assess the effect of luseogliflozin on estimated plasma volume (ePV) in patients with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF).This study was a post-hoc analysis of the MUSCAT-HF trial (UMIN000018395), a multicentre, prospective, open-label, randomized controlled trial that assessed the effect of 12 weeks of luseogliflozin (2.5 mg, once daily, n = 83) as compared with voglibose (0.2 mg, three times daily, n = 82) on the reduction in brain natriuretic peptide (BNP) in patients with type 2 diabetes and HFpEF. The analysis compared the change in ePV calculated by the Straus formula from baseline to Weeks 4, 12, and 24, using a mixed-effects model for repeated measures. We also estimated the association between changes in ePV and changes in other clinical parameters, including BNP levels. Luseogliflozin significantly reduced ePV as compared to voglibose at Week 4 {adjusted mean group-difference -6.43% [95% confidence interval (CI): -9.11 to -3.74]}, at Week 12 [-8.73% (95%CI: -11.40 to -6.05)], and at Week 24 [-11.02% (95%CI: -13.71 to -8.33)]. The effect of luseogliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in ePV at Week 12 was significantly associated with log-transformed BNP (r = 0.197, P = 0.015) and left atrial volume index (r = 0.283, P = 0.019).Luseogliflozin significantly reduced ePV in patients with type 2 diabetes and HFpEF, as compared with voglibose. The reduction of intravascular volume by luseogliflozin may provide clinical benefits to patients with type 2 diabetes and HFpEF.

TITLE: Misoprostol and oxytocin versus oxytocin alone in the active management of the third stage of labour: a randomised, double-blind, placebo-controlled trial.ABSTRACT: We investigated whether the use of misoprostol plus oxytocin in the active management of the third of stage of labour (AMTSL) would reduce the rate of primary postpartum haemorrhage (PPH) compared with intramuscular oxytocin alone. This was a multicentre, double-blind, placebo-controlled, randomised trial where 1036 pregnant women, in addition to intramuscular oxytocin (10 IU) in the third stage of labour, randomly received either 400 µg sublingual misoprostol (519 women) or a placebo (517 women). The primary outcome measure was the mean blood loss (MBL) within 1 h of delivery. The trial was registered with ClinicalTrials.gov (NCT02424201). The MBL in the oxytocin plus misoprostol group was 229.73 ± 108.12 compared to 274.58 ± 121.09 in the oxytocin plus placebo group ( = 6.289,  < .001). Twenty-eight (5.4%) women in the misoprostol group had a blood loss ≥500 ml 39 (7.5%) women in the placebo group (risk-ratio [RR] - 0·72, 95%CI 0.45-1.14;  = .1616). The combination of misoprostol with oxytocin in the AMTSL reduces MBL post-delivery but is not superior to oxytocin alone in the reduction of the rate of PPH.IMPACT STATEMENT The routine use of 10IU of intramuscular oxytocin in the active management of the third stage of labour reduces the rates of postpartum haemorrhage. The addition of 400ug of sublingual misoprostol to the routine use of 10IU of intramuscular oxytocin in the active management of the third stage of labour reduces mean blood loss when compared with intramuscular oxytocin alone, but is not better in reducing the rates of postpartum haemorrhage. Routine use of misoprostol as adjuncts to the active management of the third stage of labour does not reduce the rate of PPH.

TITLE: Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.ABSTRACT: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4.In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study.Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all 0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group.GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.

TITLE: Occurrence of hypertension during third-line anlotinib is associated with progression-free survival in patients with squamous cell lung cancer (SCC): A post hoc analysis of the ALTER0303 trial.ABSTRACT: There is a lack of targeted therapeutic options for squamous cell lung cancer (SCC). Accelerated hypertension is an issue with many targeted therapies for lung cancer. This study aimed to analyze the efficacy of anlotinib, based on progression-free survival (PFS) and overall survival (OS) in patients with SCC, stratified by hypertension and Eastern Cooperative Oncology Group (ECOG) score.This was a post hoc analysis of a multicenter, double-blind, phase III ALTER0303 randomized controlled trial. Only patients with SCC were included. The occurrence of hypertension during the study period was defined according to CTCAE 4.03. OS and PFS were the primary and secondary endpoints, respectively. The patients were stratified according to hypertension and ECOG score, respectively.The median PFS in the patients who developed hypertension was longer than in those who did not (7.2 (95% CI: 3.5-11.0) versus 3.2 (95% CI: 1.2-5.3) months, p = 0.001; HR (95% CI), 0.4 (0.2-0.8)). In the ECOG 0 patients, the median PFS in the patients who developed hypertension versus those who did not was 5.6 vs. 1.8 months, respectively (Figure 2(d)). In the ECOG 1 patients, the median PFS in the patients who developed hypertension versus those who did not was 7.0 (95% CI: 3.0-11.0) vs. 4.8 (95% CI: 1.2-8.5) months (p = 0.043). No statistically significant differences were found in OS in the stratified analyses.The occurrence of hypertension might be a clinical indicator predicting the efficacy of third-line anlotinib treatment in patients with SCC.

TITLE: Motivational Interviewing in Preventing Early Childhood Caries in Primary Healthcare: A Community-based Randomized Cluster Trial.ABSTRACT: To assess the effectiveness of motivational interviewing in preventing early childhood caries compared with conventional oral health education.Twelve health care units in southern Brazil were randomly allocated in 2 groups of 6 and professionals in 1 group were trained in motivational interviewing. The mothers/children and external examiners were blinded to the intervention. The data were collected by calibrated examiners using questionnaires and a clinical examination based on modified International Caries Detection and Assessment System criteria. Of the 674 children born in the catchment area in the year 2013, 469 received the intervention (224 in the conventional oral health education group, 245 in the motivational interviewing group), and 320 were examined by the end of the study (145 in the conventional oral health education group, 175 in the motivational interviewing group), with mean age of 30 months. The final follow-up was 68%, after 3 years.Mean of decayed, missing, and filled surfaces at the end of the study period for the whole sample was 1.34 (95% CI 0.97-1.71). The caries rate per 100 surface-year in the conventional oral health education group was 1.74 (95% CI 1.14-2.34) and in the motivational interviewing group, it was 0.92 (95% CI 0.63-1.20). To correct for clustering effect and unbalanced factors, multilevel Poisson regression was fitted and the effect of motivational interviewing on the incidence rate ratio was 0.40 (95% CI 0.21-0.79).An intervention based on the principles of motivational interviewing style was more effective in reducing the number of surfaces affected by early childhood caries compared with conventional oral health education intervention.ClinicalTrials.govNCT02578966, Brazilian Registry of Clinical Trials RBR-8fvwxq.

TITLE: Effectiveness of the population-based 'check your health preventive programme' conducted in a primary care setting: a pragmatic randomised controlled trial.ABSTRACT: Health checks have been suggested as an early detection approach aiming at lowering the risk of chronic disease development. This study aimed to evaluate the effectiveness of a health check programme offered to the general population, aged 30-49 years.The entire population aged 30-49 years (N=26 216) living in the municipality of Randers, Denmark, was invited to a health check during 5 years. A pragmatic household cluster-randomised controlled trial was conducted in 10 505 citizens. The intervention group (IG, N=5250) included citizens randomised to the second year and reinvited in the 5th year. The comparison group (CG, N=5255) included citizens randomised to the 5th year. Outcomes were modelled cardiovascular disease (CVD) risk; self-reported physical activity (PA) and objectively measured cardio respiratory fitness (CRF); self-rated health (short-form 12 (SF-12)), self-rated mental health (SF-12_Mental Component Score (MCS)) and, registry information on sick-leave and employment. Due to low participation, we compared groups matched on propensity scores for participation when reinvited.Participation in the first health check was 51% (N=2698) in the IG and 40% (N=2120) in the CG. In the IG 26% (N=1340) participated in both the first and second health checks. No intervention effects were found comparing IG and CG. Mean differences were (95% CI): modelled CVD risk: -0.052 (95% CI -0.107 to 0.003)%, PA: -0.156 (-0.331 to 0.019) days/week with 30 min moderate PA, CRF: 0.133 (-0.560 to 0.826) mL O/min/kg, SF-12: -0.003 (-0.032 to 0.026), SF-12_MCS: 0.355 (-0.423 to 1.132), sick leave periods ≥3 weeks: -0.004 (-0.025 to 0.017), employment: -0.004 (-0.032 to 0.024).Preventive health checks offered to the general population, aged 30-49 years, had no effects on a wide range of indicators of chronic disease risk.NCT02028195.

TITLE: Prognostic markers compared to CD3+TIL in locally advanced nasopharyngeal carcinoma.ABSTRACT: Locally advanced nasopharyngeal carcinoma (LA-NPC) is more prevalent in some geographic regions, including Saudi Arabia. Typically, Tumor-Node-Metastasis (TNM) staging is used in NPC. However, it is inadequate to assess the prognosis of LA-NPC.Therefore, we analyzed and compared several previously reported prognostic factors in LA-NPC patients, retrospectively, including CD3+tumor-infiltrating lymphocytes (TIL) and peripheral blood hemoglobin, EBV DNA copy number, ratios of albumin-to-alkaline phosphatase ratio (AAPR), neutrophils, or platelets-to-lymphocytes (NLR, PLR). The studied cohort was 83 LA-NPC patients previously recruited for a randomized phase II trial with a different aim.Univariate cox regression analysis showed no significant correlation between any of the tested variables with disease-free survival (DFS) or overall survival (OS) with the exception of low CD3+ TIL infiltration, which correlated significantly with DFS (HR = 6.7, P = <.001) and OS (HR = 9.1, P = .043). Similarly, in a validated multivariate cox regression analysis, only low CD3+ TIL correlated significantly with DFS (HR = 7.0, P < .001 for TIL) and OS (HR = 9.4, P = .040).Among tested parameters, CD3+ TIL was the only independent prognostic marker for DFS and OS in LA-NPC patients treated with CCRT. This study supports the use of CD3+TIL, over other factors, as an independent prognostic factor in LA-NPC.

TITLE: Empagliflozin compared with glimepiride in metformin-treated patients with type 2 diabetes: 208-week data from a masked randomized controlled trial.ABSTRACT: To report results at week 208, including a 104-week masked extension, of the EMPA-REG H2H-SU trial in patients with type 2 diabetes with inadequate glycaemic control on metformin, in which empagliflozin 25 mg given for 104 weeks provided a sustained reduction in glycated haemoglobin (HbA1c) with a small but statistically significant benefit vs glimepiride, sustained reductions in weight and blood pressure, and low risk of hypoglycaemia.Patients with type 2 diabetes and HbA1c 53-86 mmol/mol (7% to 10%) were randomized to empagliflozin 25 mg or glimepiride 1 to 4 mg for 104 weeks as add-on to metformin. Patients who completed the randomized treatment period could participate in a 104-week extension in which they continued the double-blind treatment allocated at randomization.Of 765 and 780 patients treated with empagliflozin and glimepiride, 576 and 549 patients, respectively, entered the extension period of the study. At week 208, the adjusted mean difference in change from baseline in HbA1c with empagliflozin vs glimepiride was -1.96 mmol/mol, 95% CI -3.57, -0.35 (-0.18%, 95% CI -0.33, -0.03); P = 0.0172. Rescue therapy was given to 23% of patients on empagliflozin and 34% on glimepiride (odds ratio 0.56 [95% CI 0.45, 0.71]; P < 0.0001). Confirmed hypoglycaemic adverse events (plasma glucose ≤3.9 mmol/L and/or requiring assistance) occurred in 3% of patients on empagliflozin and 28% on glimepiride (odds ratio 0.08 [95% CI 0.05, 0.13]; P < 0.0001).In patients with type 2 diabetes, empagliflozin 25 mg as add-on to metformin for 208 weeks reduced HbA1c with a significantly lower risk of hypoglycaemia and a significantly smaller proportion of patients receiving rescue therapy compared with glimepiride.

TITLE: Low-molecular-weight heparin alone versus a combination of unfractionated heparin and low-molecular-weight heparin.ABSTRACT: We analyzed the effect of the pharmacologic combination of 2 indirect antithrombin drugs--enoxaparin (low-molecular-weight heparin) and unfractionated heparin--versus enoxaparin alone on the recurrence of ischemia.Blocking some key factors of the coagulation cascade supports the concept that an antithrombin effect is needed during the acute phase of ischemia.This was a prospective, randomized, pilot trial in patients with an acute coronary ischemic event occurring within the previous 24 hours. A total of 126 patients were allocated to receive aspirin (200 mg/day orally) plus 1 mg/kg subcutaneous enoxaparin at 8 AM and 12.500 IU of subcutaneous unfractionated heparin at 8 PM (group A) or subcutaneous enoxaparin 1 mg/kg (group B).Severe recurrent ischemia provoking urgent coronary revascularization occurred in 12 patients (9.5%), 3 (5%) in group A and 9 (13%) in group B (P = .1). Refractory angina was present in 27 patients (21%), 10 (17%) in group A and 17 (25%) in group B (P = .45). The combination of severe recurrent ischemia and refractory angina occurred in 23% of group A, and 37% of group B (odds ratio 0.49; 95% confidence intervals, 0.21-1.15; P = .07). A total of 7 patients (5%) had acute nonfatal myocardial infarction develop, 3 (5%) in group A and 4 (6%) in group B. Two (1.6%) deaths were observed in the study, both in group B. The incidence of the double end point (death plus nonfatal myocardial infarction) was 5% in group A versus 9% in group B (P = .5) and the triple end point (death, nonfatal myocardial infarction, and severe recurrent ischemia) was 10.5% in group A vs 22% in group B (odds ratio 0.42, 95% confidence intervals, 0.13-1.29; P = .09).The combination of 2 indirect antithrombin drugs capable of intermittently blocking the coagulation system is not associated with a significant loss of safety.

TITLE: Relation of oxidative biomarkers, vascular dysfunction, and progression of coronary artery calcium.ABSTRACT: The relation between oxidative stress and coronary artery calcium (CAC) progression is currently not well described. The present study evaluated the relation among the biomarkers of oxidative stress, vascular dysfunction, and CAC. Sixty asymptomatic subjects participated in a randomized trial evaluating the effect of aged garlic extract plus supplement versus placebo and underwent measurement of CAC. The postcuff deflation temperature-rebound index of vascular function was assessed using a reactive hyperemia procedure. The content of oxidized phospholipids (OxPL) on apolipoprotein B-100 (apoB) particles detected by antibody E06 (OxPL/apoB), lipoprotein(a), IgG and IgM autoantibodies to malondialdehyde-low-density lipoprotein and apoB-immune complexes were measured at baseline and after 12 months of treatment. CAC progression was defined as an annual increase in CAC >15%. Vascular dysfunction was defined according to the tertiles of temperature-rebound at 1 year of follow-up. From baseline to 12 months, a strong inverse correlation was noted between an increase in CAC scores and increases in temperature-rebound (r(2) = -0.90), OxPL/apoB (r(2) = -0.85), and lipoprotein(a) (r(2) = -0.81) levels (p <0.0001 for all). The improvement in temperature-rebound correlated positively with the increases in OxPL/apoB (r(2) = 0.81, p = 0.0008) and lipoprotein(a) (r(2) = 0.79, p = 0.0001) but inversely with autoantibodies to malondialdehyde-low-density lipoprotein and apoB-immune complexes. The greatest CAC progression was noted with the lowest tertiles of increases in temperature-rebound, OxPL/apoB and lipoprotein(a) and the highest tertiles of increases in IgG and IgM malondialdehyde-low-density lipoprotein. In conclusion, the present results have documented a strong relation among markers of oxidative stress, vascular dysfunction, and progression of coronary atherosclerosis. Increases in OxPL/apoB and lipoprotein(a) correlated strongly with increases in vascular function and predicted a lack of progression of CAC.

TITLE: Pars plana vitrectomy and removal of the internal limiting membrane in diabetic macular edema unresponsive to grid laser photocoagulation.ABSTRACT: To evaluate the effectiveness of pars plana vitrectomy (PPV) with removal of the internal limiting membrane (ILM) in diabetic patients with macular edema unresponsive to grid laser photocoagulation.In this randomized controlled study, 20 eyes of 10 patients with diabetic macular edema unresponsive to grid laser photocoagulation were evaluated. PPV with ILM removal was performed randomly in one eye each of 10 patients and taken as the study group; the untreated fellow eyes were taken as the control group. Main outcome measures were foveal thickness changes measured with optical coherence tomography and preoperative and post-operative visual acuity. Mann-Whitney U, Wilcoxon, and chi-square tests were used in statistical analysis.The mean age of the patients was 61.5+/-6 years (range 51 to 71). All patients were followed up for 12 months. In the study group, mean foveal thickness was 391.3+/-91.6 microm preoperatively and 225.5+/-49.4 microm postoperatively (p=0.009). In the control group, mean foveal thickness was 356.2+/-140 microm at baseline and 318.4+/-111.1 microm at 12-month follow-up (p=0.138). Mean decrease in foveal thickness was 165.8+/-114.8 microm in the study group and 37.8+/-71.2 microm in the control group (p=0.016). In the study group, best-corrected log-MAR visual acuity was 0.71+/-0.43 preoperatively and 0.54+/-0.45 postoperatively (p=0.125). In the control group, best-corrected logMAR visual acuity was 0.43+/-0.44 at baseline and 0.59+/-0.55 at 12-month follow-up (p=0.235). In the study group, visual acuity improved by two or more lines in 4 eyes (40%) and remained stable in 6 eyes (60%). In the control group, visual acuity improved by two or more lines in 1 eye (10%) and decreased by two or more lines in 3 eyes (30%).PPV with ILM removal appears to be an effective procedure for reducing diabetic macular edema unresponsive to grid laser photocoagulation. A further study with a large number of patients is required to assess the effectiveness and safety of this procedure.

TITLE: Nicorandil reduces the incidence of minor cardiac marker elevation after coronary stenting.ABSTRACT: Minor cardiac marker elevation after percutaneous coronary intervention has long-term prognostic significance. We examined whether nicorandil, a nicotinamide-nitrate ester, reduces the incidence of minor cardiac marker elevation after coronary stenting.Patients (n=192) undergoing coronary stenting were randomly assigned to receive nicorandil (nicorandil group, n=91) or vehicle (control group, n=101). Nicorandil (2 mug/kg/min, intravenously) was administered immediately after the patients were transferred into the catheterization laboratory and continued for 6 h. We measured the serum concentrations of creatine kinase isoenzyme MB (CK-MB) before, immediately after, and 6, 12, and 24 h after the procedure, and those of cardiac troponin T (cTnT) 24 h after the procedure.There was no significant difference in clinical background between the 2 groups. The nicorandil group showed a significantly lower incidence of CK-MB elevation (>1x upper limit of control range, 20 IU/l) than the control group (8.8% vs 21.8%, p<0.05). The levels of serum CK-MB in the nicorandil group were significantly lower than those in the control group (13.4+/-5.7 vs 16.5+/-9.7 IU/l, p<0.01). Similarly, the nicorandil group showed a significantly lower incidence of cTnT elevation [>1x (0.1 ng/ml) or >2x (0.2 ng/ml)] upper limit of control range than the control group (14.3% vs 26.7%, p<0.05, or 7.7% vs 17.8%, p<0.05). Serum cTnT levels were also significantly lower in the nicorandil group than in the control group (0.05+/-0.10 vs 0.15+/-0.36 ng/ml, p<0.05).The results demonstrated that nicorandil reduces minor cardiac marker elevation after coronary stenting.

TITLE: Effect of telmisartan on forearm postischemic hyperemia and serum asymmetric dimethylarginine levels.ABSTRACT: Although telmisartan may be more beneficial for glucose metabolism than other angiotensin II receptor blockers (ARBs), it has not been determined whether telmisartan exerts more favorable effects on biological and functional parameters related to endothelial function than other ARBs.A study with a crossover design was conducted in 40 hypertensive patients (61 +/- 10 years old, mean +/- SD) who had previously been treated with ARBs other than telmisartan or valsartan (ie, ARBs were switched to either telmisartan 40 mg/day or valsartan 80 mg/day, administered alternately for 12 weeks each). Blood examinations were conducted, and the mean reactive hyperemia ratio (mRHR) was measured by plethysmography for each treatment regimen.There were no significant differences in either blood pressure or plasma levels of monocyte chemoattractant protein-1, C-reactive protein, 3-nitrotyrosine, or vascular cell adhesion molecule-1 between the two treatment regimens. The mRHR (2.7 +/- 1.0 v 2.4 +/- 1.0, mean +/- SD) was larger (P < .05), and the plasma levels of asymmetric dimethylarginine (ADMA) (0.45 +/- 0.08 v 0.50 +/- 0.17 micromol/L, mean +/- SD) and the homeostasis model assessment index of insulin resistance (HOMA-IR) (2.3 +/- 1.6 v 2.8 +/- 2.1, mean +/- SD) were lower (P < .05) in telmisartan-treated patients than in valsartan treated patients. The percent change in ADMA, but not in HOMA-IR, correlated significantly with that in the mRHR (beta = -0.33, t value = -2.00, P = .04).At doses producing equivalent hypotensive effects, telmisartan apparently had a more favorable effect on functional parameters related to endothelial function than did valsartan. The reduction in plasma ADMA levels may contribute to this more favorable effect of telmisartan.

TITLE: Machine perfusion preservation improves renal allograft survival.ABSTRACT: Machine perfusion (MP) has been used as the kidney preservation method in our center for over 10 years. The first, small (n = 74) prospective, single-blinded randomized study comparing MP and Cold Storage (CS) showed that the incidence of delayed graft function was higher after CS. There have been no reports in the literature on the effect of storage modality on long-term function of renal allografts. This paper presents an analysis of long-term results of renal transplantation in 415 patients operated on between 1994 and 1999. Of those, 227 kidneys were MP-stored prior to KTx. The control group consisted of 188 CS kidney transplants. Kidneys were not randomized to MP or to CS. Donor demographics, medical and biochemical data, cold ischemia time, HLA match and recipient data were collected. Standard triple-drug immunosuppression was administered to both groups. Mortality, graft survival and incidence of return to hemodialysis treatment were analyzed. Despite longer cold ischemia time and poorer donor hemodynamics in MP group, 5-year Kaplan-Meier graft survival was better in MP-stored than in CS-stored kidneys (68.2% vs. 54.2%, p = 0.02).In this nonrandomized analysis, kidney storage by MP improved graft survival and reduced the number of patients who returned to dialysis.

TITLE: Efficacy of real-time continuous glucose monitoring on glycaemic control and glucose variability in type 1 diabetic patients treated with either insulin pumps or multiple insulin injection therapy: a randomized controlled crossover trial.ABSTRACT: The aim of this study was to determine the efficacy of real-time continuous glucose monitoring in T1D patients treated with insulin pump therapy or multiple daily insulin therapy.Twenty adult patients (ten insulin pump therapy and ten multiple daily insulin) with poor glycaemic control (HbA1c  > 8.0%) were randomized into two groups for 6 months: the continuous glucose monitoring arm (using real-time continuous glucose monitoring) and the SMBG arm. After 2 months of wash-out, the participants crossed over. The primary outcome was HbA1c reduction. The secondary outcomes were hypoglycaemia and hyperglycaemia risk assessment (area under the curve < 70 mg/dL/day and AUC > 200 mg/dL/day, respectively) and glucose variability.Fourteen patients (eight multiple daily insulin, six insulin pump therapy) used continuous glucose monitoring appropriately (at least 40% of the time). In these patients, the improvement in glycaemic control was more evident during the real-time continuous glucose monitoring period (7.76% ± 0.4 vs 8.54% ± 0.4, p < 0.05) than during the self-monitoring of blood glucose period (8.42% ± 0.4 vs 8.56% ± 0.5, p = 0.2). Better results with continuous glucose monitoring were observed in patients using multiple daily insulin with greater improvement in both glycaemic control (7.71% ± 0.2 vs 8.58% ± 0.2, p < 0.05) and glucose variability and with a marked reduction in the risk of both hypoglycaemia and hyperglycaemia.Appropriate use of real-time continuous glucose monitoring improved glycometabolic control in T1D patients. The effects of continuous glucose monitoring were more evident in patients under multiple daily insulin treatment, compared with insulin pump therapy. Glucose variability, in addition to glycaemic control, was improved in compliant diabetic patients.

TITLE: Growth hormone as concomitant treatment in severe fibromyalgia associated with low IGF-1 serum levels. A pilot study.ABSTRACT: There is evidence of functional growth hormone (GH) deficiency, expressed by means of low insulin-like growth factor 1 (IGF-1) serum levels, in a subset of fibromyalgia patients. The efficacy of GH versus placebo has been previously suggested in this population. We investigated the efficacy and safety of low dose GH as an adjunct to standard therapy in the treatment of severe, prolonged and well-treated fibromyalgia patients with low IGF-1 levels.Twenty-four patients were enrolled in a randomized, open-label, best available care-controlled study. Patients were randomly assigned to receive either 0.0125 mg/kg/d of GH subcutaneously (titrated depending on IGF-1) added to standard therapy or standard therapy alone during one year. The number of tender points, the Fibromyalgia Impact Questionnaire (FIQ) and the EuroQol 5D (EQ-5D), including a Quality of Life visual analogic scale (EQ-VAS) were assessed at different time-points.At the end of the study, the GH group showed a 60% reduction in the mean number of tender points (pairs) compared to the control group (p < 0.05; 3.25 +/- 0.8 vs. 8.25 +/- 0.9). Similar improvements were observed in FIQ score (p < 0.05) and EQ-VAS scale (p < 0.001). There was a prompt response to GH administration, with most patients showing improvement within the first months in most of the outcomes. The concomitant administration of GH and standard therapy was well tolerated, and no patients discontinued the study due to adverse events.The present findings indicate the advantage of adding a daily GH dose to the standard therapy in a subset of severe fibromyalgia patients with low IGF-1 serum levels.NCT00497562 (ClinicalTrials.gov).

TITLE: Patterns of disease progression and outcomes in a randomized trial testing ABVD alone for patients with limited-stage Hodgkin lymphoma.ABSTRACT: In the National Cancer Institute of Canada Clinical Trials Group/Eastern Cooperative Oncology Group HD.6 trial, progression-free survival was better in patients randomized to therapy that included radiation, compared to doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) alone. We now evaluate patterns of progression and subsequent outcomes of patients with progression.After a median of 4.2 years, 33 patients have progressed. Two radiation oncologists determined whether sites of progression were confined within radiation fields. Freedom from second progression (FF2P) and freedom from second progression or death (FF2P/D) were compared.Reviewers agreed for the extended (kappa = 0.87) and involved field (kappa = 1.0) analyses. Progression after ABVD alone was more frequently confined within both the extended (20/23 vs. 3/10; P = 0.002) and involved fields (16/23 vs. 2/10; P = 0.02). There was no difference in FF2P between groups [5-year estimate 99% (radiation) versus 96% (ABVD alone)] [hazard ratio (HR) = 3.14, 95% confidence interval (CI) 0.63-15.6; P = 0.14]; the 5-year estimates of FF2P/D were 94% in each group (HR = 1.04, 95% CI 0.41-2.63; P = 0.93).Treatment that includes radiation reduces the risk of progressive Hodgkin lymphoma in sites that receive this therapy, but we are unable to detect differences in FF2P or FF2P/D.

TITLE: Compliance with joint commission measures in state-designated stroke centers.ABSTRACT: Comparison of state-designated primary and comprehensive stroke centers (PSCs and CSCs) with regard to adherence to nationally accepted performance standards are scarce. The objective of this study was to examine if a significant association exists between level of designation and fulfillment of Joint Commission (JC) stroke core measures.A retrospective comparative data analysis of the New Jersey acute stroke registry for the calendar years 2010 and 2011 was performed. JC core measures were compared by hospital level (PSCs vs CSCs). Adjusted odds ratios (aOR) were estimated for association between hospital levels and fulfillment of JC core measures. Median door-to-thrombolytic time was also compared.There were 36,892 acute stroke admissions. PSCs had 60% of the patients, whereas CSCs had 40%. Hemorrhagic stroke admissions were about 2 times more frequent at CSCs than PSCs (13.3% and 7.1%, respectively). CSCs adhered better to 6 of the 8 JC measures than PSCs. Of eligible patients, 19.5% received thrombolytic therapy at CSCs compared to 9.6% at PSCs, with a 44% difference in provision of thrombolytic therapy (aOR = 0.28, 95% confidence interval: 0.24-0.34). Median door-to-thrombolytic drug times was 65 minutes at CSCs compared to 74.0 minutes at PSCs (P < 0.0001).New Jersey state-designated CSCs are better at adhering to the JC core stroke measures and have shorter door-to-thrombolytic drug times.

TITLE: Ketoconazole-tacrolimus coadministration in kidney transplant recipients: two-year results of a prospective randomized study.ABSTRACT: In developing countries, kidney transplantation is greatly hindered by financial problems, especially due to costly newer immunosuppressive medications. Ketoconazole increases blood levels of tacrolimus and cyclosporine through inhibition of cytochrome P450 microsomal enzymes. We previously reported on the 6-month safety and the outstanding impact on treatment costs of the ketoconazole-tacrolimus combination in kidney transplant recipients. Data of this combination are still lacking in the literature. We hereby report on the 2-year results of our trial.This prospective, randomized study included 70 live-donor kidney transplant recipients receiving tacrolimus (age 16-45 years, 54 males and 16 females). Patients were randomized into two equal groups: group 1, where ketoconazole 100 mg/day was added, and group 2 (control group).After 2 years, group 1 (ketoconazole) patients still showed a highly significant reduction of the tacrolimus dose (by 53.8%) and cost (by 52.9%) compared with the control group (p < 0.001) and a significant improvement in graft function in comparison to their own initial graft function (p = 0.002). Throughout the 2 years, no side effects of ketoconazole were noted.We conclude that the long-term ketoconazole-tacrolimus combination therapy in kidney transplant recipients during the 2 years is safe, has an outstanding impact on treatment costs and improves graft outcome.

TITLE: The addition of fentanyl to local anesthetics affects the quality and duration of cervical plexus block: a randomized, controlled trial.ABSTRACT: Cervical plexus block is frequently associated with unsatisfactory sensory blockade. In this randomized, double-blind, placebo-controlled trial, we examined whether the addition of fentanyl to local anesthetics improves the quality of cervical plexus block in patients undergoing carotid endarterectomy (CEA).Seventy-seven consecutive adult patients scheduled for elective CEA were randomized to receive either fentanyl 1 mL (50 microg) or saline placebo 1 mL in a mixture of 10 mL bupivacaine 0.5% and 4 mL lidocaine 2% for deep cervical plexus block. Superficial cervical plexus block was performed using a mixture of 10 mL bupivacaine 0.5% and 5 mL lidocaine 2%. Pain was assessed using the verbal rating scale (0-10; 0 = no pain, 10 = worst pain imaginable), and propofol in 20-mg IV bolus doses was given to patients reporting verbal rating scale >3 during the procedure. Rescue medication consumption during surgery and analgesia requirements over the next 24 hours, as well as onset of sensory blockade, were recorded. A P value <0.05 was regarded as statistically significant.Fewer patients in the fentanyl group (4 of 38, 10.5%) required propofol compared with the placebo group (26 of 39, 66.7%; P < 0.001). In comparison with the placebo group, the fentanyl group consumed less propofol (median 0 [0-60] vs 60 [0-160] mg, respectively; P < 0.001), required postoperative analgesia less frequently (22 of 38 patients, 57.9% vs 35 of 39 patients, 89.7%, respectively; P = 0.002), and requested the first analgesic after surgery later (median 5.8 [1.9-15.6] vs 3.1 [1.0-11.7] hours, respectively; P < 0.001), whereas the onset time of sensory blockade was similar in both groups (median 12 [9-18] vs 15 [9-18] minutes, respectively; P = 0.18).The addition of fentanyl to local anesthetics improved the quality and prolonged the duration of cervical plexus block in patients undergoing CEA.

TITLE: Barbed sutures reduce arthrotomy closure duration compared to interrupted conventional sutures for total knee arthroplasty: a randomized controlled trial.ABSTRACT: The broad aim of this study was to compare the safety and efficacy of using barbed sutures versus standard-of-care sutures for closure of arthrotomy during total knee arthroplasty. Specifically, we compared the duration of arthrotomy closure, the number of sutures utilized for arthrotomy closure, and 90-day outcomes, including wound-related readmission, reoperation, and complications.A total of 60 patients undergoing primary total knee arthroplasty were enrolled in a prospective, blinded trial and randomized to receive either running closure of the arthrotomy with barbed sutures (n = 30) or interrupted closure with standard-of-care sutures (n = 30).Arthrotomy closure time was significantly shorter in the barbed suture group (3 min ± 2 min) versus the standard-of-care group (13 min ± 5 min, p < 0.001). The average suture utilization for arthrotomy closure was 1 suture (range 1-2) versus 3 sutures (range 2-4) in the standard-of-care group (p < 0.001). The overall number of wound-related complications in the barbed suture group was 3/30 (10%) versus 3/30 (10%) in the standard-of-care group (p = 1.00). There was one dehiscence 1/30 (3%) in the standard-of-care group versus zero in the barbed suture group (p = 1.00). The rate of superficial surgical site infection was 1/30 (3%) in barbed suture versus zero in the standard-of-care groups (p = 1.00).These results suggest barbed suture utilization may be faster and more resource-efficient than the use of standard-of-care sutures for arthrotomy closure in primary total knee arthroplasty without increased complications. CLINICALTRIALS.NCT03285529.

TITLE: Colour change of ceramic brackets with the use of coloured beverages in adolescent patients: A randomized clinical trial.ABSTRACT: To clinically evaluate colour change of ceramic orthodontic brackets with the use of coloured beverages as ceramic brackets' resistance to discoloration has become a major concern.A prospective two parallel groups-split mouth randomized trial with a 1:1 allocation ratio. Two equal groups including 40 adolescent patients from the orthodontic department (Faculty of Dentistry, Mansoura University, Egypt), scheduled for maxillary premolar extractions were bonded with 2 types of mono-crystalline ceramic brackets: Type 1 (Inspire ICETM) and Type 2 (Radiance PlusTM). Participants in each group were asked to rinse with either black tea or Cola. After extraction, the colour of the 80 debonded brackets was compared to that of 20 control brackets from each type by spectrophotometer according to the international standard CIELAB colour space (CIE L*a*b*). The latter consists of three coordinates: L* (lightness value), a* and b* (the colour channels). The total colour difference ΔE* is the distance between two colours in this three-dimensional colour space. The colour change was also assessed by digital image analysis according to the RGB model.Type 1 brackets showed mean ΔE* values of 2.24±0.25 in black tea and 1.76±0.1 in Cola groups (P<0.001), while Type 2 brackets showed means of 1.99±0.15 in black tea and 1.56±0.1 in Cola groups (P<0.001). The mean RGB values were 174.3±12.02 in black tea and 185.6±6.9 in the Cola groups of type 1 brackets (P<0.001), while were 166.5±17.8 in black tea and 190.8±8.9 in Cola groups of type 2 brackets (P<0.001).Black tea showed more significant effect than Cola on the two bracket types. Bracket type affected the colour change in each beverage group.

TITLE: Can mean platelet component be used as an index of platelet activity in stable coronary artery disease?ABSTRACT: Acute coronary syndrome is associated with intracoronary thrombosis secondary to platelet activation. Previous groups have investigated platelet activation in both stable and unstable vascular disease. Most measures of platelet activation are not routinely available or easily adaptable to large scale clinical use. Recently, measurement of the mean platelet component (MPC) has become part of the routine data provided by an automated full blood count analyser, the Advia 120. MPC measures platelet density which changes on platelet activation. Our objectives were to determine if platelet activation, as measured by MPC, is increased in patients with stable coronary artery disease (CAD) and to determine if MPC could be useful in differentiating people with stable CAD from controls on an everyday clinical basis. Three hundred and forty-five consecutive patients attending for elective coronary angiography had full blood count analysis and MPC measurement performed using an ADVIA-120 analyser. Three hundred and twenty-four were analysed in our final dataset. Two hundred and fifty-three (78%) had CAD. Patients with CAD were significantly (p<0.001) older than those without (63.8 versus 56.0 years). Results failed to demonstrate a difference (p=0.467) in MPC between patients with CAD and those with normal coronary arteries (25.8 versus 26.0). Likewise, there was no correlation between MPC and the severity of CAD (Kendall's tau b=-0.086, p=0.04). MPC is not a useful index of platelet activity in stable CAD when used in everyday clinical practice.

TITLE: Antibiotic prophylaxis at urinary catheter removal prevents urinary tract infections: a prospective randomized trial.ABSTRACT: To assess whether antibiotic prophylaxis at urinary catheter removal reduces the rate of urinary tract infections.Urinary tract infections are among the most common nosocomial infections. Antibiotic prophylaxis at urinary catheter removal is used as a measure to prevent them, albeit without supporting evidence.A prospective randomized study enrolled 239 patients undergoing elective abdominal surgery, who were randomized either for receiving 3 doses of trimethoprim-sulfamethoxazole at urinary catheter removal, or not. Urinary tract infections were diagnosed according to Center of Disease Control definitions. Urinary cultures were obtained before and 3 days after catheter removal. Subjective symptoms were assessed by an independent study-blind urologist.Patients who received antibiotic prophylaxis showed significantly fewer urinary tract infections (5/103, 4.9%) than those without prophylaxis (22/102, 21.6%), P < 0.001. The absolute risk reduction for the occurrence of a urinary tract infection was 16.7%; the relative risk reduction was 77.5%, and the number needed to treat was 6. Patients with antibiotic prophylaxis also had less significant bacteriuria 3 days after catheter removal (17/103, 16.5%) than those without (42/102, 41.2%), P < 0.001.Antibiotic prophylaxis with trimethoprim-sulfamethoxazole on urinary catheter removal significantly reduces the rate of symptomatic urinary tract infections and bacteriuria in patients undergoing abdominal surgery with perioperative transurethral urinary catheters.

TITLE: Tension-free hernioplasty versus conventional hernioplasty for inguinal hernia repair.ABSTRACT: To show the effectiveness of tension-free hernioplasty for inguinal hernia repair.We studied 106 patients who underwent inguinal hernia repair, as conventional hernioplasty in 52 and as tension-free hernioplasty in 54. We analyzed the operation time, postoperative complications, pain, time to resume daily activities, and frequency of recurrence in the short and long term.The average age of the patients was 46.2 years. The operation time was significantly shorter in the tension-free group than in the conventional group, at 33 +/- 11.1 versus 49 +/- 8.8 min, respectively (P < 0.05). The overall complication rate was 10%, being 1.5% in the tension-free group and 13% in the conventional group (P = 0.4). The visual-analogue pain scores after surgery were lower in the tension-free group than in the conventional group (P = 0.01). Patients in the tension-free group returned to their normal activities sooner than those in the conventional group (P < 0.05).Tension-free hernioplasty resulted in less pain and allowed patients to return to their daily activities sooner than conventional hernioplasty.

TITLE: Reduction of early postoperative morbidity in cardiac surgery patients treated with continuous veno-venous hemofiltration during cardiopulmonary bypass.ABSTRACT: Cardiac surgery with cardiopulmonary bypass is associated with a systemic inflammatory response syndrome. The major clinical features of this include a reduction of pulmonary compliance and increased extracellular fluids, with increased pulmonary shunt fraction similar to acute respiratory distress syndrome, thus resulting in prolonged mechanical ventilation time (VAM) and intensive care unit length of stay (ICU STAY). We evaluated the feasibility of an intraoperatory cardiopulmonary bypass (CPB) circuit connected with a monitor for continuous veno-venous hemofiltration (CVVH) to ameliorate pulmonary function after open heart surgery reducing VAM and ICU STAY. Forty patients undergoing elective coronary artery bypass grafting were randomized at the time of surgery into a control group (20 patients who received standard cardiopulmonary bypass) and a study group (20 patients who received CVVH during cardiopulmonary bypass). The analysis of postoperative variables showed a significative reduction of VAM in treated group (CVVH group mean 3.55 h +/- 0.85, control group 5.8 h +/- 0.94, P < 0.001) and ICU STAY (CVVH group mean 29.5 h +/- 6.7, control group 40.5 h +/- 6.67, P < 0.001). In our experience, the use of intraoperatory CVVH during cardiopulmonary bypass is associated with lower early postoperative morbidity.

TITLE: Local anesthesia and pain perception during amniocentesis: a randomized double blind placebo-controlled trial.ABSTRACT: To determine the effect of local anesthesia on the maternal pain perception from amniocentesis.We conducted a randomized double blind placebo controlled trial comparing use of local anesthesia (1% lidocaine) with placebo with regards to maternal perception of pain among women undergoing genetic amniocentesis. The primary outcome was the intensity of perceived maternal pain as measured by the Visual Analogue Scale (VAS) as well a 101 point Numerical Rating Scale.Seventy six women participated in the trial. 36 (47.4%) women were randomized to lidocaine, whereas 40 (52.6%) were randomized to placebo. There were no statistically significant differences between the groups in terms of baseline sociodemographic and clinical characteristics. However, pain perception as characterized by the median 9.5 (2.1-21.0) VSA scores was significantly lower among women in the lidocaine group compared with among women in the placebo group [18.4 (12.9-31.3), P = 0.005]. Similarly the mean VSA scores was significantly lower in the lidocaine group (P = 0.02). A trend toward lower scores was also observed when maternal pain perception was measured by the Numerical Rating Scale.Local anesthetic lidocaine significantly lowers maternal perceived pain during genetic amniocentesis.

TITLE: The necessity of using tenaculum for endometrial sampling procedure with pipelle: a randomized controlled study.ABSTRACT: To evaluate the use of tenaculum on pain perception of patients and on ease of endometrial sampling procedure with a pipelle.A randomized controlled trial was conducted in 118 patients for assessing pain perception and the ease of the procedure. Patients were randomly assigned to group 1 (without tenaculum) and group 2 (with tenaculum). Visual analog scale (VAS) was used to assess patients' pain at four different times during the process. VAS-3 reflected the pain during the procedure. Likert scale was employed by the surgeon to measure the ease of the procedure. Main outcome was VAS and the secondary outcomes were Likert scale and success rate in obtaining adequate samples of endometrial tissue for histopathological diagnosis.Endometrial sampling procedure could not be performed only on three patients who belonged to group 1. The VAS-3 scores were higher in group 2 than group 1 (p = 0.001). Nullipar patients had higher VAS-3 scores than multipars (p = 0.012). VAS-3 did not vary in pre-peri-postmenopausal women (p = 0.901). Likert scale was lower in postmenopausal women than peri- or pre-menopausal patients (p = 0.020, 0.017, respectively). Use of tenaculum was found by logistic regression analysis to be an independent risk factor for patients' pain perception (p = 0.0001, RR 31.8, 95 % CI 8.3-122.4). Inadequate endometrial sampling was reported in 12 patients who were all postmenopausal.Endometrial sampling procedure without tenaculum is feasible and yields less pain perception than with tenaculum.

TITLE: Randomised controlled trial of a mobile phone infant resuscitation guide.ABSTRACT: The aim of this study was to develop a mobile phone resuscitation guide (MPRG) and to evaluate its use during simulated resuscitation of a mannequin.An MPRG was developed using EpiSurveyor. A randomised controlled trial was performed in school-going children aged 15-16 years. All subjects were taught infant CPR skills using the American Heart Association Infant CPR Anytime. Two weeks later, the students were randomised to use of MPRG or not, and their CPR skills were re-assessed. The assessment was conducted using previously validated checklists.Twenty-one students participated in this trial. The MPRG group performed notably better in the areas of calling emergency services (80% vs. 36.4%, P = 0.044), completing sufficient CPR cycles (90% vs. 45.5%, P = 0.047) and following the correct CPR sequence (60% vs. 9.1%, P = 0.013). No difference in resuscitation skills of participants was observed.We have shown that participants were more likely to call emergency services if they were using the MPRG. Further trials are needed to investigate the utility of mobile phone guides and whether or not they can reduce the time taken to contact emergency services as well as if they can sustain correct CPR sequence in an in-vivo setting.

TITLE: Mechanical-ventilatory responses to peak and ventilation-matched upper- versus lower-body exercise in normal subjects.ABSTRACT: What is the central question of this study? To what extent are the mechanical-ventilatory responses to upper-body exercise influenced by task-specific locomotor mechanics? What is the main finding and its importance? When compared with lower-body exercise performed at similar ventilations, upper-body exercise was characterized by tidal volume constraint, dynamic lung hyperinflation and an increased propensity towards neuromechanical uncoupling of the respiratory system. Importantly, these responses were independent of respiratory dysfunction and flow limitation. Thus, the mechanical ventilatory responses to upper-body exercise are attributable, in part, to task-specific locomotor mechanics (i.e. non-respiratory loading of the thorax).The aim of this study was to determine the extent to which the mechanical ventilatory responses to upper-body exercise are influenced by task-specific locomotor mechanics. Eight healthy men (mean ± SD: age, 24 ± 5 years; mass, 74 ± 11 kg; and stature, 1.79 ± 0.07 m) completed two maximal exercise tests, on separate days, comprising 4 min stepwise increments of 15 W during upper-body exercise (arm-cranking) or 30 W during lower-body exercise (leg-cycling). The tests were repeated at work rates calculated to elicit 20, 40, 60, 80 and 100% of the peak ventilation achieved during arm-cranking ( ). Exercise measures included pulmonary ventilation and gas exchange, oesophageal pressure-derived indices of respiratory mechanics, operating lung volumes and expiratory flow limitation. Subjects exhibited normal resting pulmonary function. Arm-crank exercise elicited significantly lower peak values for work rate, O uptake, CO output, minute ventilation and tidal volume (p < 0.05). At matched ventilations, arm-crank exercise restricted tidal volume expansion relative to leg-cycling exercise at 60% (1.74 ± 0.61 versus 2.27 ± 0.68 l, p < 0.001), 80% (2.07 ± 0.70 versus 2.52 ± 0.67 l, p < 0.001) and 100% (1.97 ± 0.85 versus 2.55 ± 0.72 l, p = 0.002). Despite minimal evidence of expiratory flow limitation, expiratory reserve volume was significantly higher during arm-cranking versus leg-cycling exercise at 100% (39 ± 8 versus 29 ± 8% of vital capacity, p = 0.002). At any given ventilation, arm-cranking elicited greater inspiratory effort (oesophageal pressure) relative to thoracic displacement (tidal volume). Arm-cranking exercise is sufficient to provoke respiratory mechanical derangements (restricted tidal volume expansion, dynamic hyperinflation and neuromechanical uncoupling) in subjects with normal pulmonary function and expiratory flow reserve. These responses are likely to be attributable to task-specific locomotor mechanics (i.e. non-respiratory loading of the thorax).

TITLE: Pharmacodynamic effects of orally administered dexlipotam on endothelial function in type 2-diabetic patients.ABSTRACT: Diabetic endotheliopathy is the result of hyperglycemia and the production of oxygen-free radicals. In vitro and in vivo data have shown beneficial effects of dexlipotam (DEX), a tromethamine salt of R(+)-alpha-lipoic acid, on oxidative stress in hyperglycemic states, but no data are available on the effects of this agent on endothelial function. The purpose of this pilot study was to evaluate the impact of DEX on endothelial function in patients with type 2 diabetes (DM2) and to estimate the safety and tolerability of DEX.DEX 960 mg and DEX 1,920 mg were investigated in DM2 patients over a period of 4 weeks using a randomized, placebo- (PLA) controlled, double-blinded study with 3 parallel groups. The marker of arterial function after 4-week therapy with DEX was the maximum percentage change versus baseline in the flow-mediated dilation of the brachial artery (FMD) after reperfusion.A total of 114 diabetic patients were randomized to the three study groups. DEX was safe and well tolerated. Dyspepsia appeared to be the most relevant side effect of DEX treatment. Systolic (p = 0.078) and diastolic blood pressure (p = 0.059) tended to be lower in patients treated with DEX at a dose of 1,920 mg. There were no significant differences in FMD between the placebo- and the DEX-treated groups. In patients with poorer glucose control (HbA1c > 6.5% Hb), FMD increased significantly after 4-week treatment with DEX: PLA -1.51 +/- 2.98%, DEX 960 mg +1.22 +/- 3.22, p = 0.027, DEX 1,920 mg +1.47 +/- 3.78, p= 0.012. The magnitude of the mean change compared to placebo was 2.73% (DEX 920) and 2.98% (DEX 1,920) in patients with HbAlc > 7.5% Hb (DEX 960, p = 0.007, DEX 1,920, p = 0.032). The effects of treatment were usually statistically significant in subgroups with more severe vascular stress (longer duration of disease, pretreatment history, higher LDL-C, higher blood pressure).DEX therapy appears to reduce endothelial dysfunction in DM2, especially in men with long history of DM2 and having poor glucose control. These findings will be useful in patient selection in future prospective clinical trials with drugs to treat vascular stress.

TITLE: Extending low-dose epidural analgesia in labour for emergency Caesarean section - a comparison of levobupivacaine with or without fentanyl.ABSTRACT: Women in labour receiving epidural analgesia with 15 ml bupivacaine 0.1% and 2 microg.ml(-1) fentanyl followed by 10-15-ml top-ups as required, who needed Caesarean section, were randomly allocated to receive 20 ml levobupivacaine 0.5% over 3 min with either 75 microg fentanyl (1.5 ml) or 1.5 ml saline. Further top-ups or inhaled or intravenous supplementation were given for breakthrough pain. Time to onset (loss of cold sensation to T4 and touch sensation to T5 bilaterally), quality of analgesia and side-effects were recorded. The study was stopped after 112 patients had been randomly assigned, due to a unit protocol change, from midwife-administered top-ups to patient-controlled epidural analgesia. Data from 51 patients given fentanyl and 54 given saline were available for analysis. There were no significant differences in onset times or supplementation between the groups, but there was more intra-operative nausea/vomiting with fentanyl (53%) than with saline (18%; p = 0.004). We found no advantage of adding fentanyl to epidural levobupivacaine when extending epidural analgesia in women already receiving epidural fentanyl during labour and there was an increased incidence of intra-operative nausea and vomiting. Power analysis suggested the same conclusion even had the study proceeded to completion.

TITLE: Dry Needling Combined With Guideline-Based Physical Therapy Provides No Added Benefit in the Management of Chronic Neck Pain: A Randomized Controlled Trial.ABSTRACT: To determine the added benefit of combining dry needling with a guideline-based physical therapy treatment program consisting of exercise and manual therapy on pain and disability in people with chronic neck pain.Randomized controlled trial.Participants were randomized to receive either guideline-based physical therapy or guideline-based physical therapy plus dry needling. The primary outcomes, measured at 1 month post randomization, were average pain intensity in the previous 24 hours and previous week, measured with a numeric pain-rating scale (0-10), and disability, measured with the Neck Disability Index (0-100). The secondary outcomes were pain and disability measured at 3 and 6 months post randomization and global perceived effect, quality of sleep, pain catastrophizing, and self-efficacy measured at 1, 3, and 6 months post randomization.One hundred sixteen participants were recruited. At 1 month post randomization, people who received guideline-based physical therapy plus dry needling had a small reduction in average pain intensity in the previous 24 hours (mean difference, 1.56 points; 95% confidence interval [CI]: 1.11, 2.36) and in the previous week (mean difference, 1.20 points; 95% CI: 1.02, 2.21). There was no effect of adding dry needling to guideline-based physical therapy on disability at 1 month post randomization (mean difference, -2.08 points; 95% CI: -3.01, 5.07). There was no effect for any of the secondary outcomes.When combined with guideline-based physical therapy for neck pain, dry needling resulted in small improvements in pain only at 1 month post randomization. There was no effect on disability. .

TITLE: Defining the Most Informative Intermediate Clinical Endpoints for Patients Treated with Salvage Radiotherapy for Prostate-specific Antigen Rise After Radical Prostatectomy.ABSTRACT: Intermediate clinical endpoints (ICEs) might aid in trial design and potentially expedite study results. However, little is known about the most informative ICE for patients receiving salvage radiation therapy (sRT) after radical prostatectomy. To investigate the most informative ICE for patients receiving sRT, we used a multi-institutional database encompassing patients treated at eight tertiary centers. Overall, 1301 men with node-negative disease who had not received any form of androgen deprivation therapy were identified. Associations of biochemical (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery with the risk of overall mortality were evaluated using multivariable Cox regression analyses fitted at the landmark points of 1, 3, 5, and 7yr after sRT. The discriminative ability of each model for predicting overall survival (OS) was assessed using Harrell's c index. Median follow-up for survivors was 5.6yr (interquartile range 2.0-8.8). On multivariable analysis, progression to CR within 3yr from sRT (hazard ratio 4.19, 95% confidence interval 1.44-11.2; p= 0.008) was the most informative ICE for predicting OS (c index 0.78) compared to CR within 1, 5, and 7yr (c index 0.72, 0.75, and 0.71). In conclusion, progression to CR within 3yr after sRT, irrespective of the time of surgery, was the most informative ICE for prediction of OS. Our study is hypothesis-generating. If these results are confirmed in future prospective studies and surrogacy is met, this information could be applied for study design and could potentially expedite earlier release of results from ongoing randomized controlled trials. PATIENT SUMMARY: Clinical recurrence of prostate cancer within 3yr after salvage radiation therapy, irrespective of the time of radical prostatectomy, represents the most informative intermediate clinical endpoint for the prediction of overall survival. This information could be applied in the design of future studies and could potentially expedite earlier release of results from ongoing randomized controlled trials.

TITLE: The effects of nitrous oxide on recovery from isoflurane anaesthesia in dogs.ABSTRACT: To assess rate and quality of recovery from anaesthesia where isoflurane was delivered in oxygen or oxygen/nitrous oxide.Dogs anaesthetised with propofol were randomly allocated to receive isoflurane maintenance in either 100 per cent oxygen (group 1) or 66 per cent nitrous oxide (N(2)O)/34 per cent oxygen (group 2). Time from end of anaesthesia to achieving sternal recumbency was recorded. Incidence of adverse behaviours (vocalisation, uncontrolled head movement and restlessness) were assessed. Recovery quality was recorded on a visual analogue scale (VAS) (anchored at 0 with "best possible" recovery and "did not recover" at 100 mm). Age, weight, gender, anaesthetic duration, mean vaporiser setting, VAS scores, recovery times, postoperative temperature and behavioural scores were compared (chi-squared test, Mann-Whitney U test or t-test as appropriate, significance P< or =0.05).Objective data from 54 dogs were analysed, only VAS data where the observer was unaware of treatment group were used (n=33). Recovery was faster in group 2 dogs (median 10 min [range 4 to 31] compared with 14 minutes [3 to 43] in group 1, P=0.049) with less restlessness (0 [0 to 4] compared with 2 [0 to 4] in group 1, P=0.013) and uncontrolled head movement (0 [0 to 4] compared with 1 [0 to 3] in group 1, P<0.001). However, VAS scores were not statistically different between groups (group 1: mean 39.4 mm [s.d. 24.0)]; group 2: 30.1 mm [25.9]; P=0.303).Addition of N(2)O to isoflurane anaesthesia results in a lower incidence of adverse behaviour (for example restlessness) and marginally faster recovery.