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The diagnostic challenges associated with the COVID-19 pandemic resulted in rapid development of diagnostic test methods for detecting SARS-CoV-2 infection. Serology tests to detect the presence of antibodies to SARS-CoV-2 enable detection of past infection and may detect cases of SARS-CoV-2 infection that were missed by earlier diagnostic tests. Understanding the diagnostic accuracy of serology tests for SARS-CoV-2 infection may enable development of effective diagnostic and management pathways, inform public health management decisions and understanding of SARS-CoV-2 epidemiology. To assess the accuracy of antibody tests, firstly, to determine if a person presenting in the community, or in primary or secondary care has current SARS-CoV-2 infection according to time after onset of infection and, secondly, to determine if a person has previously been infected with SARS-CoV-2. Sources of heterogeneity investigated included: timing of test, test method, SARS-CoV-2 antigen used, test brand, and reference standard for non-SARS-CoV-2 cases. The COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) was searched on 30 September 2020. We included additional publications from the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) 'COVID-19: Living map of the evidence' and the Norwegian Institute of Public Health 'NIPH systematic and living map on COVID-19 evidence'. We did not apply language restrictions. We included test accuracy studies of any design that evaluated commercially produced serology tests, targeting IgG, IgM, IgA alone, or in combination. Studies must have provided data for sensitivity, that could be allocated to a predefined time period after onset of symptoms, or after a positive RT-PCR test. Small studies with fewer than 25 SARS-CoV-2 infection cases were excluded. We included any reference standard to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR), clinical diagnostic criteria, and pre-pandemic samples). We use standard screening procedures with three reviewers. Quality assessment (using the QUADAS-2 tool) and numeric study results were extracted independently by two people. Other study characteristics were extracted by one reviewer and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and, for meta-analysis, we fitted univariate random-effects logistic regression models for sensitivity by eligible time period and for specificity by reference standard group. Heterogeneity was investigated by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and summarised results for tests that were evaluated in 200 or more samples and that met a modification of UK Medicines and Healthcare products Regulatory Agency (MHRA) target performance criteria. We included 178 separate studies (described in 177 study reports, with 45 as pre-prints) providing 527 test evaluations. The studies included 64,688 samples including 25,724 from people with confirmed SARS-CoV-2; most compared the accuracy of two or more assays (102/178, 57%). Participants with confirmed SARS-CoV-2 infection were most commonly hospital inpatients (78/178, 44%), and pre-pandemic samples were used by 45% (81/178) to estimate specificity. Over two-thirds of studies recruited participants based on known SARS-CoV-2 infection status (123/178, 69%). All studies were conducted prior to the introduction of SARS-CoV-2 vaccines and present data for naturally acquired antibody responses. Seventy-nine percent (141/178) of studies reported sensitivity by week after symptom onset and 66% (117/178) for convalescent phase infection. Studies evaluated enzyme-linked immunosorbent assays (ELISA) (165/527; 31%), chemiluminescent assays (CLIA) (167/527; 32%) or lateral flow assays (LFA) (188/527; 36%). Risk of bias was high because of participant selection (172, 97%); application and interpretation of the index test (35, 20%); weaknesses in the reference standard (38, 21%); and issues related to participant flow and timing (148, 82%). We judged that there were high concerns about the applicability of the evidence related to participants in 170 (96%) studies, and about the applicability of the reference standard in 162 (91%) studies. Average sensitivities for current SARS-CoV-2 infection increased by week after onset for all target antibodies. Average sensitivity for the combination of either IgG or IgM was 41.1% in week one (95% CI 38.1 to 44.2; 103 evaluations; 3881 samples, 1593 cases), 74.9% in week two (95% CI 72.4 to 77.3; 96 evaluations, 3948 samples, 2904 cases) and 88.0% by week three after onset of symptoms (95% CI 86.3 to 89.5; 103 evaluations, 2929 samples, 2571 cases). Average sensitivity during the convalescent phase of infection (up to a maximum of 100 days since onset of symptoms, where reported) was 89.8% for IgG (95% CI 88.5 to 90.9; 253 evaluations, 16,846 samples, 14,183 cases), 92.9% for IgG or IgM combined (95% CI 91.0 to 94.4; 108 evaluations, 3571 samples, 3206 cases) and 94.3% for total antibodies (95% CI 92.8 to 95.5; 58 evaluations, 7063 samples, 6652 cases). Average sensitivities for IgM alone followed a similar pattern but were of a lower test accuracy in every time slot. Average specificities were consistently high and precise, particularly for pre-pandemic samples which provide the least biased estimates of specificity (ranging from 98.6% for IgM to 99.8% for total antibodies). Subgroup analyses suggested small differences in sensitivity and specificity by test technology however heterogeneity in study results, timing of sample collection, and smaller sample numbers in some groups made comparisons difficult. For IgG, CLIAs were the most sensitive (convalescent-phase infection) and specific (pre-pandemic samples) compared to both ELISAs and LFAs (P < 0.001 for differences across test methods). The antigen(s) used (whether from the Spike-protein or nucleocapsid) appeared to have some effect on average sensitivity in the first weeks after onset but there was no clear evidence of an effect during convalescent-phase infection. Investigations of test performance by brand showed considerable variation in sensitivity between tests, and in results between studies evaluating the same test. For tests that were evaluated in 200 or more samples, the lower bound of the 95% CI for sensitivity was 90% or more for only a small number of tests (IgG, n = 5; IgG or IgM, n = 1; total antibodies, n = 4). More test brands met the MHRA minimum criteria for specificity of 98% or above (IgG, n = 16; IgG or IgM, n = 5; total antibodies, n = 7). Seven assays met the specified criteria for both sensitivity and specificity. In a low-prevalence (2%) setting, where antibody testing is used to diagnose COVID-19 in people with symptoms but who have had a negative PCR test, we would anticipate that 1 (1 to 2) case would be missed and 8 (5 to 15) would be falsely positive in 1000 people undergoing IgG or IgM testing in week three after onset of SARS-CoV-2 infection. In a seroprevalence survey, where prevalence of prior infection is 50%, we would anticipate that 51 (46 to 58) cases would be missed and 6 (5 to 7) would be falsely positive in 1000 people having IgG tests during the convalescent phase (21 to 100 days post-symptom onset or post-positive PCR) of SARS-CoV-2 infection. Some antibody tests could be a useful diagnostic tool for those in whom molecular- or antigen-based tests have failed to detect the SARS-CoV-2 virus, including in those with ongoing symptoms of acute infection (from week three onwards) or those presenting with post-acute sequelae of COVID-19. However, antibody tests have an increasing likelihood of detecting an immune response to infection as time since onset of infection progresses and have demonstrated adequate performance for detection of prior infection for sero-epidemiological purposes. The applicability of results for detection of vaccination-induced antibodies is uncertain.

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Studies of the psychology of gifted children frequently refer to their relatively immature affective development in terms of their intellectual capacities and the relational difficulties they experience with regard to their peers, teachers, close acquaintances and sometimes their parents. From a psychopathological viewpoint, various types of problem have been observed such as depressive symptoms, motor instability coupled with hyperactivity, attentional deficits, impulsivity and a fall in self-esteem. In this study, we wished to verify the links between self-esteem and psychopathological symptoms in these children. The total population studied consisted of 58 pupils taken from two teaching establishments in Dijon who were subdivided into two groups (gifted children and adolescents versus control children and adolescents). Of these 58 subjects who took part in the tests, 8 were eliminated either due to their results on the "lie" scale of the self-esteem scale (score greater than or equal to 5) or to their age. In effect, a high score on this scale implies that the subjects want to show themselves in a better light than is actually correct. It is then assumed that the subjects had sought the examiner's approval by presenting the best possible image of themselves; 23 gifted children, referred to as GC (10 girls, 13 boys) aged between 9 and 13 years (mean age=11 years 3 months or 135 months, standard deviation=14) took part in the study. The selection criteria required the subjects to possess an Intelligence Quotient (IQ) calculated using one of the Weschler tests (WPPSI or WISC III depending on age) greater than or equal to 130 (mean IQ=145.23, standard deviation=7.93); 20 were attending private schools and 3 were in the state education system. They were all attending special "GC" classes to which they had been admitted solely on the basis of an IQ test conducted by a psychologist. Their teachers had volunteered to take these classes and had received appropriate training. The pupils had no record of any neurological or physical antecedents, were all French-speaking, were not taking any toxic substances and had never consulted a psychologist or psychiatrist. They were all in advance by one to two years in terms of academic level. They were matched with the control subjects by real age and not mental age and as a function of their parents' socio-economic level. The mean age of this latter group was 11 years, 4 months (standard deviation=14 months; minimum=8 years 11 months, maximum=13 years 1 month) and the group consisted of 14 girls and 9 boys. It was similar to the target group in terms of age, gender, key childhood experiences, divorces, separations and the death or illness of close relations. They had never consulted a child psychologist or been hospitalized for related problems, were not following any psychotherapy, were neither behind nor advanced in terms of academic age and came from normal classes. Their mean Intelligence Quotient (IQ) was 106.04 (standard deviation=5.39). Children attending special classes (European, Franco-German, music, sport, etc.) were excluded in order to obtain as "standardized" a group as possible. The following tools were used: 1) The Child Behaviour Check List (CBCL), a self-questionnaire developed in 1978 by Achenbach in the USA, which is one of the most frequently used child psychopathology measuring tools both in research and in clinical practice. It is intended to provide a standardized description of emotional and/or behavioral problems as observed by parents in children aged between 4 and 16 years. A French version, "la liste des comportements pour les enfants", has been developed and used for a subsample of the boys aged between 6 and 11 years (Fombonne and Vermeersch, 1997). 2) Carré's "self-esteem inventory" (SEI) was created by Carré (1984) in order to test the level of self-esteem. This tool is designed to measure the subject's evaluation of himself or herself in the social, family, academic and general fields. A "lie" scale makes it possible to reject invalidated tests. 3) The EDICODE is an instrument designed to gather and quantify the speech produced by the subject during a semi-structured interview. It is rated by the interviewer and is therefore dependent on his or her subjective evaluation. It was constructed within a clinical research perspective (Pierrhumbert et al., 1999) and is based on the theory of attachment (Main and Goldwyn, 1985-1994). EDICODE consists of 21 items presented in the form of differential semantic scales. These items are then grouped into 5 factors or scales (containing non-redundant items) that cover the following dimensions: fluidity (associative richness, ease of access to memories, participation in the interview), coherence (the speech is "focused" and structured), appropriateness (appropriate relational distance, confidence in relations, capacity for emotional control), reflection (consideration of one's own mental state and that of others as well as of the influence of such states), authenticity (spontaneous, lively speech). The comparison of 23 gifted children (GC) and 23 controls matched on age, sex and school grade revealed that the scores for academic self-esteem, total self-esteem and lie-scale were significantly lower than those observed in the control group (p<0.006, p=0.03, p<0.0001 respectively) and that the depression scores were significantly higher in the gifted children (p=0.021). Significant correlations are only observed in the group of gifted children. The correlation analyses reveal that the lower the general self-esteem, academic self-esteem and total self-esteem values had fallen, the higher the depression (r=- 0.59, r=- 0.67 and r=- 0.76 respectively), hyperactivity (r=- 0.47, r=- 0.82 et r=- 0.59) and total psychopathology (r=- 0.56, r=- 0.67 et r=- 0.75) scores were. Similarly, the lower the general and total self-esteem scores, the higher the aggression scores (r=- 0.56 and r=- 0.68 respectively). Academic self-esteem was the only value to be negatively correlated with communication disorders (r=- 0.79) and somatization symptoms (r=- 0.49). Finally, social self-esteem, family self-esteem and the lie scale were not correlated with any CBCL variable. The regression analyses indicate that academic self-esteem is the variable that explains the depression scores. The gifted children in our study therefore manifested a lack of self-esteem, and in particular a lack of academic self-esteem, coupled with depressive symptoms. For Coopersmith (1984), self-esteem is a function of experienced events in the various sectors in question, while Gibello (1992) sees a link between inhibition or academic disinvestment and everything that may generate anxiety and/or depression in the subject. We can hypothesize that the difficulties experienced by these children derive, at least in part, from their specific characteristics, namely their internal and social dysschynchronism (Terrassier, 1981). Among its other effects, this dyssynchronism leads to a school life that is often difficult or even chaotic, resulting in a general level of self-esteem, and more particularly an academic self-esteem, that is lower than the mean. These considerations might then, in their turn, generate psychopathological symptoms such as depression or hyperactivity (Revol et al., 2002) which have repercussions that affect the effectiveness of the children's school work. This study suggests the need to verify whether similar results are observed in gifted children who do not attend special classes and children who have not yet been identified as gifted. Furthermore, our results indicate that these children are liable to a specific vulnerability in the emotional and behavioral domains that needs to be emphasized. They stress the need for early preventive measures to combat the emotional and behavioral difficulties experienced by gifted children and emphasize the importance of continuing to conduct this type of study in order to explain and specify the origin of these difficulties.

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OBJECTIVE OF ANALYSIS: The objective of this analysis is to examine the safety and effectiveness of percutaneous vertebroplasty for treatment of osteoporotic vertebral compression fractures (VCFs) compared with conservative treatment. Osteoporosis and associated fractures are important health issues in ageing populations. Vertebral compression fracture secondary to osteoporosis is a cause of morbidity in older adults. VCFs can affect both genders, but are more common among elderly females and can occur as a result of a fall or a minor trauma. The fracture may occur spontaneously during a simple activity such as picking up an object or rising up from a chair. Pain originating from the fracture site frequently increases with weight bearing. It is most severe during the first few weeks and decreases with rest and inactivity. Traditional treatment of painful VCFs includes bed rest, analgesic use, back bracing and muscle relaxants. The comorbidities associated with VCFs include deep venous thrombosis, acceleration of osteopenea, loss of height, respiratory problems and emotional problems due to chronic pain. Percutaneous vertebroplasty is a minimally invasive surgical procedure that has gained popularity as a new treatment option in the care for these patients. The technique of vertebroplasty was initially developed in France to treat osteolytic metastasis, myeloma, and hemangioma. The indications were further expanded to painful osteoporotic VCFs and subsequently to treatment of asymptomatic VCFs. The mechanism of pain relief, which occurs within minutes to hours after vertebroplasty, is still not known. Pain pathways in the surrounding tissue appear to be altered in response to mechanical, chemical, vascular, and thermal stimuli after the injection of the cement. It has been suggested that mechanisms other than mechanical stabilization of the fracture, such as thermal injury to the nerve endings, results in immediate pain relief. Percutaneous vertebroplasty is performed with the patient in prone position and under local or general anesthesia. The procedure involves fluoroscopic imaging to guide the injection of bone cement into the fractured vertebral body to support the fractured bone. After injection of the cement, the patient is placed in supine position for about 1 hour while the cement hardens. Cement leakage is the most frequent complication of vertebroplasty. The leakages may remain asymptomatic or cause symptoms of nerve irritation through compression of nerve roots. There are several reports of pulmonary cement embolism (PCE) following vertebroplasty. In some cases, the PCE may remain asymptomatic. Symptomatic PCE can be recognized by their clinical signs and symptoms such as chest pain, dyspnea, tachypnea, cyanosis, coughing, hemoptysis, dizziness, and sweating. A literature search was performed on Feb 9, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to February 9, 2010. Studies were initially reviewed by titles and abstracts. For those studies meeting the eligibility criteria, full-text articles were obtained and reviewed. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author. Randomized controlled trials (RCTs) comparing vertebroplasty with a control group or other interventions Adult patients with osteoporotic vertebral fracturesSTUDY SAMPLE SIZE: Studies included 20 or more patientsEnglish language full-reportsPublished between Jan 1 2005 and Feb 9, 2010(eligible studies identified through the Auto Alert function of the search were also included) Non-randomized studiesStudies on conditions other than VCF (e.g. patients with multiple myeloma or metastatic tumors)Studies focused on surgical techniquesStudies lacking outcome measures RESULTS OF EVIDENCE-BASED ANALYSIS: A systematic search yielded 168 citations. The titles and the abstracts of the citations were reviewed and full text of the identified citations was retrieved for further consideration. Upon review of the full publications and applying the inclusion and exclusion criteria, 5 RCTs were identified. Of these, two compared vertebroplasty with sham procedure, two compared vertebroplasty with conservative treatment, and one compared vertebroplasty with balloon kyphoplasty. Recently, the results of two blinded randomized placebo-controlled trials of percutaneous vertebroplasty were reported. These trials, providing the highest quality of evidence available to date, do not support the use of vertebroplasty in patients with painful osteoporotic vertebral compression fractures. Based on the results of these trials, vertebroplasty offer no additional benefit over usual care and is not risk free. In these trials the treatment allocation was blinded to the patients and outcome assessors. The control group received a sham procedure simulating vertebroplasty to minimize the effect of expectations and to reduce the potential for bias in self-reporting of outcomes. Both trials applied stringent exclusion criteria so that the results are generalizable to the patient populations that are candidates for vertebroplasty. In both trials vertebroplasty procedures were performed by highly skilled interventionists. Multiple valid outcome measures including pain, physical, mental, and social function were employed to test the between group differences in outcomes. Prior to these two trials, there were two open randomized trials in which vertebroplasty was compared with conservative medical treatment. In the first randomized trial, patients were allowed to cross over to the other arm and had to be stopped after two weeks due to the high numbers of patients crossing over. The other study did not allow cross over and recently published the results of 12 months follow-up. The following is the summary of the results of these 4 trials: Two blinded RCTs on vertebroplasty provide the highest level of evidence available to date. Results of these two trials are supported by findings of an open randomized trial with 12 months follow-up. Blinded RCTs showed: No significant differences in pain scores of patients who received vertebroplasty and patients who received a sham procedure as measured at 3 days, 2 weeks and 1 month in one study and at 1 week, 1 month, 3 months, and 6 months in the other.The observed differences in pain scores between the two groups were neither statistically significant nor clinically important at any time points.The above findings were consistent with the findings of an open RCT in which patients were followed for 12 months. This study showed that improvement in pain was similar between the two groups at 3 months and were sustained to 12 months.In the blinded RCTs, physical, mental, and social functioning were measured at the above time points using 4-5 of the following 7 instruments: RDQ, EQ-5D, SF-36 PCS, SF-36 MCS, AQoL, QUALEFFO, SOF-ADLThere were no significant differences in any of these measures between patients who received vertebroplasty and patients who received a sham procedure at any of the above time points (with a few exceptions in favour of control intervention).These findings were also consistent with the findings of an open RCT which demonstrated no significant between group differences in scores of ED-5Q, SF-36 PCS, SF 36 MCS, DPQ, Barthel, and MMSE which measure physical, mental, and social functioning (with a few exceptions in favour of control intervention).One small (n=34) open RCT with a two week follow-up detected a significantly higher improvement in pain scores at 1 day after the intervention in vertebroplasty group compared with conservative treatment group. However, at 2 weeks follow-up, this difference was smaller and was not statistically significant.Conservative treatment was associated with fewer clinically important complicationsRisk of new VCFs following vertebroplasty was higher than those in conservative treatment but it requires further investigation.

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Trauma is a leading cause of mortality and morbidity worldwide, and thus represents a great global health challenge. The World Health Organization (WHO) estimated that 9% of deaths in the world are the result of trauma.<sup1</sup In addition, approximately 100 million people are temporarily or permanently disabled every year.<sup2</sup The situation is no different in Qatar, and injury related morbidity and mortality is increasing in the entire region, with road traffic collisions (RTCs) being the most common mechanism.<sup1</sup It is well recognized now that trauma care provided in high-volume, dedicated, level-one trauma centers, improves outcome. Studies have also looked at what are the components of a trauma system that contribute to their effectiveness<sup2</sup. However, in general, it usually implies a high-volume of cases, dedicated full-time trauma qualified professionals, a solid pre-hospital system, a multidisciplinary team, and excellent rehabilitation services. Similarly, critically injured trauma patients managed in a dedicated trauma intensive care unit (TICU), has been shown to improve outcomes, especially for polytrauma patients with traumatic brain injury (TBI).<sup3</sup In fact, the American College of Surgeons (ACS) Committee on Trauma requires verified trauma centers to have a designated ICU, and that a trauma surgeon be its director.<sup4</sup Furthermore, studies have shown that for TBI, it is not necessary for this ICU to be a neurocritical care unit, but rather it should be a unit that is dedicated to trauma, that has standardized protocols for TBI management.<sup5,6</sup In fact, the outcomes are better in the latter, with lower mortality in multiple-injured patients with TBI, when admitted to a TICU (versus a medical-surgical ICU or neurocritical care unit).<sup3</sup These benefits were shown to increase, with increased injury severity. The proposed reason for this is thought to be due to the associated injuries being managed better.<sup7</sup The aim of this editorial is to describe the TICU at Hamad General Hospital (HGH), at Hamad Medical Corporation (HMC), including a comparison of its data and outcomes with other similar trauma centers in the world. The Qatar Trauma Registry, as well as previous publications from our Trauma Center,<sup1,8</sup were used to obtain HGH TICU and worldwide Level-1 Trauma Center standards, respectively. With respect to HGH, the TICU is part of an integrated trauma program, the only level-1 trauma centre in Qatar. It provides the highest standard of care for critically-ill trauma patients admitted at HGH, striving to achieve the best outcomes, excellence in evidence-based patient care, up to date technology, and a high level of academics in research and teaching. This integrated program includes an excellent pre-hospital unit, emergency and trauma resuscitation unit, TICU, trauma step-down unit (TSDU), inpatient ward, and rehabilitation unit. The new TICU is a closed 19-bed unit, that was inaugurated in 2016, is managed 24/7 by highly qualified and experienced intensivists (9 senior consultants and consultants), along with 24 well-trained and experienced associate consultants or specialists, and fellows and residents in training, as well as expert nursing staff (1:1 nurse to patient ratio) and allied health professionals (respiratory therapists, pharmacists, dieticians, physiotherapists, occupational therapists, social workers, case managers, and psychologists). It is supported by all medical and surgical subspecialty services. It is equipped with the latest state-of-the-art technology and equipment, including 'intelligent ventilators", neuro-monitoring devices, ultrasound, point-of-care testing such as arterial blood gas and rotational thromboelastrometry (ROTEM), and video airway devices. The TICU is a teaching unit, linked to the HMC Medical Education department, with presence of fellows, and residents (see below for details). Medical students (Clerkship level) from Weill-Cornell Medicine Qatar also complete a one-week rotation in the TICU, as part of their exposure to critical care. The first batch of clerks from Qatar University College of Medicine are expected to start rotating in the TICU soon. The Trauma Critical Care Fellowship Program (TCCFP) is an ACGME (Accreditation Council for Graduate Medical Education) fellowship that was established over seven years ago. To date, over 40 physicians from both within, and out of, the trauma department have completed the program. Up to seven fellows, including international candidates, are trained each year. A number of physicians have succeeded in gaining the European Diploma of Intensive Care Medicine (EDIC). The program continues to attract many applicants from various specialties including surgery, anesthesia, and emergency medicine. An increasing number of international physicians from Europe and South America have expressed interest in applying for our fellowship. The first international fellows are likely to join us from early 2020. Residents (from general surgery, ER, ENT, plastics, orthopedics, and neurosurgery) rotate (one to three months' rotations) in the TICU, and are actively part of the clinical team. There were 568 admissions to the TICU in 2018. The patients admitted were either mainly polytrauma patients with varying degrees and combinations of head, chest, abdominal, pelvic, spine, and orthopedic injuries, or isolated-TBI. Of these patients, 378 were severely injured with an injury severity score (ISS)<sup9</sup greater than 16. According to previously published data from our Trauma Centre,<sup1,8</sup our mortality rates (overall approximately 6-7%, as well as when looked at in terms of early and late deaths) compare favorably with other trauma centers around the world, when looking at similarly sized retrospective studies. The TICU continues to be an active member of the Critical Care Network of HMC.<sup10</sup This network involves all of the ICU's in all the HMC facilities. The main processes that the TICU is presently involved in as part of this network are: patient flow, clinical practice guidelines, evaluation and procurement of technologies, HMC sepsis program, and in general, taking part in any process that pertains to critical care at HMC. A number of quality improvement projects are being undertaken in the TICU. Examples of such projects include: - Decreasing rates of infection in TICU- Score-guided sedation orders to decrease sedation use, ventilator days and length of stay- Reducing blood taking and associated costs- Sepsis alert response and bundle compliance- Medical and surgical management of rib fracturesA multidisciplinary team of physicians, nurses, and allied health professionals participate in these projects, and meet once a month to review all projects. Similarly, many research projects are taking place in the TICU, in coordination with the Trauma Research program, and often in collaboration with other departments (local and international). Examples of some of the research projects include: - The "POLAR" study (RCT on Hypothermia in TBI)<sup11</sup- B-blockers in TBI (RCT-ongoing)- Tranexamic acid (TXA) for bleeding in trauma (RCT-ongoing) The team is also involved in conducting systematic reviews in relation to the role of transcranial doppler in TBI,<sup12</sup sepsis in TBI patients (ongoing), self-extubation in TBI patients,<sup13</sup safety and efficacy of phenytoin in TBI (ongoing), and optic nerve diameter for predicting outcome in TBI (submitted). The TICU at HGH is a high-volume, high acuity unit that manages all the severely injured trauma patients in Qatar. It is well staffed with highly trained and qualified personnel, and utilizes the latest in technology and state-of-the-art equipment. It performs very well, when compared to other similar units in the world, and achieves a comparable, or even lower mortality rate. With continued great support from the hospital, corporation administration, and Ministry of Public Health, the future goals of the TICU will be to maintain and improve upon the high standards of clinical care it provides, as well as perform a high quality and quantity of research, quality improvement initiatives, and educational work, in order for it to be amongst the best trauma critical care units in the world.

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Lilium lancifolium Thunb., commonly known as Juandan lily and tiger lily, is widely cultivated in China for its edible bulbs and medicinal properties, with a commercial value worth of ~RMB 6 billion Yuan per year. Bulb rot is an increasingly common disease on L. lancifolium, significantly impacting both the quantity and quality of the main product, the scaled bulbs. Typically, the causal pathogens invade the plant through wounds in the root or the ends of the bulb, causing the roots and bulb to brown and rot, which can eventually lead to stem wilt and death of the whole plants. During pathogenesis, the infected bulbs typically turn from white to brown, with sunken lesions and later the scales flaking off from the base of the bulb (Figure 1A and 1B). Plants growing from infected bulbs are generally short, with discolored leaves, wilting, and death at an early stage. Bulb rot is commonly observed in fields with excess water and a history of continuous Juandan lily cultivation. For this study, wilted L. lancifolium plants with rotted bulbs were collected from Longshan in Hunan, Enshi in Hubei, Yixing in Jiangsu, and Lu'an in Anhui in 2018 and 2019. Infected bulbs were surface sterilized with 75% ethanol for 30 seconds, followed by disinfection with 2% sodium hypochlorite for 5 minutes, and then rinsing with sterile water three times. The surface-sterilized tissue was divided into small pieces of 0.5 × 0.5 cm in size, placed on potato dextrose agar (PDA) medium containing 50 mg/l streptomycin sulfate, and incubated at 25℃. Mycelia growing from diseased tissues were sub-cultured onto fresh PDA medium to obtain pure culture, which formed dense white hyphae after a few days (Figure 1C and 1D). Colonies on PDA produced abundant condia about 15 days after subculturing. Microconidia were abundant, solitary, thin walled, hyaline, ovoid, 0 to 1 septate, with an average size of 6.1 × 2.6 μm (n=50) (Figure 1E). Macroconidia had a curved apical cell and foot-like basal cell with 3 to 5 septa, with an average size of 35.4 × 4.3 μm (n=30) (Figure 1E). No chlamydospore was observed. These morphological characteristics of the causal pathogen were similar to those of Fusarium spp. (Leslie et al., 2006). To identify the Fusarium isolates to species level, DNA fragments of the internal transcribed spacer (ITS) regions of the ribosomal RNA gene cluster, translation elongation factor subunit 1-alpha (TEF1-α), and RNA polymerase II subunit 2 (RPB2) genes were amplified using primers ITS1/ITS4, EF1/EF2, and 7cF/11aR respectively and sequenced (Choi et al. 2018; Jiang et al. 2018; Choi et al. 2017). BLAST analyses showed that the ITS (GenBank Accession No. MT549849), TEF1-α (GenBank Accession No. MT553348), and RPB2 (Accession No. MW201686) sequences of our isolates shared the highest sequence identities (98-100%) with those of F. fujikuroi reference strains in GenBank. A phylogenetic tree showing the relationship between one of our strains, S106, and those of the closely related species within the F. fujikuroi species complex was constructed by the maximum likelihood method using MEGA X (Kumar et al. 2018) (Figure 2). Based on the morphological characteristics and DNA sequences, the strains were identified as F. fujikuroi sensu stricto. We used two methods, an ex vivo assay using Juandan lily bulb scales and an in vivo assay using potted Juandan lily plants, to confirm pathogenicity for one representative F. fujikuroi strain from each of the four geographic regions to fulfill Koch's postulates (Bian et al. 2016; Zeng et al. 2019). In the ex vivo assay, actively growing mycelia on PDA plates were cut into 5mm diameter fungal blocks as inocula. To prepare healthy Juandan lily bulb scales as test tissues, healthy fresh scales were first surface sterilized using 75% alcohol for 30 seconds, followed by treatment of 2% sodium hypochlorite for 5 minutes, and then rinsed with sterile water 3 times. The scales were punctured with sterilized dissecting needles, the 5mm mycelial blocks containing the PDA medium were then inoculated on the punctured wound of the scales. Sterile PDA culture medium without mycelia was inoculated on the punctured wound as a negative control. After inoculation, Juandan lily scales were placed in sterile culture dishes with two layers of sterilized filter paper and 5ml of sterile water in each dish. Six Juandan lily scales were placed in each dish, with different treatments placed in different dishes, and the dishes were placed in an incubator in the dark at 25℃. After 10 days of incubation, we found that the F. fujikuroi-inoculated Juandan lily bulb scales showed disease symptoms (brownish lesion) similar to those in the original field collected infected bulb samples (Figure 1F). However, such symptoms were not observed in the negative control group. The pathogenicity test was performed 3 times for each isolate, each with six repeats. In the in vivo pathogenicity test using potted lily plants, we prepared actively growing cultures of our F. fujikuroi strains by incubating them in a liquid medium, the potato dextrose broth, for 3 days in a shaker-incubator at 25℃ and 180rpm. The asexual spores conidia from the fungal cultures were harvested by filtration through eight layers of sterile cheese clothes and with spore concentrations adjusted to 1×107 conidia per ml. Healthy Juandan lily bulbs were selected and one bulb was planted in each pot containing sterilized soil. Each pot was inoculated with 1ml conidia suspension, at the base soil where the bulbs were planted. The pots were placed in a growth chamber at 25℃ with a 12 h light and 12 h dark cycle. Symptoms similar to those observed in diseased bulbs in the field were observed, with symptoms at 30 days after inoculations shown in Figure 3. Specifically, most of the roots, bulb plate and scale tissues of Juandan lily plants inoculated with F. fujikuroi conidia were rotten and turned black, with few new roots. In addition, the infected plants showed stunted growth (Figure 3). In contrast, the uninoculated plants grew normally, with dense new roots and healthy-looking bulbs, and no rot symptom (Figure 3). The fungi were re-isolated from the infected Juandan lily tissues from both pathogenicity assays, following the procedures described above for isolating and identifying the fungal cultures from infected field samples. These re-isolated fungi were shown to have colony morphology and DNA sequences at the three loci identical to those of our inoculated F. fujikuroi strains. Several Fusarium species have been reported as pathogens of lily plants in China, including F. oxysporum, F. solani and F. tricinctum (Li, et al., 1995; Li, et al., 2013). In addition, F. redolens has been reported previously in ornamental lily in Ukraine (Zerova, 1940). Indeed, Fusarium moniliforme, one of the disused synonyms of F. fujikuroi (Seifert et al. 2003), has been reported as a causal agent for diseases in lily. However, it's now known that the originally defined F. fujikuroi sensu lato is in fact a large species complex consisting of over 60 recognized species, including F. fujikuroi sensu stricto (Moussa et al. 2017; Choi et al. 2018). In addition, there are over 100 species in the genus Lilium as well as many other species with their common names including the word "lily" but are not in the Lilium genus. To our knowledge, this is the first confirmed report of bulb rot of Juandan lily L. lancifolium caused by F. fujikuroi sensu stricto in China. Our result should help with future monitoring and control of Juandan lily diseases.

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The results of these experiments are definite. There is, in the first place, a very striking difference with regard to precipitate formation between the acid and alkaline solutions of salvarsan when injected intravenously. Intravenous injections of alkaline solutions of salvarsan produce no precipitate in the blood, while injections of the acid solution nearly always give a precipitate. Furthermore, after injections of the acid solution, there is a striking difference between the blood from the right side of the heart and that from the left side. At the end of injections of an acid solution of salvarsan, a precipitate was seldom present in the arterial blood. Blood taken from the left ventricle at this time (at autopsy) also showed no precipitate in a large majority of cases; in eight experiments there was no precipitate, in three a doubtful trace of precipitate, and in one a definite small amount. On the other hand, blood obtained from the right ventricle and the lungs showed a very different condition. In ten out of twelve animals (rabbits and dogs), blood from the right ventricle contained a definite precipitate, and in a number of these cases the amount of precipitate was large. Blood squeezed from the lungs showed in eight out of ten cases at least as much precipitate as was found in the blood from the right ventricle. The results of injections of alkaline solutions of salvarsan, as pointed out before, are quite different from those produced by the acid solutions. In thirteen experiments upon dogs and rabbits, no trace of a precipitate was found in the arterial blood, the blood from the left ventricle, the right ventricle, or the lungs. There is no apparent difference in the process of precipitate formation whether salvarsan solutions and the blood are mixed in vivo or in vitro. In both mixtures the acid solutions produce a precipitate, while the alkaline solutions of salvarsan do not. These experiments have demonstrated the fact that a precipitate is present in the blood after an injection of an acid solution of salvarsan. One would expect that such a precipitate, consisting as it usually does of rather coarse particles, would, if brought to the medulla, cause immediate death by producing emboli. However, the freedom from such occurrences may be explained by the fact that the precipitate, which is abundantly present in the right ventricle, is only rarely seen in blood taken from the carotid or femoral arteries or even from the left ventricle itself. The fact itself, however, is quite difficult to interpret. It might perhaps be assumed that the precipitate is filtered out during its passage through the lung capillaries. If this is the case, we might expect intravenous injections of salvarsan to produce embolism in the pulmonary vessels with consequent fatal results. As a matter of fact, we have in the recent literature an instance which seems to point to such a result. Miessner (6) tried the effects of salvarsan in cattle which had foot and mouth disease. He used at first the acid solution, and though the dose was small, seven milligrams per kilo of body weight, all the animals (four) died in from ten hours to two days after the injection. They all showed labored respiration during or soon after the injection of salvarsan. He then decreased the dose to five milligrams per kilo of body weight, and repeated the experiments. He used also normal animals as controls upon those which had the foot and mouth disease. Both the sick and normal (control) animals showed labored respiration. One died after four days. At autopsy all organs except the lungs appeared to be normal. The lungs presented the following appearance: There were grayish yellow spots scattered irregularly over the surface. On the cut surface these were seen as grayish yellow spots the size of a pea, which appeared in groups and which sometimes filled a lobule completely. Other spots were surrounded by a small area of dark red lung parenchyma. The affected portion contained no air and felt solid. In adjacent parts the tissue seemed normal. A microscopic examination showed that the larger and smaller pulmonary arteries were filled with uniform, homogeneous, yellow masses. About the vessels there was a serous exudate. In brief, the changes seen indicated, he believed, that there was a thrombosis of the blood-vessels with inflammatory exudative changes of the lung parenchyma. Miessner states that a similar pathological condition was found in a normal control animal that died. He suggests that the acid solution of salvarsan might lead in man to a thrombosis of the pulmonary arteries. In support of this suggestion, he mentions a case reported to him by Ehrlich of a man who died following the injection of an acid solution. The lung picture in this case was somewhat similar to that which he had found in cattle. It may be mentioned in passing that Miessner found that alkaline solutions of salvarsan were far less toxic than the acid solutions. Animals (cattle) which received in an alkaline solution 400 milligrams of salvarsan per kilo of body weight did not show the least symptom of disturbance. In contrast to Miessner's results seem to stand my observations and those of Auer described in the introduction of this paper. Auer (5) found (in 8 rabbits) that no evident harmful effects followed the injections of very large doses of the acid solution, if they were given in a highly diluted form (one tenth per cent.). In my own experiments, it was found that a one fifth per cent. acid solution (3 rabbits) and even a one half per cent. solution (1 rabbit) produced no ill effects. The experiments described in this paper make it certain that the doses of the acid solution given to these last mentioned four animals must have produced a precipitate in the right ventricle and in the lungs, and yet the animals survived and showed no symptoms whatever of disturbance following the injection. This difference between our observations and those of Miessner might perhaps be explained by the assumption that the action of salvarsan in acid solution is more deleterious to cattle than to rabbits. Furthermore, Miessner seems to have injected the salvarsan in high concentrations. In one instance, in which figures are given, the drug was administered in a five per cent. solution. As mentioned before, Auer has shown the importance of the concentration. While in a one tenth per cent. solution twenty and thirty milligrams per kilo of body weight of the acid solution may be injected with impunity, even six or seven milligrams per kilo may prove rapidly fatal when injected in a one half per cent. solution. Our own results, however, leave us with two puzzling questions : First, if the acid solution of salvarsan causes such a coarse precipitate in the right ventricle and in the lungs, how does it happen that this precipitate does not bring about the death of the animal? Second, what is the real cause of the remarkable fact that this precipitate does not pass over into the arterial side of the circulation? Does the precipitate undergo a profound chemical or mechanical change while it passes through the lung capillaries? In future investigations we may try to answer these interesting questions. For the present, it is necessary to be content with the establishment of the bare facts as they are presented in the conclusions.

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For nearly a century, scholars have sought to understand, measure, and explain giftedness. Succeeding theories and empirical investigations have often built on earlier work, complementing or sometimes clashing over conceptions of talent or contesting the mechanisms of talent development. Some have even suggested that giftedness itself is a misnomer, mistaken for the results of endless practice or social advantage. In surveying the landscape of current knowledge about giftedness and gifted education, this monograph will advance a set of interrelated arguments: The abilities of individuals do matter, particularly their abilities in specific talent domains; different talent domains have different developmental trajectories that vary as to when they start, peak, and end; and opportunities provided by society are crucial at every point in the talent-development process. We argue that society must strive to promote these opportunities but that individuals with talent also have some responsibility for their own growth and development. Furthermore, the research knowledge base indicates that psychosocial variables are determining influences in the successful development of talent. Finally, outstanding achievement or eminence ought to be the chief goal of gifted education. We assert that aspiring to fulfill one's talents and abilities in the form of transcendent creative contributions will lead to high levels of personal satisfaction and self-actualization as well as produce yet unimaginable scientific, aesthetic, and practical benefits to society. To frame our discussion, we propose a definition of giftedness that we intend to be comprehensive. Giftedness is the manifestation of performance that is clearly at the upper end of the distribution in a talent domain even relative to other high-functioning individuals in that domain. Further, giftedness can be viewed as developmental in that in the beginning stages, potential is the key variable; in later stages, achievement is the measure of giftedness; and in fully developed talents, eminence is the basis on which this label is granted. Psychosocial variables play an essential role in the manifestation of giftedness at every developmental stage. Both cognitive and psychosocial variables are malleable and need to be deliberately cultivated. Our goal here is to provide a definition that is useful across all domains of endeavor and acknowledges several perspectives about giftedness on which there is a fairly broad scientific consensus. Giftedness (a) reflects the values of society; (b) is typically manifested in actual outcomes, especially in adulthood; (c) is specific to domains of endeavor; (d) is the result of the coalescing of biological, pedagogical, psychological, and psychosocial factors; and (e) is relative not just to the ordinary (e.g., a child with exceptional art ability compared to peers) but to the extraordinary (e.g., an artist who revolutionizes a field of art). In this monograph, our goal is to review and summarize what we have learned about giftedness from the literature in psychological science and suggest some directions for the field of gifted education. We begin with a discussion of how giftedness is defined (see above). In the second section, we review the reasons why giftedness is often excluded from major conversations on educational policy, and then offer rebuttals to these arguments. In spite of concerns for the future of innovation in the United States, the education research and policy communities have been generally resistant to addressing academic giftedness in research, policy, and practice. The resistance is derived from the assumption that academically gifted children will be successful no matter what educational environment they are placed in, and because their families are believed to be more highly educated and hold above-average access to human capital wealth. These arguments run counter to psychological science indicating the need for all students to be challenged in their schoolwork and that effort and appropriate educational programing, training and support are required to develop a student's talents and abilities. In fact, high-ability students in the United States are not faring well on international comparisons. The scores of advanced students in the United States with at least one college-educated parent were lower than the scores of students in 16 other developed countries regardless of parental education level. In the third section, we summarize areas of consensus and controversy in gifted education, using the extant psychological literature to evaluate these positions. Psychological science points to several variables associated with outstanding achievement. The most important of these include general and domain-specific ability, creativity, motivation and mindset, task commitment, passion, interest, opportunity, and chance. Consensus has not been achieved in the field however in four main areas: What are the most important factors that contribute to the acuities or propensities that can serve as signs of potential talent? What are potential barriers to acquiring the "gifted" label? What are the expected outcomes of gifted education? And how should gifted students be educated? In the fourth section, we provide an overview of the major models of giftedness from the giftedness literature. Four models have served as the foundation for programs used in schools in the United States and in other countries. Most of the research associated with these models focuses on the precollegiate and early university years. Other talent-development models described are designed to explain the evolution of talent over time, going beyond the school years into adult eminence (but these have been applied only by out-of-school programs as the basis for educating gifted students). In the fifth section we present methodological challenges to conducting research on gifted populations, including definitions of giftedness and talent that are not standardized, test ceilings that are too low to measure progress or growth, comparison groups that are hard to find for extraordinary individuals, and insufficient training in the use of statistical methods that can address some of these challenges. In the sixth section, we propose a comprehensive model of trajectories of gifted performance from novice to eminence using examples from several domains. This model takes into account when a domain can first be expressed meaningfully-whether in childhood, adolescence, or adulthood. It also takes into account what we currently know about the acuities or propensities that can serve as signs of potential talent. Budding talents are usually recognized, developed, and supported by parents, teachers, and mentors. Those individuals may or may not offer guidance for the talented individual in the psychological strengths and social skills needed to move from one stage of development to the next. We developed the model with the following principles in mind: Abilities matter, domains of talent have varying developmental trajectories, opportunities need to be provided to young people and taken by them as well, psychosocial variables are determining factors in the successful development of talent, and eminence is the aspired outcome of gifted education. In the seventh section, we outline a research agenda for the field. This agenda, presented in the form of research questions, focuses on two central variables associated with the development of talent-opportunity and motivation-and is organized according to the degree to which access to talent development is high or low and whether an individual is highly motivated or not. Finally, in the eighth section, we summarize implications for the field in undertaking our proposed perspectives. These include a shift toward identification of talent within domains, the creation of identification processes based on the developmental trajectories of talent domains, the provision of opportunities along with monitoring for response and commitment on the part of participants, provision of coaching in psychosocial skills, and organization of programs around the tools needed to reach the highest possible levels of creative performance or productivity.

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Men who have sex with men (MSM) remain at great risk for HIV infection. Program planners and policy makers need descriptions of interventions and quantitative estimates of intervention effects to make informed decisions concerning prevention funding and research. The number of intervention strategies for MSM that have been examined with strong research designs has increased substantially in the past few years. 1. To locate and describe outcome studies evaluating the effects of behavioral HIV prevention interventions for MSM.2. To summarize the effectiveness of these interventions in reducing unprotected anal sex.3. To identify study characteristics associated with effectiveness.4. To identify gaps and indicate future research, policy, and practice needs. We searched electronic databases, current journals, manuscripts submitted by researchers, bibliographies of relevant articles, conference proceedings, and other reviews for published and unpublished reports from 1988 through December 2007. We also asked researchers working in HIV prevention about new and ongoing studies. Studies were considered in scope if they examined the effects of behavioral interventions aimed at reducing risk for HIV or STD transmission among MSM. We reviewed studies in scope for criteria of outcome relevance (measurement of at least one of a list of behavioral or biologic outcomes, e.g., unprotected sex or incidence of HIV infections) and methodologic rigor (randomized controlled trials or certain strong quasi-experimental designs with comparison groups). We used fixed and random effects models to summarize rate ratios (RR) comparing intervention and control groups with respect to count outcomes (number of occasions of or partners for unprotected anal sex), and corresponding prevalence ratios (PR) for dichotomous outcomes (any unprotected anal sex vs. none). We used published formulas to convert effect sizes and their variances for count and dichotomous outcomes where necessary. We accounted for intraclass correlation (ICC) in community-level studies and adjusted for baseline conditions in all studies. We present separate results by intervention format (small group, individual, or community-level) and by type of intervention delivered to the comparison group (minimal or no HIV prevention in the comparison condition versus standard or other HIV prevention in the comparison condition). We examine rate ratios stratified according to characteristics of participants, design, implementation, and intervention content. For small group and individual-level interventions we used a stepwise selection process to identify a multivariable model of predictors of reduction in occasions of or partners for unprotected anal sex. We used funnel plots to examine publication bias, and Q (a chi-squared statistic with degrees of freedom = number of interventions minus 1) to test for heterogeneity. We found 44 studies evaluating 58 interventions with 18,585 participants. Formats included 26 small group interventions, 21 individual-level interventions, and 11 community-level interventions. Sixteen of the 58 interventions focused on HIV-positives. The 40 interventions that were measured against minimal to no HIV prevention intervention reduced occasions of or partners for unprotected anal sex by 27% (95% confidence interval [CI] = 15% to 37%). The other 18 interventions reduced unprotected anal sex by 17% beyond changes observed in standard or other interventions (CI = 5% to 27%). Intervention effects were statistically homogeneous, and no independent variable was statistically significantly associated with intervention effects at alpha=.05. However, a multivariable model selected by backward stepwise elimination identified four study characteristics associated with reduction in occasions of or partners for unprotected anal sex among small group and individual-level interventions at alpha=.10. The most favorable reductions in episodes of or partners for unprotected anal sex (33% to 35% decreases) were observed among studies with count outcomes, those with shorter intervention spans (&lt;=1 month), those with better retention in the intervention condition than in the comparison condition, and those with minimal to no HIV prevention intervention delivered to the comparison condition. Because there were only 11 community-level studies we did not search for a multivariable model for community-level interventions. In stratified analyses including only one variable at a time, the greatest reductions (40% to 54% decreases) in number of episodes of or partners for unprotected anal sex among community-level interventions were observed among studies where groups were assigned randomly rather than by convenience, studies with shorter recall periods and longer follow-up, studies with more than 25% non-gay identifying MSM, studies in which at least 90% of participants were white, and studies in which the intervention addressed development of personal skills. Behavioral interventions reduce self-reported unprotected anal sex among MSM. These results indicate that HIV prevention for this population can work and should be supported. Results of previous studies provide a benchmark for expectations in new studies. Meta-analysis can inform future design and implementation in terms of sample size, target populations, settings, goals for process measures, and intervention content. When effects differ by design variables, which are deliberately selected and planned, awareness of these characteristics may be beneficial to future designs. Researchers designing future small group and individual-level studies should keep in mind that to date, effects of the greatest magnitude have been observed in studies that used count outcomes and a shorter intervention span (up to 1 month). Among small group and individual-level studies, effects were also greatest when the comparison condition included minimal to no HIV prevention content. Nevertheless, statistically significant favorable effects were also seen when the comparison condition included standard or other HIV prevention content. Researchers choosing the latter option for new studies should plan for larger sample sizes based on the smaller expected net intervention effect noted above. When effects differ by implementation variables, which become evident as the study is conducted but are not usually selected or planned, caution may be advised so that future studies can reduce bias. Because intervention effects were somewhat stronger (though not statistically significantly so) in studies with a greater attrition in the comparison condition, differential retention may be a threat to validity. Extra effort should be given to retaining participants in comparison conditions. Among community-level interventions, intervention effects were strongest among studies with random assignment of groups or communities. Therefore the inclusion of studies where assignment of groups or communities was by convenience did not exaggerate the summary effect. The greater effectiveness of interventions including more than 25% non-gay identifying MSM suggests that when they can be reached, these men may be more responsive than gay-identified men to risk reduction efforts. Non-gay identified MSM may have had less exposure to previous prevention messages, so their initial exposure may have a greater impact. The greater effectiveness of interventions that include efforts to promote personal skills such as keeping condoms available and behavioral self-management indicates that such content merits strong consideration in development and delivery of new interventions for MSM. And the finding that interventions were most effective for majority white populations underscores the critical need for effective interventions for MSM of African and Latino descent. Further research measuring the incidence of HIV and other STDs is needed. Because most studies were conducted among mostly white men in the US and Europe, more evaluations of interventions are needed for African American and Hispanic MSM as well as MSM in the developing world. More research is also needed to further clarify which behavioral strategies (e.g., reducing unprotected anal sex, having oral sex instead of anal sex, reducing number of partners, avoiding serodiscordant partners, strategic positioning, or reducing anal sex even with condom use) are most effective in reducing transmission among MSM, the messages most effective in promoting these behaviors, and the methods and settings in which these messages can be most effectively delivered.

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Our experiments have confirmed the fact that the so called bacterial allergies are dependent upon a mechanism which differs materially from that determining true protein anaphylaxis. Anaphylaxis to protein substances of the bacteria probably occurs but plays a relatively unimportant rôle in the phenomena of infection. The bacterial allergies, however, are of great importance since they develop rapidly and render the infected animal highly vulnerable to products of the bacterial growth which are relatively innocuous for the normal animal. Neither the type-specific carbohydrate "residue antigens" (the "soluble specific substances" of Avery and Heidelberger) nor the antibodies reacting with them play any part whatever in bacterial allergy, and since these type-specific substances represent the haptophore groups of the whole bacteria by which they react with the agglutinins, precipitins, sensitizers, etc., of immune serum, allergy, as previously determined by Mackenzie and Woo, is in no way related to that phase of resistance which is determined by these antibodies. This does not, however, preclude the possibility that allergic hypersusceptibility may not in some way be related to other factors of resistance more definitely associated with cellular rather than with intravascular reactions. Our previous studies with Jennings and Ward in tuberculosis point in this direction (20). Guinea pigs can be actively sensitized with all the bacteria with which we have worked when repeated injections of whole bacteria or of the protein (nucleoprotein) fraction are administered. Large amounts of the latter are necessary since these materials are indifferent antigens, possibly because of the severe manipulations necessary in their production. Sensitiveness develops usually within 10 days after the first dose and increases with continued treatment for 3 or 4 weeks. Sensitiveness is relatively specific, by which we mean that there is a definite specificity which, however, in highly sensitive animals is not absolute and shows considerable overlapping. Continued treatment with considerable quantities of the above substances leads to gradual desensitization in animals in which there are no chronic foci present, which, as in tuberculosis, tends to continue the sensitization. Attempts at passive sensitization have been irregular and inconclusive. When any degree of sensitiveness has developed after the injection of immune sera, it has appeared late and has been of doubtful specificity. Conversely we have failed in any case to neutralize the activity of the active allergic constituents of bacterial extracts by incubation with any type of immune serum. We have failed so far to show any increased fixation of tuberculin material on the part of tuberculous tissues or on that of living tuberculous animals. These failures, however, seem to us of relatively slight importance since quantitative experiments of this nature are extremely difficult in the case of a substance as delicately potent for the tuberculous animal. On the other hand we have obtained definite, though irregular evidence that the incubation of O.T. with fragments of tuberculous lung tissue (less clearly with other tissues) leads to the formation of a substance that produces allergy-like lesions in the skin of normal guinea pigs. With somewhat greater regularity, similar treatment of O.T. has enhanced the potency of the tuberculin for tuberculous animals. And, in these experiments there was evidence that the factor responsible for this action was not easily separable from the cells themselves. When these experimental data are analytically considered they appear in many respects confusing and contradictory. There has been so much work done on the tuberculin reaction, moreover, that, in the face of experimental inconsistencies it would seem foolhardy to formulate more than tentative suggestions to explain the mechanism of these reactions. Nevertheless there are a few outstanding and sufficiently reliable facts which compel a limited number of definite deductions. In the first place there is no question of the complete independence of the true allergic phenomena from the ordinary bacterial antigen-antibody reactions. We know, moreover, that the allergic substance is chemically separable from the carbohydrate "residue" or haptophore group of the bacteria (Mueller, Laidlaw and Dudley). Indeed it has been shown by Long and Seibert (21) that the active allergic substance is either a protein in itself, or at any rate closely associated with the bacterial protein. Furthermore, the distinct, though limited, specificity of the allergic sensitiveness compels the conclusion that we are dealing with an immunological process in which the tissue cells acquire an increased specific capacity to react with this nitrogenous material, a capacity which, in principle, is not far removed from the supposed "sessile receptor" apparatus which is conventionally held responsible for protein anaphylaxis; and this analogy is further amplified by the apparent desensitization which continued treatment produced in many of our own experiments as well as in those of Mackenzie and Woo. Here, however, the analogy with protein anaphylaxis ends. Passive sensitization with any form of immune serum or with the sera of highly sensitized animals is either feeble or entirely unsuccessful and indicates quite convincingly that, whatever the receptor apparatus of the cells may be, it is not easily given up to the blood stream as are ordinary antibodies. Further than this, our tissue-tuberculin experiments, irregular and occasional as they were, nevertheless convinced us that: 1. The contact with the tissues of tuberculous animals results in the production of a toxic factor, not unlike the autolytic toxic materials of some bacteria. 2. The active cell constituent by which this action is wrought, is not easily separated from the cells, even by energetic methods of extraction. This close association of the entire process with the cells themselves is particularly significant in view of the obvious cell injury in which these delayed allergic effects differ from the ordinary urticarial, evanescent reactions associated with protein anaphylaxis. The process of allergy, as far as we can approach it then, may be conceived as follows: A nitrogenous, probably protein, constituent of the bacterial growth or of its body substance stimulates a specific reaction in the tissue cell by which its specific capacity to establish contact with this constituent is enhanced. The cell is thereby enabled to exert a, probably, enzyme-like effect upon this material in consequence of which a toxic substance is liberated, largely upon or possibly within the cell itself. Both processes may be dependent upon one and the same reaction body. But it seems more likely that increased contact and the increased cell activity are separately developed, an assumption which is rendered probable by the association of the highest degrees of allergy with inflammatory cell reactions, and by the fact that moderate and less specific allergic sensitiveness follows 10 or more days after the administration of considerable amounts of indifferent protein substances to guinea pigs. We interpret this as signifying that such injections may non-speciffcally increase cellular activity, a change which many earlier workers have spoken of as "cell irritability." Both processes are closely associated with the altered cell itself and the factors by which the reaction is brought about are not easily given up to the blood stream as are the antibodies formed in response to injections of proteins or whole bacteria. We are confronted, therefore, with an immunological mechanism which has some close analogies to those others in which circulating antibodies are formed, but which differs from these mainly in the intimacy with which the entire reacting system is associated with the cells themselves. It is difficult to conceive that a functional cell alteration, as profound as this, should be entirely unrelated to the phenomena of susceptibility or resistance.

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The atypical immunophenotype (expression of determinant from the another cell lines than line of origin) of acute leukaemia blast cells are noted in a part of cases. The characteristics and classification of atypical immunophenotypes are not unified and the clinical significance is not yet fully described. The purpose of the study was: precise description of atypical immunophenotypes and analysis of their frequency in different types of acute leukaemia, analysis of association between expression of atypical immunophenotypes and the level of initial leukocytosis, percentage of blast cells in peripheral blood, expression of CD34, analysis of frequency of multidrug resistance molecule (MDR) expression and association between MDR and immunophenotypes of leukaemia cells, analysis of association between atypical immunophenotypes and proliferation, secretion of cytokines (IL-6, TNF) and spontaneous apoptosis of leukaemia cells, analysis of association between atypical immunophenotypes and sensitivity to induction therapy. The bone marrow samples used for routine diagnosis were the basic source of leukaemia cells for the study. The morphological examination and the immunophenotypes of leukaemia cells were done for classification of leukaemia. The immunophenotype and the expression of MDR determination was performed with flow cytometry after staining the cells with monoclonal antibodies (directly labelled) for CD determinants and MDR. The spontaneous proliferation of leukaemia cells was studied with 3H-Thymidine uptake after 3-days culture in vitro. The type of proliferation (autocrine, paracrine) was defined based on comparison of shorter (3-days) and longer (6-days) culture of leukaemia cells. The percentage of apoptotic leukaemia cells was analysed with flow cytometry after staining of leukaemia cells with propidium iodide in subdiploidal region of DNA profile. The secretion of cytokines (IL-6 and TNF) was determined by ELISA technique in supernatants of leukaemia cells cultured for 24 hr in vitro. The biological activity of TNF was determined in the bioassay using L929 mouse cells line. The effect of induction therapy was estimated base on time of cytoreduction in peripheral blood and time of reaching the haematological remission in bone marrow. The study included 230 children with acute leukaemia: lymphoblastic (ALL)--189 children (ALL-proB--19, common ALL--139, ALL-B--5 and ALL-T--26) and myeloid (AML)--34 children. Moreover, into the study 2 cases of acute undifferentiated leukaemia (AUL) and 3--acute mixed lineage leukaemia (AMLL) and 2--biphenotypic leukaemia were included. The all studies of leukaemia cells had been done before the therapy was installed. Basing on the assay of immunophenotypes the following forms of atypical immunophenotypes were distinguished: immunophenotype incomplete, hyperexpression of determinants, asynchronic immunophenotype, coexpression of determinants from the other line than origin of leukaemia cells, balanced expression of determinants from two cells lines (biphenotypic leukaemia) and three cells lines (mixed lineage leukaemia). The atypical immunophenotypes were observed in: 21.1% ALL-proB cases, 34.5% common ALL cases, 42.3% ALL-T and 58.8% AML. The most common form of atypical immunophenotypes was coexpression of determinants from the other cell line. There were no associations between atypical immunophenotypes and the level of initial leukocytosis and percentage of blast cells in peripheral blood. The expression of CD34, recognised as the one of markers of poorer prognosis, was analysed regarding the leukaemia type and immunophenotype of leukaemia cells. The lowest frequency of CD34 expression was noted in ALL-T (28.5%), the highest one in common ALL (62.3%). The significant association between frequency of CD34 and atypical immunophenotypes was observed in AML and ALL-T. Moreover, in common ALL the expression of CD34 was significantly higher when myeloid determinants were present on common ALL cells (common ALL + My) in comparison to coexpression of lymphoid determinants (common ALL + Ly). The frequency of MDR expression (cases with more than 10% of MDR positive cells) was in range between 16.6% in ALL-proB and 78.9% in AML. The mean percentage of cells expressing MDR was low in ALL-proB (10.7%) and high in ALL-T (39.6%). In ALL the atypical immunophenotype was associated with expression of MDR whereas in AML this association did not appear. The common ALL + My leukaemia cells showed higher ability to proliferation in vitro compare with common ALL without atypical immunophenotype. The opposite results were observed in AML. AML leukaemia cells with coexpression of lymphoid determinants (AML + Ly) showed lower proliferation in vitro than AML without atypical immunophenotype. The autocrine type of proliferation was observed frequently in AML (35.3% of cases) than in ALL (14.2%). This type of spontaneous proliferation was observed only when the leukaemia cells without changes in immunophenotype had been cultured. The low level in common ALL and high in AML of spontaneous release of IL-6 and TNF were noted. AML leukaemia cells without changes in immunophenotype released significantly higher amount of these cytokines than AML cells with atypical immunophenotypes (AML + Ly). The above observations suggested that coexpression of myeloid determinants in ALL and lymphoid determinants in AML were leading to changes of some biological properties of these cells. The ALL + My leukaemia cells behaved similarly to myeloid leukaemia cells, while AML + Ly cells showed features of lymphoid leukaemia cells. The common ALL and AML leukaemia cells with atypical immunophenotype showed higher percentage of apoptotic cells (16.1% and 16.9% respectively) comparing to common ALL and AML without changes in immunophenotype (9.0% and 9.2% respectively). The weak negative association of MDR expression and apoptosis suggested the indirect inhibiting influence of MDR on ability of cells to undergo into the apoptosis process. In common ALL and AML with typical immunophenotype of leukaemia cells and ALL-T the level of apoptosis was associated positively with the spontaneous proliferation, whereas this relation was negative in AML with atypical immunophenotype. There were no differences of the time of cytoreduction of leukaemia cells in peripheral blood in B cell origin ALL and AML with or without changes in immunophenotype of blastic cells. In ALL-T + My the time of cytoreduction was significantly longer. However, the expression of CD10 in ALL-T had no effect on cytoreduction time. The expression of MDR in ALL-T with typical immunophenotype was independent marker associated with elongation of cytoreduction time. The time of reaching the complete haematological remission was analysed in 186 children with ALL (ALL-proB--18 children, common ALL--137 children, ALL-T--26) and only 19 children with AML. The longest period of time for reaching the remission was observed in AML, shortest--in ALL-T. In common ALL and ALL-T the expression of myeloid determinants was associated with significant elongation of time of reaching the remission. In the majority of AML cases with coexpression lymphoid determinants, the complete remission was reached. The time needed for the reaching of remission was similar in AML with or without coexpression of lymphoid determinants. The results of this study suggest that coexpression of determinants from the other cell line modify the biological properties of leukaemia cells into the cells from the line of origin of these additional determinants. In ALL the combined expression of MDR and atypical immunophenotype of leukaemia cells were associated with poorer response to induction therapy. In AML the combined expression of CD34 and atypical immunophenotype were associated with response to induction therapy by reaching the complete remission, but without any influence on the time of reaching this remission. The results of analysis of cytoreduction time and time of reaching the remission improved the usefulness of these parameters for the estimation of response to the induction therapy. The clinical importance of these observations consist in characterisation of leukaemia cells potentially resistant to the induction therapy what may suggest the modification and individualization of the induction therapy.

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<bObjective:</b To study the effects of reactive oxygen species (ROS)-responsive antibacterial microneedles (MNs) on the full-thickness skin defect wounds with bacterial colonization in diabetic mice. <bMethods:</b Experimental research methods were adopted. The ROS-responsive crosslinker N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-tetramethylpropane-1,3-diaminium (TSPBA) was first synthesized, and then the polyvinyl alcohol (PVA)-TSPBA MNs, PVA-ε-polylysine (ε-PL)-TSPBA MNs, PVA-TSPBA-sodium hyaluronate (SH) MNs, and PVA-ε-PL-TSPBA-SH MNs were prepared by mixing corresponding ingredients, respectively. The PVA-TSPBA MNs were placed in pure phosphate buffer solution (PBS) and PBS containing hydrogen peroxide, respectively. The degradation of MNs immersed for 0 (immediately), 3, 7, and 10 days was observed to indicate their ROS responsiveness. The standard strains of <iStaphylococcus aureus</i (<iS. aureus</i) and <iEscherichia coli (E. coli)</i cultured in Luria-Bertani medium containing hydrogen peroxide were divided according to the random number table (the same grouping method below) into blank control group (without any treatment, the same below) and 0 g/L ε-PL group, 1.0 g/L ε-PL group, 5.0 g/L ε-PL group, and 10.0 g/L ε-PL group with which PVA-ε-PL-TSPBA MNs containing the corresponding concentration of ε-PL were co-cultured, respectively. Bacterial growth was observed after 24 h of culture, and the relative survival rate of bacteria was calculated (<in</i=3). The mouse fibroblast cell line 3T3 cells at logarithmic growth stage (the same growth stage below) were divided into blank control group and 0 g/L ε-PL group, 1.0 g /L ε-PL group, 5.0 g /L ε-PL group, and 10.0 g /L ε-PL group in which cells were cultured in medium with the extract from PVA-ε-PL-TSPBA MNs containing the corresponding concentration of ε-PL, respectively. Cell growth was observed after 24 h of culture by optical microscopy, and the relative survival rate of cells was detected and calculated by cell counting kit 8 (CCK-8) assay to indicate the cytotoxicity (<in</i=6). Both PVA-TSPBA MNs and PVA-TSPBA-SH MNs were taken, the morphology of the two kinds of MNs was observed by optical microscopy, and the mechanical properties of the two kinds of MNs were tested by microcomputer controlled electronic universal testing machine (denoted as critical force, <in</i=6). Six male BALB/c mice aged 6-8 weeks (the same gender and age below) were divided into PVA-TSPBA group and PVA-TSPBA-SH group, with 3 mice in each group. After pressing the skin on the back of mice vertically with the corresponding MNs for 1 minute, the skin condition was observed at 0, 10, and 20 min after pressing. Another batch of 3T3 cells were divided into blank control group, 0 g/L ε-PL group and simple 5.0 g/L ε-PL group which were cultured with the extract of PVA-ε-PL-TSPBA MNs containing the corresponding concentration of ε-PL, and 5.0 g/L ε-PL+SH group which were cultured with the extract of PVA-ε-PL-TSPBA-SH MNs with 5.0 g/L ε-PL. The CCK-8 assay was performed to detect and calculate the relative survival rate of cells cultured for 24, 48, and 72 h to indicate the cell proliferation activity (<in</i=6). Eighteen BALB/c mice were induced into diabetic mice model by high-sugar and high-fat diet combined with streptozotocin injection and then divided into sterile dressing group, 0 g/L ε-PL+SH group, and 5.0 g/L ε-PL+SH group, with 6 mice in each group. A full-thickness skin defect wound was made on the back of each mouse, and <iS. aureus</i solution was added to make a full-thickness skin defect wound with bacterial colonization model for diabetic mouse. The wounds of mice in 0 g/L ε-PL+SH group and 5.0 g/L ε-PL+SH group were covered with PVA-ε-PL-TSPBA-SH MNs with the corresponding concentration of ε-PL, and the wounds of mice in the 3 groups were all covered with sterile surgical dressings. The wound healing was observed on post injury day (PID) 0, 3, 7, and 12, and the wound healing rate on PID 3, 7, and 12 was calculated. On PID 12, the skin tissue of the wound and the wound margin were stained with hematoxylin and eosin to observe the growth of new epithelium and the infiltration of inflammatory cells. Data were statistically analyzed with one-way analysis of variance, analysis of variance for repeated measurement, Mann-Whitney <iU</i test, and Bonferroni test. <bResults:</b With the extension of the immersion time, the PVA-TSPBA MNs in PBS containing hydrogen peroxide gradually dissolved and completely degraded after 10 days of immersion. The PVA-TSPBA MNs in pure PBS only swelled but did not dissolve. After 24 h of culture, there was no growth of <iS. aureus</i in 5.0 g/L ε-PL group or 10.0 g/L ε-PL group, and there was no growth of <iE. coli</i in 10.0 g/L ε-PL group. The relative survival rate of <iS. aureus</i was significantly lower in 1.0 g/L ε-PL group, 5.0 g/L ε-PL group, and 10.0 g/L ε-PL group than in blank control group (<iP</i&lt;0.05 or <iP</i&lt;0.01). The relative survival rate of <iE. coli</i was significantly lower in 5.0 g/L ε-PL group and 10.0 g/L ε-PL group than in blank control group (<iP</i&lt;0.01). After 24 h of culture, the cells in blank control group, 0 g/L ε-PL group, 1.0 g/L ε-PL group, 5.0 g/L ε-PL group, and 10.0 g/L ε-PL group all grew well, and the relative survival rate of cells was similar among the groups (<iP</i&gt;0.05). The needle bodies of PVA-TSPBA MNs and PVA-TSPBA-SH MNs were both quadrangular pyramid-shaped and neatly arranged, and the needle bodies of PVA-TSPBA-SH MNs was more three-dimensional and more angular. The critical force of PVA-TSPBA-SH MNs was significantly higher than that of PVA-TSPBA MNs (<iZ</i=3.317, <iP</i&lt;0.01). The MNs in PVA-TSPBA+SH group penetrated the skin of mice at 0 min after pressing, and the pinholes partially disappeared after 10 min and completely disappeared after 20 min, while the MNs in PVA-TSPBA group failed to penetrate the skin of mice. After 24, 48, and 72 h of culture, the proliferation activity of the cells in 5.0 g/L ε-PL+SH group was significantly higher than that of blank control group (<iP</i&lt;0.05 or <iP</i&lt;0.01). In sterile dressing group, the wounds of mice healed slowly and exuded more. The wound healing speed of mice in 0 g/L ε-PL+SH group was similar to that of sterile dressing group in the early stage but was faster than that of sterile dressing group in the later stage, with moderate exudation. The wound healing of mice in 5.0 g/L ε-PL+SH group was faster than that in the other two groups, with less exudation. The wound healing rates of mice in 5.0 g/L ε-PL+SH group were (40.6±4.2)%, (64.3±4.1)%, and (95.8±2.4)% on PID 3, 7, and 12, which were significantly higher than (20.4±2.7)%, (38.9±2.2)%, and (59.1±6.2)% in sterile dressing group and (21.6±2.6)%, (44.0±1.7)%, and (82.2±5.3)% in 0 g/L ε-PL+SH group (<iP</i&lt;0.01). The wound healing rates of mice in 0 g/L ε-PL+SH group on PID 7 and 12 were significantly higher than those in sterile dressing group (<iP</i&lt;0.05 or <iP</i&lt;0.01). On PID 12, the wounds of mice in 5.0 g/L ε-PL+SH group were almost completely epithelialized with less inflammatory cell infiltration, the wounds of mice in 0 g/L ε-PL+SH group were partially epithelialized with a large number of inflammatory cell infiltration, and no obvious epithelialization but a large number of inflammatory cell infiltration was found in the wounds of mice in sterile dressing group. <bConclusions:</b The composite MNs prepared by TSPBA, PVA, ε-PL, and SH can successfully penetrate mouse skin and slowly respond to ROS in the wound to resolve and release antibacterial substances, inhibit bacterial colonization, and promote the repair of full-thickness skin defect wounds with bacterial colonization in diabetic mice.

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This is the Fourth Annual Meeting of the Society for Gastrointestinal Intervention, a multi-disciplinary group of practitioners committed to a minimally invasive approach to both the diagnosis and treatment of digestive disorders. The key concepts are minimally invasive and multi-disciplinary which can be construed as practicing in parallel with occasional lines of procedural and clinical interaction or inter-disciplinary in which patients are acutely cared for by a team, with treatments tailored to the patient and not the discipline that touches the patient first. In reality, many of us exist in both worlds. Most universities and large clinics are structured in departments along traditional training lines. As such, Interventional Radiology is housed in the Radiology Department, Laparoscopic Surgery (and potentially NOTES), as a component of the General Surgery Division, and Therapeutic Endoscopy usually resides within a gastroenterology structural framework. These divisions have historically been kept separate by multiple forces: salaries and budgets usually reside in a larger division. As a group, the amount of practice devoted to GI disorders is variable (for instance, minimally invasive surgeons may approach the adrenal glands or lung lesions in some institutions and interventional radiologists often sample tissue in multiple areas outside the GI tract, and by virtue of access to the vascular tree, can stent, embolize, or TPA almost any area of the body), as well as inherent differences in our individual abilities to access organs. I have already mentioned that angiographic capabilities allow the interventional radiologist access to virtually every GI organ and those capabilities allow therapeutic options for bleeding, tumor embolization, stenting of stenotic lesions, and formation of intravascular shunts. As such, there is very limited interdisciplinary competition here although capsule endoscopy as well as double and single balloon enteroscopy have improved the endoscopist's diagnostic and potential therapeutic reach. However, many of these diagnostic triumphs for obscure or massive GI bleed are simply to tattoo lesions that require surgical removal by laparoscopic or traditional surgery. Cooperation. However, there are potential competitive areas in the treatment of GI vascular lesions also. Whereas endoscopic band ligation has supplanted EVS, splenic devascularization, and most shunting procedures for patients with esophageal varices, endoscopic techniques have had less long-term success with glue injection for gastric varices. Multiple randomized, prospective trials have suggested therapeutic primacy of TIPS with embolization of recalcitrant vessels as an option or back-up. Despite this, therapeutic endoscopists have learned valuable lesions from our IR colleagues and studies are underway using endoscopically injected coils in addition to cyanoacrylate in an attempt to improve acute and long-term bleeding control. Nor is there any major competition in the treatment of primary or metastatic liver tumors by chemoembolization, RF current, or other thermal modalities, although selected patients with single lesions or multiple lesions isolated to a single lobe may be better handled surgically if there is curative intent. Finally, there is little IR, and progressively less, surgical competition for the treatment of high-grade dysplasia or superficial malignancies in the setting of Barrett's esophagus which are adequately treated in most patients by mucosectomy, RF ablation, or cryotherapy but require direct mucosal visualization to direct this therapy. The same has proven true for many years for colorectal polyps, superficial gastric cancers, and ampullary adenomas that had historically all been treated with major surgical resections. Still, there are many patients with advanced lesions who are good operative candidates who should be approached with conventional or minimally invasive surgery with the intent of operative cure. Cooperative, not competitive. The potential for competition between disciplines comes in mundane situations and clinical settings that have historically been "owned" by a single discipline. On the one hand, placement of PEGS and PEJs, initially done endoscopically, can be done with equal facility and occasional failure, by endoscopists and interventional radiologists, reserving failed attempts for minimally invasive surgery. What resources are utilized with these three methods? Are there advantages to defining the mucosa of the gut lumen in all, or even a subset of patients? By way of contrast, acute cholecystectomy tubes in high surgical risk patients have usually been the domain of the radiologist, although I described transcystic duct gallbladder decompression endoscopically 2½ decades ago. With the advent of new devices delivered under EUS control, the gallbladder will now be readily accessible endoscopically. What does this mean both for the acutely ill patient without a window to approach their gallbladder radiologically? Will this play a bit part and a cooperative technique to expand our therapeutic armamentarium or will it become competitive therapeutically not only for IR but for minimally invasive surgeons? The same may be said for EUS's ability to inject genes, caustics, or chemo-therapeutic agents into organs adjacent to the lumen. What is the role of TNFerade injection into unresectable pancreatic cancers and the role of absolute alcohol or Taxitol to treat cystic neoplasms of the pancreas? The real issue of competition or cooperation between the disciplines comes when treating patients with unresectable and obstructing GI neoplasms, from my perspective. The latter may occur almost anywhere in the GI tract but, of course, are more commonly noted proximally (esophagus, stomach, duodenum) and distally (left colon) as well as proximal and distal biliary obstructions. Recognizing that the occasional mid-small bowel and many proximal colon lesions are better handled with an endoscopic approach because of loss of vector force and difficulty pushing a catheter through large diameter, acutely angulated lumens, all others are fair game from my perspective. To my knowledge, although there are studies demonstrating the superiority of SEMS over open or laparoscopic bypass for malignant gastric outlet obstruction insofar as return of gut function, hospitalization time, and resource utilization, there are no studies demonstrating the superiority of one discipline or another in the placement of SEMS. Nor have cost data emerged suggesting the superiority of one technique over another from a cost standpoint. Unless or until we have such studies, this suggests to me that institutional interest and expertise should play a major role in how these unfortunate patients have continuity of their GI tract re-established. The situation is a bit more complex in pancreaticobiliary malignancy. There are 2 prospective randomized trials (level 1 evidence) that suggest that patients with proximal strictures (Bismuth II-IV) in conjunction with bile duct and gallbladder cancer, respectively, may be more successfully stented percutaneously and certainly it is easier to deliver brachytherapy or PDT under protocol to these patients who have indwelling external drains. In contrast, there are no data, positive or negative, to suggest that PTBD is a preferable treatment for distal biliary malignant obstruction, and in most parts of the world, the endoscopic approach has supplanted the percutaneous one just as metal stents have replaced plastic prostheses to preclude recurrent bouts of stent dysfunction and need for additional ERCP. The question posed at the beginning of this syllabus contribution: Are we competitive or cooperative? The answer is obviously both but, hopefully, our choice of treatment should depend less on who touches the patient first and more on skill sets within an institution and what is the best treatment for this particular individual. The importance of the SGI is technical and informational cross-fertilization. If your university or clinic will not allow blurring of training barriers to put therapeutic endoscopists, minimally invasive surgeons, and interventional radiologists together as a department or institute, you can nevertheless work together as a team in the best interest of your patients.

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Diabetic foot ulcers (DFUs) are one of the most common indications for hyperbaric oxygen treatment (HBOT). The role of HBOT in DFUs is often debated. Recent evidence based guidelines, while recommending its use, urge further studies to identify the patient subgroups most likely to benefit from HBOT. A recent study in Diabetes Care aimed to assess the efficacy of HBOT in reducing the need for major amputation and improving wound healing in patients with chronic DFUs. In this study, patients with Wagner grade 2-4 diabetic foot lesions were randomly assigned to have HBOT (30 sessions/90 min/244 kPa) or sham treatment (30 sessions/90 min/air/125 kPa). Six weeks after the completion of treatment (12 weeks after randomization) neither the fulfillment of major amputation criteria (11/49 vs. 13/54, odds ratio 0.91 [95% CI 0.37, 2.28], P = 0.846) nor wound-healing rates (20% vs. 22%, 0.90 [0.35, 2.31], P = 0.823) significantly differed between groups. The authors concluded that HBOT does not offer any additional advantage over comprehensive wound care. Since this paper was published in Diabetes Care, one of the most prestigious diabetes journals, it is likely it will have a major impact on the clinical practice of many physicians dealing with diabetic foot problems. Although from a methodological standpoint the conduct of the study (prospective, double-blind, randomized, controlled) seems to be close to ideal, several significant flaws render the conclusions weak. Firstly, there were some problems with the assessment of the primary outcome of "meeting the criteria for amputation". In their published protocol paper, the trial lists indicated that "At the end of the 6-week follow-up phase……, the patient is sent to the participating vascular surgeon for an amputation evaluation". However, in the published report in Diabetes Care, it is evident that patients were not assessed in a face-to-face consultation, but rather by the remote examination of wound photographs and clinical data "Participant clinical data together with digital photographs of the study wound progress were presented to the vascular surgeon". This departure from the original intent undermines the primary outcome of the study significantly. Fedorko et al claim this method of assessment has been validated, but neither of their supporting citations appear to substantiate this claim. Wirthlin et al assessed the level of agreement about a collection of wounds between surgeons who were present at the bedside and a remote group who assessed the wounds using a short clinical account and digital photography. There was reasonable agreement between onsite and remote, although the specificity for particular signs ranged from just 27% (erythema) to 100% (ischaemia). Importantly, only a subset of eight of the 24 included patients had non-healing wounds and the proportion of those that were associated with diabetes mellitus is unknown. Further, the need for amputation was not among the management decisions examined. Wirthlin et al concluded "a prospective trial of remote wound management …. is needed to further validate this technology." The authors of the second supposedly supporting citation were mainly interested in the assessment of pressure ulcers by digital photography using the Photographic Wound Assessment Tool (PWAT) compared to the Pressure Sore Status Tool (PSST). Of the 81 included lower leg ulcers, it is not clear how many were associated with diabetes mellitus. Indications for amputation were not considered. The authors concluded "The PWAT may be valuable when a bedside assessment cannot be made. However, the size of circular wounds, wound depth, undermining/tunneling, and odor cannot be assessed using photographs." In the Fedorko paper, the decision that there was an indication for amputation was made by the remote vascular surgeon by meeting any of the following criteria: "persistent deep infection involving bone and tendons (antibiotics required, hospitalization required, pathogen involved); ongoing risk of severe systemic infection related to the wound; inability to bear weight on the affected limb; or pain causing significant disability". We are particularly concerned that the criteria, "persistent deep infection involving bone and tendons", is subjective. Recent studies have demonstrated that diabetic foot osteomyelitis may not necessarily require amputation and some cases may be cured with antibiotic therapy alone. It is interesting to note that despite the high numbers of participants assessed as fitting the requirements for amputation (23% overall), no patient actually had a major amputation. The amputation outcome is inappropriately assessed, done at the wrong time, and the study is grossly underpowered to find any difference in the rate of true major amputation. Finally, whether the surgeon performed a baseline assessment of amputation prior to the randomised intervention is unknown. A comparison between the pre- and post-study estimates of amputation rates could have contributed to the interpretation of the results. Secondly, the authors fail to provide a clear comparison of peripheral arterial disease (PAD) between the groups. Although patients were randomized and those who were possible candidates for major vessel revascularization were excluded from the study, microvascular status was not assessed. No transcutaneous oxygen measurements were made on any of the patients. Given that, firstly, the risk of microvascular vessel compromise increases with diabetes duration, and secondly, transcutaneous oxygen measurements correlate with the possibility of good response to HBOT, it is possible that clinically significant differences between groups were undetected. As an example, patients in the HBOT group had a markedly longer mean duration of diabetes (19.1 vs. 12.4 years) and would be likely to have more severe microvascular disease. Thirdly, the follow-up period of six weeks after completion of treatment is very short. The study to which the authors refer to justify this follow-up period enrolled only patients with ulcers of Wagner grade 1 or 2 and specifically excluded patients with infection or ischaemia. These are not representative of the patient population treated with HBOT. The outcomes in patients with DFUs treated with HBOT should be assessed over a longer period. One such randomized controlled study demonstrated that patients receiving HBOT had significantly higher healing rates than placebo at one-year follow-up (25/48 (52%) versus 12/42 (29%); P 〈 0.03), but not at 12 weeks. Fourthly, the authors also failed to describe the experience of the vascular surgeon who adjudicated the wounds for amputation; how many years he was involved in the management of diabetic foot wounds or how specialized his practice was with these patients. Objective and universally recognized indications for amputation are yet to be established. Therefore, a multidisciplinary decision-making approach, rather than a single physician's decision, would have increased the credibility of the conclusion the authors reached. Notably, all previous studies of HBOT in this area have used actual amputation rates in order to have a clear clinical endpoint. Careful patient selection is paramount for the cost-effective use of HBOT as an adjunct to normal wound care in diabetic wounds. As it is possible to identify wounds that have no potential to heal despite HBOT, all studies should incorporate transcutaneous oxygen measurements in their baseline evaluation. As the wounds in this study tended to be small (6.1cm² and 5.8cm² on average) and had persisted for (on average) one year despite state-of-the-art previous wound care, it is likely that at least some of these would not meet the predictive minimal criteria for healing potential with HBOT. The findings of this study do indeed show that the indiscriminate treatment of all diabetic wounds with HBOT is probably not (cost-) effective; however, the study conclusion that "HBO has no benefit in the treatment of chronic diabetic foot wounds" is erroneous.

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Complex femorotibial dislocation of the knee joint generally results from high-energy trauma caused by a traffic or a contact sport accident. Besides disruption of the cruciate ligaments, in 10-25% of patients present concomitant palsy of the common peroneal nerve and more rarely disruption of the popliteal artery. The purpose of this work was to assess outcome in a monocentric consecutive series of knee dislocations with ischemia due to disruption of the popliteal artery and to focus on specific aspects of management. This retrospective series included eleven men and three women, aged 18 to 74 years (mean 47 years). The right knee was injured in five and the left knee in six. Trauma resulted from a farm accident in six patients, fall from a high level in two, a traffic accident in three and a skiing accident (fall) in one. Two other patients with morbid obesity were fall victims. Nine patients had a single injury, two presented an associated serious head injury, one a severe chest injury, and one multiple trauma with coma, chest contusion, and abdominal lesions. One patient had a fracture of the distal femur with associated ischemia. Five knee dislocations were open with a popliteal wound for three and a posteromedial wound for two. Four patients presented total sciatic nerve palsy and nine palsy of the common peroneal nerve. The dislocation was documented in ten cases: lateral (n=1), anterior (n=4), posterior (n=5). For four patients, the dislocation had been reduced during pre-hospital care. Preoperative arteriography was available for eight patients and confirmed the disruption of the popliteal artery; the diagnosis was obvious in six other patients who were directed immediately to the operative theatre without pre-operative imaging. Revascularization was achieved with a upper popliteal-lower popliteal bypass using an inverted saphenous graft. The graft was harvested from the homolateral greater saphenous vein in eight patients and the contralateral vein in six. On average, limb revascularization was achieved after 10.07 hours ischemia. Intravenous heparin was instituted for 810 days followed by low-molecular-weight heparin. The dislocation was stabilized by a femorotibial fixator in nine patients and a cruropedious cast in five. An incision was made in the anterolateral and posterior leg compartments in twelve patients. A revision procedure was necessary on day one in one patient because of recurrent ischemia; a second bypass using an autologous venous graft was successful. One other 75-year-old patient also presented recurrent ischemia on day five; the bypass was reconstructed but the patient died from multiple injuries. Seven thin skin grafts were used to cover the aponeurotomy surfaces. Mean duration of the external fixator was 3.4 months. The five patients treated with a plaster case were immobilized for 2.7 months on average. Ligament repair was performed in three patients (one lateral reconstruction and one double reconstruction of the central pivot for the two others). A total prosthesis with a rotating hinge was implanted in two patients aged 67 and 74 years after removal of the external fixator at six and seven months. Failure of the ligament repair also led to arthroplasty in a third patient. Blood supply to the lower limb was successfully restored as proven by the renewed coloration of the teguments and-or presence of distal pulses in 13 patients. Transient acute renal failure required dialysis in one patient. Four patients developed pin track discharges and there was one case of septic arthritis of the knee joint which was cured after arthrotomy for wash-out and adapted antibiotics. Outcome was assessed a minimum 18 months follow-up (average 22 months) for the 13 survivors. The three sciatic palsies recovered partially at five and six months in the tibial territory but with persistent paralysis in the territory of the common peroneal nerve. The nine cases of common peroneal nerve palsy noted initially regressed completely or nearly completely in three patients, partially in three and remained unchanged in three. The results were assessed as a function of the final knee procedure: outcome was satisfactory for the patients with a total knee arthroplasty. Outcome of the three ligamentoplasties was good in one, fair in one, and a failure in one (revision arthroplasty). Patients treated by immobilization without a second surgical procedure complained of joint instability with a variable clinical impact; their knee retained active flexion greater than 90 degrees and complete extension. An analysis of the literature and the critical review of our clinical experience was conducted to propose a coherent therapeutic attitude for patients presenting this type of trauma. The prevalence of disruption of the popliteal vascular supply in patients with knee dislocation is between 4 and 20%. The rate is closely related to that of injury to nerves and soft tissue. Ischemia should be immediately suspected in all cases of knee dislocation. The pedious and tibial pulses must be carefully noted before and after reduction of the dislocation to determine whether or not there is an organic arterial lesion. If the pulses are absent initially, they should be expected to reappear strong, rapidly and permanently after reduction. Otherwise, arteriography should be performed. Dislocation stretches the artery between two points of relative anchorage in the adductor ring and the soleus arcade to the point of rupture. Repair requires a bypass between the upper popliteal artery and the tibioperoneal trunk using an inverted saphenous graft because the walls are torn over several centimeters. The traumatology and vascular surgical teams must work in concert from the beginning of the surgical work-up in order to establish a coherent operative strategy founded on primary reduction of the dislocation, installation of a fixator and then vascular repair and aponeurotomy incisions. It would be preferable to wait until the bypass is proven patent and wound healing is complete before proposing ligament repair. This should be done after a precise anatomic work-up to assess each ligament lesion. Bony avulsion or simple disinsertion can however be repaired in the emergency setting at the time of the bypass as well as any ligament rupture which is obvious and-or situated on the medial collateral approach. Secondarily, elements of the central pivot can be repaired in young patients with an important functional demand. Arthroplasty is not warranted except in the elderly patient. Dissection of the popliteal fossa or debridement of the wound enables a careful anatomic assessment of the nerve trunks. In the event of a peroneal nerve disruption, it is advisable to fix the nerve ends to avoid retraction. Beyond three months without clinical or electromyography recovery, surgical exploration is indicated. In the event more than 15 cm is lost, there is no hope for a successful graft. Complete knee dislocation is extremely rare. It can be caused by high-energy trauma associated with several ligament ruptures, particularly rupture of the central pivot observed in 10-25% of cases with common peroneal nerve palsy. Compression, contusion or disruption of the popliteal artery is very rarely caused by the displacement of the femur or the tibia. Limb survival may be compromised. Mandatory emergency restoration of blood supply will modify immediate and subsequent surgical strategies. There has not however been any study exclusively devoted to double joint and vascular involvement. Our objective was to present a critical retrospective analysis of a consecutive series of knee dislocations with ischemia due to disruption of the common popliteal artery treated in a single center and to describe the specific features of management strategies for a coherent diagnostic and therapeutic approach.

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The Federal Joint Committee (FJC; Gemeinsamer Bundesausschuss, G-BA) defines the health-care elements that are to be reimbursed by sickness funds. To define a directive, the FJC can commission benefit assessments, which provide an overview of the scientific evidence regarding the efficacy and benefits of an intervention. This paper describes the operational implementation of the legal requirements with regard to the benefit assessments of medicines. Such benefit assessments are sometimes referred to as "isolated benefit assessments," to distinguish them from benefit assessments as part of a full economic evaluation. The FJC has the freedom to commission these assessments from any agency; however, to date the majority have commissioned the Institute for Quality and Efficiency in Health Care (IQWiG). Nevertheless, the content of this paper applies integrally to any institute commissioned for such assessments. In this report, "the institute"' is used when the text refers to any of these institutes. The legal framework for benefit assessments is laid out in the German Social Code Book version V (http://www. sozialgesetzbuch.de), Sects. 35b ( section sign 1), 139a ( section sign 4-6) and Sect. 139b ( section sign 3). It is specified that: The institute must guarantee high transparency. The institute must provide appropriate participation of relevant parties for the commission-related development of assessments, and opportunity for comment on all important segments of the assessment procedure. The institute has to report on the progress and results of the work at regular intervals. The institute is held to giving the commission to external experts. Based on the legal framework, the institute must guarantee a high procedural transparency. Transparency of the whole process should be achieved, which is evidenced by clear reporting of procedures and criteria in all phases undertaken in the benefit assessment. The most important means of enhancing transparency are: 1. To implement a scoping process to support the development of the research question. 2. To separate the work of the external experts performing the evidence assessment from that of the institute formulating recommendations. Therefore, the preliminary report as produced by external experts needs to be public, and published separately from any subsequent amendments or (draft-)reports made by the institute, which includes the institute's recommendations. 3. To implement open peer review by publishing both the comments of the reviewers and their names. Based on the legal framework, the institute must provide for adequate participation of relevant parties. These include organisations representing the interests of patients; experts of medical, pharmaceutical and health economic science and practice; the professional organisations of pharmacists and pharmaceutical companies; and experts on alternative therapies. Patients and health care professionals bring in new insights with respect to research priorities, treatment and outcomes. The relevant parties should be identified and contacted whenever the global scope of the assessment has been drafted. Subsequently, the relevant parties should be involved in defining the research question, developing the protocol and commenting on the preliminary report. To implement the involvement of relevant parties in defining the research question a scoping process is suggested. For the other phases, written comments followed by an oral discussion should be used. Finally, the relevant parties should have the right to appeal the final decision on judicial grounds. None of these steps mean that the institute would lose any part of its scientific independence. From the relevant sections of the legal framework with respect to the assessment methods, it can be concluded that: 1. The institute must ensure that the assessment is made in accordance with internationally recognised standards of evidence-based medicine (EBM). 2. The assessment is conducted in comparison with other medicines and treatment forms under consideration of the additional therapeutic benefit for the patients. 3. The minimum criteria for assessing patient benefit are improvements in the state of health, shortening the duration of illness, extension of the duration of life, reduction of side effects and improvements in quality of life. EBM refers to the application of the best available evidence to answer a research question, which can inform questions about the care of patients. The optimal design, even for effectiveness questions, is not always the randomised, controlled trial (RCT) but depends on the research question and the outcomes of interest. To increase transparency for each question, the levels of evidence examined should be made explicit. There is no empirical evidence to support the use of cutoff points with respect to the number of studies before making recommendations. To get the best available evidence for the research question(s), all relevant evidence should be considered for each question, and the best available evidence should be used to answer the question. Separate levels of evidence may have to be used for each outcome. There are many ways in which bias can be introduced in systematic reviews. Some types of bias can be prevented, other types can only be reported and, for some, the influence of the bias can be investigated. Reviews must show that potential sources of bias have been dealt with adequately. Methods used by other agencies that perform benefit assessments are useful to interpret the term 'international standards' to which the institute must comply. The National Institute for Health and Clinical Excellence (NICE) is a good example in this respect. NICE shows that it is possible to have transparent procedures for benefit assessments but that this requires detailed documentation. NICE has implemented an open procedure with respect to the comments of reviewers, which makes the procedure transparent. Although the Institute for Quality and Efficiency in Health Care (IQWiG) in Germany invites comments on their protocol and preliminary report by posting them on their website, and comments are made public, the individual comments are not evaluated openly, and therefore it remains uncertain whether or not they lead to changes in the reports. The participation of relevant parties in the assessment process as implemented by NICE guarantees a process that is transparent to all relevant parties. Transparency of the whole process is assured by clear reporting of procedures and criteria in all phases undertaken in the benefit assessment. In a scoping process, a draft scope is commented on first in writing and subsequently in the form of a scoping workshop. In this way, all relevant aspects can be heard and included in the final scope. The protocol is then developed, followed by evidence assessment. The methods used should be completely reported to show readers that the assessment has been performed with scientific rigour and that bias has been prevented where possible. All relevant parties should have the opportunity to comment on the draft protocol and the draft preliminary report. Each comment should be evaluated as to whether or not it will lead to changes, and both the comments and the evaluation should be made public to ensure transparency of this process. The same procedure should be used for the peer-review phase. Based on the final report of the evidence assessment, the institute forms recommendations and the FJC appraises the evidence. During the writing of the final report, a separation between the evidence assessment and the evidence appraisal phase should be implemented. Ideally, this separation should be legally enforced to prevent any confusion about conflict of interests. Such a process guarantees a feasible combination of the legal requirements for transparency and involvement of relevant parties with international standards of EBM to ensure that the benefit assessments of medicines in Germany are performed according to the highest standards.

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The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). Extended follow-up of the randomised trial cohort through a third round could provide valuable insight into the duration of protection of a negative HPV test, which could allow extended screening intervals. If HPV primary screening is to be considered in the national programme, then determining its cost-effectiveness is key, and a detailed economic analysis using ARTISTIC data is needed. (1) To determine the round 3 and cumulative rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (2+) and CIN grade 3 or worse (CIN3+) between the revealed and concealed arms of ARTISTIC after three screening rounds over 6 years. (2) To compare the cumulative incidence of CIN2+ over three screening rounds following negative screening cytology with that following negative baseline HPV. (3) To determine whether or not HPV screening could safely extend the screening interval from 3 to 6 years. (4) To study the potential clinical utility of an increased cut-off of 2 relative light unit/mean control (RLU/Co) for Hybrid Capture 2 (HC2) and HPV genotyping in primary cervical screening. (5) To determine the potential impact of HPV vaccination with Cervarix™ in terms of preventing abnormal cytology and CIN2+. (6) To determine the cost-effectiveness of HPV primary screening compared with current practice using cervical cytology in England. The ARTISTIC study cohort was recalled for a third round of screening 3 years after round 2 and 6 years following their enrolment to the study. Both arms of the original trial used a single protocol during round 3. ARTISTIC study cohort undergoing cervical screening in primary care in Greater Manchester, UK. Between July 2007 and September 2009, 8873 women participated in round 3; 6337 had been screened in round 2 and 2536 had not been screened since round 1. All women underwent liquid-based cytology and HPV testing and genotyping. Colposcopy was offered to women with moderate dyskaryosis or worse and with HPV-positive mild dyskaryosis/borderline changes. Women with negative cytology or HPV-negative mild dyskaryosis/borderline changes were returned to routine recall. Principal outcomes were cumulative rates of CIN2+ over three screening rounds by cytology and HPV status at entry; HPV type specific rates of CIN2+; effect of age on outcomes correlated with cytology and HPV status; comparison of HC2 cut-off RLU/Co of both 1 and 2; and cost-effectiveness of HPV primary screening. The median duration of follow-up was 72.7 months in round 3. Over the three screening rounds, there was no significant difference in CIN2+ [odds ratio (OR): 1.06, 95% confidence interval (CI) 0.89 to 1.26, p = 0.5)] or CIN3+ (OR: 0.90, 95% CI 0.72 to 1.14, p = 0.4) rates between the trial arms (revealed vs. concealed). Overall, 16% of women were HC2 positive at entry, decreasing from 40% in women aged 20-24 years to around 7% in women aged over 50 years. Abnormal cytology rates at entry were 13% for borderline+ and 2% for moderate+ cytology. Following positive cytology at entry, the cumulative rate of CIN2+ was 20.5%, and was 20.1% following a HPV-positive result at baseline. The cumulative CIN2+ rate for women who were HPV negative at baseline was only 0.87% (95% CI 0.70% to 1.06%) after three rounds of screening, significantly lower than that for women with negative cytology, which was 1.41% (95% CI 1.19% to 1.65%). Women who were HPV negative at baseline had similar protection from CIN2+ after 6 years as women who were cytology negative at baseline after 3 years. Women who were HPV positive/cytology negative at baseline had a cumulative CIN2+ rate at 6 years of 7.7%, significantly higher than that for women who were cytology positive/HPV negative (3.2%). Women who were HPV type 16 positive at baseline had a cumulative CIN2+ rate over three rounds of 43.6% compared with 20.1% for any HPV-positive test. Using a HC2 cut-off of RLU/Co ≥ 2 would maintain acceptable sensitivity and result in 16% fewer HPV-positive results. Typing data suggested that around 55-60% of high-grade cytology and CIN2+, but less than 25% of low-grade cytology, would be prevented by HPV vaccine given current rates of coverage in the UK national programme. For the cost-effectiveness analysis, most of the primary HPV strategies examined where HPV was used as the sole primary test were cost saving in both unvaccinated and vaccinated cohorts under baseline cost assumptions, with a 7-18% reduction in annual screening-associated costs in unvaccinated cohorts and a 9-22% reduction for vaccinated cohorts. Utilising partial genotyping at the primary screening stage to identify women with HPV 16/18 and referring them to colposcopy was the most effective strategy (barring co-testing, which is significantly more costly than any other strategies considered), resulting in 83 additional life-years per 100,000 women for unvaccinated women when compared with current practice, and similar life-years saved compared with current practice for vaccinated women. In unvaccinated cohorts, however, this genotyping strategy is predicted to result in a 20% increase in the number of colposcopies performed in England, although in vaccinated cohorts the number of colposcopy referrals was predicted to be lower than in current practice. For all strategies in which HPV is used as the sole primary screening test, decreasing the follow-up interval for intermediate-risk women from 24 to 12 months increased the overall effectiveness of primary HPV screening. In exploratory analysis, strategies for which cytology screening was retained until either age 30 or 35 years, and for which HPV testing was used at older ages, were predicted to be of higher costs and intermediate effectiveness than those associated with full implementation of primary HPV screening from age 25 years. However, this finding should be interpreted with caution as it depends on assumptions made about screening behaviour and compliance with recommendations at the 'switch over' point. HPV testing as an initial screen was significantly more protective over three rounds (6 years) than the current practice of cytology and the use of primary HPV screening could allow a safe lengthening of the screening interval. A substantial decrease in high-grade cytology and CIN2+ can be expected as a consequence of the HPV vaccination programme. A HC2 cut-off of 2RLU/Co instead of the manufacturer's recommended cut-off of 1 would be clinically beneficial in terms of an optimal balance between sensitivity and specificity. Modelled analysis predicts that primary HPV screening would be both more effective and cost saving compared with current practice with cervical cytology for a number of potential strategies in both unvaccinated and vaccinated cohorts. Compliance with surveillance and optimal management of HPV-positive/cytology-negative women after primary HPV screening is of key importance. Limitations of the economic investigation included the need to make assumptions around compliance with screening attendance and follow-up for longer screening intervals in the future, assumptions regarding maintenance of current uptake vaccination in the future, and assumptions regarding the stability of cost of HPV and cytology tests in the future. Detailed sensitivity analysis across a range of possible assumptions was conducted to address these issues. This study and the economic evaluation lend support to convert from cytology to HPV-based screening. Future work should include researching (i) the attitudes of women who test HPV positive/cytology negative, (ii) the value of complementary biomarkers and (iii) activities relevant to primary HPV screening in unvaccinated and vaccinated populations from the point of view of QALY assessment. Current Controlled Trials ISRCTN25417821.

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Viral epidemics or pandemics of acute respiratory infections (ARIs) pose a global threat. Examples are influenza (H1N1) caused by the H1N1pdm09 virus in 2009, severe acute respiratory syndrome (SARS) in 2003, and coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in 2019. Antiviral drugs and vaccines may be insufficient to prevent their spread. This is an update of a Cochrane Review published in 2007, 2009, 2010, and 2011. The evidence summarised in this review does not include results from studies from the current COVID-19 pandemic. To assess the effectiveness of physical interventions to interrupt or reduce the spread of acute respiratory viruses. We searched CENTRAL, PubMed, Embase, CINAHL on 1 April 2020. We searched ClinicalTrials.gov, and the WHO ICTRP on 16 March 2020. We conducted a backwards and forwards citation analysis on the newly included studies. We included randomised controlled trials (RCTs) and cluster-RCTs of trials investigating physical interventions (screening at entry ports, isolation, quarantine, physical distancing, personal protection, hand hygiene, face masks, and gargling) to prevent respiratory virus transmission. In previous versions of this review we also included observational studies. However, for this update, there were sufficient RCTs to address our study aims.   DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. Three pairs of review authors independently extracted data using a standard template applied in previous versions of this review, but which was revised to reflect our focus on RCTs and cluster-RCTs for this update. We did not contact trialists for missing data due to the urgency in completing the review. We extracted data on adverse events (harms) associated with the interventions. We included 44 new RCTs and cluster-RCTs in this update, bringing the total number of randomised trials to 67. There were no included studies conducted during the COVID-19 pandemic. Six ongoing studies were identified, of which three evaluating masks are being conducted concurrent with the COVID pandemic, and one is completed. Many studies were conducted during non-epidemic influenza periods, but several studies were conducted during the global H1N1 influenza pandemic in 2009, and others in epidemic influenza seasons up to 2016. Thus, studies were conducted in the context of lower respiratory viral circulation and transmission compared to COVID-19. The included studies were conducted in heterogeneous settings, ranging from suburban schools to hospital wards in high-income countries; crowded inner city settings in low-income countries; and an immigrant neighbourhood in a high-income country. Compliance with interventions was low in many studies. The risk of bias for the RCTs and cluster-RCTs was mostly high or unclear. Medical/surgical masks compared to no masks We included nine trials (of which eight were cluster-RCTs) comparing medical/surgical masks versus no masks to prevent the spread of viral respiratory illness (two trials with healthcare workers and seven in the community). There is low certainty evidence from nine trials (3507 participants) that wearing a mask may make little or no difference to the outcome of influenza-like illness (ILI) compared to not wearing a mask (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.82 to 1.18. There is moderate certainty evidence that wearing a mask probably makes little or no difference to the outcome of laboratory-confirmed influenza compared to not wearing a mask (RR 0.91, 95% CI 0.66 to 1.26; 6 trials; 3005 participants). Harms were rarely measured and poorly reported. Two studies during COVID-19 plan to recruit a total of 72,000 people. One evaluates medical/surgical masks (N = 6000) (published Annals of Internal Medicine, 18 Nov 2020), and one evaluates cloth masks (N = 66,000). N95/P2 respirators compared to medical/surgical masks We pooled trials comparing N95/P2 respirators with medical/surgical masks (four in healthcare settings and one in a household setting). There is uncertainty over the effects of N95/P2 respirators when compared with medical/surgical masks on the outcomes of clinical respiratory illness (RR 0.70, 95% CI 0.45 to 1.10; very low-certainty evidence; 3 trials; 7779 participants) and ILI (RR 0.82, 95% CI 0.66 to 1.03; low-certainty evidence; 5 trials; 8407 participants). The evidence is limited by imprecision and heterogeneity for these subjective outcomes. The use of a N95/P2 respirator compared to a medical/surgical mask probably makes little or no difference for the objective and more precise outcome of laboratory-confirmed influenza infection (RR 1.10, 95% CI 0.90 to 1.34; moderate-certainty evidence; 5 trials; 8407 participants). Restricting the pooling to healthcare workers made no difference to the overall findings. Harms were poorly measured and reported, but discomfort wearing medical/surgical masks or N95/P2 respirators was mentioned in several studies. One ongoing study recruiting 576 people compares N95/P2 respirators with medical surgical masks for healthcare workers during COVID-19. Hand hygiene compared to control Settings included schools, childcare centres, homes, and offices. In a comparison of hand hygiene interventions with control (no intervention), there was a 16% relative reduction in the number of people with ARIs in the hand hygiene group (RR 0.84, 95% CI 0.82 to 0.86; 7 trials; 44,129 participants; moderate-certainty evidence), suggesting a probable benefit. When considering the more strictly defined outcomes of ILI and laboratory-confirmed influenza, the estimates of effect for ILI (RR 0.98, 95% CI 0.85 to 1.13; 10 trials; 32,641 participants; low-certainty evidence) and laboratory-confirmed influenza (RR 0.91, 95% CI 0.63 to 1.30; 8 trials; 8332 participants; low-certainty evidence) suggest the intervention made little or no difference. We pooled all 16 trials (61,372 participants) for the composite outcome of ARI or ILI or influenza, with each study only contributing once and the most comprehensive outcome reported. The pooled data showed that hand hygiene may offer a benefit with an 11% relative reduction of respiratory illness (RR 0.89, 95% CI 0.84 to 0.95; low-certainty evidence), but with high heterogeneity. Few trials measured and reported harms. There are two ongoing studies of handwashing interventions in 395 children outside of COVID-19. We identified one RCT on quarantine/physical distancing. Company employees in Japan were asked to stay at home if household members had ILI symptoms. Overall fewer people in the intervention group contracted influenza compared with workers in the control group (2.75% versus 3.18%; hazard ratio 0.80, 95% CI 0.66 to 0.97). However, those who stayed at home with their infected family members were 2.17 times more likely to be infected. We found no RCTs on eye protection, gowns and gloves, or screening at entry ports. The high risk of bias in the trials, variation in outcome measurement, and relatively low compliance with the interventions during the studies hamper drawing firm conclusions and generalising the findings to the current COVID-19 pandemic. There is uncertainty about the effects of face masks. The low-moderate certainty of the evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect. The pooled results of randomised trials did not show a clear reduction in respiratory viral infection with the use of medical/surgical masks during seasonal influenza. There were no clear differences between the use of medical/surgical masks compared with N95/P2 respirators in healthcare workers when used in routine care to reduce respiratory viral infection. Hand hygiene is likely to modestly reduce the burden of respiratory illness. Harms associated with physical interventions were under-investigated. There is a need for large, well-designed RCTs addressing the effectiveness of many of these interventions in multiple settings and populations, especially in those most at risk of ARIs.

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Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). To assess the effectiveness and safety of SARS-CoV-2-neutralising mAbs for treating patients with COVID-19, compared to an active comparator, placebo, or no intervention. To maintain the currency of the evidence, we will use a living systematic review approach. A secondary objective is to track newly developed SARS-CoV-2-targeting mAbs from first tests in humans onwards.  SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane COVID-19 Study Register, and three other databases on 17 June 2021. We also checked references, searched citations, and contacted study authors to identify additional studies. Between submission and publication, we conducted a shortened randomised controlled trial (RCT)-only search on 30 July 2021. We included studies that evaluated SARS-CoV-2-neutralising mAbs, alone or combined, compared to an active comparator, placebo, or no intervention, to treat people with COVID-19. We excluded studies on prophylactic use of SARS-CoV-2-neutralising mAbs. Two authors independently assessed search results, extracted data, and assessed risk of bias using the Cochrane risk of bias tool (RoB2). Prioritised outcomes were all-cause mortality by days 30 and 60, clinical progression, quality of life, admission to hospital, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE. We identified six RCTs that provided results from 17,495 participants with planned completion dates between July 2021 and December 2031. Target sample sizes varied from 1020 to 10,000 participants. Average age was 42 to 53 years across four studies of non-hospitalised participants, and 61 years in two studies of hospitalised participants. Non-hospitalised individuals with COVID-19 Four studies evaluated single agents bamlanivimab (N = 465), sotrovimab (N = 868), regdanvimab (N = 307), and combinations of bamlanivimab/etesevimab (N = 1035), and casirivimab/imdevimab (N = 799). We did not identify data for mortality at 60 days or quality of life. Our certainty of the evidence is low for all outcomes due to too few events (very serious imprecision).  Bamlanivimab compared to placebo No deaths occurred in the study by day 29. There were nine people admitted to hospital by day 29 out of 156 in the placebo group compared with one out of 101 in the group treated with 0.7 g bamlanivimab (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.02 to 1.33), 2 from 107 in the group treated with 2.8 g (RR 0.32, 95% CI 0.07 to 1.47) and 2 from 101 in the group treated with 7.0 g (RR 0.34, 95% CI 0.08 to 1.56). Treatment with 0.7 g, 2.8 g and 7.0 g bamlanivimab may have similar rates of AEs as placebo (RR 0.99, 95% CI 0.66 to 1.50; RR 0.90, 95% CI 0.59 to 1.38; RR 0.81, 95% CI 0.52 to 1.27). The effect on SAEs is uncertain. Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Bamlanivimab/etesevimab compared to placebo There were 10 deaths in the placebo group and none in bamlanivimab/etesevimab group by day 30 (RR 0.05, 95% CI 0.00 to 0.81). Bamlanivimab/etesevimab may decrease hospital admission by day 29 (RR 0.30, 95% CI 0.16 to 0.59), may result in a slight increase in any grade AEs (RR 1.15, 95% CI 0.83 to 1.59) and may increase SAEs (RR 1.40, 95% CI 0.45 to 4.37). Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Casirivimab/imdevimab compared to placebo Casirivimab/imdevimab may reduce hospital admissions or death (2.4 g: RR 0.43, 95% CI 0.08 to 2.19; 8.0 g: RR 0.21, 95% CI 0.02 to 1.79). We are uncertain of the effect on grades 3-4 AEs (2.4 g: RR 0.76, 95% CI 0.17 to 3.37; 8.0 g: RR 0.50, 95% CI 0.09 to 2.73) and SAEs (2.4 g: RR 0.68, 95% CI 0.19 to 2.37; 8.0 g: RR 0.34, 95% CI 0.07 to 1.65). Mortality by day 30 and clinical progression/improvement of symptoms or development of severe symptoms were not reported. Sotrovimab compared to placebo We are uncertain whether sotrovimab has an effect on mortality (RR 0.33, 95% CI 0.01 to 8.18) and invasive mechanical ventilation (IMV) requirement or death (RR 0.14, 95% CI 0.01 to 2.76). Treatment with sotrovimab may reduce the number of participants with oxygen requirement (RR 0.11, 95 % CI 0.02 to 0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04 to 0.48), grades 3-4 AEs (RR 0.26, 95% CI 0.12 to 0.60), SAEs (RR 0.27, 95% CI 0.12 to 0.63) and may have little or no effect on any grade AEs (RR 0.87, 95% CI 0.66 to 1.16).  Regdanvimab compared to placebo Treatment with either dose (40 or 80 mg/kg) compared with placebo may decrease hospital admissions or death (RR 0.45, 95% CI 0.14 to 1.42; RR 0.56, 95% CI 0.19 to 1.60, 206 participants), but may increase grades 3-4 AEs (RR 2.62, 95% CI 0.52 to 13.12; RR 2.00, 95% CI 0.37 to 10.70). 80 mg/kg may reduce any grade AEs (RR 0.79, 95% CI 0.52 to 1.22) but 40 mg/kg may have little to no effect (RR 0.96, 95% CI 0.64 to 1.43). There were too few events to allow meaningful judgment for the outcomes mortality by 30 days, IMV requirement, and SAEs.  Hospitalised individuals with COVID-19 Two studies evaluating bamlanivimab as a single agent (N = 314) and casirivimab/imdevimab as a combination therapy (N = 9785) were included.   Bamlanivimab compared to placebo  We are uncertain whether bamlanivimab has an effect on mortality by day 30 (RR 1.39, 95% CI 0.40 to 4.83) and SAEs by day 28 (RR 0.93, 95% CI 0.27 to 3.14). Bamlanivimab may have little to no effect on time to hospital discharge (HR 0.97, 95% CI 0.78 to 1.20) and mortality by day 90 (HR 1.09, 95% CI 0.49 to 2.43). The effect of bamlanivimab on the development of severe symptoms at day 5 (RR 1.17, 95% CI 0.75 to 1.85) is uncertain. Bamlanivimab may increase grades 3-4 AEs at day 28 (RR 1.27, 95% CI 0.81 to 1.98). We assessed the evidence as low certainty for all outcomes due to serious imprecision, and very low certainty for severe symptoms because of additional concerns about indirectness. Casirivimab/imdevimab with usual care compared to usual care alone Treatment with casirivimab/imdevimab compared to usual care probably has little or no effect on mortality by day 30 (RR 0.94, 95% CI 0.87 to 1.02), IMV requirement or death (RR 0.96, 95% CI 0.90 to 1.04), nor alive at hospital discharge by day 30 (RR 1.01, 95% CI 0.98 to 1.04). We assessed the evidence as moderate certainty due to study limitations (lack of blinding). AEs and SAEs were not reported.  AUTHORS' CONCLUSIONS: The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non-hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS-CoV-2-neutralising mAbs. Further studies and long-term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS-CoV-2 variants may impact the effectiveness of SARS-CoV-2-neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS-CoV-2-neutralising mAbs for the treatment of COVID-19 and possible subgroup differences.

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<bObjective:</b To explore the effects of porcine acellular dermal matrix (ADM) combined with human epidermal stem cells (ESCs) on wound healing of full-thickness skin defect in nude mice. <bMethods:</b The morphology of porcine ADM was analyzed by photograph of digital camera, the cell residues in porcine ADM were observed by hematoxylin-eosin (HE) staining, the surface structure of porcine ADM was observed by scanning electron microscope, the secondary structure of porcine ADM was analyzed by infrared spectrometer, the porcine ADM particle size was analyzed by dynamic light scattering particle size analyzer, and the porcine ADM potential was analyzed by nano-particle size potentiometer. The morphology of porcine ADM was observed by inverted fluorescence microscope when it was placed in culture medium for 30 min, 1 d, and 5 d (<in</i=2). The porcine ADM was divided into 5 min group, 10 min group, 20 min group, 30 min group, 60 min group, and 120 min group according to the random number table (the same grouping method below) in static state at normal temperature for the corresponding time to calculate the water absorption by weighing method (<in</i=3). Swiss white mouse embryonic fibroblasts (Fbs) were divided into blank control group (culture medium only), and 50.0 g/L ADM extract group, 37.5 g/L ADM extract group, 25.0 g/L ADM extract group, 12.5 g/L ADM extract group, and 6.5 g/L ADM extract group which were added with the corresponding final concentrations of ADM extract respectively. At post culture hour (PCH) 24, 48, and 72, the cell survival rate was detected by cell counting kit 8 and the cytotoxicity was graded (<in</i=5). The erythrocytes of a 6-week-old male Sprague-Dawley male rat were divided into normal saline group, ultra-pure water group, and 5 mg/mL ADM extract group, 10 mg/mL ADM extract group, and 15 mg/mL ADM extract group which were treated with the corresponding final concentrations of porcine ADM extract respectively. After reaction for 3 h, the absorbance value of hemoglobin was detected by microplate reader to represent the blood compatibility of porcine ADM (<in</i=3). ESCs were isolated and cultured from the discarded prepuce of a 6-year-old healthy boy who was treated in the Department of Urology of the First Affiliated Hospital of Army Medical University (the Third Military Medical University) in July 2020, and then identified by flow cytometry. The porcine ADM particles of composite ESC (hereinafter referred to as ESC/ADM) were constructed by mixed culture. After 3 days of culture, the composite effect of ESC/ADM was observed by HE staining and laser scanning confocal microscope. Thirty-six 7-8-week-old male non-thymic nude mice were divided into phosphate buffer solution (PBS) alone group, ADM alone group, ESC alone group, and ESC/ADM group, with 9 mice in each group, and the wound model of full-thickness skin defect was established. Immediately after injury, the wounds were treated with the corresponding reagents at one time. On post injury day (PID) 1, 7, 11, and 15, the wound healing was observed and the wound healing rate was counted (<in</i=3). On PID 7, the epithelialization of wounds was observed by HE staining and the length of un-epithelialized wound was measured (with this and the following sample numbers of 4). On PID 11, the dermal area and collagen deposition of wounds were observed by Masson staining and the dermal area of wound section was calculated, the number of cells expressing CD49f, a specific marker of ESC, was calculated with immunofluorescence staining, the mRNA expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in ESC after wound transplantation was detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction. Data were statistically analyzed with independent sample <it</i test, one-way analysis of variance, analysis of variance for repeated measurement, and least significant difference <it</i test. <bResults:</b The porcine ADM was white particles and composed of reticular structure, with no cells inside, disordered structure, and rough surface. The absorption peak of porcine ADM appeared at the wave numbers of 1 659, 1 549, and 1 239 cm<sup-1</sup, respectively. The main particle size distribution of porcine ADM in solution was 500 to 700 nm, with negative charge on the surface. The morphology of porcine ADM in static state at 30 min and on 1 and 5 d was relatively stable. The water absorption of porcine ADM remained relatively high level in static state from 30 min to 120 min. The cytotoxicity of mouse embryonic Fbs in 6.5 g/L ADM extract group, 12.5 g/L ADM extract group, and 25.0 g/L ADM extract group was grade 1 at PCH 24, and the cytotoxicity of the other groups was 0 grade at each time point. After reaction for 3 h, the absorbance value of hemoglobin of erythrocytes in ultra-pure water group was significantly higher than the values in normal saline group and 15 mg/mL ADM extract group (with <it</i values of 8.14 and 7.96, respectively, <iP</i&lt;0.01). After 3 days of culture, the cells of the fourth passage showed pebble-like morphology, with low expression of CD71 and high expression of CD49f, which were identified as ESCs. There was ESC attachment and growth on porcine ADM particles. On PID 1, the wound sizes of nude mice were almost the same in PBS alone group, ADM alone group, ESC alone group, and ESC/ADM group. On PID 7, 11, and 15, the wound contraction of nude mice in each group was observed, especially in ADM alone group, ESC alone group, and ESC/ADM group. On PID 7, the wound healing rates of nude mice in ESC alone group and ESC/ADM group were significantly higher than the rate in PBS alone group (with <it</i values of 2.83 and 4.72 respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). On PID 11, the wound healing rate of nude mice in ESC/ADM group was significantly higher than that in PBS alone group (<it</i=4.86, <iP</i&lt;0.01). On PID 15, the wound healing rates of nude mice in ADM alone group, ESC alone group, and ESC/ADM group were significantly higher than the rate in PBS alone group (with <it</i values of 2.71, 2.90, and 3.23 respectively, <iP</i&lt;0.05). On PID 7, the length of un-epithelialized wound of nude mice in ADM alone group, ESC alone group, and ESC/ADM group was (816±85), (635±66), and (163±32) μm, respectively, which were significantly shorter than (1 199±43) μm in PBS alone group (with <it</i values of 5.69, 10.19, and 27.54 respectively, <iP</i&lt;0.01). On PID 11, the dermal areas of wound section of nude mice in ADM alone group, ESC alone group, and ESC/ADM group were significantly larger than the area in PBS alone group (with <it</i values of 27.14, 5.29, and 15.90 respectively, <iP</i&lt;0.01); the collagen production of nude mice in ADM alone group and ESC/ADM group was more obvious than that in PBS alone group, and the collagen production of nude mice in ESC alone group and PBS alone group was similar. On PID 11, in the wounds of nude mice in ESC alone group and ESC/ADM group, the cells with positive expression of CD49f were respectively 135±7 and 185±15, and the mRNA expressions of GAPDH were positive; while there were no expressions of CD49f nor mRNA of GAPDH in the wounds of nude mice in PBS alone group and ADM alone group. <bConclusions:</b ESC/ADM particles can promote the wound healing of full-thickness skin defects in nude mice, which may be related to the improved survival rate of ESCs after transplantation and the promotion of dermal structure rearrangement and angiogenesis by ADM.

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The incidence of lung cancer is declining following a drop in smoking rates, but it is still the leading cause of death from cancer in England and Wales, with about 30,000 deaths a year. Survival rates for lung cancer are poor everywhere, but they appear to be better in the rest of the European Community and the USA than in the UK. Only about 5 per cent of people with lung cancer survive for 5 years, and nearly all of these are cured by surgery after fortuitously early diagnosis. At present, only a small proportion of patients (probably about 5 per cent) with non-small-cell lung cancer are being given chemotherapy. Some centres treat a greater proportion. This review examines the clinical effectiveness and cost-effectiveness of four of the newer drugs - vinorelbine, gemcitabine, paclitaxel and docetaxel - used for treating the most common type of lung cancer (non-small-cell lung cancer). The first three drugs are used for first-line treatment, but at present docetaxel is used only after first-line chemotherapy has failed. This report was based on a systematic literature review and economic modelling, supplemented by cost data. RESULTS - NUMBER AND QUALITY OF STUDIES: A reasonable number of randomised trials were found - three for docetaxel, six for gemcitabine, five for paclitaxel and 13 for vinorelbine. The quality of the trials was variable but good overall. There was a wide range of comparators. Some trials compared chemotherapy with best supportive care (BSC), which involves care that aims to control symptoms, with palliative radiotherapy if needed, but not to prolong life. Others compared the newer drugs against previous drugs or combinations. RESULTS - SUMMARY OF BENEFITS: The gains in duration of survival with the new drugs are modest - a few months - but worthwhile in a condition for which the untreated survival is only about 5 months. There are also gains in quality of life compared with BSC, because on balance the side-effects of some forms of chemotherapy have less effect on quality of life than the effects of uncontrolled spread of cancer. RESULTS - COSTS: The total cost to the NHS of using these new drugs in England and Wales might be about GBP 10 million per annum, but is subject to a number of factors. There would be non-financial constraints on any increase in chemotherapy for the next few years, such as staffing; the number of patients choosing to have the newer forms of chemotherapy is not yet known; and the costs of the drugs may fall, for example, as generic forms appear. RESULTS - COST PER LIFE-YEAR GAINED: The available data did not provide an entirely satisfactory basis for cost-effectiveness calculations. The main problem was the lack of direct comparisons of the new drugs. In order to strengthen the analysis, three different modelling approaches were used: pairwise comparisons using trial data; cost-minimisation analysis, as if all the new regimens were of equal efficacy; and cost-effectiveness analysis pooling the results of several trials with different comparators, giving indirect comparisons of the new drugs by using BSC as the common comparator. A number of different scenarios were explored through extensive sensitivity analysis in each model. Outcomes were expressed in incremental cost per life-year saved or incremental cost, versus BSC. There was insufficient evidence from which to derive cost per quality-adjusted life-year. In first-line treatment, vinorelbine, gemcitabine, and the lower-dose paclitaxel plus cisplatin combinations generally performed well against BSC under a range of different scenarios and especially when given as a maximum of 3 cycles. Incremental cost per life-year gained (LYG) versus BSC varied depending on scenario, but baseline figures based on trial data and protocols were: single-agent vinorelbine, pound 2194 per LYG; vinorelbine plus cisplatin, pound 5206; single-agent gemcitabine, pound 5690; gemcitabine plus cisplatin, pound 10,041; and paclitaxel plus cisplatin, pound 8537. In second-line chemotherapy, docetaxel gave a cost per LYG of pound 17,546, again well within the range usually accepted as cost-effective. However, in routine care, the impact of therapy would be regularly reviewed, and continuation would depend on response, side-effects, patient choice and clinical judgement. Chemotherapy would be stopped in non-responders, making chemotherapy more cost-effective. A 'real-life' scenario in which 60 per cent of patients receive only 1 or 2 cycles of chemotherapy gives much lower costs per LYG, with single-agent gemcitabine, single-agent vinorelbine, and paclitaxel plus platinum appearing to be cost-saving compared with BSC; the incremental cost of gemcitabine plus cisplatin would be pound 2478 per LYG, and of vinorelbine plus cisplatin, pound 2808. At the very least, gains in duration of survival were achieved without diminution of quality of life (at best, they improved quality) and with relatively low incremental cost. Comparisons among the individual drugs should be viewed with caution because they have had to be based on indirect comparisons. RESULTS - LIMITATIONS OF THE ANALYSIS: Each of the three models had limitations. The cost-effectiveness estimates from the pairwise comparisons were based on single studies. The cost-minimisation analysis assumed that the regimens have equal efficacy in practice. The cost-effectiveness analysis had to be based on pooling data from individual trials. The costs of BSC, inpatient stay and outpatient visits were from Scottish data. Median rather than mean data on duration of survival have been used in the analysis, because most of the trials reported only median data. Median survival and number of drug cycles were calculated by averaging across a number of studies, rather than being reliant on one particular study. The costs of the less expensive antiemetics cited in the trials were omitted. The use of more modern and costly antiemetics would have a modest detrimental effect on cost-effectiveness. In the absence of published data, an estimate was made of the cost of side-effects of chemotherapy, in particular hospital admissions, and applied to all the new regimens. In practice, admissions related to side-effects and their respective costs are likely to vary by regimen. The new drugs for non-small-cell lung cancer extend life by only a few months compared with BSC, but appear to do so without net loss in quality of life and at a cost per LYG that is much lower than for many other NHS activities. Depending on assumptions used, these new drugs range from being cost-effective, as conventionally accepted, to being cost-saving. CONCLUSIONS - IMPLICATIONS OF THE NEWER DRUGS: One of the present constraints on chemotherapy is availability of inpatient beds. The advent of newer and gentler forms of chemotherapy given on an outpatient basis would not only overcome this, but it would allow more patients to be treated. This might apply particularly to older patients. The treatment of more patients would increase workload for oncologists, cancer nurses and pharmacists. The Government has already announced increased expenditure on staff for cancer care. The previously pessimistic attitudes to chemotherapy in non-small-cell lung cancer are changing in the wake of the newer agents, and this shift is likely to increase referral. CONCLUSIONS - NEED FOR FURTHER RESEARCH: Recent advances in chemotherapy are welcome, but their effects remain small for patients with non-small-cell lung cancer. Much more research is needed into better drugs, better combinations, new ways of assessing the likelihood of response and especially direct comparisons between the new regimens. This research would be aided by having a greater proportion of patients involved in trials, but there will be infrastructure implications of increased participation.

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C.I. Pigment Red 23 is a bluish red commercial dye used as a coloring agent in paints, inks, rubber, plastics, lacquers, and paper. Toxicology and carcinogenicity studies were conducted by feeding groups of rats and mice diets containing C.I. Pigment Red 23 (greater than 96% pure) for 17 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary cells. 17-Day Studies: Groups of five rats and five mice of each sex were fed diets containing 0, 6,000, 12,500, 25,000, 50,000, or 100,000 ppm C.I. Pigment Red 23 for 15 to 17 days. All rats and all female mice lived until the end of the studies. Two male mice in the 12,500 ppm dose group died accidentally. No other deaths occurred among male mice. Final mean body weights of rats and mice receiving C.I. Pigment Red 23 were within 10% of those of the controls. Feed consumption by exposed animals was similar to that of the controls. Hematocrit value, hemoglobin concentration, and erythrocyte count were decreased in the 50,000 and 100,000 ppm groups of rats. A corresponding decrease was not seen in mice. Absolute and relative organ weights of exposed animals were generally similar to those of the controls. No chemical-related gross lesions were seen in rats or mice. 13-Week Studies: Groups of 10 rats and 10 mice of each sex were fed diets containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm C.I. Pigment Red 23 for 13 weeks. All rats and mice lived until the end of the studies. Final mean body weights of rats and mice receiving C.I. Pigment Red 23 were within 10% of those of the controls. Feed consumption by exposed animals was similar to that of the controls. In 50,000 ppm male rats, hematocrit and hemoglobin concentrations and erythrocyte counts were significantly less than those of the controls. In female rats receiving 3,000, 6,000 and 50,000 ppm C.I. Pigment Red 23, lymphocyte counts were significantly higher than the control values. Leukocyte counts in 3,000 ppm females were also significantly increased. Female mice in the 6,000 ppm dose group had significantly lower hematocrit and hemoglobin concentrations than did untreated females. Hematology parameters in exposed males were similar to those of untreated males. There were no biologically significant differences in organ weights among dosed and control rats. Absolute and relative liver weights of male mice receiving 12,500 ppm C.I. Pigment Red 23 were significantly increased compared to those of the controls. Absolute and relative thymus weights for all but 12,500 ppm female mice were significantly lower than those of the controls. No chemical-related gross or histopathologic lesions occurred in rats or mice. 2-Year Studies: Survival, Body Weights, Feed Consumption, and Clinical Findings Because levels of C.I. Pigment Red 23 as high as 50,000 or 100,000 ppm in the feed did not adversely affect survival and mean body weights in the 17-day and 13-week studies, nor cause any chemical- related lesions, doses of 0, 10,000, 25,000, or 50,000 ppm were selected for the 2-year studies. Doses higher than 50,000 ppm (5%) are not used in 2-year studies because they may lead to excessive dilution of nutrients in feed which in turn could produce nutritional deficiencies. Survival rates of mid- and high-dose male and of high-dose female rats were significantly greater than those of the controls, due primarily to a chemical related decreased incidence of mononuclear cell leukemia in these groups (survival in male rats: control, 22/50, low-dose, 29/50, mid-dose, 36/50, high-dose, 35/51; female rats: 29/50, 34/50, 33/50, 40/50). Survival of mice was not affected by the administration of C.I. Pigment Red 23, although survival of low-dose male mice was significantly lower than that of controls (male mice: 29/51, 17/53, 27/52, 30/51; female mice: 35/50, 34/49, 36/50, 35/49). The decreased survival in the low- dose males was associated with evidence of body trauma and secondary septicemia caused by fighting. From approximately week 20 of the study, the group mean body weight, the group mean body weights of exposed female rats were consistently lower than those of controls; at week 101, mean body weights of mid- dose (25,000 ppm) and high-dose (50,000 ppm) females were 6&amp;percnt; and 8&amp;percnt; less, respectively. The final mean body weights of exposed male rats and male and female mice were similar to those of controls. Feed consumption values for exposed male and female rats and mice were similar to those of the controls and there were no clinical signs associated with the administration of C.I. Pigment Red 23. Pathology Findings: Renal tubule adenomas occurred in two high- dose male rats. Renal tubule carcinomas occurred in one high-dose male and one mid-dose male rat. No renal tubule neoplasms were seen in the controls. Renal tubule neoplasms are uncommon and have occurred in 8/499 (1.6&amp;percnt;) untreated historical controls with a range of 0&amp;percnt; to 6&amp;percnt;. The residual halves of kidneys from control and high-dose males were step sectioned and examined; renal tubule adenomas were observed in a control male and in two additional high- dose males. Because of the low numbers of renal neoplasms, it is uncertain if they were related to chemical administration. The incidence of renal tubule hyperplasia (3/50, 6/48, 5/50, 8/50) and the mean severity of nephropathy were also slightly increased in high-dose male rats. The incidence of mononuclear cell leukemia occurred with a significant negative trend in exposed male and female rats. No chemical-related increases in the incidence of neoplasms were observed in mice of either sex. There was a chemical-related increase in the incidence of hyperplasia (male mice: 0/49, 1/48, 1/50, 7/48; female mice: 6/49, 14/49, 43/50, 47/49) and hyperkeratosis of the forestomach epithelium attributed to chemical administration. Genetic Toxicology: C.I. Pigment Red 23 was mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98 with and without exogenous metabolic activation (S9), but it was not mutagenic in strain TA1535. C.I. Pigment Red 23 induced sister chromatid exchanges in Chinese hamster ovary cells in the absence of S9, but not with S9 activation. The pigment was negative for the induction of chromosomal aberrations in Chinese hamster ovary cells both in the presence and absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of C.I. Pigment Red 23 in male F344 rats as evidenced by a marginally increased incidence of renal tubule cell neoplasms. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in female F344 rats fed diets containing 10,000, 25,000, or 50,000 ppm. Mononuclear cell leukemia occurred with a decreased incidence in male and female rats receiving C.I. Pigment Red 23. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3F1 mice fed diets containing 10,000, 25,000 or 50,000 ppm. The severity of kidney nephropathy was increased in exposed male rats. In mice, C.I. Pigment Red 23 caused an increase in hyperkeratosis and epithelial hyperplasia of the fore- stomach. Synonyms: 2-Naphthalenecarboxamide; 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-N-(3- nitrophenyl); 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-3 -2-naphthanilide; Alkali Resistant Red Dark; Calcotone Red 3B; Carnation Red Toner B; CI 12355; Congo Red R- 138; Fenalac Red FKB Extra; Malta Red X2284; Naphthol Red B; Naphthol Red T Toner 35- 6001; Naphthol Red Deep 10459; Pigment Red BH; Rubescence Red MT-21; Sanyo Fast Red 10B; Sapona Red Lake RL-6280; Sengale Light Rubin RG; Textile Red WD-263

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Receipt of key preventive health services among women and men of reproductive age (i.e., 15-44 years) can help them achieve their desired number and spacing of healthy children and improve their overall health. The 2014 publication Providing Quality Family Planning Services: Recommendations of CDC and the U.S. Office of Population Affairs (QFP) establishes standards for providing a core set of preventive services to promote these goals. These services include contraceptive care for persons seeking to prevent or delay pregnancy, pregnancy testing and counseling, basic infertility services for those seeking to achieve pregnancy, sexually transmitted disease (STD) services, and other preconception care and related preventive health services. QFP describes how to provide these services and recommends using family planning and other primary care visits to screen for and offer the full range of these services. This report presents baseline estimates of the use of these preventive services before the publication of QFP that can be used to monitor progress toward improving the quality of preventive care received by women and men of reproductive age. 2011-2013. Three surveillance systems were used to document receipt of preventive health services among women and men of reproductive age as recommended in QFP. The National Survey of Family Growth (NSFG) collects data on factors that influence reproductive health in the United States since 1973, with a focus on fertility, sexual activity, contraceptive use, reproductive health care, family formation, child care, and related topics. NSFG uses a stratified, multistage probability sample to produce nationally representative estimates for the U.S. household population of women and men aged 15-44 years. This report uses data from the 2011-2013 NSFG. The Pregnancy Risk Assessment Monitoring System (PRAMS) is an ongoing, state- and population-based surveillance system designed to monitor selected maternal behaviors and experiences that occur before, during, and shortly after pregnancy among women who deliver live-born infants in the United States. Annual PRAMS data sets are created and used to produce statewide estimates of preconception and perinatal health behaviors and experiences. This report uses PRAMS data for 2011-2012 from 11 states (Hawaii, Maine, Maryland, Michigan, Minnesota, Nebraska, New Jersey, Tennessee, Utah, Vermont, and West Virginia). The National Health Interview Survey (NHIS) is a nationally representative survey of noninstitutionalized civilians in the United States. NHIS collects data on a broad range of health topics, including the prevalence, distribution, and effects of illness and disability and the services rendered for or because of such conditions. Households are identified through a multistage probability household sampling design, and estimates are produced using weights that account for the sampling design, nonresponse, and poststratification adjustments. This report uses data from the 2013 NHIS for women aged 18-44 years. Many preventive health services recommended in QFP were not received by all women and men of reproductive age. For contraceptive services, including contraceptive counseling and advice, 46.5% of women aged 15-44 years at risk for unintended pregnancy received services in the past year, and 4.5% of men who had vaginal intercourse in the past year received services in that year. For sexually transmitted disease (STD) services, among all women aged 15-24 years who had oral, anal, or vaginal sex with an opposite sex partner in the past year, 37.5% were tested for chlamydia in that year. Among persons aged 15-44 years who were at risk because they were not in a mutually monogamous relationship during the past year, 45.3% of women were tested for chlamydia and 32.5% of men were tested for any STD in that year. For preconception care and related preventive health services, data from selected states indicated that 33.2% of women with a recent live birth (i.e., 2-9 months postpartum) talked with a health care professional about improving their health before their most recent pregnancy; of selected preconception counseling topics, the most frequently discussed was taking vitamins with folic acid before pregnancy (81.2%), followed by achieving a healthy weight before pregnancy (62.9%) and how drinking alcohol (60.3%) or smoking (58.2%) during pregnancy can affect a baby. Nationally, among women aged 18-44 years irrespective of pregnancy status, 80.9% had their blood pressure checked by a health care professional and 31.7% received an influenza vaccine in the past year; 54.5% of those with high blood pressure were tested for diabetes, 44.9% of those with obesity had a health care professional talk with them about their diet, and 55.2% of those who were current smokers had a health professional talk with them about their smoking in the past year. Among all women aged 21-44 years, 81.6% received a Papanicolaou (Pap) test in the past 3 years. Receipt of certain preventive services varied by age and race/ethnicity. Among women with a recent live birth, the percentage of those who talked with a health care professional about improving their health before their most recent pregnancy increased with age (range: 25.9% and 25.2% for women aged ≤19 and 20-24 years, respectively, to 35.9% and 37.8% for women aged 25-34 and ≥35 years, respectively). Among women with a recent live birth, the percentage of those who talked with a health care professional about improving their health before their most recent pregnancy was higher for non-Hispanic white (white) (35.2%) compared with non-Hispanic black (black) (30.0%) and Hispanic (26.0%) women. Conversely, across most STD screening services evaluated, testing was highest among black women and men and lowest among their white counterparts. Receipt of many preventive services recommended in QFP increased consistently across categories of family income and continuity of health insurance coverage. Prevalence of service receipt was highest among women in the highest family income category (&gt;400% of federal poverty level [FPL]) and among women with insurance coverage for each of the following: contraceptive services among women at risk for unintended pregnancy; medical services beyond advice to help achieve pregnancy; vaccinations (hepatitis B and human papillomavirus [HPV], ever; tetanus, past 10 years; influenza, past year); discussions with a health care professional about improving health before pregnancy and taking vitamins with folic acid; blood pressure and diabetes screening; discussions with a health care professional in the past year about diet, among those with obesity; discussions with a health care professional in the past year about smoking, among current smokers; Pap tests within the past 3 years; and mammograms within the past 2 years. Before 2014, many women and men of reproductive age were not receiving several of the preventive services recommended for them in QFP. Although differences existed by age and race/ethnicity, across the range of recommended services, receipt was consistently lower among women and men with lower family income and greater instability in health insurance coverage. Information in this report on baseline receipt during 2011-2013 of preventive services for women and men of reproductive age can be used to target improvements in the use of recommended services through the development ofresearch priorities, information for decision makers, and public health practice. Health care administrators and practitioners can use the information to identify subpopulations with the greatest need for preventive services and make informed decisions on resource allocation. Public health researchers can use the information to guide research on the determinants of service use and factors that might increase use of preventive services. Policymakers can use this information to evaluate the impact of policy changes and assess resource needs for effective programs, research, and surveillance on the use of preventive health services for women and men of reproductive age.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS-CoV-2 aim to identify previous SARS-CoV-2 infection, and may help to confirm the presence of current infection. To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS-CoV-2 infection, or has previously had SARS-CoV-2 infection, and the accuracy of antibody tests for use in seroprevalence surveys. We undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020. We included test accuracy studies of any design that evaluated antibody tests (including enzyme-linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS-CoV-2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS-CoV-2 infection. We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR) and clinical diagnostic criteria). We assessed possible bias and applicability of the studies using the QUADAS-2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random-effects logistic regression where appropriate, stratifying by time since post-symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs). We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS-CoV-2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in-house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi-group designs (n = 29), inclusion of only COVID-19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID-19 infection. There were no studies exclusively in asymptomatic participants. Two-thirds of the studies (n = 33) defined COVID-19 cases based on RT-PCR results alone, ignoring the potential for false-negative RT-PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post-symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post-symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False-positive results were more common where COVID-19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post-symptom onset. At a prevalence of 20%, a likely value in surveys in high-risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands. The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID-19, but they may still have a role complementing other testing in individuals presenting later, when RT-PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS-CoV-2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post-symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID-19 disease. The design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID-19-positive cases who are RT-PCR-negative should be included as well as those confirmed RT-PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan ongoing updates of this living systematic review.

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Anorexic and bulimic patients have a highly distorted relationship with food and eating, even though they tend to be knowledgeable about diet and nutrition. The progress of this disease, as well as its complications and associated difficulties, are increasingly understood, while the etiopathogeny of eating disorders remains obscure. The approach that we are proposing involves the study of one of the most fundamental cognitive functions of human reasoning--the cognitive process of categorization. The purpose of this study is to understand the procedures used by these patients to construct representations of food. Categorization, one of the basic features of human cognition, allows individuals to organize their subjective experience of the surrounding environment by structuring its contents. This ability to group different objects into the same category based on their common characteristics is important for explaining the major cognitive activities of planning, memorization, communication and perception. Indeed, our categories reflect our conceptions of the world. They depend on our experiences and representations, as well as the expertise acquired in a specific field. The differences that appear in the categories created by subjects when they are asked to classify objects reveal the properties that are most salient to them and, as a result, the interests, values and ideas associated with these properties. There are three types of properties: perceptive properties, which describe the object's shape, color, odor and texture; structural properties, which relate to the object's components; and functional properties, which specify the way in which the object is used and provide an answer to the question, "What is it used for?". Subjects attribute these functional properties by means of knowledge or inference according to their representation of the object's role; such properties are especially likely to emerge during top-down (theory-driven) processing. The type of processing used (bottom-up or top-down) is dependent on a certain number of factors. We hypothesize, within the context of food product categorization, that patients suffering from eating disorders largely resort to processing based on acquired information or beliefs about the objects, i.e. top-down processing. We present two studies: a naturalistic and exploratory pilot study whose goal is to identify whether the various categorization processes used by eating disorder patients differ from those employed by subjects not suffering from an eating disorder. A second study aims to identify the different categorization procedures. During the first experiment, 68 women (17 control subjects, 17 anorexics, 17 anorexic bulimics and 17 bulimics) aged 18-39 (average age: 26.6) verbalize all representations that come to mind during a limited time period as the name of a food item is read. Eighty-nine food items are presented in alphabetical order. The list is read out loud and all comments are recorded. The data is processed in three ways : an analysis based on the positive or negative valence of each representation, an analysis based on each categories of food and an analysis of representations based on themes expressed. The three analyses (valence, categories of food and theme assigned to the representations) show differences between the representations of the four experimental groups. In fact, the anorexics and anorexic bulimics mainly express strongly negative representations about food, whereas bulimics and control produce representations whose positive and negative valences balances. These negative cognitions concern mainly meat for the control subjects and cakes for the subjects reached of TCA. Concerning theme assigned to the representations, the control subjects produce mainly cognitions relating to the hedonism, the flavor of food and their purpose on health. The anorexics and anorexics-bulimics evoke mainly the fat and sugar content of the foods. The bulimics evoke mainly cognitions relating to the effect on health and the intestinal transit time of food. These results lead one to believe that it is not the bulimic binging and purging of these patients, but rather their restrictive behavior that is the determining factor in the differences in food representations observed between the two experimental groups. During the second experiment, 60 women (15 controls, 15 anorexics, 15 anorexic bulimics and 15 bulimics) aged 18-32 (average age: 25.6) classified 27 food names according to their similarities and differences, and then explained the reasons for their categorizations. The data were analyzed in terms of similarity/difference, and the verbalizations were analyzed by content. The results indicate that 10 of the 27 foods were categorized differently by the controls and the subjects with eating disorders. Subjects classified the following foods: camembert cheese, cold cuts, cheese spread, fruit in syrup, whole milk, mayonnaise, bread, fresh fish, potatoes and plain yogurt. Bulimics and controls use similar classifications for food names, while anorexics and atypical bulimics classify foods in a similar way. Examining the categorization criteria used during verbalizations allows us to better understand these differences. The control group's major criterion seems to be the succession of dishes. These subjects group into separate categories entry foods (beef, eggs, fish, etc.), vegetables, cheese or dairy foods, and finally desserts. Additional foods, like bread and mayonnaise, belong to the same category. Other categories are nutritional criteria (for example, dairy products contain calcium) and biological criteria (for example, bananas and apples are fruits). These categorization criteria include structural properties (which describe what the object is made of) and functional, "academic" properties, those which describe how foods are used, "as in cookbooks or diet books." On the other hand, the categorization criteria expressed by anorexic patients are very different from those used by control subjects: foods that are hard to eliminate, rich, high-fat and therefore indigestible are considered to be similar. Some examples are cold cuts, potatoes, mayonnaise and prepared desserts. A second categorization criterion involves the concept of natural foods : certain foods "are unhealthy because they're processed, so they're bad for you"--one such example is cheese spread. A third criterion concerns the notion of familiar foods: poultry and eggs, for example, are "familiar to us." We are clearly seeing here the importance of functional properties in the categorization of food names: certain foods are indigestible, hard to eliminate, cause heartburn or reflux, are not natural, and thus are avoided. The categorization criteria mentioned by bulimic patients also clearly take into account the functional properties of foods. The criteria are of the following type: "it's filling, it relieves a bulimic attack, it helps prevent heartburn and constipation, etc." It appears that bulimics' categorization criteria are solely associated with these foods' imagined or real effect on the body. The categorization criteria used by anorexic bulimics seem to be especially associated with weight gain or the consumption of such foods during bulimia attacks because "they make you feel full." On the other hand, light foods, which patients allow themselves to eat, are placed in the same category. This study, which seeks to understand the cognitive functioning of eating disorder patients with anorexia and bulimia, has brought new elements to light. All patients exhibit food categorization processes that differ greatly from those displayed by control subjects. Patients also attribute greater significance to the functional properties of foods as compared to controls, who give priority to structural properties. Anorexic and bulimic patients base their food categorizations on the consequences of ingestion, in terms of health, digestion and weight gain. Their processing of food stimuli is therefore radically different and gives a dominating place to top-down processes. Additional studies should supplement these findings in order to gain a better understanding of patients' disturbed processing of information.

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<bObjective:</b To investigate the effects of methacrylic anhydride gelatin (GelMA) hydrogel loaded with silver and recombinant human basic fibroblast growth factor (rh-bFGF) on deep partial-thickness burn wounds in rabbits. <bMethods:</b The experimental research method was adopted. Low-concentration GelMA materials, medium-concentration GelMA materials and high-concentration GelMA materials containing different concentrations of methacrylic anhydride (MA) were prepared, after adding photoinitiator, low-concentration GelMA hydrogels, medium-concentration GelMA hydrogels, and high-concentration GelMA hydrogels were obtained, respectively. The nuclear magnetic resonance spectroscopy was performed to detect the hydrogen nuclear magnetic resonance spectra of the above-mentioned three concentrations of GelMA materials, and to calculate the degree of substitution according to the spectrum diagram. The three-dimensional microstructure and pore size of 3 types of above-mentioned GelMA hydrogels were detected by field emission scanning electron microscopy (FESEM), with 9 samples measured. According to the selected concentration of MA, ten kinds of solutions of GelMA with different concentration of silver (silver-containing GelMA) were synthesized, and the silver-containing GelMA solution of each concentration was divided into three parts, and then exposed to ultraviolet light lasting for 20, 25, and 35 s, respectively. After adding photoinitiator,the corresponding silver-containing GelMA hydrogels were obtained. The residual degradation rate of silver-containing GelMA hydrogel with different photocrosslinking times was detected by collagenase degradation method at degradation of 12, 24, 36, and 48 h; and the time required for complete degradation was detected, and the sample number was 5. The inhibition zone diameter of GelMA hydrogel under above screened photocrosslinking times containing 10 concentrations of silver against <iStaphylococcus aureus</i was measured to reflect its antibacterial ability, and the sample numbers were all 5. The silver-containing GelMA hydrogel with statistical significance compared with the antibacterial circle diameter of the silver-containing GelMA hydrogel containing the lowest concentration (no silver) was considered as having antibacterial activity. The three-dimensional microstructure and pore size of the silver-containing GelMA hydrogels with antibacterial activity and the lowest drug concentration selected were detected by FESEM, and the sample numbers were all 9. The freeze-dried alone GelMA hydrogel and the freeze-dried silver-containing GelMA hydrogel were soaked in phosphate buffer solution for 24 h, respectively, then the swelling rate of the two GelMA hydrogel were calculated and compared by weighing method, and the sample number was 5. GelMA hydrogel containing silver and rh-bFGF, namely compound hydrogel for short, was prepared according to the preliminary experiment and the above experimental results. The appearance of the composite hydrogel was observed in general, and its three-dimensional microstructure and pore size were detected by FESEM. The deep partial-thickness burn wound was made on the back of 30 rabbits (aged 4-6 months, female half and half). Meanwhile, with the rabbit head as the benchmark, the wounds on the left side of the spine were treated as composite hydrogel treatment group, and the wounds on the right side were treated as gauze control group, and which were treated accordingly. On post injury day (PID) 3, 7, 14, 21, and 28, the healing of wounds in the two groups was observed. On PID 7, 14, 21, and 28, the wound healing area was recorded and the healing rate was calculated, with a sample number of 30. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, and independent sample <it</i test. <bResults:</b The substitution degree among low-concentration GelMA materials, medium-concentration GelMA materials, and high-concentration GelMA materials was significantly different (<iF</i=1 628.00, <iP</i&lt;0.01). The low-concentration GelMA hydrogel had a loose and irregular three-dimensional spatial network structure with a pore size of (60±17) μm; the medium-concentration GelMA hydrogel had a relatively uniform three-dimensional spatial network and pore size with a pore size of (45±13) μm; the high-concentration GelMA hydrogel had the dense and disordered three-dimensional spatial network with a pore size of (25±15) μm, the pore sizes of 3 types of GelMA hydrogels were significantly differences (<iF</i=12.20, <iP</i&lt;0.01), and medium concentration of MA was selected for the concentration of subsequent materials. The degradability of silver-containing GelMA hydrogels with different concentrations of the same photocrosslinking time was basically same. The degradation residual rates of silver-containing GelMA hydrogels with 20, 25, and 35 s crosslinking time at 12 h were (74.2±1.7)%, (85.3±0.9)%, and (93.2±1.2)%, respectively; the residual rates of degradation at 24 h were (58.3±2.1)%, (65.2±1.8)%, and (81.4±2.6)%, respectively; the residual rates of degradation at 36 h were (22.4±1.9)%, (45.2±1.7)%, and (68.1±1.4)%, respectively; the residual rates of degradation at 48 h were (8.2±1.7)%, (32.4±1.3)%, and (54.3±2.2)%, respectively, and 20, 25, and 30 s photocrosslinking time required for complete degradation of silver-containing GelMA hydrogels were (50.2±2.4), (62.4±1.4), and (72.2±3.2) h, and the difference was statistically significant (<iF</i=182.40, <iP</i&lt;0.01), 25 s were selected as the subsequent photocrosslinking time. The antibacterial diameters of 10 types of silver-containing GelMA hydrogels against <iStaphylococcus aureus</i from low to high concentrations were (2.6±0.4), (2.5±0.4), (3.2±0.4), (12.1±0.7), (14.8±0.7), (15.1±0.5), (16.2±0.6), (16.7±0.5), (16.7±0.4), and (16.7±0.6) mm, respectively, and which basically showed a concentration-dependent increasing trend, and the overall difference was statistically significant (<iF</i=428.70, <iP</i&lt;0.01). Compared with the silver-containing GelMA hydrogel with the lowest concentration, the antibacterial circle diameters of other silver-containing GelMA hydrogels with antibacterial ability from low to high concentration were significantly increased (with <it</i values of 26.35, 33.84, 43.65, 42.17, 49.24, 55.74, and 43.72, respectively, <iP</i&lt;0.01). The silver-containing GelMA hydrogel with the antibacterial diameter of (12.1±0.7) mm had the lowest antibacterial activity against <iStaphylococcus aureus</i and the lowest drug loading concentration, and the concentration of silver was selected for the concentration of subsequent materials. The microscopic morphology of the silver-containing GelMA hydrogel containing silver element with a pore size of (45±13) μm had a regular and linear strip-like structure. After soaking for 24 h, the swelling ratio of silver-containing GelMA hydrogel was similar to that of alone GelMA hydrogel. The composite hydrogel was colorless, clear and transparent, and its three-dimensional microstructure was a regular and uniform grid, with a filament network structure inside, and the pore size of (40±21) μm. On PID 3, a large amount of necrotic tissue and exudate of rabbit wound in composite hydrogel group were observed, and scattered scabs, a small amount of necrotic tissue and exudate of rabbit wound in gauze control group were observed. On PID 7, the area of rabbit wound in composite hydrogel group was significantly reduced, and adhesion of rabbit wound and gauze in gauze control group was observed. On PID 14, In composite hydrogel group, the rabbit wound surface was ruddy, and the growth of granulation tissue was observed, and in gauze control group, the rabbit wound base was pale, and the blood supply was poor. On PID 21, the rabbit wounds in composite hydrogel group healed completely, and rabbit wound in gauze control group had healing trend. On PID 28, new hair could be seen on rabbit wound surface in composite hydrogel group; oval wound of rabbit in gauze control group still remained. On PID 7, 14, 21, and 28, the wound healing areas of rabbit in composite hydrogel group were significantly larger than those in gauze control group (with <it</i values of 2.24, 4.43, 7.67, and 7.69, respectively, <iP&lt;</i0.05 or <iP</i&lt;0.01). <bConclusions:</b The medium-concentration GelMA hydrogel has good physical and chemical properties in terms of swelling and degradability. The screened silver-containing GelMA hydrogels had the lowest antibacterial activity and the lowest drug loading concentration. Composite hydrogel can significantly shorten the healing time of deep partial-thickness burn wounds in rabbits.

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Worldwide melanoma incidence and mortality are increasing (1). Despite the ongoing research, advanced melanoma is still incurable; therefore, the most appropriate solution seems to be early detection combined with complete surgical excision (2). Since the diagnostic protocol of suspicious lesions includes a complete excision with safety margins (2), the problem of unnecessary scarring is significant. The real challenge in this case is to have a properly formulated diagnosis before acquiring a biopsy. Currently available non-invasive techniques are coherence tomography, digital dermoscopy, and reflectance confocal microscopy. All these techniques allow for a presumptive diagnosis, but the most promising results are provided by reflectance confocal microscopy. Reflectance confocal microscopy (RCM) is an optical imaging technique that uses a laser diode as a source of coherent monochromatic light which penetrates the tissue and illuminates a single point. Light from the stimulated section is reflected and passes through a filter, thereby forming the image on the detector. This filter enables selective excitation of a particular point on which focus is achieved and rejects reflection from the out-of-focus area, thus obtaining a "confocal" image. Contrast is the result of differences in the refractive index of the cell organelles and microstructures, resulting in white structures on a black background. This technique allows, as opposed to conventional light microscopy, the analysis of sections obtained at a bi- or tri-dimensional level and controlling the depth of the field, permitting out-of-focus artifacts to be eliminated. In dermatology, this technique is useful for both clinical and research purposes. It is the only technique that allows horizontal viewing of the skin up to the superficial dermis (approximately 300 mm, at a cellular level resolution (0.5-1.0 μm in the lateral dimension and 4.0-5.0 μm in the axial dimension) (3). It allows both in vivo and ex vivo diagnosis, while providing the possibility for long-term monitoring. It has proved to be especially valuable for in vivo examinations of melanocytic lesions, whereas melanin and melanosomes are a powerful source of contrast, allowing the individualization of melanocytic cells (4). We report the case of a 65-year-old Caucasian woman who presented to the Dermatology Department of University of Modena and Reggio Emilia, Italy, for the examination of an atypical lesion, of unknown history, localized in the right preauricular area. The patient's personal and family histories were negative for skin malignancies and for other significant medical history. The clinical presentation was highly indicative of malignancy, as it met all the ABCD clinical criteria: an asymmetric papule composed of two areas, one pigmented and another one hypopigmented, with ill-defined borders and a diameter of approximately 2 cm. The dermatoscopic examination revealed an asymmetric multicomponent pattern with atypical network, structureless areas, peripheral irregular globules, and a blue-white veil. Because clinical and dermatoscopic features pointed towards a suspicious lesion which was situated on the face, where unnecessary scarring is unwanted, reflectance confocal microscopy (RCM) examination was proposed and performed (VivaScope 3000; MAVIG GmBH, Munich, Germany) (5). It revealed the following features: the epidermis presented a disarranged pattern; the dermo-epidermal junction and superficial dermis presented a meshwork pattern with edged AND non-edged papillae, non-homogenous junctional clusters, dense nests, dense AND sparse nests, and atypical cells in a sparse distribution (Figure 1). Figure 1. (A) Clinical examination of an atypical melanocytic lesion situated at the right preauricular area. (B) Dermatoscopic examination. (C) Confocal examination of dermo-epidermal junction and superficial dermis which reveals a meshwork pattern (yellow circle) with edged AND non-edged papillae, non-homogenous junctional clusters (yellow star), dense nests, dense AND sparse nests (red star) and atypical cells in a sparse distribution (arrow). The clinical and confocal data indicated a malignant melanocytic tumor, so an excisional biopsy with safety margins was performed. The histopathological report indicated superficial spreading melanoma with a Breslow of 0.55 mm and 0 mitosis/mm2. This case illustrates the important role confocal microscopy examination has in the management of melanocytic lesions situated in special areas like the face. Reflectance confocal microscopy is an imaging technique that allows viewing the layers of the skin up to the superficial dermis and therefore turns out to be extremely useful in obtaining a pertinent diagnosis before acquiring a biopsy. According to the data available so far, it was established that reflectance confocal microscopy increases the diagnostic accuracy for melanocytic lesions in both pigmented and hypopigmented lesions. In a study conducted by Borsari et al., reflectance confocal microscopy proved to have a sensibility and specificity of 95.3% and 83.9%, respectively (6). By improving the accuracy of clinical and dermatoscopic diagnosis, the reflectance confocal microscopy technique contributes to increasing the confidence of the clinical and dermatoscopic diagnosis (7). In this regard, confocal reflectance microscopy reduces unnecessary excisions, particularly in cases of damage to cosmetically important areas, such as the face or the neck, simultaneously detecting the malignant lesions that require a surgical approach, as seen in the case presented, where confirmation of the diagnosis by confocal microscopy allowed for a safe excision. In fact, the head and neck are the most appropriate body location for reflectance confocal examination, especially because RCM showed a high diagnostic accuracy for lesions located on sun-damaged skin, as these two areas frequently are (adjusted odds ratio (aOR), 2.13; 95% confidence interval (CI), 1.37-3.30; P=.001) (6). Reflectance confocal microscopy is very helpful in the management of special lesions, like facial lentigo maligna melanoma. This type of lesion is considered to be a real challenge for the dermatologist because of its clinical and morphological features that are similar to other lesions such as solar lentigines and pigmented actinic keratoses. In this case, reflectance confocal excels at specificity of the diagnosis, but also at to the ability to define the margins more accurately, permitting a pre-surgical mapping and for possibility of identifying the optimal site for biopsy (8,9). By improving diagnostic ability, reflectance confocal microscopy technique may contribute to the selection of lesions that may be eligible for non-surgical treatment. Facial pigmented non-melanocytic macules like solar lentigo, flat seborrheic keratosis, lichen planus-like keratosis, and pigmented actinic keratosis can mimic a lentigo maligna, or even a lentigo maligna melanoma, but with the help of the RCM, an accurate diagnosis can be established, sparing the patient can be from unwanted facial scars using a non-surgical approach (laser, cryotherapy, imiquimod) (10,11). Furthermore, reflectance confocal microscopy can be a valuable method for the monitoring of a skin lesion over time, especially melanocytic nevi, reducing unnecessary surgical excision, such as for patients with multiple atypical nevi that undergo multiple biopsies (12,13). Like all other diagnostic methods, RCM has its limitations: palmoplantar lesions (due to thickened epidermis), ulcers or crusts on a large lesion, lesions localized in inaccessible regions such as interdigital space, nasal wing (3). To summarize, reflectance confocal microscopy can improve clinical and dermatoscopic diagnosis of melanocytic lesions, detecting the lesions that need an invasive approach and preventing unnecessary excision. It has proven to be very helpful in the management of lentigo maligna and lentigo maligna melanoma, achieving high specificity in the diagnosis and simultaneously allowing an optimal approach. This technique can be a reliable bridge between dermoscopy and histopathology, being able to provide an alternative to histopathological examination. Special mention must be made of the factors that may change the result to a false negative such as hyperkeratosis, ulceration, or bleeding, so any results should be integrated with the rest of the patient's data.

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Stoddard solvent (white spirit/mineral spirit) is the most widely used solvent in the paint industry. It is used as a dry cleaning agent; as an extraction, cleaning, and degreasing solvent; and as a solvent in aerosols, paints, wood preservatives, asphalt products, lacquers, and varnishes. Stoddard solvent IIC was nominated by the International Union, United Auto Workers, for carcinogenicity testing because of the large volume used in industrial and other settings. Male and female F344/N rats and B6C3F1 mice were exposed to Stoddard solvent IIC (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Liver weights of males exposed to 550 mg/m3 or greater and of females exposed to 275 mg/m3 or greater were increased. Minimal diffuse cytoplasmic vacuolization of hepatocytes of the liver occurred in all females exposed to 2,200 mg/m3. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 17 days. All mice survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Liver weights of males and females exposed to 275 mg/m3 or greater were significantly increased. Cytomegaly of the liver occurred in all males and females exposed to 2,200 mg/m3. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 14 weeks. All rats survived to the end of the study, and the final mean body weight of females exposed to 275 mg/m3 was greater than that of the chamber controls. The relative kidney, liver, and testis weights of all exposed groups of males and the absolute kidney weights of males exposed to 550 mg/m3 or greater were increased. The sperm motility of 550 mg/m3 or greater males was significantly decreased. The incidences of renal tubule granular casts were significantly increased in males exposed to 550 mg/m3 or greater, and the severities of renal tubule hyaline droplet accumulation, granular casts, and regeneration increased with increasing exposure concentration in males. The incidences of goblet cell hypertrophy of the nasal respiratory epithelium in males and females exposed to 2,200 mg/m3 were significantly increased. Sperm motility was decreased in males exposed to 550 mg/m3 or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 14 weeks. Mean body weights of exposed groups were similar to those of the chamber controls, but liver weights of males exposed to 2,200 mg/m3 were significantly increased. The sperm motility of 2,200 mg/m3 males was significantly decreased. This reduction in sperm motility, while statistically significant, is probably of modest importance as studies in mice have found that fertility is unaffected by motility decreases of less than 40%. The incidences of hematopoietic cell proliferation of the spleen in all exposed groups of females were greater than that in the chamber controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138 (males), 550, 1,100, or 2,200 (females) mg/m3, 6 hours per day, 5 days per week for 104 to 105 weeks. Additional groups of 10 males and 10 females were exposed to the same concentrations for 3 months for renal toxicity analyses. Survival in the top exposure concentration groups of males and females was significantly less than that of the chamber controls. Mean body weights of exposed males and females were similar to those of the chamber controls. Cell proliferation analyses were performed in the left kidney of males and females after 3 months of exposure. The mean numbers of labeled cells and the labeling indices in males exposed to 550 and 1,100 mg/m3 were significantly increased. The amount of alpha2u-globulin in the right kidney of males increased with increasing exposure concentration. Also, the incidences of granular casts and cortical tubule degeneration and regeneration were generally increased in exposed males, as was the severity of hyaline droplets. These effects did not occur in females. At 2 years, the incidences of benign and benign or malignant pheochromocytoma (combined) of the adrenal medulla occurred with positive trends in males, and the incidences in the 550 and 1,100 mg/m3 groups were significantly increased. Due to increased incidences of renal tubule hyperplasia in males at 2 years, extended kidney evaluations were conducted; a slightly increased incidence of renal tubule adenoma occurred in the 1,100 mg/m3 group. Nonneoplastic lesions related to Stoddard solvent IIC exposure occurred in the kidney of males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 105 weeks. Survival of exposed mice was similar to that of the chamber controls. Mean body weights of exposed females were greater than those of the chamber controls. The incidences of hepatocellular adenoma occurred with a positive trend in females, and the incidence of multiple hepatocellular adenoma in females exposed to 2,200 mg/m3 was significantly increased. However, the incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular carcinoma alone in exposed males and females were not significantly increased. Stoddard solvent IIC was tested for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535, with and without S9 metabolic activation enzymes; all results were negative. In vivo, the frequency of micronucleated erythrocytes was assessed in peripheral blood samples from male and female B6C3F1 mice after 3 months of inhalation exposure to Stoddard solvent IIC, and results were negative. Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of Stoddard solvent IIC in male F344/N rats based on increased incidences of adrenal medulla neoplasms; the slightly increased incidences of renal tubule adenoma may have been related to Stoddard solvent IIC exposure. There was no evidence of carcinogenic activity of Stoddard solvent IIC in female F344/N rats exposed to 550, 1,100, or 2,200 mg/m3. There was no evidence of carcinogenic activity of Stoddard solvent IIC in male B6C3F1 mice exposed to 550, 1,100, or 2,200 mg/m3. There was equivocal evidence of carcinogenic activity of Stoddard solvent IIC in female B6C3F1 mice based on increased incidences of hepatocellular adenoma; this slight increase was associated with increased body weight in exposed females. Exposure of male rats to Stoddard solvent IIC resulted in nonneoplastic lesions of the kidney characteristic of alpha2u-globulin accumulation.

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Attempts were made to produce lesions in. animals by the injection of material obtained from the vesicles and involved skin of nine cases of herpes zoster. All the cases, with the exception of one (Case II), were characteristic cases of idiopathic herpes zoster and the question of their being cases of so called zosteriform herpes or symptomatic herpes zoster can hardly be raised. As regards Case II, if this case occurred alone, there might be some doubt as to its nature on account of the mildness of the symptoms and the small area of skin involvement. Taken in connection with Cases III and IV, however, which occurred in the same ward and in patients who were quite closely in contact with Patient II, it seems fairly reasonable to assume that they were all of the same character. Cases of herpes zoster have been extremely rare in this hospital and the occurrence of three cases in the same ward within a very short period of time suggests very strongly a transference of infection from one case to the other. That Case II was not one of herpes simplex also seems fairly certain from the negative results obtained by inoculation of rabbits' eyes with vesicle material. In making the animal experiments we employed various methods which were suggested largely by the technique used by previous observers, especially by those who have reported results which were considered positive. In making inoculations into the corneas the technique recommended by Lipschütz was employed as far as possible. Young rabbits were used and the material was obtained from fresh vesicles early in the disease and inoculated with as little delay as possible. The material injected into rabbits' eyes was obtained from seven cases and twenty-four rabbits were used. In judging of the results obtained in this kind of experimentation great caution must be observed. Our experience convinces us that slight opacities occurring along the lines of scarification and mild conjunctivitis cannot be held to indicate the effect of a specific virus. As regards the interpretation of the microscopic changes found, we were quite familiar with the appearance of intranuclear inclusion bodies as seen in the lesions of experimental herpes simplex and the filterable virus (Virus III) indigenous to rabbits described by Rivers and Tillett (5). We also had no difficulty in imding intranuclear inclusions in the sections of skin removed from patients. It is not likely, therefore, that these structures were overlooked in our study of the sections. Briefly stated, although the material studied was satisfactory and in spite of the fact that a considerable number of animals were used for each case, we have been unable to confirm the observations of Lipschütz regarding the experimental production of specific lesions in the corneas of rabbits. We realize that this is only negative evidence and therefore not of conclusive importance in view of Lipschütz's observations. It indicates, however, that the production of specific lesions in rabbits' eyes with material from herpes zoster vesicles is extremely difficult and that successful results may be a matter of chance, depending, possibly, on peculiar susceptibility on the part of the rabbits. In view of the fact, however, that a careful analysis of the positive results reported by other observers shows that the conclusions were based on insufficient evidence, we believe that further work is necessary before the successful inoculation of the rabbits' corneas with herpes zoster virus can be accepted as fully demonstrated. To make the evidence convincing specific lesions should be obtained with a fair degree of regularity and the virus should be successfully transmitted through at least two generations. Apparently the latter was not attempted by Lipschütz. Intracerebral inoculations into three rabbits with material from two cases (Nos. I and IV) were made. Two rabbits were also inoculated intraspinally with material from one case (No. IV). None of these animals showed any reaction. In the case of one of the animals inoculated into the brain (Case I) although this rabbit showed no symptoms, we thought it conceivable that the susceptibility of the species for the virus might be so slight that no obvious lesion had been produced. Nevertheless it was thought that the virus might possibly remain alive at the seat of inoculation and by repeated transfers become adapted to the rabbit. This phenomenon has been observed by Noguchi with vaccine virus, and by Rivers and Tillett with the rabbit virus isolated by these workers. This possibility was tested by us by making serial corneal and brain inoculations. Corneal transfers were carried through fourteen animals in series, and brain transfers through ten. No specific lesions developed in any of the animals. The work of Teague and Goodpasture suggested that the skin might be rendered more susceptible to infection by previous treatment with tar. Material from two cases (Nos. I and VIII) was inoculated into the tarred skin of guinea pigs and rabbits. The material was injected intracutaneously and also rubbed into the scarified skin. No reaction was obtained in any of the animals. Finally, the transmission of herpes zoster to monkeys was attempted. Blanc and Caminopetros, and Bastai and Busacca, as discussed in the review of the literature, inoculated monkeys (Macacus) in various ways, without success. It was thought possible that although monkeys of the genus Macacus might be refractory, monkeys of another genus might prove susceptible. Consequently, besides the inoculation of two Macacus monkeys, attempts were made to infect five vervets. Moreover, in view of the fact that the virus of vaccinia and the rabbit virus of Rivers and Tillett could be successfully cultivated in the testicle, intratesticular inoculations were employed. The testicles were removed at varying periods following inoculation. Numerous sections of these testicles were made and examined, but in no instance were any lesions found which could be interpreted as specific. No cells containing intranuclear inclusion bodies were found. These experiments, therefore, have also led to purely negative results. This report of our work is made at the present time because a considerable amount of literature has been published which gives the impression that herpes zoster has been successfully transmitted to animals. Although the observations of Lipschütz are suggestive, it is important that they be confirmed by further investigations. Until herpes zoster can be regularly transmitted to animals and cross-immunity tests be carried out, the relation of the virus of herpes zoster to that of herpes simplex remains a matter of speculation. In view of the fact that herpes simplex can be easily and regularly transmitted to rabbits, whereas in the hands of a large number of investigators similar experiments with herpes zoster are completely negative, it does not seem likely that the etiological agent concerned in these two diseases can be absolutely identical. The question of the identity or non-identity of herpes zoster and varicella is even more difficult to answer, because at present neither of these infections is readily transmissible to animals. The work of Kundratitz is extremely interesting. His observations, aside from indicating a close immunological relationship between herpes zoster and varicella, are important in that they seem to show the presence of a transmissible virus in the vesicles of herpes zoster. The only question that arises is whether the cases of herpes zoster from which Kundratitz was able to make successful transfers were true cases of idiopathic herpes zoster.

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The National Institutes of Health (NIH) estimates that stroke costs now exceed 45 billion dollars per year. Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. A number of well-designed randomized stroke trials and case series have now been reported in the literature to evaluate the safety and efficacy of thrombolytic therapy for the treatment of acute ischemic stroke. These stroke trials have included intravenous studies, intra-arterial studies, and combinations of both, as well as use of mechanical devices for removal of thromboemboli and of neuroprotectant drugs, alone or in combination with thrombolytic therapy. At this time, the only therapy demonstrated to improve outcomes from an acute stroke is thrombolysis of the clot responsible for the ischemic event. There is room for improvement in stroke lysis studies. Divergent criteria, with disparate reporting standards and definitions, have made direct comparisons between stroke trials difficult to compare and contrast in terms of overall patient outcomes and efficacy of treatment. There is a need for more uniform definitions of multiple variables such as collateral flow, degree of recanalization, assessment of perfusion, and infarct size. In addition, there are multiple unanswered questions that require further investigation, in particular, questions as to which patients are best treated with thrombolysis. One of the most important predictors of clinical success is time to treatment, with early treatment of &lt;3 hours for intravenous tissue plasminogen activator and &lt;6 hours for intra-arterial thrombolysis demonstrating significant improvement in terms of 90-day clinical outcome and reduced cerebral hemorrhage. It is possible that improved imaging that identifies the ischemic penumbra and distinguishes it from irreversibly infarcted tissue will more accurately select patients for therapy than duration of symptoms. There are additional problems in the assessment of patients eligible for thrombolysis. These include being able to predict whether a particular site of occlusion can be successfully revascularized, predict an individual patient's prognosis and outcome after revascularization, and in particular, to predict the development of intracerebral hemorrhage, with and without clinical deterioration. It is not clear to assume that achieving immediate flow restoration due to thrombolytic therapy implies clinical success and improved outcome. There is no simple correlation between recanalization and observed clinical benefit in all ischemic stroke patients, because other interactive variables, such as collateral circulation, the ischemic penumbra, lesion location and extent, time to treatment, and hemorrhagic conversion, are all interrelated to outcome. This article was written under the auspices of the Technology Assessment Committees for both the American Society of Interventional and Therapeutic Neuroradiology and the Society of Interventional Radiology. The purpose of this document is to provide guidance for the ongoing study design of trials of intra-arterial cerebral thrombolysis in acute ischemic stroke. It serves as a background for the intra-arterial thrombolytic trials in North America and Europe, discusses limitations of thrombolytic therapy, defines predictors for success, and offers the rationale for the different considerations that might be important during the design of a clinical trial for intra-arterial thrombolysis in acute stroke. Included in this guidance document are suggestions for uniform reporting standards for such trials. These definitions and standards are mainly intended for research trials; however, they should also be helpful in clinical practice and applicable to all publications. This article serves to standardize reporting terminology and includes pretreatment assessment, neurologic evaluation with the NIH Stroke Scale score, imaging evaluation, occlusion sites, perfusion grades, follow-up imaging studies, and neurologic assessments. Moreover, previously used and established definitions for patient selection, outcome assessment, and data analysis are provided, with some possible variations on specific end points. This document is therefore targeted to help an investigator to critically review the scales and scores used previously in stroke trials. This article also seeks to standardize patient selection for treatment based on neurologic condition at presentation, baseline imaging studies, and utilization of standardized inclusion/exclusion criteria. It defines outcomes from therapy in phase I, II, and III studies. Statistical approaches are presented for analyzing outcomes from prospective, randomized trials with both primary and secondary variable analysis. A discussion on techniques for angiography, intra-arterial thrombolysis, anticoagulation, adjuvant therapy, and patient management after therapy is given, as well as recommendations for posttreatment evaluation, duration of follow-up, and reporting of disability outcomes. Imaging assessment before and after treatment is given. In the past, noncontrast CT brain scans were used as the initial screening examination of choice to exclude cerebral hemorrhage. However, it is now possible to quantify the volume of early infarct by using contiguous, discrete (nonhelical) images of 5 mm. In addition, CT angiography by helical scanning and 100 mL of intravenous contrast agent can be used expeditiously to obtain excellent vascular anatomy, define the occlusion site, obtain 2D and 3D reformatted vascular images, grade collateral blood flow, and perform tissue-perfusion studies to define transit times of a contrast bolus through specific tissue beds and regions of interest in the brain. Dynamic CT perfusion scans to assess the whole dynamics of a contrast agent transit curve can now be routinely obtained at many hospitals involved in these studies. The rationale, current status of this technology, and potential use in future clinical trials are given. Many hospitals are also performing MR brain studies at baseline in addition to, or instead of, CT scans. MRI has a high sensitivity and specificity for the diagnosis of ischemic stroke in the first several hours from symptom onset, identifies arterial occlusions, and characterizes ischemic pathology noninvasively. Case series have demonstrated and characterized the early detection of intraparenchymal hemorrhage and subarachnoid hemorrhage by MRI. Echo planar images, used for diffusion MRI and, in particular, perfusion MRI are inherently sensitive for the susceptibility changes caused by intraparenchymal blood products. Consequently, MRI has replaced CT to rule out acute hemorrhage in some centers. The rationale and the potential uses of MR scanning are provided. In addition to established criteria, technology is continuously evolving, and imaging techniques have been introduced that offer new insights into the pathophysiology of acute ischemic stroke. For example, a better patient stratification might be possible if CT and/or MRI brain scans are used not only as exclusion criteria but also to provide individual inclusion and exclusion criteria based on tissue physiology. Imaging techniques might also be used as a surrogate outcome measure in future thrombolytic trials. The context of a controlled study is the best environment to validate emerging imaging and treatment techniques. The final section details reporting standards for complications and adverse outcomes; defines serious adverse events, adverse events, and unanticipated adverse events; and describes severity of complications and their relation to treatment groups. Recommendations are made regarding comparing treatment groups, randomization and blinding, intention-to-treat analysis, quality-of-life analysis, and efficacy analysis. This document concludes with an analysis of general costs associated with therapy, a discussion regarding entry criteria, outcome measures, and the variability of assessment of the different stroke scales currently used in the literature is also featured. In summary, this article serves to provide a more uniform set of criteria for clinical trials and reporting outcomes used in designing stroke trials involving intra-arterial thrombolytic agents, either alone or in combination with other therapies. It is anticipated that by having a more uniform set of reporting standards, more meaningful analysis of the data and the literature will be able to be achieved.

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The objective of this analysis is to determine the effectiveness of solid organ transplantation in persons with end stage organ failure (ESOF) and human immunodeficiency virus (HIV+) CONDITION AND TARGET POPULATION Patients with end stage organ failure who have been unresponsive to other forms of treatment eventually require solid organ transplantation. Similar to persons who are HIV negative (HIV-), persons living with HIV infection (HIV+) are at risk for ESOF from viral (e.g. hepatitis B and C) and non-viral aetiologies (e.g. coronary artery disease, diabetes, hepatocellular carcinoma). Additionally, HIV+ persons also incur risks of ESOF from HIV-associated nephropathy (HIVAN), accelerated liver damage from hepatitis C virus (HCV+), with which an estimated 30% of HIV positive (HIV+) persons are co-infected, and coronary artery disease secondary to antiretroviral therapy. Concerns that the need for post transplant immunosuppression and/or the interaction of immunosuppressive drugs with antiretroviral agents may accelerate the progression of HIV disease, as well as the risk of opportunistic infections post transplantation, have led to uncertainty regarding the overall benefit of transplantation among HIV+ patients. Moreover, the scarcity of donor organs and their use in a population where the clinical benefit of transplantation is uncertain has limited the availability of organ transplantation to persons living with ESOF and HIV. With the development of highly active anti retroviral therapy (HAART), which has been available in Canada since 1997, there has been improved survival and health-related quality of life for persons living with HIV. HAART can suppress HIV replication, enhance immune function, and slow disease progression. HAART managed persons can now be expected to live longer than those in the pre-HAART era and as a result many will now experience ESOF well before they experience life-threatening conditions related to HIV infection. Given their improved prognosis and the burden of illness they may experience from ESOF, the benefit of solid organ transplantation for HIV+ patients needs to be reassessed. What are the effectiveness and cost effectiveness of solid organ transplantation in HIV+ persons with ESOF? A literature search was performed on September 22, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1996 to September 22, 2009. Systematic review with or without a Meta analysis, RCT, Non-RCT with controlsHIV+ population undergoing solid organ transplantationHIV+ population managed with HAART therapyControls include persons undergoing solid organ transplantation who are i) HIV- ii) HCV+ mono-infected, and iii) HIV+ persons with ESOF not transplanted.Studies that completed and reported results of a Kaplan-Meier Survival Curve analysis.Studies with a minimum (mean or medium) follow up of 1-year.English language citations Case reports and case series were excluded form this review. i) Risk of Death after transplantationii) Death censored graft survival (DCGS)iii) HIV disease progression defined as the post transplant incidence of:- opportunistic infections or neoplasms,- CD4+ T-cell count &lt; 200mm(3), and- any detectable level of plasma HIV viral load.iv) Acute graft rejection,v) Return to dialysis,vi) Recurrence of HCV infection No direct evidence comparing an HIV+ cohort undergoing transplantation with the same not undergoing transplantation (wait list) was found in the literature search. The results of this review are reported for the following comparison cohorts undergoing transplantation: I) KIDNEY TRANSPLANTATION: HIV+ cohort compared with HIV- cohortII) LIVER TRANSPLANTATION: HIV+ cohort compared with HIV- negative cohortIII) LIVER TRANSPLANTATION: HIV+ HCV+ (co-infected) cohort compared with HCV+ (mono-infected) cohort KIDNEY TRANSPLANTATION: HIV+ VS. HIV#ENTITYSTARTX02212; Based on a pooled HIV+ cohort sample size of 285 patients across four studies, the risk of death after kidney transplantation in an HIV+ cohort does not differ to that of an HIV- cohort [hazard ratio (HR): 0.90; 95% CI: 0.36, 2.23]. The quality of evidence supporting this outcome is very low. Death censored graft survival was reported in one study with an HIV+ cohort sample size of 100, and was statistically significantly different (p=.03) to that in the HIV- cohort (n=36,492). However, the quality of evidence supporting this outcome was determined to be very low. There was also uncertainty in the rate of return to dialysis after kidney transplantation in both the HIV+ and HIV- groups and the effect, if any, this may have on patient survival. Because of the very low quality evidence rating, the effect of kidney transplantation on HIV-disease progression is uncertain. The rate of acute graft rejection was determined using the data from one study. There was a nonsignificant difference between the HIV+ and HIV- cohorts (OR 0.13; 95% CI: 0.01, 2.64), although again, because of very low quality evidence there is uncertainty in this estimate of effect. LIVER TRANSPLANTATION: HIV+ VS. HIV#ENTITYSTARTX02212; Based on a combined HIV+ cohort sample size of 198 patient across five studies, the risk of death after liver transplantation in an HIV+ cohort (with at least 50% of the cohort co-infected with HCV+) is statistically significantly 64% greater compared with an HIV- cohort (HR: 1.64; 95% CI: 1.32, 2.02). The quality of evidence supporting this outcome is very low. Death censored graft survival was reported for an HIV+ cohort in one study (n=11) however the DCGS rate of the contemporaneous control HIV- cohort was not reported. Because of sparse data the quality of evidence supporting this outcome is very low indicating death censored graft survival is uncertain. Both the CD4+ T-cell count and HIV viral load appear controlled post transplant with an incidence of opportunistic infection of 20.5%. However, the quality of this evidence for these outcomes is very low indicating uncertainty in these effects. Similarly, because of very low quality evidence there is uncertainty in the rate of acute graft rejection among both the HIV+ and HIV- groups LIVER TRANSPLANTATION: HIV+/HCV+ VS. HCV+ Based on a combined HIV+/HCV+ cohort sample size of 156 from seven studies, the risk of death after liver transplantation is significantly greater (2.8 fold) in a co-infected cohort compared with an HCV+ mono-infected cohort (HR: 2.81; 95% CI: 1.47, 5.37). The quality of evidence supporting this outcome is very low. Death censored graft survival evidence was not available. Regarding disease progression, based on a combined sample size of 71 persons in the co-infected cohort, the CD4+ T-cell count and HIV viral load appear controlled post transplant; however, again the quality of evidence supporting this outcome is very low. The rate of opportunistic infection in the co-infected cohort was 7.2%. The quality of evidence supporting this estimate is very low, indicating uncertainty in these estimates of effect. Based on a combined HIV+/HCV+ cohort (n=57) the rate of acute graft rejection does not differ to that of an HCV+ mono-infected cohort (OR: 0.88; 95% CI: 0.44, 1.76). Also based on a combined HIV+/HCV+ cohort (n=83), the rate of HCV+ recurrence does not differ to that of an HCV+ mono-infected cohort (OR: 0.66; 95% CI: 0.27, 1.59). In both cases, the quality of the supporting evidence was very low. Overall, because of very low quality evidence there is uncertainty in the effect of kidney or liver transplantation in HIV+ persons with end stage organ failure compared with those not infected with HIV. Examining the economics of this issue, the cost of kidney and liver transplants in an HIV+ patient population are, on average, 56K and 147K per case, based on both Canadian and American experiences.

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An annotated list is provided for the genera and species of Chilopoda Geophilomorpha recorded from Europe, including Macaronesia. The list derives from a critical evaluation of all published information. All synonyms are also listed and all taxonomic and nomenclatorial novelties are discussed. Additionally, all available genus-group and species-group names are listed, together with type species and type localities respectively.To date, 452 available species-group names and 95 available genus-group names have been applied to European geophilomorphs, together with another 10 unavailable names. A total of 179 species in 37 genera are provisionally recognized here, but the actual taxonomic identity of 84 of these species is uncertain because their morphology is in completely or imprecisely known. Another 5 species have been recorded from European localities but probably are not established in the wild, and another 8 species have been reported probably only erroneously. We introduce the following 116 new synonymies: Algerophilus hispanicus (Meinert, 1870) [= Geophilus arago nicus Daday, 1889], Bothriogaster signata (Kessler, 1874) [= Notiphilus taeniatus C.L. Koch, 1847, = N. sanguineus C.L. Koch, 1847, = B. affinis Sseliwanoff, 1879, = B. meinerti Sseliwanoff, 1879], Clinopodes C.L. Koch, 1847 [= Poabius C.L. Koch, 1847], Clinopodes carinthiacus (Latzel, 1880) [= Geophilus flavidus styriacus Attems, 1895, = G. trebevicensis poschiavensis Verhoeff, 1934], C. flavidus C.L. Koch, 1847 [= Geophilus flavidus pachypus Verhoeff, 1942, = G. flavidus faitanus Verhoeff, 1943, = G. flavidus improvisus Verhoeff, 1943, = G. flavidus karamani Verhoeff, 1943, = G. flavidus sorattinus Verhoeff, 1951], Dignathodon Meinert, 1870 [= Rhysonotum Attems, 1952], Escaryus retusidens Attems, 1904 [= E. retusidens pallidus Folkmanová, 1956], Geophilus Leach, 1814 [= Homalarthrus Agassiz, 1846, = Esthiomenus Gistel, 1847, = Geophilus (Anadenophilus) Verhoeff, 1928], Geophilus aetnensis Verhoeff, 1928 [= G. insculptus debilis Brolemann, 1930, = G. evisensis Verhoeff, 1943, = G. henroti Manfredi, 1956, = G. aetnensis pollinensis Manfredi, 1957], G. alpinus Meinert, 1870 [= G. impressus C.L. Koch, 1847, = G. palustris C.L. Koch, 1863, = G. insculptus tauerorum Verhoeff, 1928, = G. glacialis inermis Verhoeff, 1938, = G. glacialis unguiculatus Verhoeff, 1938, = G. proximus rhenanus Verhoeff, 1895, = G. anglicanus Bagnall, 1935, = G. langkofelanus Verhoeff, 1938], G. bobolianus Verhoeff, 1928 [= G. longicornis aternanus Verhoeff, 1934], G. carpophagus Leach, 1815 [= Arthronomalus similis Newport, 1845, = G. pachymeropus Eisen &amp; Stuxberg, 1868, = G. luridus Meinert, 1870], G. easoni Arthur, Foddai, Kettle, Lewis, Luczynski &amp; Minelli 2001 [= Arthronomalus crassicornis Parfitt, 1866], G. electricus (Linnaeus, 1758) [= Scolopendra phosphorica Fourcroy, 1785], G. flavus (De Geer, 1778) [= G. longicornis trisulcus Silvestri, 1895, = G. longicornis glaber Verhoeff, 1928, = G. pygmaeus styricus Verhoeff, 1895, = G. longicornis pseudotruncorum Verhoeff, 1896, = G. longicornis styricorum Verhoeff, 1934, = G. carnicus praedator Verhoeff, 1937, = Pachymerium flavum Folkmanová, 1949, = G. osquidatum  porosus Dobroruka, 1957, = Schizotaenia ornata Folkmanová &amp; Dobroruka, 1960], G. fucorum Brölemann, 1909 [= G. longicornis taorminensis Verhoeff, 1928, = G. ruinarum Verhoeff, 1931, = Pachymerium dragani Căpuşe, 1975], G. gavoyi Chalande, 1910 [= G. gavoyi elongatus Chalande, 1910], G. proximus C.L. Koch, 1847 [= G. ganonotus Attems, 1901, = G. eremophilus Lignau, 1933], G. pygmaeus Latzel, 1880 [= G. cispadanus Silvestri, 1896, = G. carnicus Verhoeff, 1928], G. pyrenaicus Chalande, 1909 [= G. pyrenaicus elongatus Chalande, 1909], G. seurati Brolemann, 1924 [= G. litorivagus Verhoeff, 1943], Gnathoribautia Brölemann, 1909 [= Turkomerium Chamberlin, 1952], Haplophilus Cook, 1896 [= Bothrohaplophilus Verhoeff, 1908, = Nesoporogaster Verhoeff, 1924], Haplophilus dimidiatus (Meinert, 1870) [= Himantarium gestri Pocock, 1890, = Ital ophilus sorattinus Verhoeff, 1951], H. excavatus (Verhoeff, 1924) [= Nesoporogaster hispanica Matic &amp; Dărăbanţu, 1969], H. souletinus Brölemann, 1907 [= H. souletinus lusitanus Verhoeff, 1925], H. subterraneus (Shaw, 1794) [= H. subterraneus elongatus Chalande &amp; Ribaut, 1909], H. superbus (Meinert, 1870) [= Himantarium filum Meinert, 1870], Haploschendyla Verhoeff, 1900 [= Dalmatodyla Verhoeff, 1938, = Aporophilus Attems, 1903], Haploschendyla grantii (Pocock, 1891) [= Geophilus barbaricus Meinert, 1870, = H. europaea latzeli Demange, 1959], Henia bicarinata (Meinert, 1870) [= H. bicarinata elongata Brolemann, 1930, = H. bicarinata lapadensis Verhoeff, 1938], H. illyrica (Meinert, 1870) [= Chaetechelyne herzegowinensis Verhoeff, 1938, = H. illyrica absoloni Dobroruka, 1959], H. montana (Meinert, 1870) [= Chaetechelyne vesuviana pharyngealis Verhoeff, 1928], H. valida (Attems, 1927) [= Chaetechelyne osellai Matic &amp; Dărăbanţu, 1968], H. vesuviana (Newport, 1845) [= Scolopendra fusca Fourcroy, 1785, = Chaetechelyne sorattina Verhoeff, 1951], Hydroschendyla submarina (Grube, 1872) [= Arthronomalus littoralis Parfitt, 1874], Pachymerium coiffaiti Demange, 1959 [= P. ferrugineum maderianum Demange, 1959], P. ferrugineum (C.L. Koch, 1835) [= Geophilus caucasicus Attems, 1903, = P. tabacarui Căpuşe, 1968], Schendyla Bergsøe &amp; Meinert, 1866 [= Astenoschendyla Brolemann, 1930, = Echinoschendyla Brölemann &amp; Ribaut, 1912, = Microschendyla Brölemann &amp; Ribaut, 1912, = Schizoschendyla Brölemann &amp; Ribaut, 1912], Schendyla carniolensis Verhoeff, 1902 [= Poabius bistriatus C.L. Koch, 1847, = S. nemorensis quarnerana Verhoeff, 1937, = S. carniolensis clausensis Verhoeff, 1938, = S. carniolensis nivalis Verhoeff, 1938, = S. tesselata Verhoeff, 1943], S. nemorensis (C.L. Koch, 1837) [= S. nemorensis fountaini Turk, 1944, = Brachygeophilus sinionus Manfredi, 1953], S. tyrolensis (Meinert, 1870) [= Brachyschendyla montana prominens Ribaut &amp; Brolemann, 1927, = S. montana herculis Verhoeff, 1938, = Brachyschendyla montana balcanica Kaczmarek, 1969, = Brachyschendyla dobrogica Matic &amp; Dărăbanţu, 1970], S. vizzavonae Léger &amp; Duboscq, 1903 [= S. pellicensis Verhoeff, 1934, = S. incubationum Verhoeff, 1943], S. walachica Verhoeff, 1900 [= S. walachica rhodope nsis Kaczmarek, 1969], Stigmatogaster gracilis (Meinert, 1870) [= Himantarium laevipes C.L. Koch, 1847, = Geophilus ilicis Fabre, 1855, = S. gracilis robusta Attems, 1929, = Diadenoschisma gracile tyrrhenum Verhoeff, 1934, = D. gracile quarneranum Verhoeff, 1937, = S. gracilis aeserniana Attems, 1947], Strigamia acuminata (Leach, 1815) [ =Scolioplanes acuminatus brevidentatus Verhoeff, 1928, = Sc. acuminatus microdon Attems, 1904, = Sc. acuminatus pachypus Verhoeff, 1935, = Sc. italicus Verhoeff, 1928], S. crassipes (C.L. Koch, 1835) [= Scolioplanes variabilis carniolensis Verhoeff, 1895, = Sc. mediterraneus alsaticus Verhoeff, 1928, = Sc. mediterraneus carynthiacus Verhoeff, 1928, = Sc. crassipes longaronensis Verhoeff, 1935, = Sc. crassipes pegliensis Verhoeff, 1935, = Sc. crassipes faitanus Verhoeff, 1943], Thracophilus bulgaricus Verhoeff, 1926 [= T. beroni Matic &amp; Dărăbanţu, 1974], T. subterraneus Verhoeff, 1943 [= T. monoporus Attems, 1947].We also propose 14 new generic combinations: Dignathodon gracilis (Attems, 1952) [from Rhysonotum], Escaryus haasei (Sseliwanoff, 1884) [from Geophilus], Geophilus ibericus (Attems, 1952) [from Brachygeophilus], Geophilus pauciporus (Machado, 1952) [from Orinophilus], Gnathoribautia syriaca (Attems, 1903) [from Geophilus], Haplophilus excavatus (Verhoeff, 1924) [from Nesoporogaster], Haploschendyla splitensis (Verhoeff, 1938) [from Dalmatodyla], Henia duboscqui (Verhoeff, 1943) and H. ruffoi (Matic &amp; Dărăbanţu, 1968) [both from Chaetechelyne], Pachymerium minutum (Sseliwanoff, 1884) [from Geophilus], Schendyla capusei (Dărăbanţu &amp; Matic, 1969), S. hispanica (Attems, 1952) and S. verneri (Folkmanová &amp; Dobroruka, 1960) [all from Brachyschendyla], Tuoba zograffi (Brölemann, 1900) [from Geophilus].Lectotypes have been selected for two species: Geophilus pusillus Meinert, 1870 and Himantarium mediterraneum Meinert, 1870.In seven cases we suggest to conserve currently used names over senior synonyms or homonyms: Geophilus alpinus Meinert, 1870 [over G. impressus C.L. Koch, 1847 and G. palustris C.L. Koch, 1863], Geophilus easoni Arthur, Foddai, Kettle, Lewis, Luczynski &amp; Minelli 2001 [over Arthronomalus crassicornis Parfitt, 1866], Gnathoribautia bonensis (Meinert, 1870) [over Necrophloeophagus punctiventris Newport, 1844], Bothriogaster signata (Kessler, 1874) [over Notiphilus sanguineus C.L. Koch, 1847 and N. taeniatus C.L. Koch, 1847], Schendyla carniolensis Verhoeff, 1902 [over Poabius bistriatus C.L. Koch, 1847]. Corresponding applications have been submitted to the International Commission on Zoological nomenclature for a ruling under the Plenary Powers. 

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After the creation of the Academy of Medical Sciences of Ukraine in 1993 the Research Center for Radiation Medicine was among the first institutions to join the Academy (fig. 1). Estab lishing the Academy was among the first steps of the independent Ukrainian government and aimed to provide a high level health care for population. It was extremely needed for the minimization of Chornobyl medical consequences. This choice was related to a growing recognition of the scientific research in fulfilling the Сenter's mission - study of the effects of low dose radiation on human body and radiation protection of the exposed population.The Center entered the Academy as a potent insti tution. Director General Dr. Anatoly Romanenko and his first deputy prof. Oles Pyatak were lucky to concentrate in three institutes of the Center a talent ed workforce including director of the Institute of Clinical Radiology prof Volodymyr Bebeshko, director of the Institute of Epidemiology and Prophylaxis of radiation Injuries prof. Volodymyr Buzunov, director of the Institute of Experimental Radiology prof. Mikhail Rudnev. Drs. T. Azaren kova, S. Galkina, V. Boer, T. Treskunova were appointed as scientific secretaries. Dosimetry divi sion was headed by brilliant prof Ilya Likhtarev and his staff Drs. I. Los, V. Korzun, V. Repin, O. Pere voznikov, O. Bondarenko, V. Chumak and others.The Center met creation of the Academy with expe rienced research and clinical staff encountering 1587 members, including 272 research staff, 28 doctors of science and 98 PhDs, modern diagnostic and labo ratory equipment, 300 beds in clinical departments and construction of hospital and out patient hospi tal in Svyatoshin. Scientific staff included experi enced prof. I. Khomaziuk, prof. B. Prevarsky, prof. V. Zamostian, prof. P. Chayalo, prof. M. Omelya nets, prof. A. Prysyazhnyuk. Dr. A. Niagu, Dr. E. Stepanova, Dr. A.Chumak, Dr. V. Klymenko, Dr. D. Komarenko, M. Pilinska, L.Ovsiannikova, O. Pi rogova. were among the first academic supervisors in studies of Chornobyl health effects and got professor certificates in this new area. First PhD theses were successfully passed by Dr. E. Gorbov, and Dr. of Sciences - by Dr. D. Bazyka. Basics of future aca demic research directions were elaborated that time by Drs. O. Kovalenko, Zh. Minchenko, V. Talko, I. Holyavka, D. Belyi, D. Yakimenko, E. Mikhai lovska, V. Malyzhev, V. Sushko, A. Cheban, K. Lo ganovsky, K. Bruslova, I. Dyagil, T. Liubarets, O. Kucher, G. Chobotko, and others. Later the major ity of these studies formed a background for Chornobyl legislation, regulatory directives, pre sented as dissertations.A quarter of century passed. The Center as a part of the National Academy of Medical Sciences resisted the challenges and moved forward, was recognized worldwide and fulfilled its main mission - providing highly qualified health care to radiation exposed. Staff numbers decreased (1,091), but work amount has increased. Since 2000, new premises were installed - a hospital with the biggest in Ukraine outpatient clin ic, new laboratory facilities, the last of which was in troduced in 2013. The Academy became a national one and since 2011 the Center was recognized as a national research institution (NRCRM), staff mem bers received 3 State Awards of Ukraine in the Field of Science and Technology, numerous personal awards.During this period, NRCRM staff conducted and published priority research data on radiation risks and molecular mechanisms of leukemia, including chronic lymphocytic, myelodysplastic syndrome, multiple myeloma, thyroid cancer, breast cancer in Chornobyl accident cleanup workers. Studies of the mechanisms of non tumor pathology - cardio vascular, cerebrovascular, cognitive disorders are in process. Of high importance are studies of possible transgenerational effects of radiation. The devel oped new technologies and protocols for the advanced care of radiation exposed were intro duced to the general health care system, the addi tional departments of oncology and chemotherapy were equipped and started activities, databases of cancer cases in exposed population and separate groups of exposed were introduced, as well as an international database of radiation injuries. The Clinical and Epidemiological registry of the NRCRM is in function and developed. An adapta tion of research directions with a respect to the pathomorphosis of radiation induced diseases in the remote period after irradiation will continue.Performed complex studies of the effects of incorporation of 131I on the fetus and the next gen eration of experimental animals became important for understanding the mechanisms of formation of radiation effects. Introduction of new foodstuffs and supplements with radiation protective proper ties was of positive effect for population protection during the first years.In the area of dosimetry a substantial progress has been achieved in reconstruction of thyroid doses in the Ukrainian population, dosimetric passportisation of settlements, radiochemistry, the creation of new methods for reconstructive dosimetry for cleanup workers - SEAD, RADRUE, and ROCKVILLE. All developments are implemented to practice, tens of thousands of doses have been restored. International recognition has received for the method of in utero doses reconstruction. As editor in chief, I regard it successful to incorporate our bilingual edition «Problems of Radiation Medicine and Radiobiology» into the NCBI MedLine, SCOPUS and other data bases, that creates an unique opportunity to widely disseminate results of the Center's research.Strategies for the future. Ukraine belongs to countries with a priority development of nuclear energy. Even with the increase in the production of clean energy, there is no other way than the further deployment of a complete nuclear fuel cycle and energy industrial complex, the expansion of the nuclear technologies to all sectors of the economy.The main potential threats to radiation safety include the aging of the material base of the NPPs with the prolongation of the working life for nuclear reactors with the expired terms of exploitation; the existence of a «nuclear legacy» sites of the former USSR in the territories of enterprises for the extrac tion and processing of uranium ores. About 5,000 institutions and enterprises use more than 25,000 sources of ionizing radiation in general. The use of radiological technologies and sources of ionizing radiation in medicine is increasing, in particular the burden on patients and staff in invasive cardiac sur gery. This will require significant efforts from the NRCRM to ensure an adequate radiation protec tion of the population, taking into account the experience collected during the mitigation of health effects of Chornobyl. Radiological threats of malev olent use of nuclear technology hasn't be forgotten.The mission of the NRCRM is to expand basic research of the health effects of ionizing radiation, elaboration and implementation of the care and radiation protection of population. Background for future is paved by a successful implementation of a special program of medical and biophysical control of personnel during transformation of the Shelter object into an environmentally safe sys tem, the State social program of increasing safty, labor hygiene and environment for 2014-2018; many years of successful cooperation with the State Nuclear Regulatory Inspectorate, the Natio nal Commission for Radiation Protection, «Ener goatom» company, the relevant departments of the Ministry of Health, international organizations such as WHO, UNSCEAR, IAEA, IARC, the US National Cancer Institute, IRSN, Nagasaki, Hiroshima, Fukushima universities and others.From the editorial board I congratulate the staff of the Center with the twenty fifth anniversary of the Academy. I would like also to wish the National Academy of Medical Sciences of Ukraine new ad vances in medical science and practice, sustainabil ity, unity, development and worldwide recognition.

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The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.

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Six Sigma is an excellent quality and performance improvement tool. Like any tool, the results of using it are highly dependent on whether you use it with competence and on the right problem. This article will help you decide if your problem is well-suited for a Six Sigma approach and will suggest the optimum approach for planning and implementing Six Sigma methodology. Performance improvement methods can be grouped into two broad categories, based on the problem to be addressed. When the problem is relatively minor and localized, "evolutionary" methods may be suitable (e.g., quality circles, problem-solving staff meetings, continuous quality improvement [CQI], total quality management [TQM]). These tools work best when modest incremental improvements are sought, when major process redesign is not thought to be necessary, and when the avoidance of workplace disruption is desired. Reengineering and Six Sigma are the best-known examples of the "revolutionary" performance improvement methods. These methods should be used when major (drastic, do or die, etc.) improvements are needed. Problems that cross departmental boundaries need these methods. When a process is so dysfunctional that you feel like you need to tear up the standard operating procedure (SOP) and start all over again, you need a revolutionary method. A Six Sigma project requires a major expenditure of money and employee time, and a willingness to make some hard decisions about jobs, employee retention and relationships among stakeholders. An institution's culture should be considered as part of the decision about using Six Sigma. If the institution has a history of making data-driven decisions, or at least has displayed openness to operating in that manner, Six Sigma has a good chance of success. A radiology-driven Six Sigma project should not be undertaken until a comprehensive written description of the scope of the project is approved by the radiology department leadership team and by the appropriate higher-level institutional leaders. This document should address the specific outcomes desired, the resources available, a rough tentative timeline, and any political constraints imposed on the project (e.g., inviolate HR policies, compatibility with enterprise strategic goals). The document should be comprehensive enough and explicit enough to be useful as a major component of the bid package for hiring a consultant or for writing the job description for the hiring of an in-house expert. A full-time project manager should be designated if an in-house expert is not hired. This person should be a senior leader in the department, but not the department director. Leading a Six Sigma project is a full-time job in itself and cannot be performed as an additional duty. Although it may be tempting to appoint a senior staff technologist or nurse, keep in mind that the project manager must have sufficient authority to expect cooperation from departmental supervisors without resorting to frequent appeals to the department director. Contact the institution's CIO and ask that a knowledgeable person on the IT staff be appointed to serve as the IT liaison for the project. This person should have in-depth familiarity with the HIS and the ways that it interfaces with the RIS (if the RIS is not a module within the HIS). Most importantly, this liaison must understand the exact data definitions and the origins of the data that are passed between the HIS and the RIS. The steering committee should consist of at least one physician and one department-level administrator from outside of the radiology department. From within the radiology department, there should be at least one radiologist and one senior modality manager (whose modality is not the primary focus), the project manager, and the manager of a radiology component that is a focus of the project (e.g., the film library manager). The consultant should be an ex officio member without vote. The steering committee should be small enough to be manageable, yet large enough to provide insight from both the radiology department and the rest of the institution. Because of the size of the steering committee and the difficulty of bringing so many people together for meetings, the day-to-day governance of the project will be provided by an informal "operations committee." When we consider "change" in the context of a Six Sigma project, we talk about a wide variety of topics, but they can be summarized usefully as dealing with processes, policies, physical plant and equipment, personnel, and politics (or culture). The first three of these lend themselves to quantitative analysis, or at least rigorously qualitative analysis. The final two, however, are subjective, ill-defined or not readily acknowledged, and fraught with potentially major challenges when it becomes necessary to implement changes in the first three. The Six Sigma process, as taught by GE, consists of five phases summarized by the acronym DMAIC: Define, Measure, Analyze, Improve and Control. This article deals mostly with the time period from first consideration of a possible Six Sigma project through the early part of the Define phase. It also discusses pitfalls that must be considered anytime throughout a project, from first thoughts of conducting a project until recommended changes become ingrained in the department's operations. Six Sigma compares baseline or historical data to data obtained after implementation of Six Sigma-driven changes in order to determine if desired changes in performance have been achieved. When historical data are not available, the Six Sigma team must collect baseline data as one of their earliest tasks. A Six Sigma project can easily last 18 to 24 months or longer. We must be sure that the data we collect during Month 18 are collected identically to the data we collected at baseline. A major performance improvement project is likely to require 12 to 24 months or longer. Upper management initially may be reluctant to appoint the "cream of the crop" to the project teams. Success is predicated on having the most knowledgeable personnel involved in the project. Without them, the chances of success are reduced. A Six Sigma project's length always exceeds the attention span of the vast majority of its participants. The department director and project manager must anticipate this and devote special efforts to maintaining motivation and momentum after the initial flurry of activity. The complexity of a Six Sigma project will be greatly increased, and all of the pitfalls discussed here will be exacerbated, if your facility has multiple sites. At the simplest, the multiple sites will introduce complications in getting personnel to come to project meetings. The complications will escalate if the sites are under different management, such as a confederated health system. The project manager and the consultant will expend additional time and effort dealing with these issues, which likely will lengthen the project unavoidably. The project manager must spend time with the department's external customers who have significant stakes in the project. At a minimum, this should include relatively formal meetings with other department directors or subordinate managers and key physician and nurse leaders, and attendance at their managerial or staff meetings (you may need to ask to be invited). Although paper or e-mail surveys can be helpful, only sustained personal contact with a stakeholder will truly allow you to understand how they interact with radiology and what their concerns are. As with daily operational management, a performance improvement project requires attention to policies, procedures, processes, physical plant and infrastructure, personnel, and perhaps most importantly, to politics.

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Liposomal amphotericin B (AmBisome) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B. It is active against clinically relevant yeasts and moulds, including Candida spp., Aspergillus spp. and filamentous moulds such as Zygomycetes, and is approved for the treatment of invasive fungal infections in many countries worldwide. It was developed to improve the tolerability profile of amphotericin B deoxycholate, which was for many decades considered the gold standard of antifungal treatment, despite being associated with infusion-related events and nephrotoxicity. In well controlled trials, liposomal amphotericin B had similar efficacy to amphotericin B deoxycholate and amphotericin B lipid complex as empirical therapy in adult and paediatric patients with febrile neutropenia. In addition, caspofungin was noninferior to liposomal amphotericin B as empirical therapy in adult patients with febrile neutropenia. For the treatment of confirmed invasive fungal infections, liposomal amphotericin B was more effective than amphotericin B deoxycholate treatment in patients with disseminated histoplasmosis and AIDS, and was noninferior to amphotericin B deoxycholate in patients with acute cryptococcal meningitis and AIDS. In adults, micafungin was shown to be noninferior to liposomal amphotericin B for the treatment of candidaemia and invasive candidiasis. Data from animal studies suggested that higher dosages of liposomal amphotericin B might improve efficacy; however, in the AmBiLoad trial in patients with invasive mould infection, there was no statistical difference in efficacy between the standard dosage of liposomal amphotericin B 3 mg/kg/day and a higher 10 mg/kg/day dosage, although the standard dosage was better tolerated. Despite being associated with fewer infusion-related adverse events and less nephrotoxicity than amphotericin B deoxycholate and amphotericin B lipid complex, liposomal amphotericin B use is still limited to some extent by these adverse events. Both echinocandins were better tolerated than liposomal amphotericin B. The cost of liposomal amphotericin B therapy may also restrict its use, but further pharmacoeconomic studies are required to fully define its cost effectiveness compared with other antifungal agents. Based on comparative data from well controlled trials, extensive clinical experience and its broad spectrum of activity, liposomal amphotericin B remains a first-line option for empirical therapy in patients with febrile neutropenia and in those with disseminated histoplasmosis, and is an option for the treatment of AIDS-associated cryptococcal meningitis, and for invasive Candida spp. or Aspergillus spp. infections. Amphotericin B, a macrocyclic, polyene antifungal agent, is thought to act by binding to ergosterol, the principal sterol in fungal cell membranes and Leishmania cells. This results in a change in membrane permeability, causing metabolic disturbance, leakage of small molecules and, as a consequence, cell death. In vitro and in vivo studies have shown that liposomal amphotericin B remains closely associated with the liposomes in the circulation, thereby reducing the potential for nephrotoxicity and infusion-related toxicity associated with conventional amphotericin B. Amphotericin B shows very good in vitro activity against a broad spectrum of clinically relevant fungal isolates, including most strains of Candida spp. and Aspergillus spp., and other filamentous fungi such as Zygomycetes. Liposomal amphotericin B has proven effective in various animal models of fungal infections, including those for candidiasis, aspergillosis, fusariosis and zygomycosis. Liposomal amphotericin B also shows immunomodulatory effects, although the mechanisms involved are not fully understood, and differ from those of amphotericin B deoxycholate and amphotericin B colloidal dispersion. In adult patients with febrile neutropenia, intravenous liposomal amphotericin B has nonlinear pharmacokinetics, with higher than dose-proportional increases in exposure being consistent with reticuloendothelial saturation and redistribution of amphotericin B in the plasma compartment. Liposomal amphotericin B is rapidly and extensively distributed after single and multiple doses, with steady-state concentrations of amphotericin B attained within 4 days and no clinically relevant accumulation of the drug following multiple doses of 1-7.5 mg/kg/day. In autopsy tissue, the highest concentrations of the drug were found in the liver and spleen, followed by the kidney, lung, myocardium and brain tissue. Elimination of liposomal amphotericin B, like that of amphotericin B deoxycholate, is poorly understood; its route of metabolism is not known and its excretion has not been studied. The terminal elimination half-life is about 7 hours. No dosage adjustment is required based on age or renal impairment. In several randomized, double-blind trials (n = 73-1095) in adult and/or paediatric patients, liposomal amphotericin B was effective as empirical therapy or as treatment for confirmed invasive fungal infections, including invasive candidiasis, candidaemia, invasive mould infection (mainly aspergillosis), histoplasmosis and cryptococcal meningitis. All agents were administered as an intravenous infusion; the typical dosage for liposomal amphotericin B was 3 mg/kg/day. Treatment was generally given for 1-2 weeks. Participants in trials evaluating empirical therapy had neutropenia and a persistent fever despite antibacterial treatment and had received chemotherapy or undergone haematopoietic stem cell transplantation. As empirical therapy in adult and paediatric patients, liposomal amphotericin B appeared to be as effective as amphotericin B deoxycholate (approximately 50% of patients in each group achieved treatment success) or amphotericin B lipid complex (approximately 40% of liposomal amphotericin B recipients experienced treatment success). Of note, in the first trial, results of the statistical test to determine equivalence between treatments were not reported. In the second trial, efficacy was assessed as an 'other' endpoint. In another trial, caspofungin was shown to be noninferior to liposomal amphotericin B, with approximately one-third of patients in each group experiencing treatment success. Liposomal amphotericin B was significantly more effective than amphotericin B deoxycholate for the treatment of moderate to severe disseminated histoplasmosis in patients with AIDS, with 88% and 64% of patients, respectively, having a successful response. Liposomal amphotericin B was noninferior to amphotericin B deoxycholate for the treatment of cryptococcal meningitis in terms of mycological success. Micafungin therapy was shown to be noninferior to liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidiasis. In a substudy in paediatric patients, which was not powered to determine noninferiority, liposomal amphotericin B was as effective as micafungin for the treatment of candidaemia or invasive candidiasis. In this patient population, within each trial, 90% of adult patients and approximately three-quarters of paediatric patients in both treatment groups experienced a successful response. In patients with invasive mould infection (mainly aspergillosis), there was no difference in efficacy between a higher dosage of liposomal amphotericin B (10 mg/kg/day) and the standard dosage (3 mg/kg/day), with 46% and 50% of patients experiencing a favourable overall response. In well designed clinical trials, liposomal amphotericin B was generally at least as well tolerated as other lipid-associated formulations of amphotericin B and better tolerated than amphotericin B deoxycholate in adult and paediatric patients. Compared with other amphotericin B formulations, liposomal amphotericin B treatment was associated with a lower incidence of infusion-related adverse events and nephrotoxicity. A higher than recommended dosage of liposomal amphotericin B (10 mg/kg/day) was associated with an increased incidence of nephrotoxicity compared with the standard dosage (3 mg/kg/day), although the incidence of infusion-related reactions did not differ between treatment groups. In general, liposomal amphotericin B treatment was not as well tolerated as echinocandin therapy in well designed clinical trials. As empirical therapy or for the treatment of confirmed invasive fungal infections in adult patients, liposomal amphotericin B recipients experienced more infusion-related events and nephrotoxicity than caspofungin or micafungin recipients. There was no difference in the incidence of these adverse events between the liposomal amphotericin B and micafungin groups in a study in paediatric patients.

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To review the physiology of breech birth; to discern the risks and benefits of a trial of labour versus planned Caesarean section; and to recommend to obstetricians, family physicians, midwives, obstetrical nurses, anaesthesiologists, pediatricians, and other health care providers selection criteria, intrapartum management parameters, and delivery techniques for a trial of vaginal breech birth. Trial of labour in an appropriate setting or delivery by pre-emptive Caesarean section for women with a singleton breech fetus at term. Reduced perinatal mortality, short-term neonatal morbidity, long-term infant morbidity, and short- and long-term maternal morbidity and mortality. Medline was searched for randomized trials, prospective cohort studies, and selected retrospective cohort studies comparing planned Caesarean section with a planned trial of labour; selected epidemiological studies comparing delivery by Caesarean section with vaginal breech delivery; and studies comparing long-term outcomes in breech infants born vaginally or by Caesarean section. Additional articles were identified through bibliography tracing up to June 1, 2008. The evidence collected was reviewed by the Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the criteria and classifications of the Canadian Task Force on Preventive Health Care. This guideline was compared with the 2006 American College of Obstetrician's Committee Opinion on the mode of term singleton breech delivery and with the 2006 Royal College of Obstetrician and Gynaecologists Green Top Guideline: The Management of Breech Presentation. The document was reviewed by Canadian and International clinicians with particular expertise in breech vaginal delivery. The Society of Obstetricians and Gynaecologists of Canada. SUMMARY STATEMENTS: 1. Vaginal breech birth can be associated with a higher risk of perinatal mortality and short-term neonatal morbidity than elective Caesarean section. (I) 2. Careful case selection and labour management in a modern obstetrical setting may achieve a level of safety similar to elective Caesarean section. (II-1) 3. Planned vaginal delivery is reasonable in selected women with a term singleton breech fetus. (I) 4. With careful case selection and labour management, perinatal mortality occurs in approximately 2 per 1000 births and serious short-term neonatal morbidity in approximately 2% of breech infants. Many recent retrospective and prospective reports of vaginal breech delivery that follow specific protocols have noted excellent neonatal outcomes. (II-1) 5. Long-term neurological infant outcomes do not differ by planned mode of delivery even in the presence of serious short-term neonatal morbidity. (I) RECOMMENDATIONS: LABOUR SELECTION CRITERIA: 1. For a woman with suspected breech presentation, pre- or early labour ultrasound should be performed to assess type of breech presentation, fetal growth and estimated weight, and attitude of fetal head. If ultrasound is not available, Caesarean section is recommended. (II-1A) 2. Contraindications to labour include a. Cord presentation (II-3A) b. Fetal growth restriction or macrosomia (I-A) c. Any presentation other than a frank or complete breech with a flexed or neutral head attitude (III-B) d. Clinically inadequate maternal pelvis (III-B) e. Fetal anomaly incompatible with vaginal delivery (III-B) 3. Vaginal breech delivery can be offered when the estimated fetal weight is between 2500 g and 4000 g. (II-2B) LABOUR MANAGEMENT: 4. Clinical pelvic examination should be performed to rule out pathological pelvic contraction. Radiologic pelvimetry is not necessary for a safe trial of labour; good progress in labour is the best indicator of adequate fetal-pelvic proportions. (III-B) 5. Continuous electronic fetal heart monitoring is preferable in the first stage and mandatory in the second stage of labour. (I-A) When membranes rupture, immediate vaginal examination is recommended to rule out prolapsed cord. (III-B) 6. In the absence of adequate progress in labour, Caesarean section is advised. (II-1A) 7. Induction of labour is not recommended for breech presentation. (II-3B) Oxytocin augmentation is acceptable in the presence of uterine dystocia. (II-1A) 8. A passive second stage without active pushing may last up to 90 minutes, allowing the breech to descend well into the pelvis. Once active pushing commences, if delivery is not imminent after 60 minutes, Caesarean section is recommended. (I-A) 9. The active second stage of labour should take place in or near an operating room with equipment and personnel available to perform a timely Caesarean section if necessary. (III-A) 10. A health care professional skilled in neonatal resuscitation should be in attendance at the time of delivery. (III-A) DELIVERY TECHNIQUE: 11. The health care provider for a planned vaginal breech delivery needs to possess the requisite skills and experience. (II-1A) 12. An experienced obstetrician-gynaecologist comfortable in the performance of vaginal breech delivery should be present at the delivery to supervise other health care providers, including a trainee. (I-A) 13. The requirements for emergency Caesarean section, including availability of the hospital operating room team and the approximate 30-minute timeline to commence a laparotomy, must be in accordance with the recommendations of the SOGC Policy Statement, "Attendance at Labour and Delivery" (CPG No. 89; update in press, 2009). (III-A) 14. The health care provider should have rehearsed a plan of action and should be prepared to act promptly in the rare circumstance of a trapped after-coming head or irreducible nuchal arms: symphysiotomy or emergency abdominal rescue can be life saving. (III-B) 15. Total breech extraction is inappropriate for term singleton breech delivery. (II-2A) 16. Effective maternal pushing efforts are essential to safe delivery and should be encouraged. (II-1A) 17. At the time of delivery of the after-coming head, an assistant should be present to apply suprapubic pressure to favour flexion and engagement of the fetal head. (II-3B) 18. Spontaneous or assisted breech delivery is acceptable. Fetal traction should be avoided, and fetal manipulation must be applied only after spontaneous delivery to the level of the umbilicus. (III-A) 19. Nuchal arms may be reduced by the Løvset or Bickenbach manoeuvres. (III-B) 20. The fetal head may deliver spontaneously, with the assistance of suprapubic pressure, by Mauriceau-Smellie-Veit manoeuvre, or with the assistance of Piper forceps. (III-B) SETTING AND CONSENT: 21. In the absence of a contraindication to vaginal delivery, a woman with a breech presentation should be informed of the risks and benefits of a trial of labour and elective Caesarean section, and informed consent should be obtained. A woman's choice of delivery mode should be respected. (III-A) 22. The consent discussion and chosen plan should be well documented and communicated to labour-room staff. (III-B) 23. Hospitals offering a trial of labour should have a written protocol for eligibility and intrapartum management. (III-B) 24. Women with a contraindication to a trial of labour should be advised to have a Caesarean section. Women choosing to labour despite this recommendation have a right to do so and should not be abandoned. They should be provided the best possible in-hospital care. (III-A) 25. The Society of Obstetricians and Gynaecologists of Canada (SOGC), in collaboration with the Association of Professors of Obstetrics and Gynaecology (APOG), The College of Family Physicians of Canada (CFPC), and The Canadian Association of Midwives (CAM) should revise the training requirements at the undergraduate and postgraduate levels. SOGC will continue to promote training of current health care providers through the MOREOB, ALARM (Advances in Labour and Risk Management), and other courses. (III-A) 26. Theoretical and hands-on breech birth training simulation should be part of basic obstetrical skills training programs such as ALARM, ALSO (Advanced Life Support Training in Obstetrics), and MOREOB to prepare health care providers for unexpected vaginal breech births. (III-B).

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Microfluidic encapsulation methods have been previously utilized to capture cells in picoliter-scale aqueous, monodisperse drops, providing confinement from a bulk fluid environment with applications in high throughput screening, cytometry, and mass spectrometry. We describe a method to not only encapsulate single cells, but to repeatedly capture a set number of cells (here we demonstrate one- and two-cell encapsulation) to study both isolation and the interactions between cells in groups of controlled sizes. By combining drop generation techniques with cell and particle ordering, we demonstrate controlled encapsulation of cell-sized particles for efficient, continuous encapsulation. Using an aqueous particle suspension and immiscible fluorocarbon oil, we generate aqueous drops in oil with a flow focusing nozzle. The aqueous flow rate is sufficiently high to create ordering of particles which reach the nozzle at integer multiple frequencies of the drop generation frequency, encapsulating a controlled number of cells in each drop. For representative results, 9.9 μm polystyrene particles are used as cell surrogates. This study shows a single-particle encapsulation efficiency P(k=1) of 83.7% and a double-particle encapsulation efficiency P(k=2) of 79.5% as compared to their respective Poisson efficiencies of 39.3% and 33.3%, respectively. The effect of consistent cell and particle concentration is demonstrated to be of major importance for efficient encapsulation, and dripping to jetting transitions are also addressed. Continuous media aqueous cell suspensions share a common fluid environment which allows cells to interact in parallel and also homogenizes the effects of specific cells in measurements from the media. High-throughput encapsulation of cells into picoliter-scale drops confines the samples to protect drops from cross-contamination, enable a measure of cellular diversity within samples, prevent dilution of reagents and expressed biomarkers, and amplify signals from bioreactor products. Drops also provide the ability to re-merge drops into larger aqueous samples or with other drops for intercellular signaling studies. The reduction in dilution implies stronger detection signals for higher accuracy measurements as well as the ability to reduce potentially costly sample and reagent volumes. Encapsulation of cells in drops has been utilized to improve detection of protein expression, antibodies, enzymes, and metabolic activity for high throughput screening, and could be used to improve high throughput cytometry. Additional studies present applications in bio-electrospraying of cell containing drops for mass spectrometry and targeted surface cell coatings. Some applications, however, have been limited by the lack of ability to control the number of cells encapsulated in drops. Here we present a method of ordered encapsulation which increases the demonstrated encapsulation efficiencies for one and two cells and may be extrapolated for encapsulation of a larger number of cells. To achieve monodisperse drop generation, microfluidic "flow focusing" enables the creation of controllable-size drops of one fluid (an aqueous cell mixture) within another (a continuous oil phase) by using a nozzle at which the streams converge. For a given nozzle geometry, the drop generation frequency f and drop size can be altered by adjusting oil and aqueous flow rates Q(oil) and Q(aq). As the flow rates increase, the flows may transition from drop generation to unstable jetting of aqueous fluid from the nozzle. When the aqueous solution contains suspended particles, particles become encapsulated and isolated from one another at the nozzle. For drop generation using a randomly distributed aqueous cell suspension, the average fraction of drops D(k) containing k cells is dictated by Poisson statistics, where D(k) = λ(k) exp(-λ)/(k!) and λ is the average number of cells per drop. The fraction of cells which end up in the "correctly" encapsulated drops is calculated using P(k) = (k x D(k))/Σ(k' x D(k)'). The subtle difference between the two metrics is that D(k) relates to the utilization of aqueous fluid and the amount of drop sorting that must be completed following encapsulation, and P(k) relates to the utilization of the cell sample. As an example, one could use a dilute cell suspension (low λ) to encapsulate drops where most drops containing cells would contain just one cell. While the efficiency metric P(k) would be high, the majority of drops would be empty (low D(k)), thus requiring a sorting mechanism to remove empty drops, also reducing throughput. Combining drop generation with inertial ordering provides the ability to encapsulate drops with more predictable numbers of cells per drop and higher throughputs than random encapsulation. Inertial focusing was first discovered by Segre and Silberberg and refers to the tendency of finite-sized particles to migrate to lateral equilibrium positions in channel flow. Inertial ordering refers to the tendency of the particles and cells to passively organize into equally spaced, staggered, constant velocity trains. Both focusing and ordering require sufficiently high flow rates (high Reynolds number) and particle sizes (high Particle Reynolds number). Here, the Reynolds number Re =uD(h)/ν and particle Reynolds number Rep =Re(a/D(h))², where u is a characteristic flow velocity, D(h) [=2wh/(w+h)] is the hydraulic diameter, ν is the kinematic viscosity, a is the particle diameter, w is the channel width, and h is the channel height. Empirically, the length required to achieve fully ordered trains decreases as Re and Re(p) increase. Note that the high Re and Re(p) requirements (for this study on the order of 5 and 0.5, respectively) may conflict with the need to keep aqueous flow rates low to avoid jetting at the drop generation nozzle. Additionally, high flow rates lead to higher shear stresses on cells, which are not addressed in this protocol. The previous ordered encapsulation study demonstrated that over 90% of singly encapsulated HL60 cells under similar flow conditions to those in this study maintained cell membrane integrity. However, the effect of the magnitude and time scales of shear stresses will need to be carefully considered when extrapolating to different cell types and flow parameters. The overlapping of the cell ordering, drop generation, and cell viability aqueous flow rate constraints provides an ideal operational regime for controlled encapsulation of single and multiple cells. Because very few studies address inter-particle train spacing, determining the spacing is most easily done empirically and will depend on channel geometry, flow rate, particle size, and particle concentration. Nonetheless, the equal lateral spacing between trains implies that cells arrive at predictable, consistent time intervals. When drop generation occurs at the same rate at which ordered cells arrive at the nozzle, the cells become encapsulated within the drop in a controlled manner. This technique has been utilized to encapsulate single cells with throughputs on the order of 15 kHz, a significant improvement over previous studies reporting encapsulation rates on the order of 60-160 Hz. In the controlled encapsulation work, over 80% of drops contained one and only one cell, a significant efficiency improvement over Poisson (random) statistics, which predicts less than 40% efficiency on average. In previous controlled encapsulation work, the average number of particles per drop λ was tuned to provide single-cell encapsulation. We hypothesize that through tuning of flow rates, we can efficiently encapsulate any number of cells per drop when λ is equal or close to the number of desired cells per drop. While single-cell encapsulation is valuable in determining individual cell responses from stimuli, multiple-cell encapsulation provides information relating to the interaction of controlled numbers and types of cells. Here we present a protocol, representative results using polystyrene microspheres, and discussion for controlled encapsulation of multiple cells using a passive inertial ordering channel and drop generation nozzle.

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A comprehensive taxonomic study is presented for the four genera and 286 species of the doryctine tribe Heterospilini occurring in Costa Rica. The tribe is represented almost entirely by the 280 species of the genus Heterospilus Haliday. Keys for identification of the genera and species are provided and the genera and species are described and illustrated. An interactive key to the species of Heterospilus also was prepared using Lucid Builder. The following new genus and species are described from Costa Rica: Paraheterospilus gen. n., P. ceciliaensis sp. n., P. eumekus sp. n., P. wilbotgardus sp. n., Heterospilus achi sp. n., H. achterbergi sp. n., H. aesculapius sp. n., H. agujas sp. n., H. agujasensis sp. n., H. alajuelus sp. n., H. albocoxalis sp. n., H. alejandroi sp. n., H. amuzgo sp. n., H. angelicae sp. n., H. angustus sp. n., H. aphrodite sp. n., H. apollo sp. n., H. arawak sp. n., H. areolatus sp. n., H. artemis sp. n., H. athena sp. n., H. attraholucus sp. n., H. aubreyae sp. n., H. austini sp. n., H. azofeifai sp. n., H. bacchus sp. n., H. barbalhoae sp. n., H. bennetti sp. n., H. bicolor sp. n., H. boharti sp. n., H. borucas sp. n., H. braeti sp. n., H. brethesi sp. n., H. breviarius sp. n., H. brevicornus sp. n., H. bribri sp. n., H. brullei sp. n., H. bruesi sp. n., H. cabecares sp. n., H. cacaoensis sp. n., H. cachiensis sp. n., H. cameroni sp. n., H. cangrejaensis sp. n., H. careonotaulus sp. n., H. caritus sp. n., H. carolinae sp. n., H. cartagoensis sp. n., H. catiensis sp. n., H. catorce sp. n., H. cero sp. n., H. chaoi sp. n., H. chilamatensis sp. n., H. chocho sp. n., H. chorotegus sp. n., H. chorti sp. n., H. cinco sp. n., H. cocopa sp. n., H. colliletus sp. n., H. colonensis sp. n., H. complanatus sp. n., H. conservatus sp. n., H. cora sp. n., H. corcovado sp. n., H. corrugatus sp. n., H. costaricensis sp. n., H. cressoni sp. n., H. cuatro sp. n., H. curtisi sp. n., H. cushmani sp. n., H. dani sp. n., H. demeter sp. n., H. dianae sp. n., H. diecinueve sp. n., H. dieciocho sp. n., H. dieciseis sp. n., H. diecisiete sp. n., H. diez sp. n., H. doce sp. n., H. dos sp. n., H. dulcus sp. n., H. eberhardi sp. n., H. ektorincon sp. n., H. emilius sp. n., H. empalmensis sp. n., H. enderleini sp. n., H. escazuensis sp. n., H. fahringeri sp. n., H. fischeri sp. n., H. flavidus sp. n., H. flavisoma sp. n., H. flavostigmus sp. n., H. foersteri sp. n., H. fonsecai sp. n., H. fournieri sp. n., H. gahani sp. n., H. garifuna sp. n., H. gauldi sp. n., H. golfodulcensis sp. n., H. gouleti sp. n., H. granulatus sp. n., H. grisselli sp. n., H. guanacastensis sp. n., H. guapilensis sp. n., H. hachaensis sp. n., H. halidayi sp. n., H. hansoni sp. n., H. hansonorum sp. n., H. haplocarinus sp. n., H. hedqvisti sp. n., H. hera sp. n., H. heredius sp. n., H. hespenheidei sp. n., H. holleyae sp. n., H. huddlestoni sp. n., H. huetares sp. n., H. hypermekus sp. n., H. itza sp. n., H. ixcatec sp. n., H. ixil sp. n., H. jabillosensis sp. n., H. jakaltek sp. n., H. janzeni sp. n., H. jennieae sp. n., H. jonmarshi sp. n., H. jupiter sp. n., H. kellieae sp. n., H. kiefferi sp. n., H. kikapu sp. n., H. kulai sp. n., H. kuna sp. n., H. lapierrei sp. n., H. lasalturus sp. n., H. laselvus sp. n., H. leenderti sp. n., H. leioenopus sp. n., H. leiponotaulus sp. n., H. lenca sp. n., H. levis sp. n., H. leviscutum sp. n., H. levitergum sp. n., H. limonensis sp. n., H. longinoi sp. n., H. longisulcus sp. n., H. longius sp. n., H. luteogaster sp. n., H. luteoscutum sp. n., H. luteus sp. n., H. macrocarinus sp. n., H. macrocaudatus sp. n., H. magnus sp. n., H. malaisei sp. n., H. mam sp. n., H. maritzaensis sp. n., H. mars sp. n., H. masneri sp. n., H. masoni sp. n., H. mellosus sp. n., H. menkei sp. n., H. mercury sp. n., H. milleri sp. n., H. miskito sp. n., H. mixtec sp. n., H. monteverde sp. n., H. mopanmaya sp. n., H. muertensis sp. n., H. muesebecki sp. n., H. nahua sp. n., H. neesi sp. n., H. nemestrinus sp. n., H. nephilim sp. n., H. nephus sp. n., H. nigracapitus sp. n., H. nigragonatus sp. n., H. nigricoxus sp. n., H. nixoni sp. n., H. noyesi sp. n., H. nueve sp. n., H. nunesi sp. n., H. once sp. n., H. orbitus sp. n., H. orosi sp. n., H. paloverde sp. n., H. pappi sp. n., H. parkeri sp. n., H. parvus sp. n., H. pech sp. n., H. penosa sp. n., H. petiolatus sp. n., H. petralbus sp. n., H. phaeocoxus sp. n., H. phaeoskelus sp. n., H. pharkidodus sp. n., H. phytorius sp. n., H. pitillaensis sp. n., H. poqomchi sp. n., H. poqomom sp. n., H. puertoviejoensis sp. n., H. puntarensis sp. n., H. qanjobal sp. n., H. quickei sp. n., H. quitirrisi sp. n., H. racostica sp. n., H. rama sp. n., H. ramirezi sp. n., H. ratzeburgi sp. n., H. reagani sp. n., H. reinhardi sp. n., H. retheospilus sp. n., H. rhabdotus sp. n., H. ricacosta sp. n., H. rinconensis sp. n., H. robbieae sp. n., H. rohweri sp. n., H. rojasi sp. n., H. romani sp. n., H. rugosus sp. n., H. sabrinae sp. n., H. saminae sp. n., H. sanjosensis sp. n., H. santarosensis sp. n., H. sanvitoensis sp. n., H. saturn sp. n., H. seis sp. n., H. sergeyi sp. n., H. sharkeyi sp. n., H. shawi sp. n., H. shenefelti sp. n., H. shonan sp. n., H. siete sp. n., H. similis sp. n., H. sinuatus sp. n., H. smithi sp. n., H. spiloheterus sp. n., H. staryi sp. n., H. stelfoxi sp. n., H. strazanaci sp. n., H. sumo sp. n., H. szepligeti sp. n., H. terrabas sp. n., H. thereospilus sp. n., H. tobiasi sp. n., H. tolupan sp. n., H. townesi sp. n., H. trece sp. n., H. tres sp. n., H. tricolor sp. n., H. trienta sp. n., H. tuberculatus sp. n., H. turrialbaensis sp. n., H. tzutujil sp. n., H. ugaldei sp. n., H. uno sp. n., H. variabilis sp. n., H. veinte sp. n., H. veintidos sp. n., H. veintitres sp. n., H. veintiuno sp. n., H. vierecki sp. n., H. villegasi sp. n., H. vittatus sp. n., H. vulcanus sp. n., H. wahli sp. n., H. warreni sp. n., H. washingtoni sp. n., H. wesmaeli sp. n., H. whartoni sp. n., H. whitfieldi sp. n., H. wildi sp. n., H. wilkinsoni sp. n., H. wrightae sp. n., H. xanthus sp. n., H. xerxes sp. n., H. xinca sp. n., H. yaqui sp. n., H. ypsilon sp. n., H. zapotec sp. n., H. zeus sp. n., H. zitaniae sp. n., H. zoque sp. n., H. zunigai sp. n., H. zurquiensis sp. n. One new combination is proposed, Pioscelus costaricensis (Marsh) comb. n.

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A comprehensive analytical review of the risk assessment, risk management, and risk communication approaches currently being undertaken by key national, provincial/state, territorial, and international agencies was conducted. The information acquired for review was used to identify the differences, commonalities, strengths, and weaknesses among the various approaches, and to identify elements that should be included in an effective, current, and comprehensive approach applicable to environmental, human health and occupational health risks. More than 80 agencies, organizations, and advisory councils, encompassing more than 100 risk documents, were examined during the period from February 2000 until November 2002. An overview was made of the most important general frameworks for risk assessment, risk management, and risk communication for human health and ecological risk, and for occupational health risk. In addition, frameworks for specific applications were reviewed and summarized, including those for (1)contaminated sites; (2) northern contaminants; (3) priority substances; (4) standards development; (5) food safety; (6) medical devices; (7) prescription drug use; (8) emergency response; (9) transportation; (10) risk communication. Twelve frameworks were selected for more extensive review on the basis of representation of the areas of human health, ecological, and occupational health risk; relevance to Canadian risk management needs; representation of comprehensive and well-defined approaches; generalizability with their risk areas; representation of "state of the art" in Canada, the United States, and/or internationally; and extent of usage of potential usage within Canada. These 12 frameworks were: 1. Framework for Environmental Health Risk Management (US Presidential/Congressional Commission on Risk Assessment and Risk Management, 1997). 2. Health Risk Determination: The Challenge of Health Protection (Health and Welfare Canada, 1990). 3. Health Canada Decision-Making Framework for Identifying, Assessing and Managing Health Risks (Health Canada, 2000). 4. Canadian Environmental Protection Act: Human Health Risk Assessment of Priority Substances(Health Canada, 1994). 5. CSA-Q8550 Risk Management: Guidelines for Decision-Makers (Canada Standards Association, 1997). 6. Risk Assessment in the Federal Government: Managing the Process (US National Research Council, 1983). 7. Understanding Risk: Informing Decisions in a Democratic Society (US National Research Council, 1996). 8. Environmental Health Risk Assessment (enHealth Council of Australia, 2002). 9. A Framework for Ecological Risk Assessment (CCME, 1996). 10. Ecological Risk Assessments of Priority Substances Under the Canadian Environmental Protection Act (Environment Canada, 1996).11. Guidelines for Ecological Risk Assessment (US EPA, 1998b). 12. Proposed Model for Occupational Health Risk Assessment and Management (Rampal &amp; Sadhra, 1999). Based on the extensive review of these frameworks, seven key elements that should be included in a comprehensive framework for human health, ecological, and occupational risk assessment and management were identified: 1. Problem formulation stage. 2. Stakeholder involvement. 3. Communication. 4. Quantitative risk assessment components. 5. Iteration and evaluation. 6. Informed decision making. 7. Flexibility. On the basis of this overarching approach to risk management, the following "checklist" to ensure a good risk management decision is proposed: - Make sure you're solving the right problem. - Consider the problem and the risk within the full context of the situation, using a broad perspective. - Acknowledge, incorporate, and balance the multiple dimensions of risk. - Ensure the highest degree of reliability for all components of the risk management process. - Involve interested and effected parties from the outset of the process. - Commit to honest and open communication between all parties. - Employ continuous evaluation throughout the process (formative, process, and outcome evaluation), and be prepared to change the decision if new information becomes available. Comprehensive and sound principles are critical to providing structure and integrity to risk management frameworks. Guiding principles are intended to provide an ethical grounding for considering the many factors involved in risk management decision making. Ten principles are proposed to guide risk management decision making. The first four principles were adapted and modified from Hattis (1996) along with the addition of two more principles by Hrudey (2000). These have been supplemented by another four principles to make the 10 presented. The principles are based in fundamental ethical principles and values. These principles are intended to be aspirational rather than prescriptive--their application requires flexibility and practical judgement. Risk management is inherently a process in search of balance among competing interests and concerns. Each risk management decision will be "balancing act" of competing priorities, and trade-offs may sometimes have to be made between seemingly conflicting principles. The 10 decision-making principles, with the corresponding ethical principle in italics are: 1. Do more good than harm (beneficence, nonmalificence).- The ultimate goal of good risk management is to prevent or minimize risk, or to "do good" as much as possible. 2. Fair process of decision making (fairness, natural justice). - Risk management must be just, equitable, impartial, unbiased, dispassionate, and objective as far as possible given the circumstances of each situation. 3. Ensure an equitable distribution of risk (equity). - An equitable process of risk management would ensure fair outcomes and equal treatment of all concerned through an equal distribution of benefits and burdens (includes the concept of distributive justice, i.e., equal opportunities for all individuals). 4. Seek optimal use of limited risk management resources (utility). - Optimal risk management demands using limited resources where they will achieve the most risk reduction of overall benefit. 5. Promise no more risk management that can be delivered (honesty).- Unrealistic expectations of risk management can be avoided with honest and candid public accounting of what we know and don't know, and what we can and can't do using risk assessment and risk management. 6. Impose no more risk that you would tolerate yourself (the Golden Rule). - The Golden Rule is important in risk management because it forces decision makers to abandon complete detachment from their decisions so they may understand the perspectives of those affected. 7. Be cautious in the face of uncertainty ("better safe than sorry"). - Risk management must adopt a cautious approach when faced with a potentially serous risk, even if the evidence is uncertain. 8. Foster informed risk decision making for all stakeholders (autonomy). - Fostering autonomous decision making involves both providing people with the opportunity to participate, and full and honest disclosure of all the information required for informed decisions. 9. Risk management processes must be flexible and evolutionary to be open to new knowledge and understanding (evolution, evaluation, iterative process). - The incorporation of new evidence requires that risk management be a flexible, evolutionary, and iterative process, and that evaluation is employed at the beginning and througthout the process. 10. the complete elimination fo risk is not possible (life is not risk free).- Risk is pervasive in our society, and cannot be totally eliminated despite an oft-expressed public desire for "zero risk". However, the level of risk that may ve tolerable by any individual is dependent on values of beliefs, as well as scientific information. Each agency must continue to employ a process that meets the needs of their specific application of risk management. A single approach cannot satisfy the diverse areas to which risk decisions are being applied. However, with increasing experience in the application of the approaches, we are evolving to a common understanding of the essential elements and principles required for successful risk assessment, risk management, and risk communication. Risk management will continue to be a balancing act of competing priorities and needs. Flexibility and good judgement are ultimately the key to successfully making appropriate risk decisions.

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Tobacco smoking is the cause of many preventable diseases and premature deaths in the UK and around the world. It poses enormous health- and non-health-related costs to the affected individuals, employers, and the society at large. The World Health Organization (WHO) estimates that, globally, smoking causes over US$500 billion in economic damage each year. This paper examines global and UK evidence on the economic impact of smoking prevalence and evaluates the effectiveness and cost effectiveness of smoking cessation measures. SEARCH METHODS We used two major health care/economic research databases, namely PubMed and the National Institute for Health Research (NIHR) database that contains the British National Health Service (NHS) Economic Evaluation Database; Cochrane Library of systematic reviews in health care and health policy; and other health-care-related bibliographic sources. We also performed hand searching of relevant articles, health reports, and white papers issued by government bodies, international health organizations, and health intervention campaign agencies. SELECTION CRITERIA The paper includes cost-effectiveness studies from medical journals, health reports, and white papers published between 1992 and July 2014, but included only eight relevant studies before 1992. Most of the papers reviewed reported outcomes on smoking prevalence, as well as the direct and indirect costs of smoking and the costs and benefits of smoking cessation interventions. We excluded papers that merely described the effectiveness of an intervention without including economic or cost considerations. We also excluded papers that combine smoking cessation with the reduction in the risk of other diseases. DATA COLLECTION AND ANALYSIS The included studies were assessed against criteria indicated in the Cochrane Reviewers Handbook version 5.0.0. OUTCOMES ASSESSED IN THE REVIEWPrimary outcomes of the selected studies are smoking prevalence, direct and indirect costs of smoking, and the costs and benefits of smoking cessation interventions (eg, "cost per quitter", "cost per life year saved", "cost per quality-adjusted life year gained," "present value" or "net benefits" from smoking cessation, and "cost savings" from personal health care expenditure). The main findings of this study are as follows: The costs of smoking can be classified into direct, indirect, and intangible costs. About 15% of the aggregate health care expenditure in high-income countries can be attributed to smoking. In the US, the proportion of health care expenditure attributable to smoking ranges between 6% and 18% across different states. In the UK, the direct costs of smoking to the NHS have been estimated at between £2.7 billion and £5.2 billion, which is equivalent to around 5% of the total NHS budget each year. The economic burden of smoking estimated in terms of GDP reveals that smoking accounts for approximately 0.7% of China's GDP and approximately 1% of US GDP. As part of the indirect (non-health-related) costs of smoking, the total productivity losses caused by smoking each year in the US have been estimated at US$151 billion.The costs of smoking notwithstanding, it produces some potential economic benefits. The economic activities generated from the production and consumption of tobacco provides economic stimulus. It also produces huge tax revenues for most governments, especially in high-income countries, as well as employment in the tobacco industry. Income from the tobacco industry accounts for up to 7.4% of centrally collected government revenue in China. Smoking also yields cost savings in pension payments from the premature death of smokers.Smoking cessation measures could range from pharmacological treatment interventions to policy-based measures, community-based interventions, telecoms, media, and technology (TMT)-based interventions, school-based interventions, and workplace interventions.The cost per life year saved from the use of pharmacological treatment interventions ranged between US$128 and US$1,450 and up to US$4,400 per quality-adjusted life years (QALYs) saved. The use of pharmacotherapies such as varenicline, NRT, and Bupropion, when combined with GP counseling or other behavioral treatment interventions (such as proactive telephone counseling and Web-based delivery), is both clinically effective and cost effective to primary health care providers.Price-based policy measures such as increase in tobacco taxes are unarguably the most effective means of reducing the consumption of tobacco. A 10% tax-induced cigarette price increase anywhere in the world reduces smoking prevalence by between 4% and 8%. Net public benefits from tobacco tax, however, remain positive only when tax rates are between 42.9% and 91.1%. The cost effectiveness ratio of implementing non-price-based smoking cessation legislations (such as smoking restrictions in work places, public places, bans on tobacco advertisement, and raising the legal age of smokers) range from US$2 to US$112 per life year gained (LYG) while reducing smoking prevalence by up to 30%-82% in the long term (over a 50-year period).Smoking cessation classes are known to be most effective among community-based measures, as they could lead to a quit rate of up to 35%, but they usually incur higher costs than other measures such as self-help quit-smoking kits. On average, community pharmacist-based smoking cessation programs yield cost savings to the health system of between US$500 and US$614 per LYG.Advertising media, telecommunications, and other technology-based interventions (such as TV, radio, print, telephone, the Internet, PC, and other electronic media) usually have positive synergistic effects in reducing smoking prevalence especially when combined to deliver smoking cessation messages and counseling support. However, the outcomes on the cost effectiveness of TMT-based measures have been inconsistent, and this made it difficult to attribute results to specific media. The differences in reported cost effectiveness may be partly attributed to varying methodological approaches including varying parametric inputs, differences in national contexts, differences in advertising campaigns tested on different media, and disparate levels of resourcing between campaigns. Due to its universal reach and low implementation costs, online campaign appears to be substantially more cost effective than other media, though it may not be as effective in reducing smoking prevalence.School-based smoking prevalence programs tend to reduce short-term smoking prevalence by between 30% and 70%. Total intervention costs could range from US$16,400 to US$580,000 depending on the scale and scope of intervention. The cost effectiveness of school-based programs show that one could expect a saving of approximately between US$2,000 and US$20,000 per QALY saved due to averted smoking after 2-4 years of follow-up.Workplace-based interventions could represent a sound economic investment to both employers and the society at large, achieving a benefit-cost ratio of up to 8.75 and generating 12-month employer cost savings of between $150 and $540 per nonsmoking employee. Implementing smoke-free workplaces would also produce myriads of new quitters and reduce the amount of cigarette consumption, leading to cost savings in direct medical costs to primary health care providers. Workplace interventions are, however, likely to yield far greater economic benefits over the long term, as reduced prevalence will lead to a healthier and more productive workforce. We conclude that the direct costs and externalities to society of smoking far outweigh any benefits that might be accruable at least when considered from the perspective of socially desirable outcomes (ie, in terms of a healthy population and a productive workforce). There are enormous differences in the application and economic measurement of smoking cessation measures across various types of interventions, methodologies, countries, economic settings, and health care systems, and these may have affected the comparability of the results of the studies reviewed. However, on the balance of probabilities, most of the cessation measures reviewed have not only proved effective but also cost effective in delivering the much desired cost savings and net gains to individuals and primary health care providers.

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Sodium nitrite is used as a color fixative and preservative in meats and fish. It is also used in manufacturing diazo dyes, nitroso compounds, and other organic compounds; in dyeing and printing textile fabrics and bleaching fibers; in photography; as a laboratory reagent and a corrosion inhibitor; in metal coatings for phosphatizing and detinning; and in the manufacture of rubber chemicals. Sodium nitrite also has been used in human and veterinary medicine as a vasodilator, a bronchial dilator, an intestinal relaxant, and an antidote for cyanide poisoning. Sodium nitrite was nominated by the FDA for toxicity and carcinogenesis studies based on its widespread use in foods. Male and female F344/N rats and B6C3F1 mice were exposed to sodium nitrite (99% pure) in drinking water for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 375, 750, 1500, 3,000, or 5000 ppm sodium nitrite (equivalent to average daily doses of approximately 30, 55, 115, 200, or 310 mg sodium nitrite/kg body weight to males and 40, 80, 130, 225, or 345 mg/kg to females) in drinking water for 14 weeks. Clinical pathology study groups of 15 male and 15 female rats were exposed to the same concentrations for 70 or 71 days. One female exposed to 3000 ppm died before the end of the study. Body weights of males exposed to 3000 or 5000 ppm and females exposed to 5000 ppm were significantly less than those of the controls. Water consumption by 5000 ppm males and 3000 and 5000 ppm females was less than that by the controls at weeks 2 and 14. Clinical findings related to sodium nitrite exposure included brown discoloration in the eyes and cyanosis of the mouth, tongue, ears, and feet of males exposed to 3000 or 5000 ppm and of females exposed to 1500 ppm or greater. Reticulocyte counts were increased in males and females exposed to 3000 or 5000 ppm. The erythron was decreased on day 19 but increased by week 14 in males and females exposed to 5000 ppm. Methemoglobin concentrations were elevated in almost all exposed groups throughout the 14 week study; a no-observed-adverse-effect level was not achieved. The relative kidney and spleen weights of males and females exposed to 3000 or 5000 ppm were significantly greater than those of the controls. Sperm motility in 1500 and 5000 ppm males was significantly decreased. Increased erythropoietic activity in the bone marrow of exposed males and females was observed. The incidences of squamous cell hyperplasia of the forestomach in 5000 ppm males and females were significantly increased. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 375, 750, 1500, 3000, or 5000 ppm sodium nitrite (equivalent to average daily doses of approximately 90, 190, 345, 750, or 990 mg/kg to males and 120, 240, 445, 840, or 1230 mg/kg to females) in drinking water for 14 weeks. Body weights of males exposed to 5000 ppm were significantly less than those of the controls. Water consumption by males exposed to 1500 ppm or greater was slightly less than that by the controls at week 13. Relative spleen weights of 3000 and 5000 ppm males and absolute and relative heart, kidney, liver, and spleen weights of females exposed to 3000 or 5000 ppm were greater than those of the control groups. Sperm motility was decreased in 5000 ppm males, and the estrous cycles of 1500 and 5000 ppm females were significantly longer than in the controls. There were increased incidences of squamous cell hyperplasia of the forestomach in 5000 ppm males and females, extramedullary hematopoiesis of the spleen in 3000 and 5000 ppm males and 1500 ppm or greater females, and degeneration of the testis in 3000 and 5000 ppm males. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 750, 1500, or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 35, 70, or 130 mg/kg to males and 40, 8d 40, 80, or 150 mg/kg to females) in drinking water for 2 years. For toxicokinetic studies of plasma nitrite and blood methemoglobin, 10 male and 10 female special study rats were exposed to the same concentrations for 12 months. Survival of exposed groups was similar to that of the controls. Mean body weights of males and females exposed to 3000 ppm were less than those of the controls throughout the study. Water consumption by males and females exposed to 3000 ppm was less than that by the controls throughout the study, and that by the other exposed groups was generally less after week 14. The incidences of hyperplasia of the forestomach epithelium in males and females exposed to 3000 ppm were significantly greater than those in the control groups. The incidence of fibroadenoma of the mam mary gland was significantly increased in females exposed to 1500 ppm, and the incidences of multiple fibroadenoma were increased in 750 ppm and 1500 ppm females; however, these neoplasms occur with a high background incidence, and no increase was seen in the 3000 ppm group. The incidences of mononuclear cell leukemia were significantly decreased in males and females exposed to 1500 or 3000 ppm. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 750, 1500, or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 60, 120, or 220 mg/kg to males and 45, 90, or 165 mg/kg to females) in drinking water for 2 years. Survival of exposed groups was similar to that of the controls; mean body weights of 3000 ppm females were less than those of the controls throughout the study. Exposed groups generally consumed less water than the control groups. The incidences of squamous cell papilloma or carcinoma (combined) in the forestomach of female mice occurred with a positive trend. The incidence of hyperplasia of the glandular stomach epithelium was significantly greater in 3000 ppm males than in the controls. Sodium nitrite was mutagenic in Salmonella typhimurium strain TA100, with and without Aroclor 1254-induced hamster and rat liver S9 enzymes; no mutagenicity was observed in strain TA98. Results of acute bone marrow micronucleus tests with sodium nitrite in male rats and mice by intraperitoneal injection were negative. In addition, a peripheral blood micronucleus assay conducted with mice from the 14-week study gave negative results. Under the conditions of this 2-year drinking water study, there was no evidence of carcinogenic activity of sodium nitrite in male or female F344/N rats exposed to 750, 1500, or 3000 ppm. There was no evidence of carcinogenic activity of sodium nitrite in male B6C3F1 mice exposed to 750, 1500, or 3000 ppm. There was equivocal evidence of carcinogenic activity of sodium nitrite in female B6C3F1 mice based on the positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the forestomach. Exposure to sodium nitrite in drinking water resulted in increased incidences of epithelial hyperplasia in the forestomach of male and female rats and in the glandular stomach of male mice. Decreased incidences of mononuclear cell leukemia occurred in male and female rats.

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The Federal Joint Committee (FJC; Gemeinsamer Bundesausschuss, G-BA) defines the health-care elements that are to be reimbursed by sickness funds. To define a directive, the FJC can commission benefit assessments, which provide an overview of the scientific evidence regarding the efficacy and benefits of an intervention. This paper describes the operational implementation of the legal requirements with regard to the benefit assessments of medicines. Such benefit assessments are sometimes referred to as "isolated benefit assessments," to distinguish them from benefit assessments as part of a full economic evaluation.The FJC has the freedom to commission these assessments from any agency; however, to date the majority have commissioned the Institute for Quality and Efficiency in Health Care (IQWiG). Nevertheless, the content of this paper applies integrally to any institute commissioned for such assessments. In this report, 'the institute' is used when the text refers to any of these institutes.The legal framework for benefit assessments is laid out in the German Social Code Book version V ( http://www.sozialgesetzbuch.de ), Sects. 35b ( section 1), 139a ( section 4-6) and Sect. 139b ( section 3). It is specified that: The institute must guarantee high transparency. The institute must provide appropriate participation of relevant parties for the commission-related development of assessments, and opportunity for comment on all important segments of the assessment procedure. The institute has to report on the progress and results of the work at regular intervals. The institute is held to giving the commission to external experts. Based on the legal framework, the institute must guarantee a high procedural transparency. Transparency of the whole process should be achieved, which is evidenced by clear reporting of procedures and criteria in all phases undertaken in the benefit assessment. The most important means of enhancing transparency are: 1. To implement a scoping process to support the development of the research question. 2. To separate the work of the external experts performing the evidence assessment from that of the institute formulating recommendations. Therefore, the preliminary report as produced by external experts needs to be public, and published separately from any subsequent amendments or (draft-)reports made by the institute, which includes the institute's recommendations. 3. To implement open peer review by publishing both the comments of the reviewers and their names. Based on the legal framework, the institute must provide for adequate participation of relevant parties. These include organisations representing the interests of patients; experts of medical, pharmaceutical and health economic science and practice; the professional organisations of pharmacists and pharmaceutical companies; and experts on alternative therapies. Patients and health care professionals bring in new insights with respect to research priorities, treatment and outcomes.The relevant parties should be identified and contacted whenever the global scope of the assessment has been drafted. Subsequently, the relevant parties should be involved in defining the research question, developing the protocol and commenting on the preliminary report. To implement the involvement of relevant parties in defining the research question a scoping process is suggested. For the other phases, written comments followed by an oral discussion should be used. Finally, the relevant parties should have the right to appeal the final decision on judicial grounds. None of these steps mean that the institute would lose any part of its scientific independence.From the relevant sections of the legal framework with respect to the assessment methods, it can be concluded that: 1. The institute must ensure that the assessment is made in accordance with internationally recognised standards of evidence-based medicine (EBM). 2. The assessment is conducted in comparison with other medicines and treatment forms under consideration of the additional therapeutic benefit for the patients. 3. The minimum criteria for assessing patient benefit are improvements in the state of health, shortening the duration of illness, extension of the duration of life, reduction of side effects and improvements in quality of life. EBM refers to the application of the best available evidence to answer a research question, which can inform questions about the care of patients. The optimal design, even for effectiveness questions, is not always the randomised, controlled trial (RCT) but depends on the research question and the outcomes of interest. To increase transparency for each question, the levels of evidence examined should be made explicit. There is no empirical evidence to support the use of cutoff points with respect to the number of studies before making recommendations. To get the best available evidence for the research question(s), all relevant evidence should be considered for each question, and the best available evidence should be used to answer the question. Separate levels of evidence may have to be used for each outcome.There are many ways in which bias can be introduced in systematic reviews. Some types of bias can be prevented, other types can only be reported and, for some, the influence of the bias can be investigated. Reviews must show that potential sources of bias have been dealt with adequately.Methods used by other agencies that perform benefit assessments are useful to interpret the term 'international standards' to which the institute must comply. The National Institute for Health and Clinical Excellence (NICE) is a good example in this respect. NICE shows that it is possible to have transparent procedures for benefit assessments but that this requires detailed documentation. NICE has implemented an open procedure with respect to the comments of reviewers, which makes the procedure transparent. Although the Institute for Quality and Efficiency in Health Care (IQWiG) in Germany invites comments on their protocol and preliminary report by posting them on their website, and comments are made public, the individual comments are not evaluated openly, and therefore it remains uncertain whether or not they lead to changes in the reports. The participation of relevant parties in the assessment process as implemented by NICE guarantees a process that is transparent to all relevant parties.Transparency of the whole process is assured by clear reporting of procedures and criteria in all phases undertaken in the benefit assessment. In a scoping process, a draft scope is commented on first in writing and subsequently in the form of a scoping workshop. In this way, all relevant aspects can be heard and included in the final scope. The protocol is then developed, followed by evidence assessment. The methods used should be completely reported to show readers that the assessment has been performed with scientific rigour and that bias has been prevented where possible. All relevant parties should have the opportunity to comment on the draft protocol and the draft preliminary report. Each comment should be evaluated as to whether or not it will lead to changes, and both the comments and the evaluation should be made public to ensure transparency of this process. The same procedure should be used for the peer-review phase. Based on the final report of the evidence assessment, the institute forms recommendations and the FJC appraises the evidence.During the writing of the final report, a separation between the evidence assessment and the evidence-appraisal phase should be implemented. Ideally, this separation should be legally enforced to prevent any confusion about conflict of interests.Such a process guarantees a feasible combination of the legal requirements for transparency and involvement of relevant parties with international standards of EBM to ensure that the benefit assessments of medicines in Germany are performed according to the highest standards.

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To critically review all literature related to pacifier use for full-term healthy infants and young children. The specific review questions addressed are: What is the evidence of adverse and/or positive outcomes of pacifier use in infancy and childhood in relation to each of the following subtopics: • breast-feeding; • sudden infant death syndrome; • infection; • dental malocclusion.  Specific criteria were used to determine which studies would be included in the review: (i) the types of participants; (ii) the types of research design; and (iii) the types of outcome measures. To be included a study has to meet all criteria.  The participants included in the review were healthy term infants and healthy children up to the age of 16 years. Studies that focused on preterm infants, and infants and young children with serious illness or congenital malformations were excluded. However, some total population studies did include these children. Types of research design: It became evident early in the review process that very few randomised controlled trials had been conducted. A decision was made to include observational epidemiological designs, specifically prospective cohort studies and, in the case of sudden infant death syndrome research, case-control studies. Purely descriptive and cross-sectional studies were excluded, as were qualitative studies and all other forms of evidence. A number of criteria have been proposed to establish causation in the scientific and medical literature. These key criteria were applied in the review process and are described as follows: (i) consistency and unbiasedness of findings; (ii) strength of association; (iii) temporal sequence; (iv) dose-response relationship; (v) specificity; (vi) coherence with biological background and previous knowledge; (vii) biological plausibility; and (viii) experimental evidence. Studies that did not meet the requirement of appropriate temporal sequencing of events and studies that did not present an estimate of the strength of association were not included in the final review. Types of outcome measures: Our specific interest was pacifier use related to: • breast-feeding; • sudden infant death syndrome; • infection; • dental malocclusion. Studies that examined pacifier use related to procedural pain relief were excluded. Studies that examined the relationship between pacifier use and gastro-oesophageal reflux were also excluded as this information has been recently presented as a systematic review.  The review comprised published and unpublished research literature. The search was restricted to reports published in English, Spanish and German. The time period covered research published from January 1960 to October 2003. A protocol developed by New Zealand Health Technology Assessment was used to guide the search process. The search comprised bibliographic databases, citation searching, other evidence-based and guidelines sites, government documents, books and reports, professional websites, national associations, hand search, contacting national/international experts and general internet searching. ASSESSMENT OF QUALITY: All studies identified during the database search were assessed for relevance to the review based on the information provided in the title, abstract and descriptor/MeSH terms, and a full report was retrieved for all studies that met the inclusion criteria. Studies identified from reference list searches were assessed for relevance based on the study title. Keywords included: dummy, dummies, pacifier(s), soother(s), comforter(s), non-nutritive sucking, infant, child, infant care. Initially, studies were reviewed for inclusion by pairs of principal investigators. Authorship of articles was not concealed from the reviewers. Next, the methodological quality of included articles was assessed independently by groups of three or more principal investigators and clinicians using a checklist. All 20 studies that were accepted met minimum set criteria, but few passed without some methodological concern.  To meet the requirements of the Joanna Briggs Institute, reasons for acceptance and non-acceptance at each phase were clearly documented. An assessment protocol and report form was developed for each of the three phases of review. The first form was created to record investigators' evaluations of studies included in the initial review. Those studies that failed to meet strict inclusion criteria were excluded at this point. A second form was designed to facilitate an in-depth critique of epidemiological study methodology. The checklist was pilot tested and adjustments were made before reviewers were trained in its use. When reviewers could not agree on an assessment, it was passed to additional reviewers and discussed until a consensus was reached. At this stage, studies other than cohort, case-control and randomised controlled trials were excluded. Issues of clarification were also addressed at this point. The final phase was that of integration. This phase, undertaken by the principal investigators, was assisted by the production of data extraction tables. Through a process of trial and error, a framework was formulated that adequately summarised the key elements of the studies. This information was tabulated under the following headings: authors/setting, design, exposure/outcome, confounders controlled, analysis and main findings.  With regard to the breast-feeding outcome, 10 studies met the inclusion criteria, comprising two randomised controlled trials and eight cohort studies. The research was conducted between 1995 and 2003 in a wide variety of settings involving research participants from diverse socioeconomic and cultural backgrounds. Information regarding exposure and outcome status, and potential confounding factors was obtained from: antenatal and postnatal records; interviews before discharge from obstetric/midwifery care; post-discharge interviews; and post-discharge postal and telephone surveys. Both the level of contact and the frequency of contact with the informant, the child's mother, differed widely. Pacifier use was defined and measured inconsistently, possibly because few studies were initiated expressly to investigate its relationship with breast-feeding. Completeness of follow-up was addressed, but missing data were not uniformly identified and explained. When comparisons were made between participants and non-participants there was some evidence of differential loss and a bias towards families in higher socioeconomic groups. Multivariate analysis was undertaken in the majority of studies, with some including a large number of sociodemographic, obstetric and infant covariates and others including just maternal age and education. As might be expected given the inconsistency of definition and measurement, the relationship between pacifier use and breast-feeding was expressed in many different ways and a meta-analysis was not appropriate. In summary, only one study did not report a negative association between pacifier use and breast-feeding duration or exclusivity. Results indicate an increase in risk for a reduced overall duration of breast-feeding from 20% to almost threefold. The data suggest that very infrequent use may not have any overall negative impact on breast-feeding outcomes. Six sudden infant death syndrome case-control studies met the criteria for inclusion. The research was conducted with information gathered between 1984 and 1999 in Norway, UK, New Zealand, the Netherlands and USA. Exposure information was obtained from a variety of sources including: hospital and antenatal records, death scene investigation, and interview and questionnaire. Information for cases was sought within 2 days after death, within 2-4 weeks after death and in one study between 3 and 11 years after death. Information for controls was sought from as early as 4 days of a nominated sudden infant death syndrome case, to between 1 and 7 weeks from the case date, and again in one study some 3-11 years later. In the majority of the studies case ascertainment was determined by post-mortem. Pacifier use was again defined and measured somewhat inconsistently. All studies controlled for confounding factors by matching and/or using multivariate analysis. Generally, antenatal and postnatal factors, as well as infant care practices, and maternal, family and socioeconomic issues were considered. (ABSTRACT TRUNCATED)

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<bObjective:</b To isolate a bacteriophage against pan-drug resistant <iKlebsiella pneumoniae</i in a burn patient, and to study its biological characteristics, genomic information, and effects on bacterial biofilm. <bMethods:</b (1) In 2018, pan-drug resistant <iKlebsiella pneumoniae</i UA168 (hereinafter referred to as the host bacteria) solution isolated from the blood of a burn patient in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (hereinafter referred to as Ruijin Hospital) was used to isolate and purify the bacteriophage against pan-drug resistant <iKlebsiella pneumoniae</i from the sewage of Ruijin Hospital with sewage co-culture method, drip plate method, and double-agar plate method. The bacteriophage was named as phage KP168 and the plaque morphology was observed. (2) The phage KP168 solution was taken for cesium chloride density gradient centrifugation and dialysis, and then the morphology of phage KP168 was observed through transmission electron microscope after phosphotungstic acid negative staining. (3) The phage KP168 solution was taken to determine the lytic ability of the phage KP168 against 20 strains of pan-drug resistant <iKlebsiella pneumoniae</i isolated from the burned patients' blood in Ruijin Hospital by the drip plate method, and then the lysis rate was calculated. (4) The phage KP168 solution at a initial titer of 9.3×10(11) plaque-forming unit (PFU)/mL (400 μL per tube) and the host bacteria solution at a concentration of 1×10(9) colony-forming unit (CFU)/mL (4 mL per tube) were conventionally shaking cultured together for 4 hours at multiplicity of infection (MOI) of 10.000, 1.000, 0.100, 0.010, or 0.001, respectively (1 tube per MOI). The titer of phage KP168 was measured by the double-agar plate method (the measurement method was the same below) to select the optimal MOI. The experiment was repeated three times. (5) The host bacteria solution at a concentration of 1×10(9) CFU/mL (4 mL per tube) and the phage KP168 solution at an adjusted titer of 5×10(7) PFU/mL (400 μL per tube) were mixed at the MOI of 0.005. The plaques were counted 0 (immediately), 1, 2, 3, 4, 5, 15, and 30 minutes (1 tube at each time point) after mixing by the double-agar plate method (the counting method was the same below), and the percentage of adsorbed phages was calculated to screen for the optimal adsorption time. The experiment was repeated three times. (6) The host bacteria solution at a concentration of 1×10(9) CFU/mL (300 μL per tube) and the phage KP168 solution at a titer of 5×10(8) PFU/mL (60 μL per tube) were mixed at MOI of 0.005 and conventionally shaking cultured after standing for the optimal adsorption time. The phage KP168 titer was measured 0 (immediately), 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 minutes after culture, and a one-step growth curve was drawn. The experiment was repeated three times. (7) The phage KP168 solution at a titer of 2.5×10(10) PFU/mL was left to stand for 1 hour at 37, 40, 50, 60, or 70 ℃ (3 tubes at each time point, 1 mL per tube) for counting the plaques, and then the thermal stability curve was drawn. SM buffer at a pH values of 5.0, 6.0, 7.0, 7.4, 8.0, 9.0, or 10.0 were added to the phage KP168 solution at a titer of 3.0×10(10) PFU/mL, respectively. The mixed solution was left to stand for 1 hour at 37 ℃ (3 tubes of each pH, each tube containing 100 μL phage KP168 solution and 900 μL SM buffer), and then the plaques were counted, and an acid-base stability curve was drawn. (8) The phage KP168 solution was taken for DNA extraction and sequencing after dialysis as in experiment (2). The whole genome was annotated with Prokka to obtain the coding sequence of phage KP168. Nucleotide's BLAST function was used to proceed nucleic acid sequence alignment for finding a known phage with the highest similarity to the phage KP168 nucleic acid sequence, and Blastx function was used to translate the coding sequence into protein for its function prediction. The comparison with Antibiotic Resistance Genes Database and Virulence Factors Database was proceeded. (9) In a 96-well plate, at a MOI of 1.000, 0.100, 0.010 or 0.001 (3 wells per MOI), 20 μL phage KP168 solution at a initial titer of 5.8×10(10) PFU/mL was added to 200 μL host bacteria solution at a concentration of 1.5×10(8) CFU/mL (the same concentration below) for co-cultivation for 48 hours. After 200 μL host bacteria solution was left to stand for 48 hours, 20 μL phage KP168 solution at a titer of 1×10(6,) 1×10(7,) 1×10(8,) 1×10(9,) or 1×10(10) PFU/mL (3 wells per titer) was added respectively for action for 4 hours. In both experiments, 200 μL host bacteria solution added with 20 μL SM buffer (3 wells) acted as a negative control, and 220 μL LB culture medium (3 wells) acted as a blank control. Absorbance values were measured by a microplate reader, and inhibition/destruction rates of biofilm were calculated. The experiments were both repeated three times. <bResults:</b (1) The plaques of phage KP168 successfully isolated and purified were transparent and round, and its diameter was approximately 1.5 mm. (2) The phage KP168 has a regular polyhedron structure with a diameter of about 50 nm and without a tail. (3) The phage KP168 could lyse 13 of 20 strains of <iKlebsiella pneumoniae</i from burned patients, with a lysis rate of 65.0%. (4) When MOI was 1.000, the titer was the highest after co-culturing the phage KP168 with the host bacteria for 4 hours, which was the optimal MOI. (5) After the mixing of the phage KP168 with the host bacteria for 4 minutes, the percentage of the adsorbed phage reached the highest, which was the optimal adsorption time. (6) The one-step growth curve showed that during the lysis of the host bacteria by phage KP168, the incubation period was about 10 minutes, and the lysis period was about 40 minutes. (7) With the condition of 40 ℃ or pH 7.4, the number of plaques and the activity of phage KP168 reached the highest. (8) The genome of phage KP168 was a linear double-stranded DNA with a length of 40 114 bp. There were 48 possible coding sequences. It had the highest similarity to Klebsiella phage_vB_Kp1. The most similar known proteins corresponding to the translated proteins of coding sequences contained 23 hypothetical proteins and 25 proteins with known functions. No resistance genes or virulence factor genes were found. The GeneBank accession number was KT367885. (9) After 48 hours of co-cultivation of the phage KP168 and the host bacteria at each MOI, the inhibition rates of biofilm were similar, with an average of about 45%. After the phage KP168 with a titer of 1×10(9) PFU/mL acted on the biofilm formed by the host bacteria for 4 h, the destruction rate of biofilm was the highest, reaching an average of 42%. <bConclusions:</b In this study, a bacteriophage against pan-drug resistant <iKlebsiella pneumoniae</i from a burn patient, phage KP168, is isolated from sewage, which belongs to the tailless phage. It has a wide host spectrum, short adsorption time, and short incubation period, with certain thermal and acid-base stability. Its genomic information is clear, and it does not contain resistance genes or virulence factor genes. It also has an inhibitory effect on the formation of bacterial biofilm and a destructive effect on the formed bacterial biofilm.

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Glycol alkyl ethers represent a class of high-production-volume chemicals with widespread industrial applications as solvents and chemical intermediates. Comparative toxicity studies with three glycol ethers, 2-methoxyethanol, 2-ethoxyethanol, and 2-butoxyethanol, were conducted in F344/N rats and B6C3F1 mice in both 2-week and 13-week drinking water studies. Toxicologic endpoints evaluated in animals included histopathology, hematology, clinical chemistry, urinalysis, and reproductive system parameters. Genetic toxicity was also evaluated for each glycol ether in several in vitro and in vivo assays. In the 2-week studies, groups of five male and five female rats and mice received 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in the drinking water. Estimates of compound consumption based on water consumption by male and female rats ranged from 100 to 400 mg/kg for 2-methoxyethanol, 200 to 1600 mg/kg for 2-ethoxyethanol, and 70 to 300 mg/kg for 2-butoxyethanol. For mice, consumption values ranged from 200 to 1300 mg/kg for 2-methoxyethanol, 400 to 2800 mg/kg for 2-ethoxyethanol, and 90 to 1400 mg/kg for 2-butoxyethanol. There were no chemical-related effects on survival for rats or mice in the 2-week studies. Decreased body weight gains were noted for both male and female rats treated with 2-methoxyethanol or 2-ethoxyethanol for 2 weeks, and there were dose-related decreases in water consumption for rats of each sex treated with the ethylene glycol ethers. Most of the changes in organ weights for rats and mice treated with the glycol ethers were sporadic (mice) or related to low final mean body weights (rats), except for thymic atrophy in male and female rats and testicular atrophy in males of both species receiving 2-methoxyethanol or 2-ethoxyethanol. In the 13-week studies in rats, groups of 10 males and 10 females received 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in the drinking water at concentrations ranging from 750 to 6000 ppm, 1250 to 20,000 ppm, or 750 to 6000 ppm, respectively. In the 13-week studies in mice, groups of 10 males and 10 females received 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol in the drinking water at concentrations ranging from 2000 to 10,000 ppm, 2500 to 40,000 ppm, or 750 to 6000 ppm, respectively. Estimates of compound consumption based on water consumption by male and female rats ranged from 70 to 800 mg/kg for 2-methoxyethanol, 100 to 2200- mg/kg for 2-ethoxyethanol, and 70 to 500 mg/kg for 2-butoxyethanol. For-mice, consumption values ranged from 300 to 1800 mg/kg for 2-methoxyethanol, 600 to 11,000 mg/kg for 2-ethoxyethanol, and 100 to 1300 mg/kg for 2-butoxyethanol. Chemical-related mortality occurred in male and female rats administered 4500 or 6000 ppm 2-methoxyethanol and in male and female rats administered 20,000 ppm 2-ethoxyethanol. No deaths occurred in rats administered 2-butoxyethanol or in mice administered 2-methoxyethanol, 2-ethoxyethanol, or 2-butoxyethanol. Decreased body weight gains occurred in dosed rats and mice in all three studies; the greatest reductions in body weight gain were seen with 2-methoxyethanol. In rats administered 2-methoxyethanol or 2-ethoxyethanol, treatment-related histopathologic changes were observed in the testes, thymus, and hematopoietic tissues (spleen, bone marrow, and liver). A dose-related degeneration of the germinal epithelium in the seminiferous tubules of the testes was more severe in 2-methoxyethanol-treated rats than in rats treated with 2-ethoxyethanol. In special stop-exposure studies in male rats in which administration of the glycol ethers was stopped after 60 days, marked degeneration of the seminiferous tubules was present in rats treated with 3000 ppm 2-methoxyethanol, and mild to moderate degeneration was observed in rats treated with 1500 ppm. Moderate to marked testicular degeneration was present in rats treated with 10,000 or 20,000 ppm 2-ethoxyethanol but not in rats treated with 5000 ppm. After 30 and 56 days of recovery from treatment with these chemicals, only partial recovery from testicular degeneration was observed. There was no testicular degeneration after 60 days of treatment with 1500 to 6000 ppm 2-butoxyethanol. 2-Methoxyethanol treatment for 13 weeks resulted in a progressive anemia associated with a cellular depletion of bone marrow and fibrosis of the splenic capsule. Anemia was also seen with 2-ethoxyethanol, but evidence of an adaptive response was indicated by increased hematopoiesis in the bone marrow, spleen, and liver. Toxicity with 2-butoxyethanol was limited to the liver and hematopoietic system. Cytoplasmic alteration and a minimal hepatocellular degeneration were present in the liver of male and female rats. A minimal anemia was present, and a hematopoietic response was evident in the bone marrow and spleen. In mice, 2-methoxyethanol and 2-ethoxyethanol had similar effects on the testes, spleen, and adrenal gland (females only). A dose-related degeneration of the germinal epithelium in seminiferous tubules of the testes was more severe with 2-methoxyethanol than with 2-ethoxyethanol. A dose-related increase in splenic hematopoiesis was also more prominent with 2-methoxyethanol. Both 2-methoxyethanol and 2-ethoxyethanol caused a prominent lipid vacuolization of the X-zone of the adrenal gland in female mice. There were no chemical-related lesions attributed to 2-butoxyethanol administration in mice. All three of the glycol ethers were negative in Salmonella typhimurium mutation tests conducted with and without induced hamster and rat liver S9. In the mouse lymphoma L5178Y cell mutation assay, 2-ethoxyethanol was negative without S9 but was weakly positive in the presence of induced rat liver S9; 2-methoxyethanol and 2-butoxyethanol were not tested in this assay. At high concentrations, 2-ethoxyethanol induced sister chromatid exchanges (SCEs) in Chinese hamster ovary cells with and without S9. Chromosomal aberrations (Abs) were also induced by 2-ethoxyethanol, but only in the absence of S9 and without a delay in cell cycle. In contrast, 2-butoxyethanol induced cell cycle delay but did not induce SCEs or Abs with or without S9. 2-Ethoxyethanol was the only glycol ether tested for induction of sex-linked recessive lethal mutations in germ cells of Drosophila melanogaster; both feeding and injection trials were negative. In summary, based on survival, decreased body weight gains, and histopathologic effects, the rank order of toxicity for the three glycol alkyl ethers was 2-methoxyethanol&gt;2-ethoxyethanol&gt;2-butoxyethanol; the toxic effects were more severe in rats than in mice. In the 13-week study of 2-methoxyethanol in rats, a no-observed-adverse-effect level (NOAEL) was not reached, since testicular degeneration in males and decreased thymus weights in males and females occurred at the lowest concentration administered (750 ppm). In the 13-week study of 2-ethoxyethanol in rats, the NOAEL for decreased thymus weights in males was 1250 ppm; for female rats treated with 2-ethoxyethanol for 13 weeks, the NOAEL for all histopathologic and hematologic effects was 5000 ppm. In rats treated with 2-butoxyethanol for 13 weeks, the NOAEL for liver degeneration was 1500 ppm in males and females. For male mice treated with 2-methoxyethanol for 13 weeks, the NOAEL for testicular degeneration and increased hematopoiesis in the spleen was 2000 ppm. A NOAEL was not reached for female mice treated with 2-methoxyethanol, since adrenal gland hypertrophy and increased hematopoiesis in the spleen occurred at the lowest concentration administered (2000 ppm). For male mice treated with 2-ethoxyethanol for 13 weeks, the NOAEL for testicular degeneration and increased hematopoiesis in the spleen was 20,000 ppm. For female mice in the 13-week study of 2-ethoxyethanol, the NOAEL for adrenal gland hypertrophy and increased hematopoiesis in the spleen was 5000 ppm. No clear chemical-related effects were seen in male or female mice administered 2-butoxyethanol for 13 weeks at concentrations as high as 6000 ppm. Synonyms: 2-Methoxyethanol: Ethylene glycol monomethyl ether; methyl cellosolve; 2-Ethoxyethanol: Ethylene glycol monoethyl ether; cellosolve; 2-Butoxyethanol: Ethylene glycol monobutyl ether; butyl cellosolve.

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As Japan's population continues to age, it is estimated that the number of people aged ≥75 years will exceed 20 million by 2025. Furthermore, over the past 10 years, we have not reduced the difference between life expectancy and healthy life expectancy. Therefore, the extension of healthy life expectancy and the development of a healthy society are the most urgent issues. In terms of medical care, the changing times have inevitably led to changes in disease structures and medical demands; therefore, the medical delivery system has had to be changed to meet these demands. As dementia rapidly increases, it is important to address "frailty," a condition in which people become more vulnerable to environmental factors as they age, and there is a need to provide services to older people, particularly the old-old, that emphasize quality of life in addition to medical care. To realize a super-aged society that will remain vigorous and vibrant for many years, we need to rethink the future of Japanese medicine and healthcare, and the state of society. Disparity between healthy life expectancy and average life expectancy in the realization of a healthy society It is a challenge to build a society with a long and healthy life expectancy through comprehensive prevention and management of lifestyle-related diseases, as well as the elucidation of the factors that explain sex differences in healthy life expectancy, based on the recognition that lifestyle-related diseases in midlife are risk factors for frailty and dementia in old age. Challenges in medical care for building a super-aged and healthy society The challenges include promoting clinical guidelines suitable for older people, including lifestyle-related disease management, promoting comprehensive research on aging (basic research, clinical research and community collaboration research), and embodying a paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care." Furthermore, the key to the future of integrated community care is the development of a comprehensive medical care system for older people in each region and the development of the next generation of medical personnel. Dissemination of frailty prevention measures in a super-aged society The concept of frailty encompasses the meaning of multifacetedness and reversibility; therefore, a comprehensive approach is required, including the renewal of conventional prevention activities in each region, such as the nutritional status of older people, physical activity including exercise, and various opportunities for social participation and participation conditions. Challenges of an unstable diet and undernutrition in older people According to the National Health and Nutrition Examination Survey of Japan, energy and protein intakes are low in Japanese people aged ≥75 years; particularly in people aged ≥80 years, low and insufficient intake of nutrients are prominent. Undernutrition in older people is increasing and is more pronounced in women. There are multiple factors behind this, including social factors, such as living alone, eating alone, poverty and other social factors, as well as problems with access to food security. Pharmacotherapy for older people: measures against polypharmacy In addition to the problems of adverse drug events, drug interactions, duplication of effects and the presence of drugs that "require particularly careful administration," it is also necessary to take measures against polypharmacy in older people, as well as medical economic issues, such as high drug costs and large amounts of remaining drugs. Barriers to this measure include multiple medical institution visits for each disease, lack of coordination between professions, and lack of understanding by patients and families. Role of local communities in a healthy society The decline in the working-age population is also a major challenge; however, we need to make a shift to use this declining birthrate and aging population as an opportunity rather than a crisis. As we look ahead to the coming of the 100-year age of life, we rethink the creation of a comprehensive society and community, and aim to create an age-free society where everyone can play an active role and live in peace, regardless of age. In this report, we have put together a vision for the future of an aging Japanese society from a broader perspective of how the environment and local communities should be, rather than simply from the perspective of individual health. We aim to convey this proposal to the Ministry of Health, Labor and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, the Cabinet Office, and various professional organizations. The paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care" should be promoted for the development of a healthy society While further promoting pre-emptive medical care in the medical care for older people, the development of multidisciplinary medical guidelines appropriate for older people should be promoted at the same time. In addition, we should promote basic aging research, clinical research (including the long-term care field) and transitional research that cover regional areas. Furthermore, while promoting the paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care," the development of various comprehensive medical treatment systems for older people and the strengthening of integrated community care systems should be promoted. Development of the next generation of medical personnel to comprehensively deal with geriatric care, including training geriatric specialists, should be promoted As the number of older people with multimorbidities and frailty rapidly increases in the future, we should promote the development of the next generation of medical personnel who can comprehensively handle medical care for older people, including training leading geriatricians in cooperation with multiple professions in the integrated community care system to provide sufficient medical care. Countermeasures for frailty in older people should be promoted from medical and community planning perspectives To address frailty, which requires comprehensive evaluation and intervention, the three pillars of frailty prevention (nutrition, exercise and social participation) should be incorporated and addressed as part of community development within each municipality, taking into account local characteristics. In particular, it is necessary to revise the way of thinking about nutrition management in older people and the guidelines of the societies in the field. In addition, it is important to strengthen industry-academia-government-private partnerships in each region, taking into account not only medical issues, but also social factors, and encourage the development of momentum in the entire region regarding measures against undernutrition in older people. Polypharmacy measures should be promoted in pharmacotherapy for older people It is necessary to promote cooperation between physicians and pharmacists, establish other multiprofessional cooperation systems, and develop medical and long-term care insurance systems to support this. It is also essential to change the public's mindset, and awareness-raising activities at all levels are required, including the enhancement of educational materials for medical caregivers and the general public. In addition, the economic impact of healthcare using big data should be timely clarified. Innovation in medical and urban planning perspectives should be promoted In the future, it will be necessary to modify and update multidisciplinary approaches such as social participation (e.g. participation in a salon) with a view to innovation in both medical care and community development, especially on the idea of a symbiotic community. In addition, industry-academia-government-private partnership is necessary, including all aforementioned, such as places where people can play an active role in the rest of their lives (such as employment), promotion of human connections, promotion of technology to support older people and support for daily life. Geriatr Gerontol Int 2021; 21: 601-613.

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Teamwork is seen as an important element of patient care in acute hospital settings. The complexity of the journey of care for patients highlights the need for health professionals to collaborate and communicate clearly with each other. Health organizations in western countries are committed to improving patient safety through education of staff and teamwork education programs have been integral to this focus. There are no current systematic reviews of the experience of health professionals who participate in teamwork education in acute hospital settings. The objective of this systematic review was to search for the best available evidence on the experiences of health professionals who participate in teamwork education in acute hospital settings. This review considered studies reporting on experiences of registered health professionals who work in acute hospitals. This included medical, nursing and midwifery and allied health professionals. The focus of the meta-synthesis was the experiences and reflections of health professionals who were involved in teamwork education in acute hospital settings. The geographical context for this review was acute hospitals in rural or metropolitan settings in Australia and overseas countries. The review focused on the experiences of health professionals who work in acute hospitals and participated in teamwork education programs. This review considered studies that focused on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research.In the absence of research studies, other text such as opinion papers, discussion papers and reports were considered. Studies published in English and from 1990 to 2013 were included in this review. The literature search for relevant papers occurred between 13 September and 26 October 2013. A three-step search strategy was utilized in this review. The databases searched were PubMed, CINAHL, Embase and Scopus. The standardized critical appraisal tool the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) was used to assess the methodological quality of included papers. Data that included statements and text of interest was extracted from papers included in the study using the standardized data extraction tool from JBI-QARI. Qualitative research findings were pooled using JBI-QARI. This involved the aggregation and synthesis of findings to generate a set of statements that represented that aggregation. In total, 116 papers were selected for analysis of full text, 11 papers were selected for critical appraisal and seven papers were selected for data synthesis. This resulted in 44 findings. The findings were assigned to 16 categories based on identified similarities across the papers. The categories were integrated into six meta-syntheses. These were: Meta-synthesis One: It is important to recognize that organizational culture and expectations have an impact on health professionals' participation and experience of teamwork education. Meta-synthesis Two: Understanding how successful teams function is central to the development of teamwork education programs and the experience of participants. Meta-synthesis Three: A health professional's experience of teamwork education will be influenced by his/her starting point of learning. Meta-synthesis Four: Participants highly value teamwork education programs that are implemented by facilitators who create practical authentic learning opportunities and foster reflection and debriefing for participants. Meta-synthesis Five: High fidelity simulation used with specific communication strategies provides a powerful learning opportunity for health professions to practice teamwork skills. Meta-synthesis Six: Participants have increased confidence and are motivated to apply their newly learnt teamwork skills into their daily practice. The review identified qualitative evidence that can guide organizations and education facilitators in the development and implementation of teamwork education in acute hospital settings. Although the quality of the specific teamwork education programs was an important factor, there were a number of issues that also impacted on the experiences of health professionals who participated in teamwork education programs. These included the context that the program was delivered in, the diversity of health care teams, starting points of individual learners, the type of tools utilized in education programs, the levels of confidence and motivation of learners post training and the opportunity to transfer into practice new learning. Drawing from the synthesized findings of the review, recommendations for practice have been devised in order to guide the development and implementation of teamwork education in acute hospital settings and to improve the experience of participating health professionals. The Joanna Briggs Institute utilizes Grades of Recommendation to rate a health management strategy in terms of its desirable effects, evidence of adequate quality supporting its use, benefits of use, and the inclusion of patient experience, values and preferences. A strong recommendation has a Grade A and a weak recommendation has a Grade B. The FAME (Feasibility, Appropriateness, Meaningfulness and Effectiveness) scale was used to inform the strength of the following six recommendations for practice from the review: RECOMMENDATION ONE: All members of a team should be encouraged by their organization/managers to participate in teamwork education programs in order to foster a positive culture of learning and teamwork within the team.JBI Recommendation: Grade A. This recommendation is appropriate and applicable to all health professionals in acute hospital settings, is associated with positive experiences for participants of teamwork education programs and has a beneficial effect on participants. Facilitators of teamwork education programs should understand how successful teams function and consider these factors when planning or delivering training.JBI Recommendation: Grade A. This recommendation is associated with positive experiences for participants and creates a beneficial effect to the quality of a teamwork education program. Facilitators of teamwork education programs need to explore participant learning needs and their prior experiences of working in teams before implementing teamwork education programs.JBI Recommendation: Grade A. This recommendation creates a beneficial effect to the participants of teamwork education programs and to the quality of education provided by facilitators. Facilitators of teamwork education programs should provide learning opportunities that are practical, authentic to participants and foster constructive debriefing and reflection.JBI Recommendation: Grade A. This recommendation is applicable to all health professionals and circumstances in which teamwork education occurs, is associated with positive experiences and has a beneficial effect on participants. High fidelity simulation should be considered in acute hospitals for the training of teamwork skills in addition to clinical skills. Scenarios provide realistic opportunities for participants to practice communication strategies that enhance teamwork.JBI Recommendation: Grade A. This recommendation is applicable to all health professionals and circumstances in which teamwork education occurs and has a beneficial effect on participants of education programs. Team managers should harness the new confidence and motivation of staff around teamwork skills following participation in teamwork education programs and ensure that there are opportunities in the workplace to apply new skills and knowledge into daily practice.JBI Recommendation: Grade A. This recommendation is applicable to all health professionals and circumstances in which teamwork education occurs, is adaptable to a variety of circumstances and has a beneficial effect on health professional's daily practice of teamwork skills. In order to strengthen the evidence base about teamwork education in acute hospital settings there needs to be quantitative and qualitative research into:How organizations that have successfully embedded a culture of collaboration and safety in health teams have planned, implemented and evaluated teamwork education programs in acute hospital settings?What are the characteristics of teams that have led to successful participation in teamwork education and positive outcomes for team performance?What are the experiences, training and support provided to education facilitators who successfully implement teamwork education programs in acute hospitals?

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<bObjective:</b To investigate the effects of astragalus polysaccharide (AP) on cardiac dysfunction in rabbits with severe scald injury. <bMethods:</b Sixty-four New Zealand white rabbits were divided into pure scald group and AP group according to the random number table, with 32 rabbits in each group. Rabbits in the two groups were all inflicted with 30% total body surface area full-thickness scald on the back. Immediately after injury, rabbits in two groups were intraperitoneally injected with lactated Ringer's solution once for antishock. Rabbits in AP group were intraperitoneally injected with 10 mL AP solution with the dosage of 200 mg/kg 10 min after injury and the following 6 days respectively, once a day. Rabbits in pure scald group were injected with 10 mL normal saline instead. Eight rabbits of each group were respectively selected before injury hour (BIH) 1 and on post injury day(PID) 1, 3, 7, and 14 to collect blood samples from ear marginal vein, and then sacrificed immediately to collect hearts at each time point post injury. The morphology of myocardium was observed after HE staining. The serum content of cardiac troponin I (cTnI) was detected by enzyme-linked immunosorbent assay (ELISA). The serum content of aspartate transaminase (AST), creatine kinase (CK), CK isoenzyme-MB (CK-MB), lactate dehydrogenase (LDH) was detected by fully automatic chemistry analyzer. The content of angiotensin Ⅱ (Ang Ⅱ) in serum and myocardium was detected with radioimmunoassay and the content of endothelin 1 (ET-1) in serum and myocardium was detected by ELISA. Another 8 normal rabbits were sacrificed to detect the content of Ang Ⅱ and ET-1 in the myocardium as the value of the two groups of scalded rabbits at BIH 1. The serum content of superoxide dismutase (SOD) and malondialdehyde (MDA) was detected by ELISA. The values of whole blood viscosity (ηb), reductive viscosity of whole blood (ηr), plasma viscosity (ηp), hematocrit (HCT), erythrocyte rigidity index (TK), erythrocyte aggregation index (EAI), and erythrocyte sedimentation rate (ESR) were detected by fully automatic hematology analyzer. Data were processed with analysis of variance of factorial design, independent sample <it</i test, and Dunnett test. <bResults:</b (1) Compared with those in pure scald group, the degrees of cardiomyocyte swelling, steatosis, necrosis and rupture of muscle fiber were significantly alleviated in rabbits of AP group on PID 1 and 3. There was no obvious increase in cell size, no breakage of muscle fiber or infiltration of inflammatory cells in myocardial interstitium on PID 7. The myocardial tissue structure and muscle fiber arrangement returned to normal condition on PID 14, with no interstitial fibroblast hyperplasia or excessive extra cellular matrix deposition. (2) Serum content of cTnI, CK, and LDH of rabbits in AP group was significantly lower than that in pure scald group on PID 1, 3, and 7 (with <it</i values from 2.69 to 13.99, <iP</i&lt;0.05 or <iP</i&lt;0.01), while there was no significant difference between the two groups on PID 14 (with <it</i values from -0.32 to 0.68, <iP</i values above 0.05). Serum content of AST and CK-MB of rabbits in AP group was significantly lower than that in pure scald group on PID 1 and 3 (with <it</i values from 2.21 to 12.65, <iP</i&lt;0.05 or <iP</i&lt;0.01), while there was no significant difference between the two groups on PID 7 and 14 (with <it</i values from 0.03 to 1.67, <iP</i values above 0.05). (3) Serum content of Ang Ⅱ of rabbits in AP group was significantly lower than that in pure scald group from PID 1 to 14 (with <it</i values from 3.38 to 32.58, <iP</i values below 0.01). Serum content of ET-1 of rabbits in AP group was significantly lower than that in pure scald group from PID 3 to 14 (with <it</i values from 3.54 to 11.02, <iP</i values below 0.01), while there was no obvious difference on PID 1 (<it</i=0.39, <iP</i&gt;0.05). Content of Ang Ⅱ and ET-1 in myocardial tissue of rabbits in AP group was significantly lower than that in pure scald group from PID 1 to 7 (with <it</i values from 1.27 to 13.79, <iP</i values below 0.01), while there was no obvious difference on PID 14 (with <it</i values respectively 0.07 and 0.81, <iP</i values above 0.05). (4) Serum content of SOD of rabbits in AP group was respectively (15.65±2.64), (14.67±0.74), and (8.43±0.56) ng/mL on PID 1, 3, and 7, which was significantly higher than (6.35±0.83), (2.62±0.75), and (2.84±0.41) ng/mL in pure scald group (with <it</i values from -29.79 to -9.10, <iP</i values below 0.01); while there was no obvious difference on PID 14 [with (4.02±0.26) ng/mL in pure scald group and (4.11±0.52) ng/mL in AP group, <it</i=-0.01, <iP</i&gt;0.05]. Serum content of MDA of rabbits in AP group was respectively (1.31±0.61), (1.72±0.64), and (0.65±0.42) μmol /mL on PID 1, 3, and 7, which was significantly lower than (1.68±0.57), (2.34±0.79), and (1.06±0.32) μmol/mL in pure scald group (with <it</i values from 1.63 to 3.16, <iP</i&lt;0.05 or <iP</i&lt;0.01), while there was no obvious difference on PID 14 [with (0.31±0.09) μmol/mL in pure scald group and (0.24±0.08) μmol/mL in AP group, <it</i=2.11, <iP</i&gt;0.05]. (5) Values of ηb1 and EAI of rabbits in AP group were significantly lower than those in pure scald group from PID 1 to 7 (with <it</i values from 2.718 to 11.170, <iP</i&lt;0.05 or <iP</i&lt;0.01), while there were no obvious differences on PID 14 (with <it</i values respectively 2.078 and -1.423, <iP</i values above 0.05). Values of ηb2 and ηr2 of rabbits in AP group were significantly lower than those in pure scald group on PID 3 and 7 (with <it</i values from 2.178 to 19.205, <iP</i&lt;0.05 or <iP</i&lt;0.01), while there were no obvious differences on PID 1 and 14 (with <it</i values from -0.730 to 1.320, <iP</i values above 0.05 ). Values of ηr1 and ESR of rabbits in AP group were significantly lower than those in pure scald group on PID 3, 7, and 14 (with <it</i values from 3.021 to 8.058, <iP</i values below 0.01), while there were no obvious differences on PID 1 (with <it</i values respectively 1.200 and 1.263, <iP</i values above 0.05 ). Value of ηp of rabbits in AP group was significantly lower than that in pure scald group on PID 1 (<it</i=2.430, <iP</i&lt;0.05), while there were no obvious differences on PID 3, 7, and 14 (with <it</i values from 0.002 to 1.446, <iP</i values above 0.05 ). Value of HCT of rabbits in AP group was close to that in pure scald group on PID 1 (<it</i=1.079, <iP</i&gt;0.05), and the values were significantly lower than those in pure scald group on PID 3 and 14 (with <it</i values respectively 3.849 and 4.208, <iP</i values below 0.01), while the value was significantly higher than that in pure scald group on PID 7 (<it</i=-4.925, <iP</i&lt;0.01). Value of TK of rabbits in AP group was lower than that in pure scald group on PID 7 (<it</i=2.847, <iP</i&lt;0.05), while there were no obvious differences on PID 1, 3, and 14 (with <it</i values from -1.102 to 0.875, <iP</i values above 0.05). <bConclusions:</b AP can alleviate the damage of myocardium of rabbits with severe scald by reducing the production of vasoactive substances Ang Ⅱ and ET-1, decreasing oxidative stress injury by increasing the content of SOD and decreasing the production of MDA, improving blood flow performance and microcirculation perfusion.

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Alcohol Denat. is the generic term used by the cosmetics industry to describe denatured alcohol. Alcohol Denat. and various specially denatured (SD) alcohols are used as cosmetic ingredients in a wide variety of products. Many denaturants have been previously considered, on an individual basis, as cosmetic ingredients by the Cosmetic Ingredient Review (CIR) Expert Panel, whereas others, including Brucine and Brucine Sulfate, Denatonium Benzoate, and Quassin, have not previously been evaluated. Quassin is a bitter alkaloid obtained from the wood of Quassia amara. Quassin has been used as an insect antifeedant and insecticide and several studies demonstrate its effectiveness. At oral doses up to 1000 mg/kg using rats, Quassin was not toxic in acute and short-term tests, but some reversible piloerection, decrease in motor activity, and a partial loss of righting reflex were found in mice at 500 mg/kg. At 1000 mg/kg given intraperitoneally (i.p.), all mice died within 24 h of receiving treatment. In a cytotoxicity test with brine shrimp, 1 mg/ml of Quassin did not possess any cytotoxic or antiplasmodial activity. Quassin administered to rat Leydig cells in vitro at concentrations of 5-25 ng/ml inhibited both the basal and luteinizing hormone (LH)-stimulated testosterone secretion in a dose-related fashion. Quassin at doses up to 2.0 g/kg in drinking water using rats produced no significant effect on the body weights, but the mean weights of the testes, seminal vesicles, and epididymides were significantly reduced, and the weights of the anterior pituitary glands were significantly increased. The sperm counts and levels of LH, follicle-stimulating hormone (FSH), and testosterone were significantly lower in groups treated with Quassin. Brucine is a derivative of 2-hydroxystrychnine. Swiss-Webster mice given Brucine base, 30 ml/kg, had an acute oral LD(50) of 150 mg/kg, with central nervous system depression followed by convulsions and seizures in some cases. In those animals that died, respiratory arrest was the cause. The acute i.p. LD(50) for 15 ml/kg of Brucine base was 62.0 mg/kg, with central nervous system depression prior to the onset of convulsions, just as with oral Brucine. The acute intravenous (i.v.) LD(50) was 12.0 mg/kg. Brucine was nonmutagenic in an Ames assay at levels up to 6666 mu g/plate, with and without metabolic activation. In a repeat-insult patch test, for a hair care product containing 47% SD Alcohol 40 (95%), it was reported that Brucine Sulfate may be considered a nonprimary irritant and a nonprimary sensitizer. Three different sunscreen products (35% SD Alcohol 40-B, 72.4% SD Alcohol 40, and 74.5% SD Alcohol 40) did not show any signs of photoallergy in human subjects. Also, these three formulas did not exhibit any evidence of phototoxicity in humans. Denatonium Benzoate is a bitter substance detectable at a concentration of 10 ppb, discernibly bitter at 50 ppb, and unpleasantly bitter at 10 ppm. The distribution of topically applied lidocaine, a topical anesthetic chemically related to Denatonium Benzoate demonstrated that virtually no lidocaine appears in the plasma, suggesting that the larger Denatonium Benzoate molecule also would have little or no systemic exposure. Denatonium Benzoate (0.1%) did not show adverse effects in 10 rats in an acute inhalation toxicity test and 0.005% to 0.05% was nonirritating to ocular mucosa in 6 albino rabbits. The acute oral LD(50) for the male rats was 640 mg/kg and for females, 584 mg/kg. The LD(50) for the male rabbits was 508 mg/kg and for the female rabbits, 640 mg/kg. In two chronic toxicity studies, Denatonium Benzoate was administered (by gavage) at 1.6, 8, and 16 mg/kg/day, one using cynomologus monkeys and the other rats, resulted in no compound-related toxicity. The toxicity of SD Alcohols has also been tested, with implications for the particular denaturant used. An irritation test of 55.65% SD Alcohol 40-B denatured with Denatonium Benzoate using rabbits produced minimal effects. A spray formula containing 12% SD Alcohol 40-B was found to be nonirritating when evaluated for vaginal mucosal irritation in New Zealand white rabbits. Cosmetic formulations containing SD Alcohol 40-B (denatured with Denatonium Benzoate) were not sensitizers in repeated insult patch tests. A gel formula containing 29% SD Alcohol 40-B and a spray liquid containing 12% SD Alcohol 40-B did not induce photoallergy, dermal sensitization, or phototoxic response in human subjects. Although the absorption of ethanol (aka Alcohol for purposes of cosmetic ingredient labeling) occurs through skin, ethanol does not appear to affect the integrity of the skin barrier nor reach a very high systemic concentration following dermal exposure. Ethanol may be found in the bloodstream as a result of inhalation exposure and ingestion. Topically applied, ethanol can act as a penetration enhancer. Most of the systemic toxicity of ethanol appears to be associated with chronic abuse of alcohol. Although ethanol is denatured to make it unfit for consumption, there have been reports of intentional and unintentional consumption of products containing denatured alcohol. Ethanol is a reproductive and developmental toxicant. Ethanol is genotoxic in some test systems and it has been proposed that the genotoxic effects of ethanol are mediated via its metabolite, acetaldehyde. A brief summary is provided of the effects of chronic ingestion of alcohol including intoxication, liver damage, brain damage, and possible carcinogenicity. The CIR Expert Panel recognizes that certain ingredients in this group are reportedly used in a given product category, but the concentration of use is not available. Because dermal application or inhalation of cosmetic products containing these ingredients will not produce significant systemic exposure to ethanol, the CIR Expert Panel concluded that safety of the ingredients should be predicated on the safety of the denaturants used. The Panel considered that the adverse effects known to be associated with Alcohol ingestion included in this safety assessment do not suggest a concern for Alcohol Denat. or SD Alcohols because of the presence of the denaturants, which are added for the express purpose of making the Alcohol unpotable. The CIR Expert Panel has previously conducted safety assessments of t-Butyl Alcohol, Diethyl Phthalate, Methyl Alcohol, Salicylic Acid, Sodium Salicylate, and Methyl Salicylate, in which each was affirmed safe or safe with qualifications. Given their use as denaturants are at low concentrations of use in Alcohol, the CIR Expert Panel determined that Alcohol Denat. denatured with t-Butyl Alcohol, Diethyl Phthalate, Methyl Alcohol, Salicylic Acid, Sodium Salicylate, and Methyl Salicylate is safe as used in cosmetic formulations with no qualifications. Likewise, because they are denatured with either t-Butyl Alcohol, Diethyl Phthalate, or Methyl Alcohol, SD Alcohols 3-A, 30, 39-B, 39-C, and 40-C all are considered safe as used. The Panel considered the available data for Denatonium Benzoate and SD Alcohol 40-B to be sufficient to support the safety of these ingredients in cosmetics. Denatonium Benzoate is sufficiently bitter that it is an effective denaturant at only 0.0006%. The Panel recognized that data on dermal penetration of Denatonium Benzoate were not available, but considered that the available data on lidocaine, a smaller structurally related chemical, indicates that dermal exposure does not result in measurable systemic exposure. The available data, however, were not sufficient to support the safety of Quassin, Brucine, and Brucine Sulfate, Alcohol Denat. denatured with those denaturants, or SD Alcohol 39 and SD Alcohol 40 (SD Alcohols denatured with Quassin, Brucine, and/or Brucine Sulfate), and in order for the Expert Panel to reach a conclusion for these denaturants, additional data are needed.

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Although the results we have recorded merely serve to indicate the possibilities of this interesting field of investigation, we have sufficient data to enable us to draw certain general conclusions. In the first place it is evident that the bloods of the more highly developed marine invertebrates, such as the active Crustacia and the Cephalopods, are specially adapted for the carriage of carbon dioxide. The quantity of carbon dioxide taken up by the blood of Maia, Palinurus, or Octopus at any given tension of the gas is, in general, about twice or three times as great as that which is taken up by sea water under the same conditions. On the other hand, the blood of a slow, creeping form, such as Aplysia, or of a sessile animal such as the ascidian Phallusia shows no more adaptation for the carriage of carbon dioxide than does sea water. But our estimations of the CO(2) content of the blood as it circulates in the bodies of these more active invertebrates show that the conditions of transport of this gas differ considerably in some respects from those which obtain in mammals. For the invertebrate blood in the body contains only a relatively small quantity of carbon dioxide, averaging in the forms we examined from 3 to 10 cc. per 100 cc. of blood. This forms a marked contrast with the condition found in mammals where even the arterial blood contains about 50 cc. of CO(2) per 100 cc. of blood. The invertebrate, therefore, works at a very low CO(2) tension. There is a twofold significance in this circumstance. In the first place, it means that only the first portion of the carbon dioxide dissociation curve is in use in the respiratory mechanism. Now an inspection of our curves will show that at these low carbon dioxide tensions the dissociation curves tend to be steeper than at higher tensions. As we intend to show in a later paper it can be proved mathematically that, other things being equal, a blood with a carbon dissociation curve of moderate steepness, i.e. one in which the carbon dioxide content of the blood increases fairly rapidly with increase of carbon dioxide tension, is a more efficient carrier of the gas from the tissues to a respiratory surface than a blood in which the dissociation curve is either steeper or flatter. It would seem as if the active invertebrates avoid the use of too flat a part of their CO(2) dissociation curves by working over the initial steeper portion. Furthermore, it is seen that over the range of this initial steep portion of the curves the changes of reaction produced by the uptake of carbon dioxide are much smaller than at higher tensions of the gas; for these initial portions of the curves are more nearly parallel to the lines of constant reaction calculated for a temperature of 15 degrees C. according to Hasselbalch's method (10) on the assumption that the whole of the combined CO(2) is in the form of sodium bicarbonate. It is evident also that on this assumption the hydrogen ion concentration of the blood of invertebrates (with the exception of the tunicates) would appear to be practically the same as that of the warm-blooded vertebrates-a conclusion confirmed by the direct measurements of Quagliariello (9). On the other hand, our measurements do not lend support to the idea put forward by Collip (4) that in order to maintain an appropriate faintly alkaline reaction an invertebrate needs to retain carbon dioxide in its blood at a comparatively high tension. This idea was based on the observation that at comparatively high CO(2) tensions the blood of invertebrates contains considerably more sodium bicarbonate than does sea water. But our curves show that this is no longer true at the lower values of carbon dioxide tension, the amount of sodium bicarbonate falling off more rapidly in the blood than in the sea water with diminution of the carbon dioxide tension so that in order to maintain an appropriate reaction in the blood only a comparatively small tension of CO(2) is required. The largest amount of carbon dioxide that we found present in the circulating blood of any of the types examined was 9.7 cc. per 100 cc. of blood in the case of Maia, and in most cases the amount was considerably less. But even this lowest value corresponds to a tension of CO(2) of only about 3 mm., so that the tension gradient across the gill membrane must be even less than this. We would emphasize rather the circumstances that as the portion of the dissociation curve over which the reaction is approximately constant is of but small extent, it is necessary that in an active form like Octopus the carbon dioxide produced should be removed rapidly lest an accumulation of it should cause the limits of normal reaction to be exceeded; and this need is correlated with the extreme efficiency of the respiratory apparatus in this animal. It is interesting to notice that the mammal which, in order to obtain an appropriate reaction in the blood, has to work at relatively high carbon dioxide tensions where the dissociation curve is comparatively flat, secures a steeper physiological CO(2) dissociation curve in the body, and with it a more efficient carriage of carbon dioxide and a more constant reaction in the circulating fluid, in virtue of the effect of oxygenation on the carbon dioxide-combining power of its blood (3, 6). Returning now to the consideration of the actual form of the dissociation curves we have obtained-it is a significant fact that it is in those forms such as Maia, Palinurus, and Octopus whose bloods are rich in proteins-particularly hemocyanine-that the initial steep portion of the curve is observed. This suggests that in these forms the blood proteins act as weak acids and expel carbon dioxide from the blood at the low tensions which include the physiological range, just as in vertebrates the hemoglobin similarly displaces carbonic acid from its combination with alkali metal. On the other hand the coelomic fluid of Aplysia contains no pigment and only 0.00672 per cent of protein nitrogen (Bottazzi (11)) and shows no initial rapidly ascending portion of the CO(2) dissociation curve. This is supported by the observation of Quagliariello (9) that the acid-neutralising power of the blood of an invertebrate is roughly proportional to its protein content. It seems as if the proteins of invertebrate blood like the blood proteins of vertebrates, exist in the form of sodium salts which are capable of giving up sodium for the transport of carbon dioxide as sodium bicarbonate. That this is so in the case of hemocyanine follows from the fact that the isoelectric point of this pigment occurs at a hydrogen ion concentration of 2.12 x 10(-5)N, i.e. at a pH of 4.67 (Quagliariello (12)) so that in the alkaline blood of the invertebrates possessing it, hemocyanine will act as a weak acid. It is probable that the initial steep portion of the carbon dioxide dissociation curves which we have found to be of such importance in the respiration physiology of Octopus, Palinurus, and Maia is produced by the competition of this acid with carbonic acid for the available sodium of the blood.

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Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long-term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder. CLASSIFICATION TABLES 1 AND 2 AND FIGURE 1: [Table: see text] [Table: see text] Figure 1 A scheme of the relationship between etiology (mechanism) and patho-physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as 'diabetes mellitus'. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare.imageThe classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic β-cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non-insulin- requiring, insulin-requiring for glycemic control, and insulin-dependent for survival. The two former conditions are called non-insulin-dependent diabetes and the latter is known as insulin-dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. DIAGNOSIS TABLES 3–7 AND FIGURE 2: [Table: see text] [Table: see text] [Table: see text] [Table: see text] [Table: see text] Figure 2 Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).imageCategories of the State of Glycemia:  Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≥126 mg/dL (≥7.0 mmol/L); (ii) 2-h value of ≥200 mg/dL (≥11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L). Normal type is defined as fasting plasma glucose level of &lt;110 mg/dL (&lt;6.1 mmol/L) and 2-h value of &lt;140 mg/dL (&lt;7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≥6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS). Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0-6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6-5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently. Clinical Diagnosis: 1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be 'diabetic type'. Re-examination is conducted on another day, and if 'diabetic type' is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re-examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose.2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination.• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)• The presence of definite diabetic retinopathy3 If it can be confirmed that the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results.4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re-examined after an appropriate interval.5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. Epidemiological Study:  For the purpose of estimating the frequency of diabetes mellitus, 'diabetes mellitus' can be substituted for the determination of 'diabetic type' from a single examination. In this case, HbA1c≥6.5% alone can be defined as 'diabetes mellitus'. Health Screening:  It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level. Gestational Diabetes Mellitus:  There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy: 1 Fasting plasma glucose level of ≥92 mg/dL (5.1 mmol/L)2 1-h value of ≥180 mg/dL (10.0 mmol/L)3 2-h value of ≥153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00074.x, 2010).

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<bObjective:</b To investigate the effect of human antigen R on lysosomal acidification during autophagy in mouse cardiomyocytes cultured in vitro. <bMethods:</b The hearts of 20 C57BL/6 mice aged 1-2 days no matter male or female were isolated to culture primary cardiomyocytes which were used in the following experiments. (1) The cells were divided into 5 groups according to the random number table (the same grouping method below), i. e., normal control group and sugar-free serum-free 0.5, 1.0, 3.0, and 6.0 h groups. The cells in normal control group were routinely cultured for 54.0 h with Dulbecco's modified Eagle medium/nutrient mixture F12 (DMEM/F12) medium (the same regular culture condition below), and the cells in sugar-free serum-free 0.5, 1.0, 3.0, and 6.0 h groups were firstly regularly cultured for 53.5, 53.0, 51.0, 48.0 h and then cultured with replaced sugar-free serum-free medium for 0.5, 1.0, 3.0, and 6.0 h, respectively. The protein expressions of microtubule-associated protein 1 light chain 3 Ⅱ (LC3Ⅱ), autophagy-related protein 5, and adenosine triphosphatase V1 region E1 subunit (ATP6V1E1) were detected by Western blotting. (2) The cells were divided into normal control group and sugar-free serum-free 3.0 h group. The cells in corresponding groups were treated the same as those in experiment (1), and the cell lysosomal acidification level was observed and detected under a laser scanning confocal microscope. (3) Two batches of cells were grouped and treated the same as those in experiment (1). The protein expression of human antigen R in the whole protein of cells of one batch and its protein expression in the cytoplasm and nucleus protein of cells of the other batch were detected by Western blotting. (4) The cells were divided into normal control group, simple control small interfering RNA (siRNA) group, simple human antigen R-siRNA1 (HuR-siRNA1) group, simple HuR-siRNA2 group, sugar-free serum-free 3.0 h group, sugar-free serum-free+ control siRNA group, sugar-free serum-free+ HuR-siRNA1 group, and sugar-free serum-free+ HuR-siRNA2 group. After 48 hours of regular culture, the cells in simple control siRNA group and sugar-free serum-free+ control siRNA group were transfected with negative control siRNA for 6 h, the cells in simple HuR-siRNA1 group and sugar-free serum-free+ HuR-siRNA1 group were transfected with HuR-siRNA1 for 6 h, and the cells in simple HuR-siRNA2 group and sugar-free serum-free+ HuR-siRNA2 group were transfected with HuR-siRNA2 for 6 h. Hereafter, the cells in these 8 groups were continuously cultured for 48 h with regular conditon, and then the cells in normal control group and each simple siRNA-treated group were replaced with DMEM/F12 medium, the cells in the other groups were replaced with sugar-free serum-free medium, and they were cultured for 3 h. The protein expression of human antigen R in the whole protein of cells was detected by Western blotting. (5) Two batches of cells were divided into sugar-free serum-free+ control siRNA group and sugar-free serum-free+ HuR-siRNA1 group, and the cells in corresponding groups were treated the same as those in experiment (4). The distribution and expression of human antigen R in the cells of one batch were observed and detected by immunofluorescence method, and the lysosomal acidification level in the cells of the other batch was observed and detected under a laser scanning confocal microscope. (6) Three batches of cells were divided into sugar-free serum-free 3.0 h group, sugar-free serum-free+ control siRNA group, sugar-free serum-free+ HuR-siRNA1 group, and sugar-free serum-free+ HuR-siRNA2 group, and the cells in corresponding groups were treated the same as those in experiment (4). The protein expressions of cathepsin D in the whole protein of cells of one batch, human antigen R in the cytoplasm protein of cells of one batch, and ATP6V1E1 in the whole protein of cells of the other batch were detected by Western blotting. (7) The cells were divided into normal control group, sugar-free serum-free 3.0 h group, sugar-free serum-free+ control siRNA group, and sugar-free serum-free+ HuR-siRNA1 group, and the cells in corresponding groups were treated the same as those in experiment (4). The mRNA expression of ATP6V1E1 in cells was detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction. The sample number of each experiment was 3. Data were processed with independent data <it</i test, one-way analysis of variance, least significant difference <it</i test, and Bonferroni correction. <bResults:</b (1) Compared with those of normal control group, the protein expressions of LC3Ⅱ and ATP6V1E1 in the whole protein of cells of sugar-free serum-free 1.0, 3.0, and 6.0 h groups were significantly increased (<it</i=12.16, 4.05, 4.82, 11.64, 3.29, 8.37, <iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with that of normal control group, the protein expression of autophagy-related protein 5 in the whole protein of cells of sugar-free serum-free 0.5, 1.0, 3.0, and 6.0 h groups was significantly increased (<it</i=6.88, 10.56, 5.76, 9.91, <iP</i&lt;0.05 or <iP</i&lt;0.01). (2) Compared with 1.03±0.08 of normal control group, the lysosomal acidification level in the cells of sugar-free serum-free 3.0 group (2.92±0.30) was significantly increased (<it</i=6.01, <iP</i&lt;0.01). (3) There was no statistically significant difference in the overall comparison of protein expression of human antigen R in the whole protein of cells among the 5 groups (<iF</i=1.09, <iP</i&gt;0.05). Compared with that of normal control group, the protein expression of human antigen R in the cytoplasm protein of cells was significantly increased in sugar-free serum-free 1.0, 3.0, and 6.0 h groups (<it</i=43.05, 11.07, 5.39, <iP</i&lt;0.05 or <iP</i&lt;0.01), while the protein expression of human antigen R in the nucleus protein of cells was significantly decreased in sugar-free serum-free 3.0 and 6.0 h groups (<it</i=11.18, 12.71, <iP</i&lt;0.01). (4) Compared with that of simple control siRNA group, the protein expression of human antigen R in the whole protein of cells of simple HuR-siRNA1 group and simple HuR-siRNA2 group was significantly decreased (<it</i=4.82, 4.44, <iP</i&lt;0.05). Compared with that of sugar-free serum-free+ control siRNA group, the protein expression of human antigen R in the whole protein of cells of sugar-free serum-free+ HuR-siRNA1 group and sugar-free serum-free+ HuR-siRNA2 group was significantly decreased (<it</i=4.39, 6.27, <iP</i&lt;0.05). (5) Compared with those of sugar-free serum-free+ control siRNA group, the distribution of human antigen R in the cytoplasm of cells and its expression level were significantly decreased in sugar-free serum-free+ HuR-siRNA1 group (<it</i=10.13, <iP</i&lt;0.01). Compared with 1.00±0.06 of sugar-free serum-free+ control siRNA group, the lysosomal acidification level (0.73±0.06) in the cells of sugar-free serum-free+ HuR-siRNA1 group was significantly decreased (<it</i=3.28, <iP</i&lt;0.01). (6) Compared with those of sugar-free serum-free+ control siRNA group, the protein expressions of cathepsin D in the whole protein of cells, human antigen R in the cytoplasm protein of cells, and ATP6V1E1 in the whole protein of cells were significantly decreased in sugar-free serum-free+ HuR-siRNA1 group and sugar-free serum-free+ HuR-siRNA2 group (<it</i=4.16, 3.99, 4.81, 5.07, 11.68, 12.97, <iP</i&lt;0.05 or <iP</i&lt;0.01). (7) Compared with that of normal control group, the mRNA expression of ATP6V1E1 in the cells of sugar-free serum-free 3.0 h group was significantly increased (<it</i=5.51, <iP</i&lt;0.05). Compared with that of sugar-free serum-free+ control siRNA group, the mRNA expression of ATP6V1E1 in the cells of sugar-free serum-free+ HuR-siRNA1 group was significantly decreased (<it</i=5.97, <iP</i&lt;0.05). <bConclusions:</b After sugar-free serum-free treatment in vitro, the autophagy in mouse primary cardiomyocytes is activated, the lysosomal acidification is enhanced, and the expression of human antigen R in cytoplasm is increased. Human antigen R function is activated and involved in maintaining lysosomal acidification during autophagy in mouse cardiomyocytes.

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Role of basal ganglia: Vesalius and Piccolomini distinguished subcortical nuclei from cortex and white matter in the 16th century. Willis' mistaken concept in the late 17th century that the corpus striatum was the seat of motor power persisted for 200 years and formed the basis of mid-19th-century localizations of movement disorders to the striatum (chorea by Broadbent and Jackson, and athetosis by Hammond). By the late 19th century, many movement disorders were described but for most no pathologic correlate was known. Tremor: Descriptions of tremors progressed from Galen's definition in the 2nd century; to Galileo's physiologic tremor in 1610; separation of involuntary movements during action and at rest in the 17th and 18th centuries by de la Boë Sylvius and van Sweiten; description of Parkinson's disease by Parkinson, discrimination of the rest tremor of Parkinson's disease from the intention tremor of multiple sclerosis by Charcot, and recognition of familial action tremors by Dana and others in the late 19th century; and recognition of autosomal dominant essential tremor in the mid-20th century. Parkinsonism: Pathologic changes in Parkinson's disease were recognized in the substantia nigra by Blocq and Marinescu in the late 19th century, and around 1920 Trértiakoff established Lewy bodies in the substantia nigra as a pathologic hallmark while the Vogts instead emphasized pathologic changes in the striatum; it was only in the mid-1960s that a nigrostriatal dopaminergic pathway was demonstrated and found to be critical to pathogenesis. Early treatment approaches with anticholinergic medications or crude neurosurgical ablation procedures were eclipsed in the 1960s by the advent of L-DOPA therapy due to the work of Carlsson and colleagues, Birkmayer and Hornykiewicz, Barbeau, and Cotzias. Later progress in understanding and treating Parkinson's disease included recognition of neuroleptic-induced parkinsonism beginning in the 1950s, development of dopamine agonists and elaboration of different dopamine receptors beginning in the 1960s, recognition of MPTP-induced parkinsonism in 1982 and subsequent development of experimental models of MPTP-induced parkinsonism. Since the 1980s, stereotactic neurosurgical ablation procedures such as stereotactic pallidotomy were revisited and improved, and stimulation or ablation procedures that modulate subthalamic nucleus activity were developed. Since 1990, rare genetic forms of Parkinson's disease were discovered, which accelerated progress in understanding pathogenesis, and established roles for alpha synuclein and the ubiquitin-proteasome proteolytic system. Separation of atypical forms of parkinsonism (e.g. Wilson's disease, multisystem atrophy, progressive supranuclear palsy, and corticobasal degeneration) from Parkinson's disease in the 20th century also led to important discoveries of basal ganglia function, and in the case of Wilson's disease to recognition of genetic mutations and effective treatments. Choreoathetosis: Since the middle ages, the term chorea has been used to describe both organic and psychological disorders of motor control. Paracelcus introduced the concept of chorea as an organic medical condition in the 16th century. Sydenham's description of childhood chorea (1686) was followed by recognition in the 19th and 20th centuries that Sydenham's chorea was a manifestation of rheumatic fever; by the 1930s, rheumatic fever was recognized as a sequel of group A streptococcal pharyngitis, which could be effectively prevented with sulfonamides. Athetosis was described by Hammond (1871) and later linked by him to a malignant growth in the contralateral corpus striatum; nevertheless, athetosis has been controversial and often dismissed as a form of post-hemiplegic chorea or part of a continuum between chorea and dystonia. Huntington's classic description of adult-onset hereditary chorea (1872) was followed a century later by demonstration that Huntington's disease is caused by an unstable CAG trinucleotide repeat expansion in the Huntington disease gene on chromosome 4; this triggered a surge in research, development of various animal models, and numerous important discoveries of cell function and disease pathogenesis. Hemiballismus and the subthalamic nucleus: The relationship between a lesion of the subthalamic nucleus of Luys and contralateral hemiballismus was first convincingly demonstrated by Martin in 1927; this led 20 years later to development of an animal model by Whittier and Mettler, who produced experimental hemichorea-hemiballismus in monkeys by lesioning the contralateral subthalamic nucleus. Since the late 1980s, the neurochemistry and neurophysiology of the subthalamic nucleus have been substantially revised with the demonstration that the subthalamic nucleus is not fundamentally inhibitory but instead provides excitatory glutaminergic inputs to the globus pallidus, and appreciation that the subthalamic nucleus serves an important role in both hyperkinetic and hypokinetic movement disorders. Dystonia: Dystonias were often interpreted in psychological or psychiatric terms since the original descriptions of generalized dystonia by Barraquer Roviralta (1897), and familial forms of generalized primary tortion dystonia by Schwalbe (1908) and Oppenheim (1911). Although Oppenheim had first insisted that dystonia was an organic disease, it was only in the late-20th century that an organic framework was firmly established with the identification of genetic mutations in some families with dystonia and with the demonstration that the basal ganglia were often damaged contralateral to acquired hemidystonia. Focal and segmental forms of dystonia, including writer's cramp, other occupational dystonias, and torticollis, were also recognized in the 19th century. Writer's cramp was clearly described in the 1830s by Bell and Kopp, and increasingly recognized in the late 19th century due in part to Solly's influential lectures on "scriviner's palsy" in the 1860s, and to increasing prevalence because of the increase in writing using primitive writing instruments. Myoclonus: In 1903, Lundborg proposed a classification of myoclonus that remains in use, with primary (essential), epileptic, and secondary or symptomatic categories: essential myoclonus was described by Friedrich in 1881; forms of myoclonic epilepsy were described beginning in the late 19th century by West (1861), Unverricht (1891), and Lundberg (1903); and secondary multifocal myoclonus was recognized in a wide variety of disorders beginning in the 1920s. Asterixis was described in patients with hepatic encephalopathy by Adams and Foley in 1949 and found to result from electrically silent pauses in muscle activity, which led to the concept of negative myoclonus in the 1980s. Posthypoxic action myoclonus (Lance-Adams syndrome) was described by Lance and Adams in 1963 and found to incorporate both positive and negative components. Startle syndromes: Early descriptions of pathologic startle syndromes included Beard's description of the jumping Frenchmen of Maine (1878) and Hammond's description of miryachit (1884), both of which may have had psychological origins. In contrast, hyperekplexia or "startle disease" was described in the late 1950s and early 1960s, and genetic forms were later found to result from various mutations affecting glycinergic synapses. Tics: Tic disorders were described by Itard (1825) and Trousseau (1873), but only gained wider recognition in the late 19th century after Charcot presented cases before his classroom audiences and after Gilles de la Tourette's classic description in 1885. Gilles de la Tourette and Charcot initially considered tic disorders and startle syndromes to be similar if not identical, but these disorders were later recognized as distinct. Psychodynamic and psychological theories or etiology gave way in the 1960s to biological theories supporting an important role for dopamine in pathogenesis, particularly with the discovery that neuroleptic medications could be useful in treatment. In the last two centuries, neuroscientists and clinicians contributed greatly to our understanding of basal ganglia anatomy and physiology, as well as to movement disorder semiology, pathophysiology, treatment, and prevention. The development of animal models, and the increasing use of genetic and molecular biological techniques will lead to further advances in the coming years.

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The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is even too short (see postprandial glycaemic excursions with test meals in the publication by Rosenstock et al. in The Lancet (1)). In the end a number of aspects are of relevance for the success of a given product; one key aspect is clearly the price. However, for patients also practical aspects (handling, need for regular pulmonary function test etc.) are of importance. We shall have to see how creatively MannKind will handle all such questions. Until now Al Mann and his colleagues were able to manage a number of challenges during the clinical development process successfully, so one can have hopes for the market success of TI. However, it is clear that at the same time, if TI fails like Exubera did before, this will be the end for pulmonary insulin in general. Not too many original publications presenting data from clinical trials were published in the last year when it comes to oral insulin (OI), nasal insulin or transdermal insulin developments; simply none with transdermal insulin. Also at the last international congresses not many studies about ARIA were presented. At least in part this might be still a reflection of the shockwaves that the failure of Exubera has sent out to pharmaceutical companies and venture capitalists; they are quite reluctant to invest in any of these developments. However, a considerable number of reviews (in some cases more than original papers!) were published about ARIA. These reviews are listed for completeness, but in most cases are not further commented. OI is still the area of research most companies are active in; however, in some cases it is not clear how active they really are (e.g. Diabetology). Nevertheless, at least some companies are quite active and progressed in their clinical development programme close to market approval, e.g. the large Indian company Biocon is in late phase 3 with IN-105 and the small Israel-based company Oramed is in phase 2b. It appears that other interesting OI developments (e.g. Diasome) were not very active in the last year; at least they have not published new study results. It is clear that for companies that produce insulin themselves (e.g. Biocon) the costs of the good are not of such relevance as for companies that have to buy it commercially. For the latter ones a low bioavailability/biopotency compared with SC insulin administration can be a real hurdle when it comes to the price of their product. Despite some publications about nasal insulin, the overall activity with this route of insulin administration appears to be low; the same holds true for transdermal insulin. Insulin pens have gained more scientific interest in recent years, which is also reflected by an increase in publications, starting from practically nil 10 years ago to a solid number of five to 10 papers per year nowadays. Besides ARIA there are also attempts to increase the speed of insulin absorption after injection into the skin by applying it not into the SC tissue but intradermally or by heating up the skin above the SC insulin depot. Reading a number of papers that were not included in this chapter because they do not present any clinical data but are novel developments tested only in animal experiments so far, the clear message is that there is definitely not a lack of creativity/imagination amongst scientists; each year a plethora of new ideas for insulin application show up. Unfortunately not too many make it towards a full clinical development. As long as there is not a single successful product on the market that is based on a given ARIA approach, this area of research will not mature. For many patients, avoiding the need for SC injections is attractive; however, as long as no clear 'advantage' can be demonstrated, reimbursement will be difficult to achieve. Living in the time of evidence-based medicine it is clear that 'relevant' clinical advantages must be proven. The question is what is relevant. Is it just an improvement in metabolic control (= decrease in HbA1c)? Can this also mean that more patients are willing to start insulin therapy earlier than with conventional SC insulin therapy? With TI we have a product that has improved pharmacological properties (also in comparison to Exubera) for coverage of prandial insulin requirements. Subsequently, in the clinical trials performed, postprandial glycaemic excursions were lower than with SC injection of RHI or rapid-acting insulin analogues. This only in part (if at all) results in an improved metabolic control in general (= lower HbA1c) (see below). The outlook for 2011 is that there are chances that we shall have an inhaled insulin product on the market. Probably also the first OI will be submitted to the regulatory authorities for market approval or will even be available in less regulated markets. In order to select all relevant publications about new ways of insulin delivery I performed a PUBMED search and also checked the table of contents of a number of journals that publish heavily in this area of research as well references in the publications I found for additional references. Selection of the manuscripts from all publications was predominately based on the fact whether they presented data from clinical studies or not. The selected studies were critically reviewed for novelty and appropriate study design etc. In some cases also reviews about a given topic were selected if they provide relevant novel insights.

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In early August 2007, the Medical Advisory Secretariat began work on the Aging in the Community project, an evidence-based review of the literature surrounding healthy aging in the community. The Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the ministry's newly released Aging at Home Strategy.After a broad literature review and consultation with experts, the secretariat identified 4 key areas that strongly predict an elderly person's transition from independent community living to a long-term care home. Evidence-based analyses have been prepared for each of these 4 areas: falls and fall-related injuries, urinary incontinence, dementia, and social isolation. For the first area, falls and fall-related injuries, an economic model is described in a separate report.Please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html, to review these titles within the Aging in the Community series.AGING IN THE COMMUNITY: Summary of Evidence-Based AnalysesPrevention of Falls and Fall-Related Injuries in Community-Dwelling Seniors: An Evidence-Based AnalysisBehavioural Interventions for Urinary Incontinence in Community-Dwelling Seniors: An Evidence-Based AnalysisCaregiver- and Patient-Directed Interventions for Dementia: An Evidence-Based AnalysisSocial Isolation in Community-Dwelling Seniors: An Evidence-Based AnalysisThe Falls/Fractures Economic Model in Ontario Residents Aged 65 Years and Over (FEMOR) OBJECTIVE: To identify interventions that may be effective in reducing the probability of an elderly person's falling and/or sustaining a fall-related injury. Although estimates of fall rates vary widely based on the location, age, and living arrangements of the elderly population, it is estimated that each year approximately 30% of community-dwelling individuals aged 65 and older, and 50% of those aged 85 and older will fall. Of those individuals who fall, 12% to 42% will have a fall-related injury. Several meta-analyses and cohort studies have identified falls and fall-related injuries as a strong predictor of admission to a long-term care (LTC) home. It has been shown that the risk of LTC home admission is over 5 times higher in seniors who experienced 2 or more falls without injury, and over 10 times higher in seniors who experienced a fall causing serious injury. Falls result from the interaction of a variety of risk factors that can be both intrinsic and extrinsic. Intrinsic factors are those that pertain to the physical, demographic, and health status of the individual, while extrinsic factors relate to the physical and socio-economic environment. Intrinsic risk factors can be further grouped into psychosocial/demographic risks, medical risks, risks associated with activity level and dependence, and medication risks. Commonly described extrinsic risks are tripping hazards, balance and slip hazards, and vision hazards. NOTE: It is recognized that the terms "senior" and "elderly" carry a range of meanings for different audiences; this report generally uses the former, but the terms are treated here as essentially interchangeable. EVIDENCE-BASED ANALYSIS OF EFFECTIVENESS: Since many risk factors for falls are modifiable, what interventions (devices, systems, programs) exist that reduce the risk of falls and/or fall-related injuries for community-dwelling seniors? English language;published between January 2000 and September 2007;population of community-dwelling seniors (majority aged 65+); andrandomized controlled trials (RCTs), quasi-experimental trials, systematic reviews, or meta-analyses. special populations (e.g., stroke or osteoporosis; however, studies restricted only to women were included);studies only reporting surrogate outcomes; orstudies whose outcome cannot be extracted for meta-analysis. number of fallers, andnumber of falls resulting in injury/fracture. A search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing &amp; Allied Health Literature (CINAHL), The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 2000 and September 2007. Furthermore, all studies included in a 2003 Cochrane review were considered for inclusion in this analysis. Abstracts were reviewed by a single author, and studies meeting the inclusion criteria outlined above were obtained. Studies were grouped based on intervention type, and data on population characteristics, fall outcomes, and study design were extracted. Reference lists were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology. The following 11 interventions were identified in the literature search: exercise programs, vision assessment and referral, cataract surgery, environmental modifications, vitamin D supplementation, vitamin D plus calcium supplementation, hormone replacement therapy (HRT), medication withdrawal, gait-stabilizing devices, hip protectors, and multifactorial interventions. Exercise programs were stratified into targeted programs where the exercise routine was tailored to the individuals' needs, and untargeted programs that were identical among subjects. Furthermore, analyses were stratified by exercise program duration (&lt;6 months and ≥6 months) and fall risk of study participants. Similarly, the analyses on the environmental modification studies were stratified by risk. Low-risk study participants had had no fall in the year prior to study entry, while high-risk participants had had at least one fall in the previous year. A total of 17 studies investigating multifactorial interventions were identified in the literature search. Of these studies, 10 reported results for a high-risk population with previous falls, while 6 reported results for study participants representative of the general population. One study provided stratified results by fall risk, and therefore results from this study were included in each stratified analysis. Executive Summary Table 1:Summary of Meta-Analyses of Studies Investigating the Effectiveness of Interventions on the Risk of Falls in Community-Dwelling Seniors(*)InterventionRR [95% CI]GRADEExercise programs  1. Targeted programs        General population0.81 [0.67-0.98]Low      High-risk population0.93 [0.82-1.06]High      Short duration0.91 [0.73-1.13]High      Long duration0.89 [0.79-1.01]Moderate  2. Untargeted programs        General population0.78 [0.66-0.91]Moderate      High-risk population0.89 [0.72-1.10]Very low      Short duration0.85 [0.71-1.01]Low      Long duration0.76 [0.64-0.91]Moderate  3. Combined targeted vs. untargeted programs        General populationN/AN/A      High-risk population0.87 [0.57-1.34]Moderate      Short duration1.11 [0.73-1.70]High      Long duration0.73 [0.57-0.95]HighVision intervention      Assessment/referral1.12 [0.82-1.53]Moderate      Cataract surgery1.11 [0.92-1.35]ModerateEnvironmental modifications      Low-risk population1.03 [0.75-1.41]High      High-risk population0.66 [0.54-0.81]High      General population0.85 [0.75-0.97]HighDrugs/Nutritional supplements      Vitamin D (men and women)0.94 [0.77-1.14]High      Vitamin D (women only)0.55 [0.29-1.08]Moderate      Vitamin D and calcium (men and women)0.89 [0.74-1.07]Moderate      Vitamin D and calcium (women only)0.83 [0.73-0.95]Moderate      Hormone replacement therapy0.98 [0.80-1.20]Low      Medication withdrawal0.34 [0.16-0.74]†LowGait-stabilizing device0.43 [0.29-0.64]ModerateMultifactorial intervention      Geriatric screening (general population)0.87 [0.69-1.10]Very low      High-risk population0.86 [0.75-0.98]Low*CI refers to confidence interval; RR, relative risk.†Hazard ratio is reported, because RR was not available.Executive Summary Table 2:Summary of Meta-Analyses of Studies Investigating the Effectiveness of Interventions on the Risk of Fall-Related Injuries in Community-Dwelling Seniors*InterventionRR [95% CI]GRADEExercise programs      Targeted programs0.67 [0.51-0.89]Moderate    Untargeted programs0.57 [0.38-0.86]Low    Combined targeted vs untargeted programs0.31 [0.13-0.74]HighDrugs/nutritional supplements      Vitamin D plus calcium (women only)0.77 [0.49-1.21]ModerateGait-stabilizing device0.10 [0.01-0.74]ModerateHip protectors3.49 [0.68-17.97]†LowMultifactorial intervention      Geriatric screening (general population)0.90 [0.53-1.51]Low    High-risk population0.86 [0.66-1.11]Moderate*CI refers to confidence interval; RR, relative risk.†Odds ratio is reported, because RR was not available. High-quality evidence indicates that long-term exercise programs in mobile seniors and environmental modifications in the homes of frail elderly persons will effectively reduce falls and possibly fall-related injuries in Ontario's elderly population.A combination of vitamin D and calcium supplementation in elderly women will help reduce the risk of falls by more than 40%.The use of outdoor gait-stabilizing devices for mobile seniors during the winter in Ontario may reduce falls and fall-related injuries; however, evidence is limited and more research is required in this area.While psychotropic medication withdrawal may be an effective method for reducing falls, evidence is limited and long-term compliance has been demonstrated to be difficult to achieve.Multifactorial interventions in high-risk populations may be effective; however, the effect is only marginally significant, and the quality of evidence is low.

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de Vos RJ, van Veldhoven PLJ, Moen MH, Weir A, Tol JL. Autologous growth factor injections in chronic tendinopathy: a systematic review. Br Med Bull. 2010;95:63-77. The authors of this systematic review evaluated the literature to critically consider the effects of growth factors delivered through autologous whole-blood and platelet-rich-plasma (PRP) injections in managing wrist-flexor and -extensor tendinopathies, plantar fasciopathy, and patellar tendinopathy. The primary question was, according to the published literature, is there sufficient evidence to support the use of growth factors delivered through autologous whole-blood and PRP injections for chronic tendinopathy? The authors performed a comprehensive, systematic literature search in October 2009 using PubMed, MEDLINE, EMBASE, CINAHL, and the Cochrane library without time limits. The following key words were used in different combinations: tendinopathy, tendinosis, tendinitis, tendons, tennis elbow, plantar fasciitis, platelet rich plasma, platelet transfusion, and autologous blood or injection. The search was limited to human studies in English. All bibliographies from the initial literature search were also viewed to identify additional relevant studies. Studies were eligible based on the following criteria: (1) Articles were suitable (inclusion criteria) if the participants had been clinically diagnosed as having chronic tendinopathy; (2) the design had to be a prospective clinical study, randomized controlled trial, nonrandomized clinical trial, or prospective case series; (3) a well-described intervention in the form of a growth factor injection with either PRP or autologous whole blood was used; and (4) the outcome was reported in terms of pain or function (or both). All titles and abstracts were assessed by 2 researchers, and all relevant articles were obtained. Two researchers independently read the full text of each article to determine if it met the inclusion criteria. If opinions differed on suitability, a third reviewer was consulted to reach consensus. The data extracted included number of participants, study design, inclusion criteria, intervention, control group, primary outcome measures (pain using a visual analog or ordinal scale or function), time of follow-up, and outcomes for intervention and control group (percentage improvement) using a standardized data-extraction form. Function was evaluated in 9 of the 11 studies using (1) the Nirschl scale (elbow function) or the modified Mayo score for wrist flexors and extensors, (2) the Victorian Institute of Sports Assessment-Patella score, a validated outcome measure for patellar tendinopathy, or the Tegner score for patellar tendinopathy, and (3) the rearfoot score from the American Orthopaedic Foot and Ankle Scale for plantar fasciopathy. The Physiotherapy Evidence Database (PEDro) scale contains 11 items; items 2-11 receive 1 point each for a yes response. Reliability is sufficient (0.68) for the PEDro scale to be used to assess physiotherapy trials. A score of 6 or higher on the PEDro scale is considered a high-quality study; below 6 is considered a low-quality study. The PEDro score results determined the quality of the randomized controlled trial (RCT), nonrandomized clinical trial, or prospective case series (≥6 or &lt;6). A qualitative analysis was used with 5 levels of evidence (strong, moderate, limited, conflicting, or no evidence) to determine recommendations for the use of the intervention. The number of high-quality or low-quality RCT or nonrandomized clinical trial studies with consistent or inconsistent results determined the level of evidence (1-5). Using the specific search criteria, the authors identified 418 potential sources. After screening of the title or abstract (or both), they excluded 405 sources, which left 13 studies. After viewing the full text, they excluded 2 additional sources (a case report and a study in which the outcome measure was remission of symptoms and not pain or function), leaving 11 studies for analysis. Six of the 11 studies were characterized by an observational, noncontrolled design; the remaining 5 studies were controlled clinical trials, 2 of which had proper randomization. The mean number of participants included in the studies was 40.5 (range = 20 to 100). Three of the studies were on "tennis elbow," 1 on "golfer's elbow," 1 on wrist extensor or flexor tendinopathy, 3 on plantar fasciopathy, and 3 on chronic patellar tendinopathy. Based on the information reported, there was no standardization of frequency or method of growth factor injection treatment or of preparation of the volume, and an optimal mixture was not described. Autologous whole-blood injections were used in 8 studies; in 5 studies, the autologous whole-blood injection was combined with a local anesthetic. In contrast, a local anesthetic was used in only 1 of the 3 PRP injection studies. The authors of the other 2 studies did not report whether a local anesthetic was used. The number of autologous whole-blood and PRP injections varied, ranging from 1 to 3. The centrifuging process was single or double for the PRP injections. In 2 studies, calcium was added to activate the platelets. A visual analogue or ordinal pain scale was used in 10 of the 11 studies. Function was evaluated in 9 of the 11 studies using (1) the Nirschl scale in 4 elbow studies or the modified Mayo score at baseline in 1 elbow study, (2) the Victorian Institute of Sports Assessment-Patella score for 1 study and the Tegner score for 2 of the patellar tendinopathy studies, and (3) the rearfoot score of the American Orthopaedic Foot and Ankle Scale for 1 plantar fasciopathy study. Only 1 study used an appropriate, disease-specific, validated tendinopathy measure (Victorian Institute of Sports Assessment-Patella). All intervention groups reported a significant improvement in pain or function score (or both), with a mean improvement of 66% over a mean follow-up of 9.4 months. The control groups in these studies also showed a mean improvement of 57%. None of the pain benefits among the intervention groups were greater than those for the control group at final follow-up. In 4 of the studies, the control group and the autologous growth factor injection group had similar results in pain or function or both, whereas in 2 studies, the control group had greater relief in pain than the injection group. Eleven studies were assessed using the PEDro scale. The PEDro scores for these studies ranged from 1 to 7, with an average score of 3.4. Only 3 studies had PEDro scores of ≥6 and were considered high quality. The 3 high-quality plantar fasciopathy studies used autologous growth factor injections but did not show a significant improvement over the control group. One of the studies that showed no beneficial effect for the autologous growth factor injections was compared with corticosteroids. Compared with other treatments, level 1 (strong) evidence demonstrated that autologous growth factor injections did not improve pain or function in plantar fasciopathy. The PRP injection results were based on 3 low-quality studies, 2 for the patellar tendon and 1 for the wrist flexors-extensors; level 3 (limited) evidence suggests that PRP injections improve pain or function. Strong evidence indicates that autologous growth factor injections do not improve plantar fasciopathy pain or function when combined with anesthetic agents or when compared with corticosteroid injections, dry needling, or exercise therapy treatments. Furthermore, limited evidence suggests that PRP injections are beneficial. Except for 2 high-quality RCT studies, the rest were methodologically flawed. Additional studies should be conducted using proper control groups, randomization, blinding, and validated disability outcome measures for pain and function. Until then, the results remain speculative because autologous whole-blood and PRP injection treatments are not standardized.

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The objective of this quantitative systematic review is to determine the effects of ondansetron as an adjunct to lidocaine on the tourniquet pain and postoperative pain of American Society of Anesthesiologists (ASA) class 1 or 2 adult patients undergoing elective hand surgery with intravenous regional anesthesia. Both injury and deformity of the upper extremity can result in dysfunction to nerves, tendons and bones which can lead to disability and pain. Hand injuries and deformities encompass an area of upper extremity surgery, wherein isolation and accessibility to peripheral nerves allows for a wide range of anesthesia techniques. Common hand surgeries include carpal tunnel or trigger finger release, Dupuytren's contracture fasciectomy, tendon repair, and ganglion cyst removal. According to the extent of injury or deformity, a general anesthetic, regional anesthetic, monitored anesthetic care (MAC) or local anesthetic may be used for these hand surgeries. Depending on the injury or deformity, local anesthesia may not provide sufficient anesthesia, but a general anesthesia may not be completely warranted either. Typical elective hand surgeries performed under regional anesthesia and MAC may be the ideal anesthetic plan that balances adequate sedation and analgesia. Intravenous regional anesthesia (IVRA), commonly known as a bier block, is a safe and effective anesthetic and is typically utilized in uncomplicated hand or forearm surgeries lasting less than an hour. Intravenous regional anesthesia was first developed by August Bier in 1908 for anesthesia of the hand and forearm. It is a regional anesthetic technique that is easy to perform, with success rates up to 98%. Intravenous regional anesthesia is a simple, reliable and cost-effective anesthesia technique for short ambulatory hand surgery. The IVRA technique is ideal for American Society of Anesthesiologists (ASA) class 1 or 2 patients, which according to ASA classification, are individuals who are healthy with well controlled to no comorbidities.The IVRA technique consists of inserting an intravenous catheter into a peripheral vein of the affected extremity. A double pneumatic tourniquet is applied to the same arm. The extremity is lifted and exsanguinated from distal to proximal with an Esmarch bandage. The proximal cuff of the tourniquet is then inflated to the appropriate pressure; standard 250mmHg for an upper extremity followed by the distal cuff. Insufflation times are limited to a maximum of one and a half to two hours, whereas the total insufflation time should never be less than 20 minutes. The Esmarch bandage is removed, and the local anesthetic is injected via the intravenous catheter to promote anesthesia in the operative area. In addition to the advantages of IVRA, there are disadvantages as well. These disadvantages include, but are not limited to, local anesthetic (LA) toxicity, delayed onset of action, poor muscle relaxation, tourniquet pain, and minimal postoperative analgesia. A method for improving analgesia and IVRA is to add medications to the IVRA solution. The ideal IVRA should include rapid onset of sensory and motor block, reduced LA dose, reduced intraoperative and tourniquet pain, prolonged postoperative analgesia, and minimal side effects.Adjuncts to LA can help offset some of the disadvantages mentioned above. In a systematic review of adjuncts for intravenous regional anesthesia conducted by Choyce and Peng, 29 studies were systematically reviewed to include various adjuncts to LA in IVRA. Adjuncts studied in this review included opioids, tramadol, non-steroidal anti-inflammatory drugs (NSAIDs), clonidine, muscle relaxants, sodium bicarbonate and potassium. The results of this systematic review suggest that NSAIDs have the most potential to offer as adjuncts to IVRA, while opioid adjuncts to IVRA proved to be disappointing as a form of postoperative analgesia. The search for the optimal IVRA adjunct that improves analgesia but has limited side effects is ongoing. More recent studies on adjuncts to IVRA have included medications such as neostigmine, dexmetomidine, nitroglycerin, and ondansetron.Ondansetron is a specific 5-hydroxytryptamine-3 (5-HT3 or serotonin) antagonist, commonly used as an antiemetic drug for prevention or treatment of postoperative nausea and vomiting. Used in the recommended dose range, there are minimal reported side effects, with constipation, dizziness and headache being the most common. 5-HT3 antagonists such as ondansetron possess anti-inflammatory, anesthetic, and analgesic properties which may have a potential role in decreasing pain. 5-HT3 antagonists participate in the pathway of nociception by interfering with peripheral effects of serotonin on nociception. By binding to opioid mu receptors and acting as a potential opioid agonist, the result is a peripheral nociceptive analgesic effect. A study by Deegan shows that there are 5-HT3 receptors on the central spinal terminal, which suggests that ondansetron could have both peripheral and central nociceptive effects. Ambesh et al. found that pain during injection of propofol can be successfully prevented by the administration of 4 mg of ondansetron. In a study performed by Reddy et al., it was shown that 4 mg of ondansetron could significantly reduce pain during the intravenous (IV) injection of rocuronium and propofol.Ondansetron may be useful for its potential anti-in-ammatory effect as an adjunct to medication to reduce acute inflammation. Ondansetron can block sodium channels similar to local anesthetics and produce a local anesthetic effect. It has been shown to be approximately fifteen times more potent than lidocaine. A study by Farouk suggests the addition of ondansetron to lidocaine may improve the quality of IVRA and prolong postoperative analgesia in patients undergoing hand surgery. A study conducted by Honarmand, concluded that the addition of ondansetron to lidocaine for IVRA reduced intraoperative and postoperative analgesic use.Tourniquet pain, which is described as a dull and aching pain sensation, is caused by the nerve compression from the tourniquet. Neuropathic pain produced by nerve compression plays an important role in the etiology of this discomfort. Tourniquet pain is thought to be mediated by impulse propagation via small, unmyelinated, slow-conducting C fibers. The duration of the tourniquet time is directly proportional to the onset of tourniquet pain. In a study by Asik, onset of tourniquet pain ranged from eight to fifteen minutes. Tourniquet pain is a well-known limitation of IVRA and is a factor that can limit the number of times which IVRA can be used for extremity surgery. Lidocaine is one of the most frequently used LAs for IVRA. It has a relatively brief duration of action which may limit the postoperative analgesia. Duration of postoperative analgesia, measured as time to first analgesic requirement ranged from 34 to 45 minutes (median) with LA alone.Outcome measures will include pain assessment for intraoperative tourniquet pain and postoperative pain measured by first analgesic requirement time (the time elapsed after tourniquet release to the first request by the patient for analgesic). Pain will be assessed with a visual analog scale (VAS) (0 = no pain and 10 = worst pain imaginable). A VAS score of more than three would indicate pain threshold has been exceeded.A preliminary search of the Joanna Briggs Database of Systematic Reviews and Implementation Reports, the Cochrane Library, CINAHL, PubMed and PROSPERO has revealed that there are currently no systematic reviews (either published or underway) on the topic of ondansetron as an adjunct to lidocaine intravenous regional anesthesia. Search terms included Zofran, ondansetron, intravenous regional anesthesia, and IVRA. Outcomes of this review will determine if ondansetron, admixed with lidocaine, has an effect on tourniquet pain, and secondly to determine if ondansetron, admixed with lidocaine, has an effect on the duration of postoperative analgesia.

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<bObjective:</b To investigate the effects of basic fibroblast growth factor (bFGF) on healing of <iMycobacterium tuberculosis</i infective wound in New Zealand rabbit after debridement. <bMethods:</b Thirty-two New Zealand rabbits (3 to 4 months old, no matter male or female) were intradermally injected with 0.1 mL of complete Freund's adjuvant on the buttocks. Six weeks later, each rabbit was injected with 0.5 mL 5×10(7) colony forming unit/mL <iBacillus Calmette</i-<iGuerin</i on both sides of the back to reproduce the model of <iMycobacterium tuberculosis</i infective wound in New Zealand rabbit. After successful modeling, the 32 rabbits were divided into growth factor (GF) group, antituberculosis drug (AD) group, combined treatment (CT) group, and blank control (BC) group according to the random number table, with 8 rabbits in each group. After a complete debridement, the wounds of rabbits in group GF were treated with recombinant bovine bFGF gel (300 IU/cm(2,) about 0.45 g for each wound), the wounds of rabbits in group AD were covered with gauze which was impregnated with 6 mL isoniazid injection and 0.15 g rifampicin powder-injection, the wounds of rabbits in group CT were covered with gauze which was impregnated with isoniazid injection and rifampicin powder-injection after being treated with recombinant bovine bFGF gel as before, the wounds of rabbits in group BC were covered with sterile gauze, with dressing change of once every two days until the wounds were completely healed. Immediately after surgery and on post surgery day (PSD) 7, 14, 21, and 28, the wounds of rabbits in each group were observed with naked eyes and photos. On PSD 7, 14, 21, and 28, the wound healing rate was calculated and the complete healing time of wound was recorded. On PSD 7, 14, 21, and 28, the tissue samples of wound edge were collected for histomorphological observation with hematoxylin and eosin staining and Masson staining. On PSD 21, the number of microvessels was counted with immunohistochemical method. On PSD 7, 14, 21, and 28, the content of hydroxyproline in wound edge was determined by enzyme-linked immunosorbent assay. The numbers of samples of above-mentioned experiments were all 8. Data were processed with analysis of variance for repeated measurement, analysis of variance of factorial design, one-way analysis of variance, least significant difference test and Bonferroni correction. <bResults:</b (1) The rabbits in four groups all survived to the end of experiment. Immediately after surgery, edema was observed in basal wounds of rabbits in the four groups. On PSD 7, the wounds of rabbits in the 4 groups were contracted with scabs and less edema. The wounds of rabbits in groups GF and CT became redder. On PSD 14, the wounds of rabbits in the 4 groups contracted obviously. There were no obvious exudates in wounds of rabbits in groups AD and CT, while 1 wound of rabbit in group GF and 2 wounds of rabbits in group BC became red and swelling with purulent exudates. On PSD 21, wounds of rabbits in groups GF and CT were basically healed, while 2 wounds of rabbits in group BC healed slowly with purulent secretion. On PSD 28, wounds of rabbits in the 4 groups were basically healed, while 2 wounds of rabbits in group BC hardly healed with redness and swelling. (2) From PSD 7 to 28, the wound healing rates of rabbits in groups GF, AD, and CT were significantly higher than those in group BC (<iP</i&lt;0.05). On PSD 14 and 21, the wound healing rates of rabbits in groups GF and CT were significantly higher than those in group AD (<iP</i&lt;0.05). From PSD 7 to 28, the wound healing rates of rabbits in group GF were close to those in group CT (<iP</i&gt;0.05). (3) The complete healing time of wounds of rabbits in groups GF, AD, and CT was significantly shorter than that in group BC (<iP</i&lt;0.05). The complete healing time of wounds of rabbits in groups GF and CT was significantly shorter than that in group AD (<iP</i&lt;0.05). The complete healing time of wounds of rabbits in group GF was close to that in group CT (<iP</i&gt;0.05). (4) On PSD 7, a large number of inflammatory cells infiltration were observed in wound tissue of rabbits in the 4 groups and a few epithelial cells were observed in wound tissue of rabbits in groups GF, AD, and CT. On PSD 14, more epithelial cells were observed in wound tissue of rabbits in groups GF and CT, and an obvious reduction of inflammatory cells infiltration was observed in wound tissue of rabbits in groups AD and CT. On PSD 21, there was a complete wound tissue structure and distinctive nuance of dyeing in wound tissue of rabbits in groups GF and CT while thinner new epithelium in wound tissue of rabbits in groups AD and BC, and inflammatory cell infiltration was observed in wound tissue of rabbits in group BC. On PSD 28, there was a complete wound tissue structure in wound tissue of rabbits in the 4 groups, the new epithelium in wound tissue of rabbits in groups GF, AD, and CT was thicker than that in group BC. (5) On PSD 7 and 14, the quantity of collagen fibers in wound tissue of rabbits in groups GF and CT was larger than that in the other two groups. On PSD 21, a large quantity of fibroblasts and well reorganized collagen fibers were observed in wound tissue of rabbits in groups GF and CT, a moderate quantity of fibroblasts and collagen fibers in a random arrangement were observed in wound tissue of rabbits in group AD, and a little quantity of fibroblasts and collagen fibers were observed in wound tissue of rabbits in group BC. On PSD 28, the quantity of collagen fibers in wound tissue of rabbits in the 4 groups was close to that of normal skin tissue, and the collagen fibers performed more well reorganized in wound tissue of rabbits in groups GF and CT. (6) On PSD 21, the numbers of microvessels per 200-time visual field in wound edge of rabbits in groups GF (31.6±1.2), AD (27.5±1.3), and CT (32.8±1.6) were significantly higher than the number in group BC (22.3±1.7, <iP</i&lt;0.05). The numbers of microvessels in wound edge of rabbits in groups GF and CT were significantly higher than the number in group AD (<iP</i&lt;0.05). The number of microvessels in wound edge of rabbits in group GF was close to that in group CT (<iP</i&gt;0.05). (7) On PSD 7 and 28, there were no statistically significant differences in content of hydroxyproline in wound edge of rabbits in the 4 groups (<iF</i=0.916, 1.752, <iP</i&gt;0.05). On PSD 14 and 21, the content of hydroxyproline in wound edge of rabbits in groups GF, AD, and CT was significantly higher than that in group BC (<iP</i&lt;0.05). The content of hydroxyproline in the wound edge of rabbits in groups GF and CT was significantly higher than that in group AD (<iP</i&lt;0.05). The content of hydroxyproline in the wound edge of rabbits in group GF was close to that in group CT (<iP</i&gt;0.05). <bConclusions:</b bFGF can be used solely or combined with AD to promote <iMycobacterium tuberculosis</i infective wound healing in New Zealand rabbit after complete debridement of wound, which is better than single use of AD.

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<bObjective:</b To assess the current situation of early treatment of partial-thickness burn wounds by professional burn medical staff in China, and to further promote the standardized early clinical treatment of partial-thickness burn wounds. <bMethods:</b A cross-sectional investigation was conducted. From November 2020 to February 2021, the self-designed questionnaire for the early treatment of partial-thickness burn wounds was published through the "questionnaire star" website and shared through WeChat to conduct a convenient sampling survey of domestic medical staff engaged in burn specialty who met the inclusion criteria. The number, region, and grade of the affiliated hospital, the age, gender, occupation, and seniority of the respondents were recorded. The respondents were divided into physician group and nurse group, senior group and junior group, eastern region group and non-eastern region group, primary and secondary hospital group and tertiary hospital group. Then the seniority, grade of the affiliated hospital, region of the affiliated hospital of the respondents in physician group and nurse group, conventional treatment of partial-thickness burn blisters, reasons for retaining vesicular skin, reasons for removing vesicular skin, and the conventional selection and optimal solution recommendation of topical drugs or dressings for partial-thickness burn wounds in the early stage of respondents in each of all the groups were recorded. Data were statistically analyzed with chi-square test. <bResults:</b The survey covered 31 provinces, municipalities, and autonomous regions in China (except for Hong Kong, Macau, and Taiwan regions). A total of 979 questionnaires were recovered, which were all valid. The 979 respondents came from 449 hospitals across the country, including 203 hospitals in the eastern region, 116 hospitals in the western region, 99 hospitals in the central region, and 31 hospitals in the northeast region, 348 tertiary hospitals, 79 secondary hospitals, and 22 primary hospitals. The age of the respondents was (39±10) years. There were 543 males and 436 females, 656 physicians and 323 nurses, 473 juniors and 506 seniors, 460 in the eastern regions and 519 in the non-eastern regions, 818 in tertiary hospitals and 161 in primary and secondary hospitals. There were statistically significant differences in the composition of different seniority in the respondents between physician group and nurse group (<iχ</i<sup2</sup=44.32, <iP</i&lt;0.01), while there were no statistically significant differences in grade or region of the affiliated hospital of the respondents between physician group and nurse group (<iP</i&gt;0.05). There were no statistically significant differences in the conventional treatment of partial-thickness burn blisters among respondents between different occupational groups, seniority groups, and region of the affiliated hospital groups (<iP</i&gt;0.05).The respondents in different grade of the affiliated hospital groups differed significantly in the conventional treatment of partial-thickness burn blisters (<iχ</i<sup2</sup=6.24, <iP</i&lt;0.05). Compared with respondents in nurse group, larger percentage of respondents in physician group chose to retain vesicular skin for protecting the wounds and providing a moist environment, and alleviating the pain of dressing change (with <iχ</i<sup2</sup values of 21.22 and 19.96, respectively, <iP</i values below 0.01), and smaller percentage of respondents in physician group chose to retain vesicular skin for prevention of wound infection (<iχ</i<sup2</sup=23.55, <iP</i&lt;0.01). The reasons for retaining vesicular skin of respondents between physician group and nurse group were similar in accelerating wound healing, alleviating pigmentation and scar hyperplasia post wound healing (<iP</i&gt;0.05). Compared with respondents in junior group, larger percentage of respondents in senior group chose to retain vesicular skin for protecting the wounds and providing a moist environment and alleviating the pain of dressing change (with <iχ</i<sup2</sup values of 10.36 and 4.60, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01), and smaller percentage of respondents in senior group chose to retain vesicular skin for prevention of wound infection (<iχ</i<sup2</sup=8.20, <iP</i&lt;0.01). The reasons for retaining vesicular skin of respondents in senior group and junior group were similar in accelerating wound healing, alleviating pigmentation and scar hyperplasia post wound healing (<iP</i&gt;0.05). The 5 reasons for the respondents between eastern region group and non-eastern region group, primary and secondary hospital group and tertiary hospital group chose to retain vesicular skin were all similar (<iP</i&gt;0.05). Compared with those in physician group, significantly higher percentage of respondents in nurse group were in favor of the following 6 reasons for removing the vesicular skin, including convenience for using more ideal dressings to protect the wounds, prevention of wound infection, facilitating the effect of topical drugs on the wounds, the likely rupture of blisters and wound contamination, accelerating wound healing, and alleviating pigmentation and scar hyperplasia post wound healing (with <iχ</i<sup2</sup values of 4.35, 25.59, 11.83, 16.76, 46.31, and 17.54, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with respondents in senior group, larger percentage of respondents in junior group chose to remove vesicular skin for the reasons such as the likely blister rupture and wound contamination, preventing wound infection, accelerating wound healing, and alleviating pigmentation and scar hyperplasia post wound healing (with <iχ</i<sup2</sup values of 17.25, 18.63, 14.83, and 10.23, respectively, <iP</i values below 0.01). Compared with respondents in non-eastern region group, larger percentage of respondents in eastern region group chose to remove vesicular skin for preventing wound infection and the likely rupture of blisters and wound contamination (with <iχ</i<sup2</sup values of 9.30 and 8.65, respectively, <iP</i values below 0.01). The 6 reasons for the respondents between tertiary hospital group and primary and secondary hospital group choose to remove vesicular skin were similar (<iP</i&gt;0.05). Compared with respondents in physician group, larger percentage of respondents in nurse group chose to use moisturizing materials for partial-thickness burn wounds in the early stage (<iχ</i<sup2</sup=6.18, <iP</i&lt;0.05), and smaller percentage of respondents in nurse group chose other topical drugs or dressings (<iχ</i<sup2</sup=5.20, <iP</i&lt;0.05). Compared with respondents in junior group, larger percentage of respondents in senior group chose to use moisturizing materials and other topical drugs or dressings for partial-thickness burn wounds in the early stage (with <iχ</i<sup2</sup values of 4.97 and 21.80, respectively, <iP</i&lt;0.05 or <iP</i&lt;0.01). Compared with respondents in non-eastern region group, larger percentage of respondents in eastern region group chose to use topical antimicrobial drugs for partial-thickness burn wounds in the early stage (<iχ</i<sup2</sup=4.09, <iP</i&lt;0.05), and smaller percentage of respondents in eastern region group chose to use other topical drugs or dressings for the partial-thickness burn wounds in the early stage (<iχ</i<sup2</sup=5.63, <iP</i&lt;0.05). Compared with respondents in primary and secondary hospital group, larger percentage of respondents in tertiary hospital group chose to use biological dressings for partial-thickness burn wounds in the early stage (<iχ</i<sup2</sup=9.38, <iP</i&lt;0.01). The optimal solution recommendation of topical drugs or dressings for partial-thickness burn wounds in the early stage varied significantly among the respondents between different occupational groups and seniority groups (with <iχ</i<sup2</sup values of 39.58 and 19.93, respectively, <iP</i values below 0.01). There were no statistically significant differences between eastern and non-eastern region groups, tertiary hospital group and primary and secondary hospital groups in optimal solution recommendation of topical drugs or dressings for partial-thickness burn wounds in the early stage (<iP</i&gt;0.05). <bConclusions:</b The conventional treatment measures of partial-thickness burn blisters and reasons for preserving blister skin by professional burn medical staff in China are relatively consistent, but there are great differences in the selection of reasons for removing blister skin, the conventional selection and optimal solution recommendation of topical drugs or dressings for partial-thickness burn wounds in the early stage. Therefore, it is urgent to establish a clinical treatment standard for partial-thickness burn wounds.

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The cow-calf (Bos taurus) industry in subtropical United States and other parts of the world depends almost totally on grazed pastures. Establishment of complete, uniform stand of bahiagrass (BG) in a short time period is important economically. Failure to obtain a good BG stand early means increased encroachment of weeds and the loss of not only the initial investment costs, but production and its cash value. Forage production often requires significant inputs of lime, N fertilizer, and less frequently of P and K fertilizers. Domestic sewage sludge or biosolids, composted urban plant debris, waste lime, phosphogypsum, and dredged materials are examples of materials that can be used for fertilizing and liming pastures. Perennial grass can be a good choice for repeated applications of sewage sludge. Although sewage sludge supply some essential plant nutrients and provide soil property-enhancing organic matter, land-application programs still generate some concerns because of possible health and environmental risks involved. The objectives of this study were to evaluate the cumulative and residual effects of repeated applications of sewage sludge on (i) bahiagrass (BG, Paspalum notaturn Flügge) production over years with (1997-2000) and without (2001-2002) sewage sludge applications during a 5-yr period, and (ii) on nutrients status of soil that received annual application of sewage sludge from 1997 to 2000 compared with test values of soils in 2002 (with no sewage sludge application) in South Florida. The field experiment was conducted at the University of Florida Agricultural Research and Education Center, Ona, FL (27 degrees 26'N, 82 degrees 55'W) on a Pomona fine sandy soil. With the exception of the control, BG plots received annual sewage sludge and chemical fertilizers applications to supply 90 or 180 kg total N ha(-1) yr(-1) from 1997 to 2000. Land application of sewage sludge and fertilizer ceased in 2001 season. In early April 1998, 1999, and 2000, plots were mowed to 5-cm stubble and treated with the respective N source amendments. The experimental design was three randomized complete blocks with nine N-source treatments: ammonium nitrate (AMN), slurry biosolids of pH 7 (SBS7), slurry biosolids of pH 11 (SBS11), lime-stabilized cake biosolids (CBS), each applied to supply 90 or 180 kg N ha(-1), and a nonfertilized control (Control). Application rates of sewage sludge were calculated based on the concentration of total solids in materials as determined by the American Public Health Association SM 2540G method and N in solids. The actual amount of sewage sludge applications was based on the amount required to supply 90 and 180 kg N ha(-1). Sewage sludge materials were weighed in buckets and uniformly applied to respective BG plots. Soil samples were collected in June 1997, June 1999, and in June 2002 from 27 treatment plots. In 1997 and 1999, soil samples were collected using a steel bucket type auger from the 0- to 20-, 20- to 40-, 40- to 60-, and 60- to 100-cm soil depths. Forage was harvested on 139, 203, 257, and 307 day of year (DOY) in 1998; 125, 202, 257, and 286 DOY in 1999; 179, 209, 270, and 301 DOY in 2000; and on 156 and 230 DOY in 2002 (no sewage sludge applications) to determine the residual effect of applied sewage sludge following repeated application. Forage yield and soils data were analyzed using analysis of variance (PROC ANOVA) procedures with year and treatment as the main plot and sub-plot, respectively. As a result of significant year effects on forage yield, data were reanalyzed annually (i.e., 1998, 1999, 2000, and 2002). All sewage sludges used in this study were of class B in terms of USEPA's pathogens and pollutant concentration limit. Pathogen and chemical composition of the class B sewage sludge that were used in the study were all in compliance with the USEPA guidelines. The liquid sludge (SBS11) had the lowest fecal coliform counts (0.2 x 10(6) CFU kg(-1)) while the cake sewage sludge (CBS) had the greatest coliform counts of 178 x 10(6) CFU kg(-1). The fecal coliform counts for SBS7 was about 33 x 10(6) CFU kg(-1). Average soil test values in June 2002 exhibited: i) decrease in TIN (NO3-N + NH4-N), TP, K, Ca, Mg, Mn, and Fe; and ii) slight increase in Zn and Cu when compared with the June 1997 soil test results. The overall decrease in soil test values in 2002 might be associated with nutrient cycling and plant consumption. Although the average BG forage yield in 2002 (2.3 +/- 0.7 Mg ha(-1)) was slightly lower than in 2000 (3.5 +/- 1.2 Mg ha(-1)), yield differences in 2002 between the control (1.2 +/- 0.2 Mg ha(-1)) and treated plots (2.3 +/- 0.5 Mg ha(-1) to 3.3 +/- 0.6 Mg ha(-1)) were indicative of a positive residual effect of applied sewage sludge. This study has shown that excessive build up of plant nutrients may not occur in beef cattle pastures that repeatedly received sewage sludge while favoring long-term increased forage yield of BG. All sources of N (sewage sludge and AMN) gave better forage production than the unfertilized control during years with sewage sludge application (1997-2000) and also during years with no sewage sludge application (2001-2002). The favorable residual effects of applied sewage sludge in 2002 may have had received additional boost from the amount of rainfall in the area. Repeated applications of sewage sludge indicate no harmful effects on soil quality and forage quality. Our results support our hypothesis that repeated land application of sewage sludge to supply 90 and 180 kg N ha(-1) would not increase soil sorption for nutrients and trace metals. Results have indicated that the concentrations of soil TIN and TP declined by almost 50% in plots with different nitrogen sources from June 1997 to June 2002 suggesting that enrichment of nitrogen and phosphorus is insignificant. The concentrations of soil nitrogen and phosphorus in 2002 following repeated application of sewage sludge were far below the contamination risk in the environment. The residual effect of these sewage sludge over the long term can be especially significant in many areas of Florida where only 50% of the 1 million ha of BG pastures are given inorganic nitrogen yearly. Successive land application of sewage sludge for at least three years followed by no sewage sludge application for at least two years may well be a good practice economically because it will boost and/or maintain sustainable forage productivity and at the same time minimize probable accumulation of nutrients, especially trace metals. Consecutive applications of sewage sludge may result in build up of some trace metals in some other states with initial high metallic content, but in this study, no detrimental effects on soil chemical properties were detected. The possibilities for economically sound application strategies are encouraging, but more and additional research is required to find optimal timing and rates that minimizes negative impacts on soil quality in particular or the environment in general. For proper utilization of sewage sludge, knowledge of the sewage sludges' composition, the crop receiving it, are absolutely crucial, so that satisfactory types and rates are applied in an environmentally safe manner. There is still much to be learned from this study and this investigation needs to continue to determine whether the agricultural and ecological objectives are satisfied over the longer term.

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To review and synthesize the literature in the following areas: the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age, postmenopausal women and elderly men; the effect of dietary intakes (foods fortified with vitamin D and/or vitamin D supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on bone mineral density (BMD) and fracture or fall risk; and the identification of potential harms of vitamin D above current reference intakes. MEDLINE(R) (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February 2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter 2006). Two independent reviewers completed a multi-level process of screening the literature to identify eligible studies (title and abstract, followed by full text review, and categorization of study design per key question). To minimize bias, study design was limited to randomized controlled trials (RCTs) wherever possible. Study criteria for question one were broadened to include observational studies due to a paucity of available RCTs, and question four was restricted to systematic reviews to limit scope. Data were abstracted in duplicate and study quality assessed. Differences in opinion were resolved through consensus or adjudication. If clinically relevant and statistically feasible, meta-analyses of RCTs on vitamin D supplementation and bone health outcomes were conducted, with exploration of heterogeneity. When meta-analysis was not feasible, a qualitative systematic review of eligible studies was conducted. 167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30 case-controls and six before-after studies). The largest body of evidence on vitamin D status and bone health was in older adults with a lack of studies in premenopausal women and infants, children and adolescents. The quality of RCTs was highest in the vitamin D efficacy trials for prevention of falls and/or fractures in older adults. There was fair evidence of an association between low circulating 25(OH)D concentrations and established rickets. However, the specific 25(OH)D concentrations associated with rickets is uncertain, given the lack of studies in populations with dietary calcium intakes similar to North American diets and the different methods used to determine 25(OH)D concentrations. There was inconsistent evidence of an association of circulating 25(OH)D with bone mineral content in infants, and fair evidence that serum 25(OH)D is inversely associated with serum PTH. In adolescents, there was fair evidence for an association between 25(OH)D levels and changes in BMD. There were very few studies in pregnant and lactating women, and insufficient evidence for an association between serum 25(OH)D and changes in BMD during lactation, and fair evidence of an inverse correlation with PTH. In older adults, there was fair evidence that serum 25(OH)D is inversely associated with falls, fair evidence for a positive association with BMD, and inconsistent evidence for an association with fractures. The imprecision of 25(OH)D assays may have contributed to the variable thresholds of 25(OH)D below which the risk of fractures, falls or bone loss was increased. There was good evidence that intakes from vitamin D-fortified foods (11 RCTs) consistently increased serum 25(OH)D in both young and older adults. Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar exposure) were small and heterogeneous with respect to determination of the exact UV-B dose and 25(OH)D assay but there was a positive effect on serum 25(OH)D concentrations. It was not possible to determine how 25(OH)D levels varied by ethnicity, sunscreen use or latitude. Seventy-four trials examined the effect of vitamin D(3) or D(2) on 25(OH)D concentrations. Most trials used vitamin D(3), and the majority enrolled older adults. In three trials, there was a greater response of serum 25(OH)D concentrations to vitamin D(3) compared to vitamin D(2), which may have been due to more rapid clearance of vitamin D(2) in addition to other mechanisms. Meta-analysis of 16 trials of vitamin D(3) was consistent with a dose-response effect on serum 25(OH)D when comparing daily doses of &lt;400 IU to doses &gt;/= 400 IU. An exploratory analysis of the heterogeneity demonstrated a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose. Vitamin D(3) in combination with calcium results in small increases in BMD compared to placebo in older adults although quantitative synthesis was limited due to variable treatment durations and BMD sites. The evidence for fracture reduction with vitamin D supplementation was inconsistent across 15 trials. The combined results of trials using vitamin D(3) (700 - 800 IU daily) with calcium (500 - 1,200 mg) was consistent with a benefit on fractures although in a subgroup analysis by setting, benefit was primarily in elderly institutionalized women (fair evidence from two trials). There was inconsistent evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis showed a benefit of vitamin D in postmenopausal women, and in trials that used vitamin D(3) plus calcium. In addition, there was a reduction in fall risk with vitamin D when six trials that adequately ascertained falls were combined. Limitations of the fall and fracture trials included poor compliance with vitamin D supplementation, incomplete assessment of vitamin D status and large losses to follow-up. We did not find any systematic reviews that addressed the question on the level of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations but minimizes risk of melanoma and non-melanoma skin cancer. There is little evidence from existing trials that vitamin D above current reference intakes is harmful. In most trials, reports of hypercalcemia and hypercalciuria were not associated with clinically relevant events. The Women's Health Initiative study did report a small increase in kidney stones in postmenopausal women aged 50 to 79 years whose daily vitamin D(3) intake was 400 IU (the reference intake for 50 to 70 years, and below the reference intake for &gt; 70 years) combined with 1000 mg calcium. The increase in renal stones corresponded to 5.7 events per 10,000 person-years of exposure. The women in this trial had higher calcium intakes than is seen in most post-menopausal women. The results highlight the need for additional high quality studies in infants, children, premenopausal women, and diverse racial or ethnic groups. There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD). However, the evidence for an association was inconsistent for other outcomes (e.g., BMC in infants and fractures in adults). It was difficult to define specific thresholds of circulating 25(OH)D for optimal bone health due to the imprecision of different 25(OH)D assays. Standard reference preparations are needed so that serum 25(OH)D can be accurately and reliably measured, and validated. In most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (&gt;700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms.

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Dong Y, Qi B, Feng XY, Jiang CM. Meta-analysis of Barrett's esophagus in China. World J Gastroenterol 2013;19(46):8770-8779 The disease pattern of Barrett's esophagus (BE) in China is poorly characterised particularly in comparison with other developed countries. This meta-analysis of 3873 cases of BE collated from 69 clinical studies conducted in 25 provinces between 2000 and 2011 investigated the epidemiology and characteristics of BE in China compared to Western countries. The total endoscopic detection rate of BE was 1.0% (95%CI: 0.1%-1.8%) with an average patient age of 49.07 ± 5.09 years, lower than many Western countries.The authors postulate this may be attributed to environmental risk factor variation, distinct genetics and different medical practice including diagnostic criteria for BE and expertise in endoscopy. This study identified a 1.781 male predominancefor BE in China, consistent with Western reports. Short-segment BE accounted for 80.3% of cases with island type and cardiac type the most common endoscopic (44.8%) and histological (40.0%) manifestations respectively. Of the 1283 BE cases followed up for three to 36 months the incidence of esophageal cancer was 1.418 per 1000 person-years, lower than the incidence reported in Western countries. Lee HS, Jeon SW. Barrett esophagus in Asia: same disease with different pattern. ClinEndosc 2014;47(1):15-22 Barrett's esophagus (BE) is a common, pre-cancerous condition characterised by intestinal metaplasia of squamous esophageal epithelium usually attributed to chronic gastric acid exposure. This review article explores important differences in the disease pattern of BE between Asian and the Western countries. Overall the prevalence of BE is lower in Asia compared to the West with a greater proportion of short-segment type. The authors identify great variability in the endoscopic and pathologic diagnostic criteria for BE. Many of the studies in Asian countries did not use a standardised four-quadrant biopsy protocol which may have led to an underestimation of BE prevalence. The review highlights an increasing incidence of esophageal adenocarcinoma in the West but unclear disease trend in Asia with inter-country variability. Similarly in Asian and Western countries BE is associated with the presence of hiatus hernia, advancing age, male gender, alcohol consumption, smoking, abdominal obesity and longer duration of gastro-esophageal reflux disease. The authors postulate that Helicobacter pylori infection, more prevalent in Asia than the West, may have a protective effect on BE. There is a need for larger, prospective studies to further clarify the disease pattern of BE in Asian countries. Clearly standardisation of the diagnostic process for BE is important to validate the differences in disease trends between Asian and Western countries. Kiadaliri AA. Gender and social disparities in esophagus cancer incidence in Iran, 2003-2009: a time trend province-level study.Asian Pac J Cancer Prev 2014;15(2):623-7 Esophageal cancer (EC) is a major cause of morbidity and mortality particuarly in Iran where the incidence rate exceeds the global average. An understanding of the factors influencing the province-specific incidence of EC in Iran is important to inform disease-prevention strategies and address health inequalities. This ecological study used cancer registry data to investigate the relationship between gender and social class and the incidence of EC in Iran at province-level between 2003 and 2009. The age standardised incidence rates (ASIR) of EC were greatest in the Northern provinces of Iran, specifically Razavi Khorasan in males and Kordestan in females. Overall the EC incidence did not significantly differ according to gender. Interestingly, during the study period the ASIR increased by 4.6% per year in females (p=0.08) and 6.5% per year in males (p=0.02). This may reflect increasing rates of establised risk factors for EC including obsesity and gastro-esophageal reflux disease alongside more vigilant recording of new cases. Social class was inversely associated with the ASIR of EC regardless of gender which may be attributed to class differences in risk factor distribution particularly smoking, diet and obesity. An appreciation for the limitations of an epidemiological study is important when interpreting results which should be further evaluated in future studies. Islami F et al.Determinants of gastroesophageal reflux disease, including hookah smoking and opium use- A cross-sectional analysis of 50,000 individuals. PLoS One 2014;9(2):e89256 Gastroesophageal reflux disease (GERD) is a highly prevalent cause of gastrointestinal symptoms worldwide incurring great cost to the primary and secondary healthcare sectors. An improved understanding of the factors which influence GERD symptoms in low- to medium- income countries may inform public health initiatives. This study analysed prospective data from the Golestan cohort study, primarily established to investigate determinants of upper gastrointestinal cancers, toexplore the risk factors influencing GERD symptoms (regurgitation and/or heartburn) in 50,045 individuals aged 40-75 years in Golestan Province, Iran enrolled between 01/2004 and 06/2008.Of note, 39.12% of individuals denied ever experiencing GERD symptoms. A further 19.89% reported at least once weekly GERD symptoms with 11.83% experiencing daily symptoms. Severe symptoms, defined as disturbing daily work or sleep, were recorded by 11.33% of individuals. Separately the occurrence of daily GERD symptoms and severe symptoms were inversely associated with male gender (OR 0.36, 95% CI 0.33-0.39 both), level of formal education (p=0.01 and p=0.001 respectively), wealth score (p&lt;0.001 both) and regular nass chewing (OR 0.86, 95% CI 0.75-0.98 and OR 0.87, 95% CI 0.76-0.99 respectively)and were positively associated with body mass index (p&lt;0.001 both), intensity of physical activity (p=0.04 both), cigarette pack years (p&lt;0.001 both), alcohol consumption (OR 1.36, 95% CI 1.13-1.64 and OR 1.53, 95% CI 1.28-1.83 respectively) and opium use (OR 1.82, 95% CI 1.67-1.99 and OR 1.70, 95% CI 1.55-1.87 respectively).In addition hookah smoking had a borderline significant correlation with mild and moderate severity GERD symptoms in individuals who had never smoked cigarettes (OR 1.41, 95% CI 1.00-1.99 and OR 1.25, 95% CI 0.99-1.57 respectively). Overall this large study contributes useful data to inform the prevention and management of GERD symptoms particularly regarding the use of hookah, opium and nass which was previously unclear. Barbera M et al. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut 2014;0:1-9. doi:10.1136/gutjnl-2013-306171 Current knowledge on human esophageal tissue homeostasis and injury repair is derived predominantly from murine models and hence may be inaccurate due to cellular and architectural differences. This study used 3D imaging in conjunction withstaining for cell lineage markers to investigate the cellular mechanisms involved in homeostasis of the normal human squamous esophagus in 10 participants undergoing esophagectomy for esophageal cancer. The self-renewal potential of cell subpopulations was also assessed using in vitro and in vivo assays. A decreasing gradient of cell proliferation was observed from the inter-papillary basal layer to the tip of the papilla where there was no evidence of mitosis. The expression ofβ1-integrin, a putative stem cell marker, was consistent throughout the basal layer and therefore the entire basal layer can be considered undifferentiated. Quiescent β1-integrin/CD34-positive cells which failed to stain for CD45, S-100 or F4-80were identified at the tip of the papilla suggesting this is an extension of the basal layer. Contrary to previous data, this study found progenitor cells widely distributed in human esophageal tissue and included already differentiated epithelial cells. This insight into esophageal homeostasis may inform future studies exploring the pathological mechanisms underpinning homeostatic disruption in disease states such as Barrett's esophagus. Papers were prepared by: Drs Ishfaq Ahmad and Luke Materacki, Department of Medicine, Alexandra Hospital, Redditch, UK.

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Surgical adverse events contribute significantly to postoperative morbidity, yet the measurement and monitoring of events is often imprecise and of uncertain validity. Given the trend of decreasing length of hospital stay and the increase in use of innovative surgical techniques--particularly minimally invasive and endoscopic procedures--accurate measurement and monitoring of adverse events is crucial. The aim of this methodological review was to identify a selection of common and potentially avoidable surgical adverse events and to assess whether they could be reliably and validly measured, to review methods for monitoring their occurrence and to identify examples of effective monitoring systems for selected events. This review is a comprehensive attempt to examine the quality of the definition, measurement, reporting and monitoring of selected events that are known to cause significant postoperative morbidity and mortality. METHODS - SELECTION OF SURGICAL ADVERSE EVENTS: Four adverse events were selected on the basis of their frequency of occurrence and likelihood of evidence of measurement and monitoring: (1) surgical wound infection; (2) anastomotic leak; (3) deep vein thrombosis (DVT); (4) surgical mortality. Surgical wound infection and DVT are common events that cause significant postoperative morbidity. Anastomotic leak is a less common event, but risk of fatality is associated with delay in recognition, detection and investigation. Surgical mortality was selected because of the effort known to have been invested in developing systems for monitoring surgical death, both in the UK and internationally. Systems for monitoring surgical wound infection were also included in the review. METHODS - LITERATURE SEARCH: Thirty separate, systematic literature searches of core health and biomedical bibliographic databases (MEDLINE, EMBASE, CINAHL, HealthSTAR and the Cochrane Library) were conducted. The reference lists of retrieved articles were reviewed to locate additional articles. A matrix was developed whereby different literature and study designs were reviewed for each of the surgical adverse events. Each article eligible for inclusion was independently reviewed by two assessors. METHODS - CRITICAL APPRAISAL: Studies were appraised according to predetermined assessment criteria. Definitions and grading scales were assessed for: content, criterion and construct validity; repeatability; reproducibility; and practicality (surgical wound infection and anastomotic leak). Monitoring systems for surgical wound infection and surgical mortality were assessed on the following criteria: (1) coverage of the system; (2) whether or not denominator data were collected; (3) whether standard and agreed definitions were used; (4) inclusion of risk adjustment; (5) issues related to data collection; (6) postdischarge surveillance; (7) output in terms of feedback and wider dissemination. RESULTS - SURGICAL WOUND INFECTION: A total of 41 different definitions and 13 grading scales of surgical wound infection were identified from 82 studies. Definitions of surgical wound infection varied from presence of pus to complex definitions such as those proposed by the Centres for Disease Control in the USA. A small body of literature has been published on the content, criterion and construct validity of different definitions, and comparisons have been made against wound assessment scales and multidimensional indices. There are examples of comprehensive hospital-based monitoring systems of surgical wound infection, mainly under the auspices of nosocomial surveillance. To date, however, there is little evidence of systematic measurement and monitoring of surgical wound infection after hospital discharge. RESULTS - ANASTOMOTIC LEAK: Over 40 definitions of anastomotic leak were extracted from 107 studies of upper gastrointestinal, hepatopancreaticobiliary and lower gastrointestinal surgery. No formal evaluations were found that assessed the validity or reliability of definitions or severity scales of anastomotic leak. One definition was proposed during a national consensus workshop, but no evidence of its use was found in the surgical literature. The lack of a single definition or gold standard hampers comparison of postoperative anastomotic leak rates between studies and institutions. RESULTS - DEEP VEIN THROMBOSIS: Although a critical review of the DVT literature could not be completed within the realms of this review, it was evident that a number of new techniques for the detection and diagnosis of DVT have emerged in the last 20 years. The group recommends a separate review be undertaken of the different diagnostic tests to detect DVT. RESULTS - SURGICAL MORTALITY MONITORING SYSTEMS: The definition of surgical mortality is relatively consistent between monitoring systems, but duration of follow-up of death postdischarge varies considerably. The majority of systems report in-hospital mortality rates; only some have the potential to link deaths to national death registers. Risk assessment is an important factor and there should be a distinction between recording pre-intervention factors and postoperative complications. A variety of risk scoring systems was identified in the review. Factors associated with accurate and complete data collection include the employment of local, dedicated personnel, simple and structured prompts to ensure that clinical input is complete, and accurate and automated data capture and transfer. The use of standardised, valid and reliable definitions is fundamental to the accurate measurement and monitoring of surgical adverse events. This review found inconsistency in the quality of reporting of postoperative adverse events, limiting accurate comparison of rates over time and between institutions. The duration of follow-up for individual events will vary according to their natural history and epidemiology. Although risk-adjusted aggregated rates can act as screening or warning systems for adverse events, attribution of whether events are avoidable or preventable will invariably require further investigation at the level of the individual, unit or department. CONCLUSIONS - RECOMMENDATIONS FOR RESEARCH: (1) A single, standard definition of surgical wound infection is needed so that comparisons over time and between departments and institutions are valid, accurate and useful. Surgeons and other healthcare professionals should consider adopting the 1992 Centers for Disease Control (CDC) definition for superficial incisional, deep incisional and organ/space surgical site infection for hospital monitoring programmes and surgical audits. There is a need for further methodological research into the performance of the CDC definition in the UK setting. (2) There is a need to formally assess the reliability of self-diagnosis of surgical wound infection by patients. (3) There is a need to assess formally the reliability of case ascertainment by infection control staff. (4) Work is needed to create and agree a standard, valid and reliable definition of anastomotic leak which is acceptable to surgeons. (5) A systematic review is needed of the different diagnostic tests for the diagnosis of DVT. (6) The following variables should be considered in any future DVT review: anatomical region (lower limb, upper limb, pelvis); patient presentation (symptomatic, asymptomatic); outcome of diagnostic test (successfully completed, inconclusive, technically inadequate, negative); length of follow-up; cost of test; whether or not serial screening was conducted; and recording of laboratory cut-off values for fibrinogen equivalent units. (7) A critical review is needed of the surgical risk scoring used in monitoring systems. (8) In the absence of automated linkage there is a need to explore the benefits and costs of monitoring in primary care. (9) The growing potential for automated linkage of data from different sources (including primary care, the private sector and death registers) needs to be explored as a means of improving the ascertainment of surgical complications, including death. This linkage needs to be within the terms of data protection, privacy and human rights legislation. (10) A review is needed of the extent of the use and efficiency of routine hospital data versus special collections or voluntary reporting.

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Tetrahydrofuran is used as a reaction medium for Grignard and metal hydride reactions; in the synthesis of butyrolactone, succinic acid, and 1,4-butanediol diacelate; in the fabrication of articles for packaging, transporting, and storing of foods; as a solvent for dyes and lacquers; and as a chemical intermediate in polymerization solvent for fat oils, unvulcanized rubber, resins, and plastics. Tetrahydrofuran is also an indirect food additive when it is in contact with the surface of articles intended for use in food processing. Tetrahydrofuran was nominated for study because of the potential for occupational exposure in humans. Male and female F344/N rats and B6C3F1 mice were exposed to tetrahydrofuran (approximately 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, mouse bone marrow cells, and mouse peripheral blood cells erythrocites. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0 (chamber control), 66, 200, 600, 1,800, or 5,000 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 14 weeks. All rats survived until the end of the study. Final mean body weights and mean body weight gains of exposed groups of male and female rats were similar to those of the chamber controls. Immediately after exposure, male and female rats in the 5,000 ppm groups exhibited ataxia. Hematologic and serum chemistry changes were minimal, with most values falling within physiologic ranges. Absolute and relative thymus and spleen weights of male and female rats exposed to 5,000 ppm were significantly less than those of the chamber controls. Absolute and relative liver weights of female rats exposed to 5,000 ppm were significantly greater than those of the chamber controls. Increased incidences of minimal to mild hyperplasia of the forestomach were observed in male and female rats exposed to 5,000 ppm. Minimal suppurative inflammation was associated with forestomach hyperplasia in two male rats and four female rats exposed to 5,000 ppm. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 66, 200, 600, 1,800, or 5,000 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 14 weeks. Two male mice exposed to 5,000 ppm died during weeks 2 and 8 of the study; one male mouse from the 5,000 ppm group was killed in a moribund state during week 4. All female mice survived until the end of the study. The final mean body weights and mean body weight gains of all exposed groups of male mice were similar to those of the chamber controls. The final mean body weight and mean body weight gain of the 5,000 ppm female mice were significantly greater than those of the chamber controls. Male and female mice exposed to 1,800 or 5,000 ppm were observed in a state of narcosis (described by stupor) during exposure periods. Mice exposed to 1,800 ppm were fully awake and alert immediately after exposure; however, mice exposed to 5,000 ppm required up to 2 hours for recovery. Absolute and relative liver weights of male mice exposed to 600 ppm or greater and of female mice exposed to 1800 or 5,000 ppm were significantly greater than those of the chamber controls. Absolute and relative thymus weights of male mice exposed to 600, 1,800, or 5,000 ppm were significantly less than those of the chamber controls. The incidences of minimal to mild centrilobular cytomegaly of the liver in male and female mice exposed to 5,000 ppm were significantly greater than those in the chamber controls. The adrenal glands of all female mice exposed to 5,000 ppm had mild degeneration of the X-zone of the innermost cortex. Uterine atrophy was observed in all female mice exposed to 5,000 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings Survival and mean body weights of male and femand female rats exposed to tetrahydrofuran were similar to those of the chamber controls. Pathology Findings: The incidences of renal tubule epithelial adenoma or carcinoma (combined) in exposed males occurred with a positive trend, and the incidences in 600 and 1,800 ppm males exceeded the historical range for chamber controls in 2-year NTP inhalation studies. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings After week 36, the survival of male mice exposed to 1,800 ppm was significantly less than that of the chamber controls. Mean body weights of male and female mice exposed to tetrahydrofuran were similar to those of the chamber controls throughout the study. Male mice exposed to 1,800 ppm were observed to be in a state of narcosis during and up to 1 hour after the exposure periods. Pathology Findings: The incidences andmultiplicity of hepatocellular neoplasms were significantly greater in female mice exposed to 1,800 ppm than in the chamber controls. The incidence of nephropathy in 200 ppm male mice was significantly greater than that in the chamber control group. Male mice exposed to 1,800 ppm had significantly greater incidences of nonneoplastic lesions of the urogenital tract than did the chamber controls. The incidences of inflammation of the penis and urethra and necrosis of the urethra in 1,800 ppm males were slightly greater than those in the chamber controls; these may have been secondary effects of ascending urinary tract infection. GENETIC TOXICOLOGY: Tetrahydrofuran showed little evidence of mutagenic activity in a variety of in vitro and in vivo assays. It was not mutagenic in Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were conducted with and without exogenous metabolic activation from induced liver S9 enzymes. No increase in sex-linked recessive lethal mutations was detected in germ cells of male D. melanogaster exposed to tetrahydrofuran by feeding or injection. Results of in vivo assays for induction of chromosomal aberrations and sister chromatid exchanges in mouse bone marrow cells were negative. A micronucleus test in male and female mice exposed to tetrahydrofuran for 14 weeks showed no significant increases in the frequency of micronucleated erythrocytes in peripheral blood of female mice, but in male mice, analysis of micronucleated normochromatic erythrocyte levels revealed a small increase above baseline that was concluded to be equivocal. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of tetrahydrofuran in male F344/N rats based on increased incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of tetrahydrofuran in female F344/N rats exposed to 200, 600, or 1,800 ppm or male B6C3F1 mice exposed to 200, 600, or 1,800 ppm. There was clear evidence of carcinogenic activity of tetrahydrofuran in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Synonyms: Butylene oxide; cyclotetramethylene oxide; diethylene oxide; 1,4-epoxybutane; furanidine; hydrofuran; oxacyclopentane; oxolane; tetramethylene oxide

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The purpura accompanying the two foregoing cases of sarcoimatosis would seem to find its explanation in the coexistence of several factors, the main feature being an involvement of the vascular system by the sarcomatous elements. There existed in Case I a direct lesion of the vessel wall whereby the sarcoma cells invaded directly the various coats, and were found mainly between the intima and the adventitia, dissecting their way, as it were, along these tracts in the vessel walls. There was further an extensive involvement of the perivascular lymphatics, from which point, indeed, it would seem that the sarcoma cells had invaded the walls of the vessels themselves. In Case II, moreover, not only was there a definite invasion of the lymph spaces near the vessels, but, furthermore, there was undoubted evidence of the existence of emboli of sarcoma cells in the lumina of the blood vessels; and in the immediate vicinity of such conditions haemorrhages were invariably found. While some vessels, and indeed a great many, were quite free from such emboli, in others the lumina were completely occluded by spindle cells, so as to preclude the possibility that these were merely a collection of desquamated endothelial cells, such as is frequently found as the result of post-mortem changes. That such an embolic condition can exist is by no means an unreasonable supposition, and, while it is generally recognised that multiple sarcomata are usually made up of small round cells, in this case we have an undoubted example of sarcomatosis of the spindle-celled variety. There are numerous instances of this " embolic purpura," as it may be called, especially in French and German literature, the condition being associated with rheumatism, valvular lesions of the heart, and other diseases which induce directly or indirectly the formation of emboli. Krauss, Gimard, Leloir, and others have insisted with considerable emphasis on the embolic origin of many purpuric conditions, and in some instances they have verified their observations by histological examination. Leloir assumes that, in addition to the presence of the ordinary emboli and the changes in the vessel walls with desquamative endarteritis, the blood itself may be much altered chemically, and that in the cachectic conditions clots may be thrown down from the circulating blood and be carried onward to form capillary emboli, with resulting haemorrhagic infarctions. Krogerer, some ten years ago, in examining the skin removed from patients with symptomatic purpura, found definite thromboses in the smaller veins, and even in the arteries. According to his view, the alterations in the vessel walls gave rise to slowed circulation and tendency to thrombosis, bringing about a liability to haemorrhages. His plates bear out his theories regarding the thrombi, many of which show considerable organization. But a careful examination of the purpuric areas shows further that a mere invasion of the vascular system by sarcoma cells can not explain all the various blood effusions present. On examining the skin, for instance, in those areas where large irregular haemorrhages had occurred, there was but little evidence of vascular invasion, while the emboli, on the other hand, seemed to exist mainly in the localized smaller and more circumscribed patches. One must therefore conclude that in such instances a combination of factors will alone afford a rational explanation of the purpura, and that in the general condition of the patient we shall find another cause for the enormous effusions of blood. In both of our cases there were high fever, cachexia, and a rapid progressive asthenia, all being the results of a sarcomatosis, and implying also grave alterations in the composition of the blood. From this we may infer an altered condition of the vessel walls, and hence probably a combination of circumstances sufficient to explain the incidence of haemorrhage. The raised cutaneous nodules in our second case, some of which were haemorrhagic, can not be regarded as pure sarcomatous metastases, for on microscopic examination they merely revealed haemorrhage or necrosis, or both, and sometimes plugging of the vessels. There was nowhere in these nodules evidence of new growths. Such elevations, then, must have been produced rather by a temporary serous or cellular exudation coincident with or following upon the haemorrhage-a probability which is emphasized by the fact that during the last days of the patient's illness many of the nodules diminished in size. Whether the oedema and infiltration were secondary to the embolic process in the subcutaneous vessels or whether they were merely coincident with the haemorrhage would be difficult to decide. The ringlike spots, however, are of special interest, inasmuch as it has been shown that they have been present in more than one case of sarcoma. It is not impossible that such spots may be definitely related either to the embolic processes or to a direct invasion of the cutaneous vessels, though, so far as we know, there do not exist any experimental proofs to bear out such a theory. From what has been said, however, it is evident that the cutaneous vessels were plugged during the last few days of the illness, at a time when the walls of the smaller vessels and capillaries were already greatly enfeebled. The result of the embolic formation may therefore mean a decided deficiency in the supply of nutriment to the involved area, the collateral circulation naturally being poor under the circumstances. As soon, then, as the vessels had become plugged, the surrounding blood supply would be poured in to a limited extent, and, on meeting the enfeebled vessels, might possibly break through their thin walls, thus producing a zone of haemorrhage around the area deprived of its normal nutrition. In other words, the condition may be regarded as in many respects analogous to that presented in embolic infarcts in regions with end arteries, central necrosis with peripheral congestion and haemorrhage being induced, the latter being chiefly limited to the outer zone of the necrotic area. The cutaneous vessels under such circumstances may be regarded as end arteries in a functional sense, since the collateral circulation would be so diminished under the altered conditions that no complete nourishment could be afforded to the area supplied normally by the plugged vessel. Von Recklinghausen has directed especial attention to the occurrence of cutaneous haemorrhages following embolic or thrombotic occlusion of peripheral arteries. The possibility of some toxic condition as a factor in the production of the purpura in our cases may also be suggested; but while we would not exclude this possibility, we are unable to find any positive evidence in its favour. Focal necroses, which are often associated with toxic and infectious processes, were present only in direct association with the haemorrhages, and were not distributed in the liver, spleen, and kidneys in the manner characteristic of toxic infections. Nevertheless the absence of these necroses does not exclude the possibility of the existence of some form of toxaemia. Infection demonstrable by bacteriological examination was absent, and there is no reason to regard our cases as allied to the infectious purpuras. The thermic theory suggested by Fagge at all events finds no place in the production of the multiple tumours in our cases, inasmuch as in each instance extensive visceral growths had given rise to the metastases.

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Genetic correlations between two types of leg deformities, valgus and varus angulations, and some growth or conformation traits were estimated in two commercial broiler strains. 14 264 chickens of both sexes in line A were measured for leg defects at 6 weeks and body weight at 3 (BW3) or 6 (BW6) weeks. The same measures were taken in line B on 8 164 chickens, as well as breast angle (BRA) and breast meat yield (BRM) at 6 weeks on 70% of the male birds. The multinomial logit model previously developed for the genetic analysis of valgus and varus deformities was extended to deal with the joint analysis of one unordered categorical trait and one continuous variable. The model assumed a competition between latent susceptibility variates related to the various deformities and linearly dependent on the continuous performances. Location parameters for latent susceptibilities and continuous trait were estimated by the 'Maximum A Posteriori' approach and dispersion parameters by the 'Maximum Marginal Likelihood' using a tilda-hat approximation. The genetic model took into account the effects of the sire, maternal grandsire and dam within maternal grandsire. As described in a previous study, leg deformities showed moderate heritabilities. Mean heritability estimate for both lines, based on the sire/maternal-grandsire (S/MGS) component, was equal to 0.22 for valgus and varus; when based on the dam component, mean estimates were equal to 0.37 and 0.29 for the two deformities respectively. Except for BRA, heritability of growth and conformation traits appeared to be smaller when based on S/MGS component (from 0.18 to 0.47) than on dam component (from 0.41 to 0.63). Very low genetic correlations were found between susceptibilities to leg deformities and growth performances: average estimates for both lines of the genetic correlation with BW3 were -0.03 and -0.05 for valgus and varus respectively. Respective genetic correlations with BW6 were estimated to be +0.05 and +0.01. According to a simulation study these small estimates were unlikely to be due to the negative back effects of severe disorders on growth performances. According to these results, including leg defects in breeding schemes would not delay improvement on growth through unfavourable genetic correlations. Susceptibility to valgus deformity appeared to be genetically independent of conformation traits (genetic correlation was estimated to be -0.06 and -0.08 with BRA and BRM respectively), whereas moderate unfavourable genetic correlations were found for varus (+0.16 and +0.19 with BRA and BRM respectively). Care must be taken when considering the impact of the actual intensive selection for greater conformation on the incidence of varus deformity. RÉSUMÉ: Les corrélations génétiques entre deux types de déformations osseuses, le valgus et le varus, et des caractères de croissance et de conformation ont été estimées dans deux lignées commerciales de poulet de type chair. Dans la lignée "A", 14 264 poulets des deux sexes ont été mesurés pour les problèmes de pattes à 6 semaines, ainsi que pour le poids vif aux âges de 3 et 6 semaines. Ces mêmes mesures ont été faites dans la lignée "B"sur 8 164 poulets; on disposait en plus pour un échantillon des animaux de cette lignée de la mesure de l'angle de poitrine et du rendement en filet à 6 semaines. Des développements du modèle logistique multinomial déjà utilisé pour l'analyse génétique des valgus et varus ont été réalisés pour permettre l'analyse conjointe de plusieurs caractères discrets non ordonnés et d'une variable continue. Le modèle d'analyse fait l'hypothèse d'une compétition entre plusieurs variables sous-jacentes de sensibilité aux déformations, dépendant linéairement de la performance continue. Les paramètres de position pour les sensibilités sous-jacentes et le caractère continu ont été estimés par l'approche bayésienne du "Maximum A Posteriori"et les paramètres de dispersion par une approximation de type tilde-hat du "Maximum de Vraisemblance Marginale". Le modèle génétique d'analyse comprenait les effets des père, grand-père maternel et mère intra grand-père. Comme démontré dans une étude précédente, la sensibilité aux problèmes de patte présente une héritabilité modérée. En moyenne sur les deux lignées, l'estimation obtenue par la voie père/grand-père maternel (P-GPM) est de 0.22 pour les deux déformations et celle pour la voie mère de 0.37 pour le valgus et de 0.29 pour le varus. A l'exception de l'angle de poitrine, l'héritabilité des caractères de croissance et de conformation apparaît largement supérieure par la voie mère (de 0.41 à 0.63) que par la voie P-GPM (de 0.18 à 0.47). Les corrélations génétiques entre les sensibilités aux déformations osseuses et les performances de croissance apparaissent très faibles: la moyenne des estimations de la corrélation avec le poids vif à 3 semaines est de -0.03 pour le valgus et -0.05 pour le varus. Les corrélations avec le poids à 6 semaines sont du même ordre, estimées à respectivement +0.05 et +0.01 pour les valgus et varus. Une étude par simulation a permis de vérifier que ces faibles corrélations n'étaient pas dues à des biais éventuels liés aux effets secondaires négatifs des pathologies sévères sur les performances de croissance. D'après ces rèsultats, la prise en compte en sélection de la sensibilité aux problèmes de pattes n'introdurait pas, par une corrélation génétique défavorable, de réponse indirecte négative sur le poids. Si la sensibilité au valgus apparaît génétiquement indépendante des caractères de conformation (avec des corrélations génétiques avec l'angle de poitrine et le pourcentage de filet estimées à -0.06 et -0.8 respectivement), la liaison génétique apparaît plutôt défavorable pour le varus: +0.16 et +0.19 respectivement avec l'angle et le pourcentage de filet. Ces résultats doivent inciter à surveiller l'impact sur l'incidence des varus des fortes pressions de sélection appliquées actuellement sur les caractères de conformation. ZUSAMMENFASSUNG: Genetische Korrelationen zwischen verbogenen Füßen und Wachstums- und Formmerkmalen in Broilern Genetische Korrelationen zwischen 2 Arten von Beindeformationen, Valgus und Varus Angulationen, und einigen Wachtums- und Formmerkmalen wurden bei zwei kommerziellen Broiler Herkünften geschätzt, 14 264 Hühner beiderlei Geschlechter wurden in Linie A auf Beinfehler bei 6 Wochen Alter und Körpergewicht bei 3 (BW3) und 6 Wochen (BW6) untersucht, in Linie B 8 164 Tiere, wo aber auch Brustwinkel (BRA) und Brustfleisch (BRM) von ca. 70% der Hähne erhoben worden ist. Das für die genetische Analyse von Valgus und Varus Deformationen entwickelte multinomiale logit Modell wurde für die gemeinsame Analyse eines ungeordneten kategorischen Merkmals und einer kontinuierlichen Variablen erweitert. Dieses unterstellt Kompetition zwischen latenter Anfälligkeiten für verschiedene Deformationen und lineare Beziehung zu kontinuierlich verteilter Leistung. Lokationsparameter wurden mittels "Maximum A Posteriori" Ansatz und Dispersionsparameter mittels "Maximum Marginaler Likelihood" unter Verwendung von 'tilde-hat' Approximation geschätzt. Das genetische Modell berücksichtigte Vater-, maternale Großvater- und Muttertier-innerhalb der letzteren-Wirkungen. Beindeformationen zeigen mittlere Heritabilitätswerte, 0.22 für Valgus and Varus aus Vater/maternalem Großvater Komponenten, 0.37 bez. 0.29 aus der Muttertierkomponente. Mit Ausnahme von BRA waren Heritabilitätswerte für Wachstum- und Formmerkmale aus S/MGS-Komponenten (0.18-0.47) kleiner als die aus Muttertierkomponenten (0.41-0.63). Genetische Korrelationen zwischen letzeren und Anfällikeiten waren sehr niedrig: zwischen BW3 und Valgus und Varus -0.03 bzw. -0.05, BW6 +0.05 und 0.01. Simulation zeigte, daß die niedrigen Werte kaum auf negative Rückwirkung der Defekte auf Leistung zurückzuführen sind, sodaß deren Berücksichtigung in der Selektion den Zuchtfortschritt nicht beeinträchtigen sollte. Valgusdeformation scheint genetisch unabhängig von Formmerkmalen zu sein (r(G) -0.06, -0.08 mit BRA und BRM), während Varus mäßig ungünstige Korrelationen zeigt (+0.16, -0.19 mit BRA und BRM), sodaß Selektion auf Bemuskelung dies zu beachten hat.

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This historical review addresses major neurological disorders associated with deficiencies of water-soluble B vitamins: beriberi, Wernicke-Korsakoff syndrome, pellagra, neural tube defects, and subacute combined degeneration of the spinal cord. Beriberi: Beriberi was known for millennia in Asia, but was not described by a European until the 17th century when Brontius in the Dutch East Indies reported the progressive sensorimotor polyneuropathy. The prevalence of beriberi increased greatly in Asia with a change in the milling process for rice in the late 19th century. In the 1880s, Takaki demonstrated the benefits of dietary modification in sailors, and later instituted dietary reforms in the Japanese Navy, which largely eradicated beriberi from the Japanese Navy by 1887. In 1889 Eijkman in Java serendipitously identified dietary factors as a major contributor to "chicken polyneuritis," which he took to be an animal model for beriberi; the polyneuritis could be cured or prevented by feeding the chickens either unpolished rice or rice polishings. By 1901, Grijns, while continuing studies of beriberi in Java, suggested a dietary deficiency explanation for beriberi after systematically eliminating deficiencies of known dietary components and excluding a toxic effect. Wernicke-Korsakoff syndrome: In the late 1870s, Wernicke identified a clinicopathological condition with ophthalmoparesis, nystagmus, ataxia, and encephalopathy, associated with punctate hemorrhages symmetrically arranged in the grey matter around the third and fourth ventricles and the aqueduct of Sylvius. In the late 1880s, Korsakoff described a spectrum of cognitive disorders, including a confabulatory amnestic state following an agitated delirium, occurring in conjunction with peripheral polyneuropathy. Beginning around 1900, investigators recognized the close relationship between Korsakoff's psychosis, delirium tremens, and Wernicke's encephalopathy, but not until several decades later were Wernicke's encephalopathy, Korsakoff's psychosis, and beriberi all linked to the deficiency of a specific dietary factor, i.e. thiamin. Thiamin: Thiamin was crystallized from rice polishings by Jansen and Donath in 1926, and synthesized by Williams and Cline in 1936. In the late 1930s and early 1940s, characteristic pathological changes of Wernicke-Korsakoff syndrome were produced in animal models, the biochemical roles of thiamin in intermediary carbohydrate metabolism were elaborated by Peters and others, and the therapeutic benefits of thiamin for Wernicke-Korsakoff syndrome and beriberi were demonstrated. By the 1950s synthetic forms of the vitamin were produced cheaply, allowing both therapeutic administration and prevention with food enrichment. Pellagra and niacin: Pellagra was unknown prior to the introduction of maize into Europe from the New World. In the 18th century, Casàl and Frapolli described the clinical features of pellagra in Europe, and linked it with poverty and subsistence on nutritionally marginal corn-based diets. In the United States, pellagra became epidemic among poor Southerners in the early 20th century, in part because of economically-driven reliance on monotonous, nutritionally inadequate diets, combined with new manufacturing methods that removed vitamins from processed grain. From 1914-1929, Goldberger completed well-designed epidemiologic investigations, tested theories with human experiments, and utilized an animal model ("black tongue" in dogs) - all strongly supporting a dietary deficiency explanation for pellagra over prevailing toxic and infectious theories. Initial prevention and treatment approaches proved inadequate because of complex social issues linked to poverty, even after Goldberger and colleagues established that dried brewer's yeast could cure or prevent pellagra less expensively than dietary modification. During the depression, the collapse of cotton as an economically viable crop facilitated crop diversification, which contributed to an abrupt decline in pellagra mortality in the early 1930s. In 1937 Elvehjem isolated the P-P (pellagra preventive) factor, identified it as nicotinic acid (niacin), and demonstrated that nicotinic acid and nicotinic acid amide cure black tongue in dogs. Although clinical trials soon confirmed dramatic therapeutic effects in individual people, therapeutic administration of niacin had relatively little impact on population-level morbidity and mortality. Vitamin fortification of foodstuffs during World War II ultimately eradicated endemic pellagra in the United States. In the 1940s and 1950s, with expanded biochemical knowledge, pellagra was reformulated as a deficiency disease due to inadequate niacin and its amino acid precursor tryptophan. Neural tube defects and folate: Folate deficiency was initially recognized clinically as a macrocytic anemia in the 1920s, and only clearly separated from pernicious anemia by the mid-20th century. When folic acid was isolated and synthesized in the 1940s, it was shown to correct the macrocytic anemia associated with pernicious anemia, while the neurological manifestations progressed. In the 1950s and 1960s, the biochemical role of folates in transferring single carbon units was elucidated. Beginning in the 1960s, folate deficiency was increasingly recognized as the major cause of preventable neural tube defects. In the early 1990s well-designed randomized trials established that folate supplementation could prevent neural tube defects. Trial data, collectively indicating that periconceptual folate administration reduces both the occurrence and recurrence risks of neural tube defects by at least 70%, helped establish governmental recommendations concerning folic acid intake and health policy concerning vitamin fortification of foodstuffs. When dietary modification and supplementation strategies proved inadequate, folic acid food fortification was legally mandated in the US in the late 1990s, which significantly improved population folate status and produced an abrupt decline (20%-27%) in the prevalence of neural tube defects at birth. Recent studies have established genetic predispositions for neural tube defects, including both infant and maternal gene polymorphisms for enzymes involved in folate-dependent homocysteine metabolism, which help explain how the genotype of the mother, the genotype of the unborn child, and environmental factors (e.g. folate intake) can all impact on the risk of neural tube defects. Subacute combined degeneration and B(12) deficiency: Pernicious anemia was recognized clinically in the mid-19th century by Addison, but the most important neurological manifestation - subacute combined degeneration of the spinal cord - was not recognized clinically and linked with pernicious anemia until the end of the 19th century, particularly by Lichtheim, Putnam, and Dana. At the beginning of the 20th century, pernicious anemia and the associated subacute combined degeneration of the spinal cord were considered, by many investigators, to result from infectious or toxic causes. During the first quarter of the 20th century, various therapies were employed, but, with the possible exception of transfusion, were largely ineffective. In the 1920s, Minot and Murphy showed that large quantities of ingested liver could be used to effectively treat pernicious anemia, and specifically could improve or prevent progression of neurological manifestations, and could extend life expectancy beyond 2 years. Beginning in the late 1920s, Castle demonstrated that a substance elaborated by the gastric mucosa ("intrinsic factor") was essential for the absorption of a dietary factor ("extrinsic factor," later shown to be vitamin B(12)) needed to prevent pernicious anemia. Over two decades, from the late 1920s until the late 1940s, increasingly potent liver extracts were manufactured that could be given either intramuscularly or intravenously. In 1947, vitamin B(12) was isolated by Folkers and colleagues, and nearly simultaneously by Smith. Shortly thereafter the therapeutic efficacy of vitamin B(12) on subacute combined degeneration was demonstrated by West and Reisner and others. By 1955, Hodgkin determined the molecular structure of cyanocobalamin using computer-assisted x-ray crystallography, allowing complete chemical synthesis of vitamin B(12) in 1960 by an international consortium. Beginning in the late 1950s, the absorption and biochemistry of vitamin B(12) were elaborated, and several lines of evidence converged to support an autoimmune basis for pernicious anemia.

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Since the first U.S. infant conceived with Assisted Reproductive Technology (ART) was born in 1981, both the use of advanced technologies to overcome infertility and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which both eggs and sperm are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely to deliver multiple-birth infants than those who conceive naturally because more than one embryo might be transferred during a procedure. Multiple births pose substantial risks to both mothers and infants, including pregnancy complications, preterm delivery, and low birthweight infants. This report provides state-specific information on U.S. ART procedures performed in 2010 and compares infant outcomes that occurred in 2010 (resulting from procedures performed in 2009 and 2010) with outcomes for all infants born in the United States in 2010. 2010. In 1996, CDC began collecting data on all ART procedures performed in fertility clinics in the United States and U.S. territories, as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web-based data collecting system developed by CDC. In 2010, a total of 147,260 ART procedures performed in 443 U.S. fertility clinics were reported to CDC. These procedures resulted in 47,090 live-birth deliveries and 61,564 infants. The largest numbers of ART procedures were performed among residents of six states: California (18,524), New York (excluding New York City) (14,212), Illinois (10,110), Massachusetts (9,854), New Jersey (8,783), and Texas (8,754). These six states also had the highest number of live-birth deliveries as a result of ART procedures and together accounted for 48.0% of all ART procedures performed, 45.0% of all infants born from ART, and 45.0% of all multiple live-birth deliveries but only 34.0% of all infants born in the United States and U.S. territories. Nationally, the average number of ART procedures performed per 1 million women of reproductive age (15-44 years), which is a proxy indicator of ART use, was 2,331. In 13 states (California, Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Virginia), this proxy measure was higher than the national rate, and in four states (Connecticut, Massachusetts, New Jersey, and New York) and the District of Columbia, it exceeded twice the national rate. Nationally, among cycles in which at least one embryo was transferred, the average number of embryos transferred increased with increasing age (2.0 among women aged &lt;35 years, 2.4 among women aged 35-40 years, and 3.0 among women aged &gt;40 years). Elective single-embryo transfer (eSET) rates decreased with increasing age (10.0% among women aged &lt;35 years, 3.8% among women aged 35-40 years, and 0.6% among women aged &gt;40 years). ESET rates also varied substantially between states (range: 0 to 45.0% among women aged &lt;35 years). The number of ART births as a percentage of total infants born in the state or territory is considered as another measure of ART use. Overall, ART contributed to 1.5% of U.S. births (range: 0.1% in Guam to 4.8% in Massachusetts) with the highest rates (&gt;3.5% of all infants born) observed in four states (Connecticut, Massachusetts, New Jersey, and New York), and the District of Columbia. The proportion of ART births was ≤2.5% in the remaining states and territories. Infants conceived with ART comprised 20.0% of all multiple-birth infants (range: 0 in Guam to 40.5% in Massachusetts), 19.0% of all twin infants (range: 0 in Guam to 40.0% in Massachusetts), and 33.0% of triplet or higher order infants (range: 0 in several states to 60.0% in Arizona). Among infants conceived with ART, 46.0% were born in multiple deliveries (range: 0 in Guam to 55.4% in Utah), compared with only 3.0% of infants among all births in the general population (range: 1.3% in Guam to 4.7% in Connecticut). A substantial proportion (43.4%) of ART-conceived infants were twin infants, and a smaller proportion (3.0%) were triplets and higher order infants. Nationally, infants conceived with ART comprised 5.6% of all low birthweight (&lt;2,500 grams) infants (range: 0 in Guam to 16.0% in Massachusetts) and 5.6% of all very low birthweight (&lt;1,500 grams) infants (range: 0 in Guam to 15.8% in Massachusetts). Overall, among ART-conceived infants, 31.6% were low birthweight (range: 22.6% in New Hampshire to 48.2% in Puerto Rico), compared with 8.0% among all infants (range: 5.7% in Alaska to 12.6% in Puerto Rico); 5.6% of ART infants were very low birthweight (range: 1.9% in Maine to 14.3% in Montana), compared with 1.4% among all infants (range: 0.9% in Alaska to 2.3% in the District of Columbia). Finally, ART-conceived infants comprised 4.4% of all infants born preterm (&lt;37 weeks; range: 0 in Guam to 13.3% in Massachusetts) and 4.9% of all infants born very preterm (&lt;32 weeks; range: 0 in Guam to 16.2% in Massachusetts). Overall, among infants conceived with ART, 36.6% were born preterm (range: 23.6% in New Hampshire to 56.8% in Wyoming), compared with 12.0% among all infants born in the general population (range: 8.4% in Vermont to 17.9% in Guam); 6.6% of ART infants were born very preterm (range: 0 in Maine to 14.5% in Puerto Rico), compared with 2.0% among all infants born in the general population (range: 1.3% in Alaska to 3.0% in the District of Columbia). The percentage of infants conceived with ART varied considerably by state and territory (range: 0.1% to 4.8%). In most states, multiples from ART comprised a substantial proportion of all twin, triplet, and higher-order infants born in the state, and the rates of low birthweight and preterm infants were disproportionately higher among ART infants than in the birth population overall. Even among women aged &lt;35 years, for whom single embryo transfers should be considered (particularly in patients with a favorable prognosis) according to American Society of Reproductive Medicine (ASRM) guidelines, on average, two embryos were transferred per cycle in ART procedures, influencing the overall multiple infant rates in the United States. ART use per population unit was distributed disproportionately in the United States, with only 13 states showing ART use above the national rate, which might suggest barriers to ART services in the remaining states. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (e.g., coverage for at least four cycles of IVF), three states (Illinois, Massachusetts, and New Jersey) also had rates of ART use &gt;1.5 times the national level. This type of mandated insurance has been associated with greater use of ART and might account for the differences observed in other states. Reducing the number of embryos transferred per ART procedure among all age groups and promotion of eSET procedures, when clinically appropriate, is needed to reduce multiple births, including twin births, and related adverse consequences of ART. Improved patient education and counseling on the risks of twins might be useful in reducing twin births because twins account for the majority of multiples. Although ART contributes to increasing rates of multiple births, it does not explain all of the increases, and therefore the possible role of non-ART fertility treatments warrants further study.

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Autism spectrum disorder (ASD) is estimated to affect up to 3% of children in the United States. Public health surveillance for ASD among children aged 4 years provides information about trends in prevalence, characteristics of children with ASD, and progress made toward decreasing the age of identification of ASD so that evidence-based interventions can begin as early as possible. 2010, 2012, and 2014. The Early Autism and Developmental Disabilities Monitoring (Early ADDM) Network is an active surveillance system that provides biennial estimates of the prevalence and characteristics of ASD among children aged 4 years whose parents or guardians lived within designated sites. During surveillance years 2010, 2012, or 2014, data were collected in seven sites: Arizona, Colorado, Missouri, New Jersey, North Carolina, Utah, and Wisconsin. The Early ADDM Network is a subset of the broader ADDM Network (which included 13 total sites over the same period) that has been conducting ASD surveillance among children aged 8 years since 2000. Each Early ADDM site covers a smaller geographic area than the broader ADDM Network. Early ADDM ASD surveillance is conducted in two phases using the same methods and project staff members as the ADDM Network. The first phase consists of reviewing and abstracting data from children's records, including comprehensive evaluations performed by community professionals. Sources for these evaluations include general pediatric health clinics and specialized programs for children with developmental disabilities. In addition, special education records (for children aged ≥3 years) were reviewed for Arizona, Colorado, New Jersey, North Carolina, and Utah, and early intervention records (for children aged 0 to &lt;3 years) were reviewed for New Jersey, North Carolina, Utah, and Wisconsin; in Wisconsin, early intervention records were reviewed for 2014 only. The second phase involves a review of the abstracted evaluations by trained clinicians using a standardized case definition and method. A child is considered to meet the surveillance case definition for ASD if one or more comprehensive evaluations of that child completed by a qualified professional describes behaviors consistent with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnostic criteria for any of the following conditions: autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS, including atypical autism), or Asperger disorder (2010, 2012, and 2014). For 2014 only, prevalence estimates based on surveillance case definitions according to DSM-IV-TR and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) were compared. This report provides estimates of overall ASD prevalence and prevalence by sex and race/ethnicity; characteristics of children aged 4 years with ASD, including age at first developmental evaluation, age at ASD diagnosis, and cognitive function; and trends in ASD prevalence and characteristics among Early ADDM sites with data for all 3 surveillance years (2010, 2012, and 2014), including comparisons with children aged 8 years living in the same geographic area. Analyses of time trends in ASD prevalence are restricted to the three sites that contributed data for all 3 surveillance years with consistent data sources (Arizona, Missouri, and New Jersey). The overall ASD prevalence was 13.4 per 1,000 children aged 4 years in 2010, 15.3 in 2012, and 17.0 in 2014 for Early ADDM sites with data for the specific years. ASD prevalence was determined using a surveillance case definition based on DSM-IV-TR. Within each surveillance year, ASD prevalence among children aged 4 years varied across surveillance sites and was lowest each year for Missouri (8.5, 8.1, and 9.6 per 1,000, for 2010, 2012, and 2014, respectively) and highest each year for New Jersey (19.7, 22.1, and 28.4 per 1,000, for the same years, respectively). Aggregated prevalence estimates were higher for sites that reviewed education and health care records than for sites that reviewed only health care records. Among all participating sites and years, ASD prevalence among children aged 4 years was consistently higher among boys than girls; prevalence ratios ranged from 2.6 (Arizona and Wisconsin in 2010) to 5.2 boys per one girl (Colorado in 2014). In 2010, ASD prevalence was higher among non-Hispanic white children than among Hispanic children in Arizona and non-Hispanic black children in Missouri; no other differences were observed by race/ethnicity. Among four sites with ≥60% data on cognitive test scores (Arizona, New Jersey, North Carolina, and Utah), the frequency of co-occurring intellectual disabilities was significantly higher among children aged 4 years than among those aged 8 years for each site in each surveillance year except Arizona in 2010. The percentage of children with ASD who had a first evaluation by age 36 months ranged from 48.8% in Missouri in 2012 to 88.9% in Wisconsin in 2014. The percentage of children with a previous ASD diagnosis from a community provider varied by site, ranging from 43.0% for Arizona in 2012 to 86.5% for Missouri in 2012. The median age at earliest known ASD diagnosis varied from 28 months in North Carolina in 2014 to 39.0 months in Missouri and Wisconsin in 2012. In 2014, the ASD prevalence based on the DSM-IV-TR case definition was 20% higher than the prevalence based on the DSM-5 (17.0 versus 14.1 per 1,000, respectively). Trends in ASD prevalence and characteristics among children aged 4 years during the study period were assessed for the three sites with data for all 3 years and consistent data sources (Arizona, Missouri, and New Jersey) using the DSM-IV-TR case definition; prevalence was higher in 2014 than in 2010 among children aged 4 years in New Jersey and was stable in Arizona and Missouri. In Missouri, ASD prevalence was higher among children aged 8 years than among children aged 4 years. The percentage of children with ASD who had a comprehensive evaluation by age 36 months was stable in Arizona and Missouri and decreased in New Jersey. In the three sites, no change occurred in the age at earliest known ASD diagnosis during 2010-2014. The findings suggest that ASD prevalence among children aged 4 years was higher in 2014 than in 2010 in one site and remained stable in others. Among children with ASD, the frequency of cognitive impairment was higher among children aged 4 years than among those aged 8 years and suggests that surveillance at age 4 years might more often include children with more severe symptoms or those with co-occurring conditions such as intellectual disability. In the sites with data for all years and consistent data sources, no change in the age at earliest known ASD diagnosis was found, and children received their first developmental evaluation at the same or a later age in 2014 compared with 2010. Delays in the initiation of a first developmental evaluation might adversely affect children by delaying access to treatment and special services that can improve outcomes for children with ASD. Efforts to increase awareness of ASD and improve the identification of ASD by community providers can facilitate early diagnosis of children with ASD. Heterogeneity of results across sites suggests that community-level differences in evaluation and diagnostic services as well as access to data sources might affect estimates of ASD prevalence and age of identification. Continuing improvements in providing developmental evaluations to children as soon as developmental concerns are identified might result in earlier ASD diagnoses and earlier receipt of services, which might improve developmental outcomes.

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Abstract  The effects of ketoconazole on intradermal skin test results and on leukotriene C<sub4</sub (LTC<sub4</sub ) concentration in the skin of atopic dogs were evaluated in a pilot study. Twelve atopic dogs without a detectable Malassezia dermatitis were selected. All dogs had positive immedíate reaction to intradermal injection of house dust mite (HDM) at 25 PNU mL<sup-1</sup . Six dogs received a control sugar tablet and six dogs received ketoconazole at 5 mg kg<sup-1</sup PO b.i.d. for 3 weeks. On days 0 and 21, intradermal injections of saline, lipopolysaccharide (LPS) and house dust mite (HDM) were performed and biopsies of the injection sites were taken at 90 min postinjection to measure the concentration of LTC<sub4</sub in the skin. Intradermal skin test results were not affected by ketoconazole therapy. Ketoconazole significantly decreased the concentration of LTC<sub4</sub that could be elicited by the intradermal injection of saline and LPS. Ketoconazole also decreased the HDM-induced LTC<sub4</sub but differences between the prevalues and postvalues were not statistically significant. The mean decrease of LTC<sub4</sub concentration in the ketoconazole group was 37% for the saline injection, 42% for the LPS injection and 26% for HDM injection. In the control group no significant changes in the LTC<sub4</sub concentrations were found over the 3-week time of the study. This pilot study showed that ketoconazole has anti-inflammatory properties and suggests that this drug may be effective in decreasing the skin concentrations of LTC<sub4</sub in atopic dogs. Résumé- Les effets de kétoconazole sur les résultats des tests intradermiques et la concentration en leucotriène C4 (LTC<sub4</sub ) dans la peau de chiens atopiques ont étéévalués dans une étude en double aveugle. Douze chiens atopiques sans dermite à Malassezia ont été selectionnés. Tous les chiens ont des tests intradermiques positifs aux acariens de la poussière de maison à 25 PNU mL<sup-1</sup à 20 minutes. Six chiens ont reçu des comprimés de sucre, six autres ont reçu du kétoconazole à 5 mg kg<sup-1</sup , 2 fois par jour par voie orale pendant 3 semaines. Aux jours 0 et 21, des injections intradermiques de liposaccharides (LPS), d'eau salée et d'aeariens de la poussière de maison sont réalisées et des biopsies des points d'injections sont effectuées 90 minutes après l'injection afin de mesurer la concentration en LTC<sub4</sub dans la peau. Les résultats des tests intradermiques ne sont pas modifies par la thérapeutique au kétoconazole. Par contre, le kétoconazole diminue significativement la concentration en LTC<sub4</sub induit par les injections intradermiques de LPS et d'eau salee. Le kétoconazole diminue également le LTC<sub4</sub induit par les acariens de la poussière de maison, mais il n'existe pas de différence significative entre les valeurs avant et après. La diminution moyenne de LTC<sub4</sub dans le groupe traité au kétoconazole est de 37% pour l'injection intradermique d'eau salée, de 42% pour l'injection intradermique de LPS et de 26% pour l'injection intradermique d'acariens de la poussière de maison. Dans le groupe de contrôle, aucune différence significative dans les concentrations en LTC<sub4</sub n'est observée durant les 3 semaines de l'étude. Cette étude démontre que le kétoconazole a des propriétés antiinflammatoires et suggèrent qu'il peut être efficace dans la diminution des concentrations en LTC<sub4</sub chez les chiens atopiques. [Marsella R, Kunkle, GA, Vaughn, DM, Macdonald, J. Double-blind pilot study in the effects of kétoconazole on intradermal skin test and leukotriene C<sub4</sub concentration in the skin of atopic dogs. (Etude en double aveugle sur les effets du kétoconazole sur les tests intradermiques et la concentration en leucotriène C<sub4</sub dans la peau de chiens atopiques.) Veterinary Dermatology 1997; 8: 3-10.] Resumen  Se evaluaron en un estudio piloto los efectos del ketoconazol sobre los resultados del test intradérmico cutáneo y sobre las concentraciones de leucotrieno C<sub4</sub (LTC<sub4</sub ) en la piel de perros atópicos. Se seleccionaron doce perros atópicos sin Dermatitis por Malassezia detectable. Todos los perros mostraban respuesta positiva inmedíata a la inyección del ácaro del polvo doméstico (HDM) a 25 PNU mL<sup-1</sup . Seis perros recibieron una tableta control de azúcar y seis recibieron ketoconazol a dosis de 5 mg kg<sup-1</sup PO BID durante 3 semanas. En los días 0 y 21 se realizaron inyecciones intradérmicas de suero salino, lipopolisacárido (LPS) y ácaro del polvo doméstico, y se tomaron biopsias de las zonas inyectadas a los 90 minutos postinyección para cuantificar la concentración de LTC<sub4</sub en la piel. Los resultados de los tests intradérmicos no se afectaron por la terapia con ketoconazol. El ketoconazol disminuyó significativamente la concentración de LTC<sub4</sub que pudo haber provocado la inyección intradérmica de suero salino y LPS. El ketoconazol también disminuyó el LTC<sub4</sub inducido por el HDM pero las diferencias entre los valores previos y posteriores no fueron estadisticamente significativos. La disminución en la concentración medía de LTC<sub4</sub en el grupo de ketoconazol fue del 37% para la inyección de suero salino, 42% para la de LPS y 26% para la de HDM. En el grupo control no se encontraron alteraciones significativas en las concentraciones de LTC<sub4</sub durante las 3 semanas que duró el estudio. Este estudio piloto mostró que el ketoconazol posee propiedades antiinflamatorias y sugiere que este fármaco puede ser efectivo en disminuir las concentraciones cutáneas de LTC<sub4</sub en perros atópicos. [Marsella R, Kunkle, GA, Vaughn, DM, Macdonald, J. Double-blind pilot study in the effects of ketoconazole on intradermal skin test and leukotriene C<sub4</sub concentration in the skin of atopic dogs. (Estudio doble ciego sobre los efectos del ketoconazol en los tests intradérmicos cutaneos y en la concentración de leucotrieno C<sub4</sub en la piel de perros atópicos.) Veterinary Dermatology 1997; 8: 3-10.] Zusammenfasung In einer Pilotstudie wurden die Wirkung von Ketoconazol auf Ergebnisse des intrakutanen Hauttests und der Leukotrien C<sub4</sub (LTC<sub4</sub )-Konzentration in der Haut atopischer Hunde bewertet. Zwölf atopische Hunde ohne feststellbare Malassezia Dermatitis wurden ausgewählt. Alle Hunde hatten eine positive Sofortreaktion zu Hausstaubmilbenextrakt von 25 PNU mL<sup-1</sup . Sechs Hunde erhielten eine Zuckertablette als Kontrolle und sechs Hunde erhielten Ketoconazol in einer Dosis von 5 mg kg<sup-1</sup oral zweimal täglich für drei Wochen. An den Tagen 0 und 21 wurden intrakutane Injektionen von physiologischer Kochsalzlösung, Lipopolysaccharid (LPS) und Hausstaubmilbenextrakt durchgeführt und 90 Minuten danach Biopsien an den Injektionsstellen entnommen, um die Konzentration von LTC<sub4</sub in der Haut zu messen. Ketoconazoltherapie hatte keinen Einfluss auf die Ergebnisse des Intrakutantests. Ketoconazol verminderte die LTC<sub4</sub Konzentration in den intrakutanen Injektionsstellen von physiologischer Kochsalzlösung und LPS. Die Konzentrationen des von Hausstaubmilbenextrakt-induzierten LTC<sub4</sub waren ebenfalls vermindert, die Unterschiede zwischen den Werten vor und nach der Injektion waren jedoch nicht statistisch significan. Die durchschnittliche Verminderung der LTC<sub4</sub Konzentration in der Ketoconazol-Gruppe betrug 37% für die Injektion mit Kochsalzlösung, 42% für die Injektion mit LPS und 26% für die Injektion mit Hausstaubmilbenextrakt. In der Kontrollgrupe wurden während der dreiwöchigen Studie keine signifikanten Veränderungen in der LTC<sub4</sub Konzentration festgestellt. Diese Pilotstudie zeigt die entzündungshemmende Wirkung von Ketoconazol und deutet darauf hin, daß dieses Medikament geeignet sein könnte, die Hautkonzentration von LTC<sub4</sub in atopischen Hunden zu verringern. [Marsella R, Kunkle, GA, Vaughn, DM, Macdonald, J. Double-blind pilot study in the effects of ketoconazole on intradermal skin test and leukotriene C<sub4</sub concentration in the skin of atopic dogs. (Doppelblind-Pilotstudie über die Wirkung von Ketoconazol auf den intrakutanen Hauttest und die Konzentration von Leukotrien C<sub4</sub in der Haut atopischer Hunde.) Veterinary Dermatology 1997; 8: 3-10.].

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"Fetuses can hear ultrasound and the sound is as loud as a subway train entering a station." This statement originates in a single report in a non-peer reviewed journal, despite its name 1, of a presentation at a scientific meeting by researchers who reported measuring the sound intensity in the uterus of pregnant women and being able to demonstrate the above. This was later published in a peer-review journal 2 probably not very widely read by clinicians or the general public. From time to time, the popular press or various pregnancy-related websites repeat the assertion or a worried pregnant patient inquires about the truthfulness of this statement. A second, oft-quoted concern is that ultrasound leads to heating of the amniotic fluid. These two assertions may be very concerning to expectant parents and merit scientific scrutiny. In this editorial, we shall examine the known facts about the physical properties of ultrasound as they relate to these two issues. Diagnostic ultrasound employs a pulsed sound wave with positive and negative pressures and the Mayo team, quoted in the New Scientist, predicted that the pulsing would translate into a "tapping" effect 1. According to their report, they placed a tiny hydrophone inside a woman's uterus while she was undergoing an ultrasound examination. They stated that they picked up a hum at around the frequency of the pulsing generated when the ultrasound is switched on and off. The sound was similar to the highest notes on a piano. They also indicated that when the ultrasound probe was pointed right at the hydrophone, it registered a level of 100 decibels, as loud as a subway train coming into a station. Sound levels in decibels are defined for audible frequencies with the reference level being the threshold for hearing at a given frequency. Although the operating frequencies used in sonography are inaudible, it is possible for the pulsing rate (pulse repetition frequency, PRF) to be heard, thus falling in the audible range. A previous report had hinted at similar phenomena 3.Ultrasound is a pressure wave with a frequency beyond (ultra) that detectable in the human auditory system. The human ear can discern sound at roughly 20 - 20 000 cycles (hertz) per second. The frequencies of diagnostic ultrasound are roughly 1 - 10 megahertz (MHz) or 1 000 000 to 10 000 000 cycles per second. It is a form of energy and, as such, may have effects in tissues it traverses. Any consequences occurring in living tissues secondary to an external influence are called biological effects or bioeffects. This term does not imply damage or harm. The two major mechanisms for bioeffects are thermal and non-thermal. Thermal effects are secondary to ultrasound energy being converted into heat in the tissue (indirect effect of ultrasound) and non-thermal effects are secondary to the alternating positive and negative pressures generated by the wave (direct effect). The definition of moderately loud sound is 60 - 70 dB (2 × 10-3-2 × 10-2 Pa), defined as high urban ambient sound, normal conversation at 1 m, or living room music 4. In comparison, quiet conversation is 40 dB, a railway diesel engine passing at 45 mph at 100 feet is 80 - 85 dB and a rock band is 110 dB 4. There have been a few publications describing harm to fetuses exposed to elevated levels of ambient noise, particularly industrial noise 567, specifically in the aircraft and textile industries, but while there have been reports of impaired hearing in infants who were exposed to ultrasound in the womb, several rigorous studies have disproved that notion 891011. Furthermore, a study of fetuses exposed in utero to vibroacoustic stimulation 12 and a recent study of fetuses exposed to noise generated during an MR exam of the pregnant women 13 showed no ill effect on the auditory system. There have been some reports of being able to hear a "hum" during transcranial ultrasound. This may be the pulse-repetition frequency (PRF), but, if so, it would be described as a higher pitch, and probably not a "hum". To our knowledge, this phenomenon has not been investigated. Although the report mentioned above suggested that diagnostic ultrasound is detectable at measurable levels in the uterus, there is no independently confirmed, peer-reviewed, published evidence that the fetus actually hears the PRF, responds to it or is harmed by it."The fetus cannot regulate its own body temperature, so amniotic fluid can reach very high temperatures over long periods" 14. Does this statement reflect a real risk? What does it mean if this statement is scientifically true? The fear is, of course, that this will raise the temperature of the fetus. Thermally induced teratogenesis has been demonstrated in many animal studies, as well as several controlled human studies 1516. A temperature increase of 1.5 °C above the normal value has been suggested as a universal threshold 17. It is important to note that diagnostic ultrasound was not the source of the temperature elevation in any of these studies. Some believe that there are temperature thresholds for hyperthermia-induced birth defects (hence the ALARA [as low as reasonably achievable] principle), but there is some evidence that any positive temperature differential for any period of time has some effect, in other words there may be no thermal threshold for hyperthermia-induced birth defects 18. In experimental animals the most common defects are microcephaly with associated functional and behavioral problems 17, microphthalmia and cataracts. There are reports on the effects of hyperthermia and measurements of in vivo temperature induced by pulsed ultrasound but not in humans 192021. Temperature increases of 1 °C are easily reached in routine scanning 22. Elevation of up to 1.5 °C can be obtained in the first trimester and up to 4 °C in the second and third trimesters, particularly with the use of pulsed Doppler 23. When the ultrasound wave travels through tissue, its intensity diminishes with distance (attenuation). In completely homogeneous materials, the signal amplitude is reduced only by beam divergence and absorption (conversion of sound to heat). However, biologic tissues are non-homogeneous and further weakening occurs due to scattering. The issue of temperature increase in the amniotic fluid is based on the fact that the energy of the ultrasound waves is partially converted to heat in the tissue traversed by the waves. Tissues with a high absorption coefficient (such as bone) will produce a high conversion rate while the conversion will be lower in tissues with low absorption. Fluids have very low absorption characteristics and, therefore, the risk of temperature elevation in the amniotic fluid is minimal. The only available study on the topic did not demonstrate any increase in temperature in the amniotic fluid when performing diagnostic ultrasound, both in grayscale anatomic imaging (sonography) and Doppler ultrasound 24. ConclusionWhile ultrasound is a sound wave which can produce mechanical effects and temperature elevation in tissues that it traverses, the risk to human fetuses when using diagnostic ultrasound appears to be minimal if certain rules are followed, such as performing a scan when medically indicated, and observing the ALARA principle (using the lowest output power consistent with acquiring the necessary diagnostic information and keeping the exposure time as low as possible for accurate diagnosis).

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o-Benzyl-p-chlorophenol (BCP), an aryl halide, is a broad spectrum germicide used in disinfectant solutions and soap formulations in United States hospitals and households. Human exposure to BCP occurs by absorption through the skin and mucous membranes and by ingestion. BCP was studied because of the widespread human exposure and because BCP is an irritant and certain phenolic compounds are weak promoters of skin neoplasia. Groups of Swiss (CD-1(R)) mice were used to study BCP in a 1-year mouse skin initiation/promotion protocol. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 1-YEAR INITIATION/PROMOTION STUDY: Groups of 50 male and 50 female Swiss (CD-1(R)) mice were topically exposed to BCP to study its effect as an initiator, promoter, and complete carcinogen. A number of control groups were included in these studies as a reference for the responses of the mouse skin to o -benzyl- p -chlorophenol (see following table). See report abstract or full report for Dose Regimen for Reference Controls in the 1-Year Initiation/Promotion Study of o -Benzyl- p - Chlorophenol. BCP in acetone was tested as an initiator with the promoter 12- O -tetradecanoylphorbol-13-acetate (TPA). The potential of BCP as an initiator was studied by applying a single 100 mL dose of BCP in acetone at a concentration of 10 mg/mL to the dorsal interscapular region of the backs of mice during week 1 of the study. Following the initial BCP application, mice were administered promoting doses of 5 mg TPA three times per week in 100 mL acetone for the first 6 months of the study and once weekly for the final 6 months of the study. BCP in acetone was tested as a promoter with the initiator 7,12-dimethylbenz(a)anthracene (DMBA). Mice were administered a single initiating dose of 50 mL DMBA in 100 mL acetone. Beginning on the second week of the study, mice received 100 mL applications of 0.1, 1.0, or 3.0 mg BCP in acetone three times weekly for up to 51 weeks. Comparative control groups used during the study of BCP as a promoter included: vehicle control (acetone/acetone); promoter control (TPA/TPA); and initiator control (DMBA/acetone). The potential for BCP to act as a complete carcinogen was studied by applying a single initiating dose of 10 mg BCP in 100 mL of acetone, followed by tri-weekly 100 mL applications of 0.1, 1.0, or 3.0 mg BCP to 50 male and 50 female Swiss (CD-1(R)) mice for 52 weeks. The responses of these groups were compared to vehicle control (acetone/acetone) and complete carcinogen control (acetone/DMBA) groups. The following table shows the various groups with BCP as a promoter, an initiator, and as a complete carcinogen. See full report or abstract for Dose Regimen in the 1-Year Initiation/Promotion Study of o - Benzyl- p -Chlorophenol. Results in the Study of BCP as a Complete Carcinogen: BCP acted as an irritant when tested as a complete carcinogen using a single initiating dose of 10 mg BCP followed by repetitive applications of 0.1, 1.0, or 3.0 mg BCP for up to 52 weeks, and many of the mice developed cutaneous lesions of scaling/crusts and ulceration. During the course of the study, a single papilloma was first observed after 12 weeks in one 0.1 mg BCP male mouse. One 3.0 mg BCP female was observed with a papilloma at week 10, and three 0.1 mg BCP females were observed with papillomas between weeks 22 and 27. No mice administered BCP/BCP had papillomas at the end of the study, and no malignant cutaneous epithelial tumors were observed at the application sites on any BCP/BCP mice. Thus, in the present study, BCP was not a complete carcinogen. Results in the Study of BCP as an Initiator: One vehicle control (acetone/acetone) male mouse had developed crusts at the site of application at necropsy, but no male or female vehicle controls had developed papillomas. Mice administered BCP/TPA developed application site lesions including scaling/crusts, ulceration, and irritation; the incidences of these lesions were similar to those in the initiator/promoter control (DMBA/TPA) /TPA) groups. After 22 weeks papillomas were observed in 12/50 male mice administered BCP/TPA. After 12 weeks papillomas were observed in 7/50 female mice administered BCP/TPA. However, the incidences of papillomas in mice administered BCP/TPA were lower than those in mice administered TPA/TPA (males, 16/50; females, 16/50) and were much lower than those in DMBA/TPA mice (males, 40/50; females, 48/50). Although the incidences of papillomas in mice administered BCP as an initiator were significantly greater than those in the vehicle controls, the incidences were not significantly different from those in TPA/TPA mice. Thus, in the present study, BCP did not demonstrate initiating potential. Results in the Study of BCP as a Promoter: During the course of the study, incidences of scaling and/or crusts, ulceration, and irritation were observed at the site of application in DMBA/BCP male and female mice, and the incidences were dose-related. Incidences of scaling and/or crusts, ulceration, and irritation in 3.0 mg BCP mice were similar to the incidences of these lesions in initiator/promoter control (DMBA/TPA) group, but much higher than the incidences of these lesions in the initiator control (DMBA/acetone) group. A dose-related increased incidence of papillomas was observed in males (DMBA/acetone, 8/50; DMBA/0.1 mg BCP, 3/50;DMBA/1.0 mg BCP, 5/50; and DMBA/3.0 mg BCP, 14/50) and females (2/50, 6/50, 6/50, and 18/50). The incidence of papillomas in DMBA/3.0 mg BCP females was significantly greater (P&amp;lt;0.001) than that in DMBA/acetone females; the incidence of papillomas in DMBA/3.0 mg BCP males was marginally increased (P=0.077). No acetone/acetone mice developed papillomas. Although a higher percentage of DMBA/3.0 mg BCP mice developed papillomas over the course of the study than did DMBA/acetone controls, the time it took for half of the number of responding animals to develop papillomas was similar between DMBA/acetone groups and DMBA/3.0 mg BCP groups (DMBA/acetone males, week 38; DMBA/acetone females, week 34; DMBA/3.0 mg BCP males, week 36; DMBA/3.0 mg BCP females, week 37). However, the time to appearance of the first papilloma was shorter in DMBA/3.0 mg BCP mice (males, week 18; females, week 10) than in DMBA/acetone mice (males, week 26; females, week 27). BCP was considered to have promotion potential because the incidences of papillomas in mice treated with DMBA/3.0 mg BCP were greater than those in DMBA/acetone (initiator control) mice and because topical exposure to BCP alone caused no significant increased incidence of papillomas. However, the incidences of papillomas in DMBA/3.0 mg BCP mice (males, 14/50; females, 18/50) were much less than the incidences in DMBA/TPA (promoter control) mice (males, 40/50; females, 48/50); thus, BCP was classified as a weak promoter. GENETIC TOXICOLOGY: o -Benzyl- p -chlorophenol did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. All tests were performed with and without S9 activation. CONCLUSIONS: Under the conditions of this 1-year mouse skin initiation/promotion study in Swiss (CD-1&amp;reg;) mice, o -benzyl- p -chlorophenol was a cutaneous irritant and a weak skin tumor promoter relative to strong promoters such as TPA. BCP had no activity as an initiator or as a complete carcinogen.

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Bromodichloromethane (99% pure), one of several trihalomethanes commonly formed after chlorination of water, was selected for study because no carcinogenicity data were available for this compound and because chloroform, a related trihalomethane, had been found to cause tumors in rodents. The general population might be exposed to bromodichloromethane in drinking water supplies, in swimming pools, and in a variety of food substances. Single-administration, 14-day, 13-week, and 2-year studies were conducted in F344/N rats and B6C3F1 mice. The chemical was administered by gavage in corn oil because human exposure is primarily oral. Additional studies were performed to evaluate the potential for genetic damage in bacteria and mammalian cells. Results of the Short-Term Studies: In the single-administration studies, the chemical was administered at doses of 150-2,500 mg/kg per day. All rats and female mice at 1,250 and 2,500 mg/kg and all male mice at 600, 1,250, and 2,500 mg/kg died; 2/5 male rats, 1/5 female rats, and 2/5 female mice at 600 mg/kg died; all animals at lower dose levels survived. In the 14-day studies, rats received doses of 38-600 mg/kg, and mice received doses of 19-300 mg/kg per day. One female rat at 38 mg/kg and one female rat at 600 mg/kg died. Weight loss or decreased weight gain was seen at 300 and 600 mg/kg in male and female rats. All male mice at 150 and 300 mg/kg died, and one female mouse at 300 mg/kg died; no weight effects were observed in surviving mice. Dose-related necropsy findings included reddened renal medullae in male rats at 600 mg/kg and in male mice at 150 and 300 mg/kg. Clinical signs seen in high dose groups after dosing were hyperactivity in rats and lethargy in mice. In the 13-week studies, male and female rats received doses of 19-300 mg/kg per day, male mice received doses of 6.25-100 mg/kg per day, and female mice received doses of 25-400 mg/kg per day. Five of 10 male rats and 2/10 female rats at 300 mg/kg died. None of the mice died. Final body weights of male and female rats at 150 and 300 mg/kg were lower than those of vehicle controls (45%-88% of vehicle control weights); final body weights of male mice at 100 mg/kg and female mice at 400 mg/kg were 92% and 94% of those of the vehicle controls. Centrilobular degeneration in the liver and degeneration and necrosis of the kidney were seen in male rats at 300 mg/kg; centrilobular degeneration was seen in female rats at 300 mg/kg; degeneration andnecrosis of the kidney were seen in male mice at 100 mg/kg, and centrilobular degeneration of the liver was seen in female mice at 200 and 400 mg/kg. Experimental Design of the Two-Year Studies: The 2-year toxicology and carcinogenesis studies of bromodichloromethane were conducted by administering the chemical in corn oil by gavage, 5 days per week for 102 weeks, to groups of 50 male and female rats at doses of 0, 50, or 100 mg/kg per day; to groups of 50 male mice at doses of 0, 25, or 50 mg/kg per day; and to groups of 50 female mice at doses of 0, 75, or 150 mg/kg per day. The study in male rats was restarted because at 10.5 months into the original study, a temperature elevation killed 45/50 vehicle control male rats. Survival and Body Weight in the Two-Year Studies: Final survival of dosed rats was comparable to that of vehicle controls (male: vehicle control, 28/50; low dose, 36/50; high dose, 28/50; female: 34/50; 27/50; 41/50). Mean body weights of high dose male and female rats were decreased during the last 1.5 years of the study; final mean body weights of high dose male and female rats were 88% and 79% of the vehicle control mean weights. Final mean body weights of low dose male and female rats were comparable to those of the vehicle controls. Final survival of dosed male mice was comparable to that of the vehicle controls (34/50; 32/50; 42/50). At week 84, survival of female mice was greater than 50% in all dose groups. After week 84, survival of dosed and vehicle control female mice was reduced (final survival: 26/50; 13/50; 15/50), and this decreased survival was ass6/50; 13/50; 15/50), and this decreased survival was associated with ovarian abscesses (8/50; 19/47; 18/49). The final mean body weight of high dose male mice was 95&amp;percnt; that of the vehicle controls; the final mean body weight of low dose male mice was comparable to that of the vehicle controls. Mean body weights of the high dose female mice were decreased during the last 1.5 years of the study; the final mean body weight was 75&amp;percnt; that of the vehicle controls. The final mean body weight of the low dose female mice was 91&amp;percnt; that of the vehicle controls. Nonneoplastic Effects in the Two-Year Studies: Compound-related nonneoplastic lesions included cytomegaly and tubular cell hyperplasia of the kidney and necrosis and fatty metamorphosis of the liver in male rats; eosinophilic cytoplasmic change, clear cell change, focal cellular change, and fatty metamorphosis of the liver and tubular cell hyperplasia of the kidney in female rats; fatty metamorphosisof the liver, renal cytomegaly, and follicular cell hyperplasia of the thyroid gland in male mice; and follicular cell hyperplasia of the thyroid gland in female mice. Neoplastic Effects in the Two-Year Studies: Bromodichloromethane caused compound-related increases in the incidences of neoplasms of the large intestine and kidney in male and female rats, the kidney in male mice, and the liver in female mice, as shown in the table (see page 5 of the Technical Report). The neoplasms of the large intestine and kidney are uncommon tumors in F344/N rats and B6C3F1 mice. Administration of bromodichloromethane was also associated with a decrease in the tumors of the adrenal glands in male rats, the pituitary and mammary glands in female rats, and the pituitary gland in female mice. Genetic Toxicology: Bromodichloromethane was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested by the preincubational protocol at concentrations up to 1,000 ug/plate with or without metabolic activation. The compound was not mutagenic in the mouse lymphoma L5178Y/TK&amp;plusmn; assay in the presence of S9 but did induce forward mutations in the system in the presence of metabolic activation from rat liver S9. Cytogenetic tests with Chinese hamster ovary cells demonstrated no induction of chromosomal aberrations orsister chromatid exchanges following treatment with bromodichloromethane in either the presence or absence of metabolic activation. Data Audit: An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of bromodichloromethane. No discrepancies were found that influenced the final interpretations of the results of these studies. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats and B6C3F1 mice as shown by increased incidences of tubular cell adenomas and adenocarcinomas in the kidney and adenocarcinomas and adenomatous polyps in the large intestine in male and female rats, increased incidences of tubular cell adenomas and adenocarcinomas in the kidney of male mice, and increased incidences of hepatocellular adenomas and carcinomas in female mice. Synonym: dichlorobromoethane

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Quetiapine, a dibenzothiazepine derivative, is one of several new 'atypical' antipsychotic agents. In preclinical studies, the drug was predicted to have antipsychotic efficacy and a low propensity to induce extrapyramidal effects. Quetiapine has been shown to be effective in the short term (up to 6 weeks) treatment of patients with schizophrenia in several large well designed trials. In general, clinical efficacy is dose related, with maximum effects occurring at a dosage ≥ 250 mg/day. Quetiapine is at least as effective as chlorpromazine and haloperidol, with similar between- treatment improvements in the various rating scales used to assess overall and negative symptoms. Quetiapine is associated with significantly fewer extrapyramidal effects than haloperidol and may have some advantages over chlorpromazine in this regard. There have been no reports of agranulocytosis attributed to quetiapine and the drug did not produce an elevation in serum prolactin levels in patients with schizophrenia. Headache, somnolence and dizziness are common adverse events that are reported more often with quetiapine than with placebo. Quetiapine is associated with small dose-related decreases in total and free thyroxine; however, cessation of treatment usually results in reversal of these effects. The drug is also associated with asymptomatic, generally transient elevations in hepatic transaminases. Although the antipsychotic activity of quetiapine has been well demonstrated in 6-week studies, its long term effectiveness, position relative to other atypical antipsychotic agents and efficacy in refractory schizophrenia remain to be fully determined. Nevertheless, on the basis of available data, quetiapine should provide a valuable alternative to classical antipsychotic agents in the short term treatment of patients with schizophrenia. Quetiapine is a dibenzothiazepine derivative with greater in vitro binding affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors. 12 hours after the final dose of a 4-week course of quetiapine 150mg 3 times daily, in vivo dopamine D2 and 5-HT2 receptor occupancies were 27 and 58%, respectively. Electrophysiological studies in rats have not consistently demonstrated selectivity of quetiapine for mesolimbic dopaminergic pathways. However, immediate-early gene expression studies indicate that the drug has preferential action on limbic structures. Quetiapine is active in many animal behavioural models that are predictive of antipsychotic activity. Notably, studies in animal models considered predictive of the potential to induce extrapyramidal effects indicate that quetiapine is less likely to induce these effects than the classical antipsychotic haloperidol. Quetiapine also significantly improved performance on measures of neurocognitive function that are generally ascribed to the prefrontal cortex in patients with schizophrenia. Quetiapine is not associated with elevations in plasma prolactin levels in patients with schizophrenia. Quetiapine is rapidly absorbed after oral administration. Maximum steady-state plasma concentrations (C(SS) max) and areas under the plasma concentration-time curves from 0 to 8 hours at steady state (AUC(SS) 0-l8h) were dose proportional and similar in men and women. The drug has a large volume of distribution (approximately 700L). Quetiapine is extensively metabolised in the liver. The major metabolic pathway involves sulphoxidation by cytochrome P450 3A4. Pharmacokinetic drug interactions may occur when quetiapine is coadministered with inducers or inhibitors of this enzyme. The half-life of quetiapine is approximately 6 hours. In elderly patients, C(SS) max and AUC(SS) 0-8h values were approximately 20 to 30% higher and apparent oral clearance values were up to 50% lower than in younger patients. Mean oral clearance was reduced by approximately 25% in patients with hepatic cirrhosis or severe renal impairment, compared with healthy controls. In short term trials (6 weeks), quetiapine was generally significantly more effective than placebo in improving the positive and negative symptoms of schizophrenia. These improvements appeared to be dose dependent: in a recent study, while there was no significant difference in major efficacy criteria between low-dose quetiapine (maximum daily dose 250 mg/day) and placebo, high-dose quetiapine (maximum daily dose 750 mg/day) was significantly more effective than placebo. Results of a recent trial support twice daily administration of quetiapine. There was no significant difference in efficacy parameters between 2 and 3 times daily administration of a total dose of 450 mg/day. Data from a large comparative trial indicate that quetiapine and chlorpromazine are equally effective in treating patients with schizophrenia; mean Brief Psychiatric Rating Scale (BPRS) total scores decreased by about 18 points in each treatment group from a baseline of &gt;40. In addition, reductions from baseline in the negative scale score of the Positive and Negative Symptom Scale were not significantly different between treatments. Quetiapine 300 mg/day was found to have therapeutic equivalence with haloperidol 12 mg/day as measured by the BPRS, Clinical Global Impression Scale severity of Illness item and the Modified Scale for the Assessment of Negative Symptoms. Preliminary data from patients enrolled in open-label extensions to short term trials suggest that initial reductions in BPRS scores with quetiapine are maintained over 1 year of treatment. Pooled tolerability data from placebo-controlled trials show that the most common adverse events which were reported more often with quetiapine than with placebo were headache (19.4 vs 17.5%), somnolence (17.5 vs 10.7%) and dizziness (9.6 vs 4.4%). Postural hypotension, tachycardia, constipation, dry mouth, dyspepsia and transient liver enzyme elevations also occurred in ≥5% of quetiapine recipients. Agitation and insomnia, which were seen with quetiapine therapy (but were observed at a similar incidence with placebo) are thought to be an expression of the underlying psychotic illness. Quetiapine treatment is associated with weight gain of approximately 2.1kg in short term clinical trials. There were no statistically significant differences in the proportions of quetiapine-versus placebo-treated patients experiencing potentially important changes in ECG parameters including QT, QTc and PR intervals. Quetiapine demonstrated little potential for the induction of extrapyramidal effects across the range of doses used in clinical trials. The drug was not significantly different from placebo with respect to the incidence of extrapyramidal signs/symptoms but showed significant advantages over haloperidol. In addition, quetiapine may have some advantages over chlorpromazine with respect to these symptoms. Quetiapine has not been associated with agranulocytosis or elevations in plasma prolactin levels in patients with schizophrenia. However, asymptomatic elevations in hepatic transaminases (particularly alanine aminotransferase) have been measured. These were transient with continued treatment in most instances. Treatment with quetiapine is associated with small dose-related decreases in levels of total and free thyroxine. These changes usually reverse with treatment cessation. Preliminary data indicate that quetiapine is well tolerated for up to 2 years in patients with schizophrenia. Although causality has not been established, the possibility of lenticular changes with long term quetiapine treatment cannot be excluded and 6-monthly slit lamp eye examinations are recommended in some countries. The recommended target dosage of quetiapine in otherwise healthy adults with schizophrenia is 300 to 450 mg/day administered as 2 doses. Treatment should be initiated at a dosage of 50 mg/day. Daily incremental adjustments should then be made until target dose is reached by day 4. Thereafter, dosage may be titrated according to clinical response and tolerability within the range 150 to 750 mg/day. Quetiapine should be used with caution in the elderly and in patients with renal or hepatic impairment. A starting dose of 25 mg/day is recommended in these patients, with daily dosage increases of 25 to 50mg to an effective dose, which is likely to be lower than that in other patients.

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Sexual violence, stalking, and intimate partner violence are public health problems known to have a negative impact on millions of persons in the United States each year, not only by way of immediate harm but also through negative long-term health impacts. Before implementation of the National Intimate Partner and Sexual Violence Survey (NISVS) in 2010, the most recent detailed national data on the public health burden from these forms of violence were obtained from the National Violence against Women Survey conducted during 1995-1996. This report examines sexual violence, stalking, and intimate partner violence victimization using data from 2011. The report describes the overall prevalence of sexual violence, stalking, and intimate partner violence victimization; racial/ethnic variation in prevalence; how types of perpetrators vary by violence type; and the age at which victimization typically begins. For intimate partner violence, the report also examines a range of negative impacts experienced as a result of victimization, including the need for services. January-December, 2011. NISVS is a national random-digit-dial telephone survey of the noninstitutionalized English- and Spanish-speaking U.S. population aged ≥18 years. NISVS gathers data on experiences of sexual violence, stalking, and intimate partner violence among adult women and men in the United States by using a dual-frame sampling strategy that includes both landline and cellular telephones. The survey was conducted in 50 states and the District of Columbia; in 2011, the second year of NISVS data collection, 12,727 interviews were completed, and 1,428 interviews were partially completed. In the United States, an estimated 19.3% of women and 1.7% of men have been raped during their lifetimes; an estimated 1.6% of women reported that they were raped in the 12 months preceding the survey. The case count for men reporting rape in the preceding 12 months was too small to produce a statistically reliable prevalence estimate. An estimated 43.9% of women and 23.4% of men experienced other forms of sexual violence during their lifetimes, including being made to penetrate, sexual coercion, unwanted sexual contact, and noncontact unwanted sexual experiences. The percentages of women and men who experienced these other forms of sexual violence victimization in the 12 months preceding the survey were an estimated 5.5% and 5.1%, respectively. An estimated 15.2% of women and 5.7% of men have been a victim of stalking during their lifetimes. An estimated 4.2% of women and 2.1% of men were stalked in the 12 months preceding the survey. With respect to sexual violence and stalking, female victims reported predominantly male perpetrators, whereas for male victims, the sex of the perpetrator varied by the specific form of violence examined. Male rape victims predominantly had male perpetrators, but other forms of sexual violence experienced by men were either perpetrated predominantly by women (i.e., being made to penetrate and sexual coercion) or split more evenly among male and female perpetrators (i.e., unwanted sexual contact and noncontact unwanted sexual experiences). In addition, male stalking victims also reported a more even mix of males and females who had perpetrated stalking against them. The lifetime and 12-month prevalences of rape by an intimate partner for women were an estimated 8.8% and 0.8%, respectively; an estimated 0.5% of men experienced rape by an intimate partner during their lifetimes, although the case count for men reporting rape by an intimate partner in the preceding 12 months was too small to produce a statistically reliable prevalence estimate. An estimated 15.8% of women and 9.5% of men experienced other forms of sexual violence by an intimate partner during their lifetimes, whereas an estimated 2.1% of both men and women experienced these forms of sexual violence by a partner in the 12 months before taking the survey. Severe physical violence by an intimate partner (including acts such as being hit with something hard, being kicked or beaten, or being burned on purpose) was experienced by an estimated 22.3% of women and 14.0% of men during their lifetimes and by an estimated 2.3% of women and 2.1% of men in the 12 months before taking the survey. Finally, the lifetime and 12-month prevalence of stalking by an intimate partner for women was an estimated 9.2% and 2.4%, respectively, while the lifetime and 12-month prevalence for men was an estimated 2.5% and 0.8%, respectively. Many victims of sexual violence, stalking, and intimate partner violence were first victimized at a young age. Among female victims of completed rape, an estimated 78.7% were first raped before age 25 years (40.4% before age 18 years). Among male victims who were made to penetrate a perpetrator, an estimated 71.0% were victimized before age 25 years (21.3% before age 18 years). In addition, an estimated 53.8% of female stalking victims and 47.7% of male stalking victims were first stalked before age 25 years (16.3% of female victims and 20.5% of male victims before age 18 years). Finally, among victims of contact sexual violence, physical violence, or stalking by an intimate partner, an estimated 71.1% of women and 58.2% of men first experienced these or other forms of intimate partner violence before age 25 years (23.2% of female victims and 14.1% of male victims before age 18 years). A substantial proportion of U.S. female and male adults have experienced some form of sexual violence, stalking, or intimate partner violence at least once during their lifetimes, and the sex of perpetrators varied by the specific form of violence examined. In addition, a substantial number of U.S. adults experienced sexual violence, stalking, or intimate partner violence during the 12 months preceding the 2011 survey. Consistent with previous studies, the overall pattern of results suggest that women, in particular, are heavily impacted over their lifetime. However, the results also indicate that many men experience sexual violence, stalking, and, in particular, physical violence by an intimate partner. Because of the broad range of short- and long-term consequences known to be associated with these forms of violence, the public health burden of sexual violence, stalking, and intimate partner violence is substantial. RESULTS suggest that these forms of violence frequently are experienced at an early age because a majority of victims experienced their first victimization before age 25 years, with a substantial proportion experiencing victimization in childhood or adolescence. Because a substantial proportion of sexual violence, stalking, and intimate partner violence is experienced at a young age, primary prevention of these forms of violence must begin early. Prevention efforts should take into consideration that female sexual violence and stalking victimization is perpetrated predominately by men and that a substantial proportion of male sexual violence and stalking victimization (including rape, unwanted sexual contact, noncontact unwanted sexual experiences, and stalking) also is perpetrated by men. CDC seeks to prevent these forms of violence with strategies that address known risk factors for perpetration and by changing social norms and behaviors by using bystander and other prevention strategies. In addition, primary prevention of intimate partner violence is focused on the promotion of healthy relationship behaviors and other protective factors, with the goal of helping adolescents develop these positive behaviors before their first relationships. The early promotion of healthy relationships while behaviors are still relatively modifiable makes it more likely that young persons can avoid violence in their relationships.

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Previous studies have identified associations between traffic exposures and a variety of adverse health effects, but many of these studies relied on proximity measures rather than measured or modeled concentrations of specific air pollutants, complicating interpretability of the findings. An increasing number of studies have used land-use regression (LUR) or other techniques to model small-scale variability in concentrations of specific air pollutants. However, these studies have generally considered a limited number of pollutants, focused on outdoor concentrations (or indoor concentrations of ambient origin) when indoor concentrations are better proxies for personal exposures, and have not taken full advantage of statistical methods for source apportionment that may have provided insight about the structure of the LUR models and the interpretability of model results. Given these issues, the primary objective of our study was to determine predictors of indoor and outdoor residential concentrations of multiple traffic-related air pollutants within an urban area, based on a combination of central site monitoring data; geographic information system (GIS) covariates reflecting traffic and other outdoor sources; questionnaire data reflecting indoor sources and activities that affect ventilation rates; and factor-analytic methods to better infer source contributions. As part of a prospective birth cohort study assessing asthma etiology in urban Boston, we collected indoor and/or outdoor 3-to-4 day samples of nitrogen dioxide (NO2) and fine particulate matter with an aerodynamic diameter or = 2.5 pm (PM2.5) at 44 residences during multiple seasons of the year from 2003 through 2005. We performed reflectance analysis, x-ray fluorescence spectroscopy (XRF), and high-resolution inductively coupled plasma-mass spectrometry (ICP-MS) on particle filters to estimate the concentrations of elemental carbon (EC), trace elements, and water-soluble metals, respectively. We derived multiple indicators of traffic using Massachusetts Highway Department (MHD) data and traffic counts collected outside the residences where the air monitoring was conducted. We used a standardized questionnaire to collect data on home characteristics and occupant behaviors. Additional housing information was collected through property tax records. Ambient concentrations of pollutants as well as meteorological data were collected from centrally located ambient monitors. We used GIS-based LUR models to explain spatial and temporal variability in residential outdoor concentrations of PM2.5, EC, and NO2. We subsequently derived latent-source factors for residential outdoor concentrations using confirmatory factor analysis constrained to nonnegative loadings. We developed LUR models to determine whether GIS covariates and other predictors explain factor variability and thereby support initial factor interpretations. To evaluate indoor concentrations, we developed physically interpretable regression models that explored the relationship between measured indoor and outdoor concentrations, relying on questionnaire data to characterize indoor sources and activities. Because outdoor pollutant concentrations measured directly outside of homes are unlikely to be available for most large epidemiologic studies, we developed regression models to explain indoor concentrations of PM2.5, EC, and NO2 as a function of other, more readily available data: GIS covariates, questionnaire data reflecting both sources and ventilation, and central site monitoring data. As we did for outdoor concentrations, we then derived latent-source factors for residential indoor concentrations and developed regression models explaining variability in these indoor latent-source factors. Finally, to provide insight about the effects of improved characterization of exposures for the results of subsequent epidemiologic investigations, we developed a simulation framework to quantitatively compare the implications of using exposure models derived from validation studies with the use of other surrogate models with varying amounts of measurement error. The concentrations of outdoor PM2.5 were strongly associated with the central site monitor data, whereas EC concentrations showed greater spatial variability, especially during colder months, and were predicted by the length of roadway within 200 m of the home. Outdoor NO2 also showed significant spatial variability, predicted in part by population density and roadway length within 50 m of the home. Our constrained factor analysis of outdoor concentrations produced loadings indicating long-range transport, brake wear and traffic exhaust, diesel exhaust, fuel oil combustion, and resuspended road dust as sources; corresponding LUR models largely corroborated these factor interpretations through covariate significance. For example, long-range transport was predicted by central site PM2.5, and season, brake wear and traffic exhaust and resuspended road dust by traffic and residential density, diesel exhaust by the percentage of diesel traffic on the nearest major road, and fuel oil combustion by population density. Our modeling of the concentrations of indoor pollutants demonstrated substantial variability in indoor-outdoor relationships across constituents, helping to separate constituents dominated by outdoor sources (e.g., S, Se, and V) from those dominated by indoor sources (e.g., Ca and Si). Regression models indicated that indoor PM2.5 was not influenced substantially by local traffic but had significant indoor sources (cooking activity and occupant density), while EC was associated with distance to the nearest designated truck route, and NO2 was associated with both traffic density within 50 m of the home and gas stove usage. Our constrained factor analysis of indoor concentrations helped to separate outdoor-dominated factors from indoor-dominated factors, though some factors appeared to be influenced by both indoor and outdoor sources. Subsequent factor analyses of the indoor-attributable fractions from indoor-outdoor regression models provided generally consistent interpretations of indoor-dominated factors. The use of regression models on indoor factors demonstrated the limited predictive power of questionnaire data related to indoor sources, but reinforced the viability of modeling indoor concentrations of pollutants of ambient origin. In spite of the relatively weak predictive power of some of the indoor-concentration regression models, our epidemiologic simulations illustrated that exposure models with fairly modest R2 values (in the range of 0.3 through 0.4, corresponding with the regression models for PM2.5 and NO2) yielded substantial improvements in epidemiologic study performance relative to the use of exposure proxies that could be applied in the absence of validation studies. In spite of limitations related to sample size and available covariate data, our study demonstrated significant outdoor spatial variability within an urban area in NO2 and in several constituents of airborne particles. LUR techniques combined with constrained factor analysis helped to disentangle the contributions to temporal variability of local, long-range transport, and other sources, ultimately allowing exposures from defined source categories to be investigated in epidemiologic studies. For the indoor residential environment, we demonstrated substantial variability in indoor-outdoor relationships among particle constituents; then, using information from public databases and focused questionnaire data, we were able to predict indoor concentrations for a subset of key pollutants. Constrained factor analysis methods applied to the indoor environment helped to separate indoor sources from outdoor sources. The corresponding indoor regression models had limited predictive power, reinforcing the complexity of characterizing the indoor environment when only limited information about key predictors is available. This finding also underscores the likelihood that these regression models might characterize indoor concentrations of pollutants with ambient origins better than they can the indoor concentrations from all sources. Our findings provide direction for future studies characterizing indoor exposure sources and patterns, and our epidemiologic simulation reinforced the importance of reducing measurement error in a context where many traffic-related air pollutants are influenced by both indoor and outdoor sources. The combination of analytical techniques used in our study could ultimately allow for more refined exposure characterization and evaluation of the relative contributions of various sources to health outcomes in epidemiologic studies.

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C.I. Direct Blue 15 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. The dye, industrial grade C.I. Direct Blue 15, was chosen for study as a product to which workers are potentially exposed. Because of the high salt content, the dye was desalted prior to use. The purity was determined to be approximately 50%, with high-performance liquid chromatography indicating one major peak and approximately 35 impurities. Toxicology and carcinogenesis studies were conducted by administering the dye, C.I. Direct Blue 15, in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 22 months. Planned as 24-month studies, the 22-month studies were terminated early because of rapidly declining animal survival, which was due primarily to neoplasia. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Rats were given C.I. Direct Blue 15 in drinking water at doses of 1,250, 2,500, 5,000, 10,000, or 30,000 ppm. All control and treated rats survived. Body weight gain in high-dose females was less than that in controls. Water consumption declined as the dose increased. Male and female rats receiving 30,000 ppm had slight degeneration and necrosis of individual hepatocytes in the liver, and females also had mild to moderate renal tubule degeneration and thymic lymphoid depletion. 13-Week Studies: C.I. Direct Blue 15 was administered in drinking water at doses of 0, 1,250, 2,500, 5,000, 10,000, or 30,000 ppm to male rats, and at doses of 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm to female rats. Seven of 10 male rats receiving 30,000 ppm died; all rats in the other groups survived until the end of the studies. Mean final body weights of males receiving 10,000 or 30,000 ppm were 92% and 69% of those of controls, and mean final body weights of females receiving 5,000 or 10,000 ppm were 97% and 94% of those of controls. Tissues from treated animals were stained blue. Compound-related lesions were seen in the kidney and liver of male rats given 30,000 ppm and in the kidney of males and females given 10,000 ppm. The renal lesions included necrosis, degeneration, pigmentation and regeneration of the tubule epithelium, and tubule mineralization. Liver lesions included centrilobular hepatocellular degeneration, fatty metamorphosis, and individual cell necrosis with slight periportal hepatocellular hypertrophy. Lymphoid depletion in the thymus was also seen in the high-dose males. Based on the results of the 14-day and 13-week studies, the high dose chosen for the 22-month studies was 2,500 ppm. 22-Month Studies: At study initiation, 70 rats of each sex were given 0 or 2,500 ppm C.I. Direct Blue 15, 45 rats of each sex were given 630 ppm, and 75 rats of each sex were given 1,250 ppm. Interim evaluations were made at 9 and 15 months. The average amounts of compound consumed per day by the six dose groups after week 52 of the studies were estimated to be 45, 90, and 215 mg/kg for male rats and 50, 100, and 200 mg/kg for female rats. Survival and Body Weights: The studies were terminated at 22 months due to extensive mortality associated with chemical-related neoplasia. Survival of control, 630, 1,250, and 2,500 ppm males at 22 months was 37/50, 8/35, 11/65, and 2/50; survival of females was 40/50, 13/35, 22/65, and 4/50. At 22 months, the mean final body weights of the 630, 1,250, and 2,500 ppm groups were 95%, 91%, and 81% of those of the control for male rats and 91% of those of the control for all female dose groups. Histopathologic Effects in the 22-Month Studies: At the 9-month interim evaluations, one adenoma of the Zymbal's gland was seen in a high-dose male rat, and three carcinmbal's gland was seen in a high-dose male rat, and three carcinomas of the clitoral gland were seen in the high-dose females. At the 15-month interim evaluations, Zymbal's gland neoplasms were seen in low- and high-dose males and all treated female dose groups. Mid- and high-dose males and females also had preputial or clitoral gland neoplasms, and a few neoplasms were present in the skin, small and large intestine, liver, and oral cavity of treated animals at 15 months. At the end of the study, neoplasms related to chemical administration were found in the Zymbal's gland, skin, oral cavity, and the preputial or clitoral gland in both male and female rats. Neoplasms related to chemical administration were also seen at other sites including the small and large intestine, liver, uterus, and brain. The incidence of mononuclear cell leukemia was also increased in treated rats. Genetic Toxicology: C.I. Direct Blue 15 was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 when tested in a standard preincubation protocol with or without exogenous metabolic activation; however, when a specialized reductive metabolism protocol was used, C.I. Direct Blue demonstrated mutagenic activity in Salmonella strain TA1538. C.I. Direct Blue 15 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. Conclusions: Under the conditions of these 22-month drinking water studies, there was clear evidence of carcinogenic activity of C.I. Direct Blue 15 (desalted industrial grade) in male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, and small and large intestine. Increased incidences of mononuclear cell leukemia and neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity of C.I. Direct Blue 15 in female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, and uterus, and by mononuclear cell leukemia. Synonyms: Airedale Blue D, Aizen Direct Sky Blue 5BH, Amanil Sky Blue, Atlantic Sky Blue A, Atul Direct Sky Blue, Azine Sky Blue 5B, Belamine Sky Blue A, Benzanil Sky Blue, Benzo Sky Blue S, Benzo Sky Blue A-CF, Cartasol Blue 2GF, Chloramine Sky Blue A, Chloramine Sky Blue 4B, Chrome Leather Pure Blue, C.I. 24400, Cresotine Pure Blue, Diacotton Sky Blue 5B, Diamine Blue 6B, Diamine Sky Blue, Diaphtamine Pure Blue, Diazol Pure Blue 4B, 3,3'-[(3,3'-dimethoxy[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[5-amino-4-hydroxy-2,-naphthalenedisulfonic acid] tetrasodium salt, Diphenyl Brilliant Blue, Diphenyl Sky Blue 6B, Direct Blue 10G, Direct Blue HH, Direct Pure Blue, Direct Pure Blue M, Direct Sky Blue (6CI), Direct Sky Blue A, Direct Sky Blue 5B, Enianil Pure Blue AN, Fenamin Sky Blue, Hispamin Sky Blue 3B, Kayafect Blue Y, Kayaku Direct Sky Blue 5B, Mitsui Direct Sky Blue 5B, Naphtamine Blue 10G, Niagara Blue 4B, Niagara Sky Blue, Nippon Direct Sky Blue, Nitto Direct Sky Blue 5B, Paper Blue S, Phenamine Sky Blue A, Pontamine Sky Blue 5BX, Shikiso Direct Sky Blue 5B, Sky Blue 4B, Sky Blue 5B, Tertrodirect Blue F, Vondacel Blue HH

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Knowledge of cognitive performance earlier in life is essential in order to characterize precisely the extent to which these abilities have declined when an individual is diagnosed as having a dementing illness. The National Adult Reading Test (NART) was developed by Nelson and O'Connell to estimate premorbid intellectual ability in patients suffering from intellectual deterioration due to dementia. The test consists of 50 words, graded in difficulty, whose pronunciation cannot be determined from their spelling. The ability to successfully read irregularly spelt words is relatively robust in the face of current cognitive impairment and is a sensitive marker of intellectual attainment. Because the NART relies on orthographic irregularities in the English language, the construction of analogues of the test in other languages is not simply a matter of translation of the test content. Rather, words in the target language that have comparable properties to those in the NART must be sought. A French adaptation of the NART--the fNART--was developed by Bovet and calibrated on a small French-speaking Swiss sample. In a sample of 30 nondemented subjects, number of words pronounced correctly correlated highly with WAIS-R verbal and total IQ scores and less strongly with performance IQ (r = 0.43). Data available from an epidemiological survey undertaken in Geneva, Switzerland provided an opportunity to establish the measurement properties and construct validity of the fNART in a large sample unselected with respect to cognitive decline. In addition to the fNART, the survey incorporated a brief test battery assessing the domains of crystallized intelligence, memory and cognitive speed. An interview that enabled the diagnosis of dementia according to DSM IV criteria, the Mini Mental State Examination and the Psychogeriatric Assessment Scales (PAS) were also administered. If the fNART measures intellectual ability, substantial correlations between it and the test battery would be expected. Further validation of the test was sought by exploring its relation with years of education. The stability of the fNART was assessed by comparing the scores of subjects with and without dementia, and by examining the relationship of fNART scores to an informant-based report of change in cognitive performance from earlier in life assessed in the PAS. If the fNART is stable in the face of cognitive deterioration, no between-group differences or association with reported cognitive change would be expected. Subjects were randomly selected from residents of the canton of Geneva aged over 65 years. The analyses reported here were undertaken on a sample of 368 persons who gave codable responses to at least 90% of the fNART items. They ranged in age from 65 to 94 years. Subjects were interviewed in their homes by trained lay interviewers. Cronbach's alpha for the forty-item scale was high (0.89). The percentage of subjects correctly pronouncing words ranged from 7.3% for "chamsin" to 96.7% for "agenda". Item response theory (IRT) models were fitted to the data. In a three-parameter model the value of the guessing (asymptote) parameter was vanishing small for all items. Accordingly, a two-parameter model was adopted. The discriminating power (slope) of items ranged considerably from 0.281 (rébus) to 1.192 (béotien). The average slope was 0.656. This corresponds to average factor loading of 0.528 (range 0.270 to 0.766.) The items measure a broad range of ability (mean threshold--0.719, sd = 1.540). Most items, however, discriminate at moderate levels. The parameter values obtained in the current study were compared to those estimated in a French sample of persons at risk of dementia . The correlation between item pairs for slope and parameter estimates was 0.53 and 0.70 respectively. This indicated substantial concordance between the samples regarding the difficulty of the items, but some differences in the power of groups to differentiate ability. In particular, a small number of words that performed very well in the "at risk" sample showed more moderate discrimination in the current study. Scores on the fNART were correlated with measures of crystallised intelligence, memory and cognitive speed. All correlations were statistically significant. With all tests entered a regression equation the multiple correlation coefficient was 0.63. Mean fNART scores of those suffering from DSM IV dementia and those meeting only Criterion A (multiple cognitive deficits) were lower than those of subjects meeting neither set of criteria. However subjects in the first two groups were older than subjects in the undemented group and had significantly lower educational attainment. When these two factors were controlled in an analysis of covariance, the magnitude of the differences between the groups, while still overall significantly different, was substantially reduced. A similar pattern of results applied when psychometric measures of cognitive state--the MMSE and the PAS Cognitive Impairment Scale--were used instead of diagnostic categories. The partial correlations of the fNART with the MMSE and PAS cognitive impairment scale controlling for age and education were 0.25 (P &lt; 0.01) and -0.33 (P &lt; 0.01) respectively. fNART scores did not differ between the sexes, nor were they significantly correlated with PAS Depression, Stroke or Behaviour Change scales. There was a small but significant correlation between the fNART and informant-assessed Cognitive Decline on the PAS. This study demonstrated the excellent measurement properties of a French adaptation of the National Adult Reading Test in a large probability sample of elderly native speakers and provided the first large-sample evidence to support the validity of the fNART as a test of intellectual functioning relatively robust to dementia status. The negligible values of the pseudo-guessing parameters suggest that the goal of choosing words whose pronunciation is not susceptible to guessing has been achieved. The average item discriminability was high and the words used covered the spectrum of ability. The finding of substantial relationships of cognitive performance and educational attainment with fNART scores is important in validating the test as a measure of premorbid cognitive ability. The low correlations of the fNART with informant-based assessment of cognitive decline and age support the fNART as being relative robust to decline in ability. The relationships observed in this French adaptation are comparable to those reported for the English instrument . However, subjects meeting DSM IV criteria for dementia or Criterion A only had lower scores than other subjects. Decline in NART scores with dementia has been observed, particularly in moderate and severe cases. Given that the mechanism of the fNART is the same as the NART it is to be expected that while generally robust to current dementia status, some decline in performance will occur with the progression of the disease. The relationships between the fNART and PAS scales was remarkably similar to those reported by Jorm et al. in an English-speaking sample between the PAS and NART. Although small, the correlation between the fNART and the PAS Cognitive Decline scale might have been expected to be non-significant if the measure were truly stable in the face of intellectual deterioration. However this correlation is mirrored in the original English instruments and may reflect the higher risk of dementia in persons of lower intellectual ability. Further research is desirable to improve the precision of the calibration of the scale against the WAIS-R. Nevertheless, this study has demonstrated that the fNART is a reliable and valid method of assessing premorbid intellectual ability in French speakers.

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This volume provides an update of the health status of the populations living in the National Priority Contaminated Sites (NPCSs) included in the SENTIERI Project. This update is part of an epidemiological surveillance programme carried out in NPCSs, promoted by the Italian Ministry of Health as a further step of a project started in 2006, when the health status of residents in contaminated sites was first addressed within the National Strategic Program "Environment and Health". The Report focuses on five health outcomes: mortality, cancer incidence, hospital discharges, congenital anomalies, and children, adolescents and young adults' health. A key element of SENTIERI project is the a priori evaluation of the epidemiological evidence of a causal association between the considered cause of disease and the exposure. When an a priori evidence is identified, it is given a greater importance in the comment of the study findings. The present update of the SENTIERI Project concerns 45 NPCSs including in all 319 Italian Municipalities (out of over 8,000 Municipalities), with an overall population of 5,900,000 inhabitants at the 2011 Italian Census. Standardized Mortality Ratios (SMRs) and Standardized Hospitalization Ratios (SHRs), referring to a time window of 2006-2013, were computed for all the 45 NPCSs, using as a reference the corresponding mortality and hospitalization rates of the Regions where each NCPS is located. Standardized Incidence Ratios (SIRs) were computed by the Italian Association of Cancer Registries (AIRTUM) for the 22 NPCSs served by a Cancer Registry. AIRTUM covers about 56% of Italy, with partly different time-windows. SIRs have been estimated using as reference population the 4 macroareas in which Italy is divided (North-West, North-East, Centre, South). Prevalence of congenital anomalies was computed for 15 NPCSs. An all-cause excess of 5,267 and 6,725 deaths was observed, respectively, in men and women; the cancer death excess was of 3,375 in men and 1,910 in women. It was estimated an excess of cancer incidence of 1,220 case in men and 1,425 in women over a five-year time window. With regard to the diseases with an a priori environmental aetiological validity, an excess for malignant mesothelioma, lung, colon, and gastric cancer, and for non-malignant respiratory diseases was observed. Cancer excess mainly affected NPCSs with presence of chemical and petrochemical plants, oil refineries, and dumping hazardous wastes. An excess of non-malignant respiratory disease was also detected in NPCSs in which steel industries and thermoelectric plants were present. An excess of mesothelioma was observed in NPCSs characterized by presence of asbestos and fluoro-edenite; it was also observed where the presence of asbestos was not reported in the legislative national decrees which define the NPCS areas. It is worth noting that, even if the presence of asbestos is not reported in many NPCSs legislative decrees, petrochemical plants and steel industries, for instance, are often characterized by the presence of a large amount of this mineral that, in the past, was extensively used as an insulating material. For the first time, the present Report includes a focus on the health status of children and adolescents (1,160,000 subjects, aged 0-19 years), and young adults (660,000 subjects, aged 20-29 years). Among infants (0-1 year), an excess of 7,000 hospitalizations was observed, 2,000 of which due to conditions of perinatal origin. In the age class 0-14, an excess of 22,000 hospitalizations for all causes was observed; 4,000 of them were due to acute respiratory diseases, and 2,000 to asthma. Data on cancer incidence for subjects aged 0-24 years were derived from general population cancer registries for twenty NPCSs, and from children cancer registries (age group: 0-19 years) for six NPCSs; 666 cases where diagnosed in the age group 0-24 years, corresponding to an excess of 9%. The main contributions to this excess are from soft tissue sarcomas in children (aged 0-14 years), acute myeloid leukaemia in children (aged 0-14 years) and in the age group 0-29 years, non-Hodgkin lymphoma and testicular cancer in young adults (aged 20-29 years). In seven out of 15 NPCSs, an excess prevalence rate of overall congenital anomalies at birth was observed. Congenital anomalies excesses included the following sites: genital organs, heart, limbs, nervous system, digestive system, and urinary system. The main findings of SENTIERI Project have been the detection of excesses for the diseases which showed an a priori epidemiological evidence of a causal association with the environmental exposures specific for each considered NPCS. These observations are valuable within public health, because they contribute to priority health promotion activities. Looking ahead, the health benefits of an improved environmental quality might be appreciated in terms of reduction of the occurrence of adverse health effects attributable to each Site major pollutant agents. Due to the methodological approach of the present study, it was not possible to adjust for several confounding factors reported to be risk factors for the studied diseases (e.g., smoking, alcohol consumption, obesity). Even if excesses of mortality, hospitalization, cancer incidence, and prevalence of congenital anomalies were found in several NPCSs, the study design and the multifactorial aetiology of the considered diseases do not permit, for all of them, to draw conclusions in terms of causal links with environmental contamination. Moreover, it must be taken into consideration that economic factors and the availability of health services may also play a relevant role in a diseases outcome. A few observations regarding some methodological limitations of SENTIERI Project should be made. There is not a uniform environmental characterisation of the studied NPCSs in term of quality and detection of the pollutants, because this information is present in different databases which at present are not adequately connected. Moreover, the recognition of a contaminated site as a National Priority Site is based on soil and groundwater pollution, and the available information on air quality is currently sparse and not homogenous. Another limitation, in term of statistical power, is the small population size of many NPCSs and the low frequency of several health outcomes. A special caution must be paid in data interpretation when considering the correspondence between the contaminated areas and the municipality boundaries, as they do not always coincide perfectly: in some cases, a small municipality with a large industrial site, while in other settings only a part of the municipality is exposed to the sources of pollution. Furthermore, all available health information systems are currently accessible at municipality level. The real breakthrough is essentially comprised of the development and fostering of a networking system involving all local health authorities and regional environmental protection agencies operating in the areas under study. The possibility to integrate the geographic approach of SENTIERI Project with a set of ad hoc analytic epidemiological investigations, such as residential cohort studies, case control studies, children health surveys, biomonitoring surveys, and with socioepidemiological studies, might greatly contribute to the identification of health priorities for environmental remediation activities. Finally, as discussed in the last section of the report, there is a need to adopt, in each NPCS, a two-way oriented communication plan involving public health authorities, scientific community, and resident population, taking into account that the history, the cultural frame and the network of relationships specific of each local context play a major role in the risk perception perspective.

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To assess the clinical and cost-effectiveness of magnesium sulphate compared with sotalol, and to assess the clinical effectiveness of magnesium sulphate compared with placebo in the prevention of atrial fibrillation (AF) in patients who have had a coronary artery bypass graft (CABG). Major electronic databases were searched from December 2003 to May 2007. Selected studies were assessed, subjected to data extraction using a standard template and quality assessment using published criteria. A simple short-term economic model was developed, informed by a systematic review of economic evaluations and populated with data from a review of costing/resource-use studies and other published studies. The cost-effectiveness of magnesium sulphate as prophylaxis was estimated for a set of base-case assumptions and the robustness of these results was assessed using deterministic and probabilistic sensitivity analysis. Twenty-two papers met the inclusion criteria reporting 15 trials which all compared magnesium sulphate with placebo or control. They ranged in size from 15 to 176 patients randomised, and were conducted in Europe, the USA and Canada. The standard of reporting was generally poor, with details of key methodological attributes difficult to elucidate. No trials were identified that specifically aimed to compare magnesium sulphate with sotalol. Of 1070 patients in the pooled magnesium group, 230 (21%) developed postoperative AF, compared with 307 of 1031 (30%) patients in the placebo or (control) group. Meta-analysis using a fixed-effects model generated a pooled odds ratio (OR) that was significantly less than 1.0 [OR=0.65, 95% confidence interval (CI) 0.53 to 0.79, test for overall effect p&lt;0.0001], but with statistically significant heterogeneity (I2=63.4%, p=0.0005). Two randomised controlled trials (RCTs) were notable as they had relatively lower ORs in favour of magnesium sulphate. When these were removed from the analyses the pooled OR remained statistically significant, but heterogeneity no longer remained significant. These two studies tended to impart a highly significant reduction in the odds of AF to whichever subgroup they were analysed in. When studies were ordered by total duration of prophylaxis, an apparent relationship between duration and odds of AF was evident, with decreasing odds of AF as duration of prophylaxis increased. This was confirmed by linear regression analysis (R2=0.743, p&lt;0.001). When the data were grouped into three classes according to duration, a statistically significant intervention effect was only present for the longest duration (OR=0.12, 95% CI 0.06 to 0.23, p=0.00001). Statistically significant intervention effects were associated with the initiation of prophylaxis 12 hours or more before surgery (OR 0.26; 95% CI 0.16 to 0.44, test for overall effect p=0.00001, fixed-effects model) and less than 12 hours before surgery or during the surgery itself (OR=0.73, 95% CI 0.56 to 0.97, test for overall effect p = 0.03, fixed-effects model), but not when prophylaxis was initiated at the end of surgery or postsurgery (OR=0.85, 95% CI 0.59 to 1.22, p=0.37, fixed-effects model). When studies were ordered by total dose of intravenous magnesium sulphate (&lt;25 g), the odds of AF were independent of the dose. A notable exception was that for a total dose of 9 g magnesium sulphate; here the odds of AF were significantly reduced relative to the control group, although this may be explained by the fact that these studies had excluded patients who were on antiarrhythmic drugs and so may have been at higher risk of AF. Sixty-three potentially relevant references about cost-effectiveness were identified, but no economic evaluations of intravenous magnesium alone as prophylaxis against AF following CABG, compared with sotalol as prophylaxis or no prophylaxis, were identified. Studies reporting resource use by patients with AF following CABG suggest that while AF significantly increased inpatient stays, by up to 2.3 days in the intensive care unit (ICU) and 3.4 days on the ward, differences in length of stay and costs between patients receiving prophylaxis and those not receiving prophylaxis were not statistically significant. In the base-case analysis, magnesium sulphate prophylaxis resulted in 0.081 fewer cases of AF at an incremental cost of 2.55 pounds sterling. The incremental cost-effectiveness ratio (ICER) was 32 pounds sterling per AF case avoided. The estimated difference in average length of stay between the prophylaxis and no-prophylaxis strategies was only 0.24 days, despite a large assumed difference of 3 days for patients experiencing AF in each group (1 extra day in the ICU and 2 extra days on the ward). In a deterministic sensitivity analysis the greatest variation in ICERs was observed for input parameters relating to the baseline risk of AF following CABG and the effectiveness of prophylaxis, cost of prophylaxis and the resource consequences of postoperative AF. The largest ICER (2092 pounds sterling) in the sensitivity analysis was associated with increasing the length of patients' preoperative stay. In the base case it was assumed that admission routines would be identical under both strategies. However, patients receiving prophylaxis by intravenous infusion may have longer preoperative stays. In a probabilistic analysis the majority of the simulations were associated with improved outcomes (in this case fewer cases of AF), but also higher costs. Prophylaxis was the dominant strategy (better outcome at lower cost) in about 41% of the simulations using the base-case assumptions. Under an alternative scenario where patients receiving prophylaxis are admitted for longer before their operation, to receive their initial infusion, the proportion of simulations where prophylaxis dominates fell to around 5%. The probability of being cost-effective was 99% at a willingness to pay (WTP) threshold of 2000 pounds sterling per AF case avoided and 100% at a WTP threshold of 5000 pounds sterling per AF case avoided under the base-case assumptions. Under the alternative scenario of longer preoperative stays the probability of being cost-effective at these two threshold values fell to 48% and 93%, respectively. It is unclear what the appropriate decision threshold should be, given that this model used intermediate rather than final outcomes. No RCTs were identified that specifically aimed to compare intravenous magnesium with sotalol as prophylaxis for AF in patients undergoing CABG. Intravenous magnesium, compared with placebo or control, is effective in preventing postoperative AF, as confirmed by a statistically significant intervention effect based on pooled analysis of 15 RCTs. It was also found that AF was less likely to occur when a longer duration of prophylaxis was used, and the earlier that prophylaxis is started; however, this finding was associated with two RCTs that had more favourable results than the other trials. No clear relationship between dose and AF was observed, although a lower constant dose rate was associated with the lowest odds of AF. Further research should investigate the relationship between dose, dose rate, duration of prophylaxis, timing of initiation of therapy and patient characteristics, such as degree of risk for AF. This will provide stronger evidence for the optimum delivery of intravenous magnesium in patients undergoing CABG. In the base-case analysis in the economic model, magnesium sulphate prophylaxis reduced the number of postoperative AF cases at a modest increase in cost. The results of the economic analysis are highly sensitive to variation in certain key parameters. Prophylaxis is less likely to be a cost-effective option if it requires changes in admission routines that result in longer preoperative stays than would be the case without prophylaxis.

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C.I. Acid Red 114 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. C.I. Acid Red 114 was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering desalted, industrial grade C.I. Acid Red 114 in drinking water to groups of F344/N rats of each sex for 13 days, 13 weeks, 9 or 15 months, or 2 years. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila melanogaster. 13-Day Studies: Rats were exposed to C.I. Acid Red 114 in drinking water at doses of 0, 10,000, 20,000, or 30,000 ppm. All control and dosed rats survived except one male rat in the 20,000 ppm dose group. Final mean body weights in the three dosed groups were 94%, 83%, or 77% of controls for males and 92%, 88%, or 80% of controls for females. Water consumption declined with increased dose. Clinical findings included red stained fur, ears, and tail in all test animals. On gross necropsy, organs and tissues were also stained red. 13-Week Studies: C.I. Acid Red 114 was administered in drinking water at doses of 0, 600, 1,200, 2,500, 5,000, or 10,000 ppm. All control and dosed animals survived until the end of the study. Final mean body weights in the five dosed groups were 97%, 89%, 87%, 87%, or 85% of controls for males and 97%, 94%, 94%, 92%, or 89% of controls for females. Water consumption was decreased in dosed animals. As was seen in the 13-day studies, major organs and tissues from treated animals were stained red. Kidney toxicity characterized by regeneration and karyomegaly of tubule epithelial cells with chronic inflammation was observed in female rats at doses of 1,200 ppm or above. Treatment-related increases in relative liver weights and elevated liver enzyme levels were seen in males and females, centrilobular pallor in the liver was seen in all male dose groups. Because of these body weight differences, decreases in water consumption, and organ toxicity, the doses chosen for the 2-year studies were 70,150, and 300 ppm for males and 150, 300, and 600 for females. 2-Year Studies: Male rats received doses of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150, 300, or 600 ppm. Seventy animals were in the control and high-dose groups, 45 in the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated from the control and high-dose groups at 9 months, and ten animals from all dose groups were evaluated at 15 months. The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Survival and Body Weights: Survival at 105 weeks for male rats receiving 0, 70, 150, or 300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300 ppm, survival was 36/50, 13/35, and 6/64. All female rats receiving 600 ppm died by week 89. The decreased survival in treated groups was due primarily to the development of chemical-related neoplasms. Of the surviving animals, the final mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight differences began in the second year of the studies and were attributed in part to the development of neoplasms in the dosed groups. Histopathologic Effects in the 2-Year Studies: At 9 and 15 months, a few neoplasms were seen in the liver, lung, clitoral gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as the studies progressed. At 2 years, there was a clear carcinogenic response in the skin, Zymbal's gland, and liver of male and female rats, and in the clitoral gland, oral cavity epithelium, small and large intestine, and lung in female rats. Treatment-related increases were also seen in the incidence in neoplasms of the oral cavity epithelium, adrenal gland, and lung of male rats, and in mononuclear cell leukemia and in neoplasms of the mammary gland and adrenal gland in female rats. The incidence of these neoplasms was generally lower, but was significant and considered to be marginally related to chemical treatment. The same neoplastic effects have been previously observed in some or all of the NTP studies with dimethoxybenzidine, dimethylbenzidine, or C.I. Direct Blue 15. Genetic Toxicology: In a standard preincubation protocol, C.I. Acid Red 114 was mutagenic in Salmonella typhimurium strain TA98 in the presence of induced hamster liver S9, and an equivocal response was noted in strain TA100 with hamster liver S9. However, no significant mutagenic activity was noted in strains TA1535 or TA1537 with or without S9 activation. In a modified S. typhimurium gene mutation test which employed reductive metabolism followed by oxidative metabolism with S9 liver enzymes, C.I. Acid Red 114 was strongly mutagenic in strain TA1538. C.I. Acid Red 114 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. No increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster administered C.I. Acid Red 114 by feeding or injection. Conclusions: Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. Synonyms: 1,3-Naphthalenedisulfonic acid, 8-((3,3'-dimethyl-4'-((4-(((4-methylphenyl)sulfonyl)oxy)phenyl)azo)(1,1'-bipheny)-4-yl)azo)-7-hydroxy, disodium salt, Acid Leather Red BG, Acid Red 114, Amacid Milling Red PRS, Benzyl Fast Red BG, Benzyl Red BR, Cerven Kysela, C.I. 23635, Erionyl Red RS, Folan Red B, Kayanol Milling Red RS, Leather Fast Red B, Levanol Red GG, Midlon Red PRS, Milling Red B, Milling Red BB, Milling Red SWB, NCI C61096, Polar Red RS, Sandolan Red N-RS, Sella Fast Red RS, Sulphonol Fast Red R, Supranol Fast Red GG, Supranol Red PBX-CF, Supranol Red R, Telon Fast Red GG, Tertracid Milling Red B, Vondamol Fast Red RS

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Foreword The International Association of Breath Research (IABR) meetings are an eclectic gathering of researchers in the medical, environmental and instrumentation fields; our focus is on human health as assessed by the measurement and interpretation of trace chemicals in human exhaled breath. What may have escaped our notice is a complementary field of research that explores the creation and maintenance of artificial atmospheres practised by the submarine air monitoring and air purification (SAMAP) community. SAMAP is comprised of manufacturers, researchers and medical professionals dealing with the engineering and instrumentation to support human life in submarines and spacecraft (including shuttlecraft and manned rockets, high-altitude aircraft, and the International Space Station (ISS)). Here, the immediate concerns are short-term survival and long-term health in fairly confined environments where one cannot simply 'open the window' for fresh air. As such, one of the main concerns is air monitoring and the main sources of contamination are CO(2) and other constituents of human exhaled breath. Since the inaugural meeting in 1994 in Adelaide, Australia, SAMAP meetings have been held every two or three years alternating between the North American and European continents. The meetings are organized by Dr Wally Mazurek (a member of IABR) of the Defense Systems Technology Organization (DSTO) of Australia, and individual meetings are co-hosted by the navies of the countries in which they are held. An overriding focus at SAMAP is life support (oxygen availability and carbon dioxide removal). Certainly, other air constituents are also important; for example, the closed environment of a submarine or the ISS can build up contaminants from consumer products, cooking, refrigeration, accidental fires, propulsion and atmosphere maintenance. However, the most immediate concern is sustaining human metabolism: removing exhaled CO(2) and replacing metabolized O(2). Another important concern is a suite of products from chemical reactions among oxidizing compounds with biological chemicals such as amines, thiols and carbonyls. SAMAP Meeting We (Armin and Joachim) attended the 2011 SAMAP conference in Taranto, Italy (10-14 October), which occurred just a few weeks after the IABR meeting in Parma, Italy (11-15 September 2011). It was held at the Officers' Club of the Taranto Naval Base under the patronage of the Italian navy; the local host was Lucio Ricciardi of the University of Insubria, Varese, Italy. At the 2011 SAMAP meeting, the theme was air-independent propulsion (AIP), meaning the capability of recharging the main batteries of the submarine without the need to surface. Only a few navies (e.g. US, UK, France, Russia, China) have historically had this capability using nuclear-powered submarines that can function underwater for extended periods of time (months). Most navies operate submarines with conventional diesel-electric propulsion, wherein diesel-powered generators charge battery banks which then drive an electric motor connected to the propeller. The batteries are charged while the boat is on the surface or during snorkelling, when the boat is submerged a few meters below the surface and a snorkel tube is extended to the surface. The period between battery charges can vary from several hours to one or two days depending on the power requirements and the nature of the mission. The process is necessary for breathing air revitalization (flushing out accumulated contaminants) and for the operation of the diesel engines. However, during this period the submarine is vulnerable to detection. Since the 1940s there have been various attempts to develop a power generation system that is independent of external air (AIP). To this end hydrogen peroxide was initially used and later liquid oxygen (LOX). Currently, most AIP submarines use fuel cell technology (LOX and hydrogen) to supplement the conventional diesel-electric system in order to extend the underwater endurance to 2-3 weeks. These propulsion engineering changes also reduce periodic ventilation of the submarine's interior and thus put a greater burden on the various maintenance systems. We note that the spaceflight community has similar issues; their energy production mechanisms are essentially air independent in that they rely almost entirely on photovoltaic arrays for electricity generation, with only emergency back-up power from alcohol fuel cells. In response to prolonged underwater submarine AIP operations, months-long spaceflight operations onboard the ISS and planning for future years-long missions to Mars, there has been an increasing awareness that bio-monitoring is an important factor for assessing the health and awareness states of the crewmembers. SAMAP researchers have been proposing various air and bio-monitoring instruments and methods in response to these needs. One of the most promising new methodologies is the non-invasive monitoring of exhaled breath. So, what do the IABR and SAMAP communities have in common? Inhalation toxicology. We are both concerned with contamination from the environment, either as a direct health threat or as a confounder for diagnostic assessments. For example, the exhaled breath from subjects in a contaminated and enclosed artificial environment (submarine or spacecraft) can serve as a model system and a source of contamination for their peers in a cleaner environment. In a similar way, exhaled anaesthetics can serve as a source of contamination in hospital/clinical settings, or exhalation of occupational exposures to tetrachloroethylene can impact family members at home. Instrumentation development. Both communities have similar needs for better, more specific and more sensitive instruments. Certainly, the analytical instruments to be used onboard submarines and spacecraft have severe restrictions on energy use, physical size and ease of operation. The medical and clinical communities have similar long-term plans for their analytical tools, in this case to take breath analysis away from the large complex instruments in the laboratory to the outpatient clinic and eventually to the home care market. Similarly, for environmental and public health research, it is always desirable to have easily operated and deployable instruments that can be taken to the field, rather than bringing numerous subjects to a central laboratory. Bio-monitoring. Although the SAMAP community is much more focused on air rather than breath measurement, this is changing because of the realization that longer deployment times (on submarines and spacecraft) will affect more than just acute health. To monitor longer-term health outcomes, there is a great deal of commonality between our respective research communities. Any instrument that monitors for contaminants in environmental air could certainly be adapted to breath analysis for assessing exposures and health state. Instruments that simultaneously provide rapid response and high specificity to a broad range of analytes, such as those based on optical spectroscopy and mass spectrometry, are particularly valued. The path forward We found the SAMAP meeting to be a worthwhile experience, largely from the discovery that another high-tech community exists with similar needs as the IABR community. Some collaboration could be fruitful for us; we suggest that the IABR community stay in contact with SAMAP in the future and attempt to attend each other's meetings if possible. SAMAP meetings tend to run on a two year cycle and so the next one has not yet been announced. We will let the IABR community know when the next meeting is scheduled, and will certainly make the SAMAP people aware of IABR meetings and the Journal of Breath Research. This article has been subjected to EPA Agency review and approved for publication. Statements do not necessarily reflect official Agency policy.

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Predictive models of vehicular ultrafine particles less than 0.1 microm in diameter (UFPs*) and other urban pollutants with high spatial and temporal variation are useful and important in applications such as (1) decision support for infrastructure projects, emissions controls, and transportation-mode shifts; (2) the interpretation and enhancement of observations (e.g., source apportionment, extrapolation, interpolation, and gap-filling in space and time); and (3) the generation of spatially and temporally resolved exposure estimates where monitoring is unfeasible. The objective of the current study was to develop, test, and apply the Aerosol Screening Model (ASM), a new physically based vehicular UFP model for use in near-road environments. The ASM simulates hourly average outdoor concentrations of roadway-derived aerosols and gases. Its distinguishing features include user-specified spatial resolution; use of the Weather Research and Forecasting (WRF) meteorologic model for winds estimates; use of a database of more than 100,000 road segments in the Los Angeles, California, region, including freeway ramps and local streets; and extensive testing against more than 9000 hours of observed particle concentrations at 11 sites. After initialization of air parcels at an upwind boundary, the model solves for vehicle emissions, dispersion, coagulation, and deposition using a Lagrangian modeling framework. The Lagrangian parcel of air is subdivided vertically (into 11 levels) and in the crosswind direction (into 3 parcels). It has overall dimensions of 10 m (downwind), 300 m (vertically), and 2.1 km (crosswind). The simulation is typically started 4 km upwind from the receptor, that is, the location at which the exposure is to be estimated. As parcels approach the receptor, depending on the user-specified resolution, step size is decreased, and crosswind resolution is enhanced through subdivision of parcels in the crosswind direction. Hourly concentrations and size distributions of aerosols were simulated for 11 sites in the Los Angeles area with large variations in proximal traffic and particle number concentrations (ranging from 6000 to 41,000/cm3). Observed data were from the 2005-2007 Harbor Community Monitoring Study (HCMS; Moore et al. 2009), in Long Beach, California, and the Coronary Health and Air Pollution Study (CHAPS; Delfino et al. 2008), in the Los Angeles area. Meteorologic fields were extracted from 1-km-resolution meteorologic simulations, and observed wind direction and speed were incorporated. Using on-road and tunnel measurements, size-resolved emission factors ranging from 1.4 x 10(15) to 16 x 10(15) particles/kg fuel were developed specifically for the ASM. Four separate size-resolved emissions were used. Traffic and emission factors were separately estimated for heavy-duty diesel and light-duty vehicles (LDV), and both cruise and acceleration emission factors were used. The light-duty cruise size-resolved number emission factor had a single prominent mode at 12 nm. The diesel cruise size-resolved number emission factor was bimodal, with a large mode at 16 nm and a secondary mode at around 100 nm. Emitted particles were assumed to be nonvolatile. Data on traffic activity came from a 2008 travel-demand model, supplemented by data on diurnal patterns. Simulated ambient number size distributions and number concentrations were compared to observations taking into account estimated losses from particle transmission efficiency in instrument inlet tubing. The skill of the model in predicting number concentrations and size distributions was mixed, with some promising prediction features and some other areas in need of substantial improvement. For long-term (-15-day) average concentrations, the variability from site to site could be modeled with a coefficient of determination (r2) of 0.76. Model underprediction was more common than overprediction. The average of the absolute normalized bias was 0.30; in other words, long-term mean particle concentrations at each site were on average predicted to within 30% of the measured values. Observed 24-hour number concentrations were simulated to within a factor of 1.6 on 48% of days at HCMS sites and 81% at CHAPS sites, lower than the original design goal of 90%. Extensive evaluation of hourly concentrations, diurnal patterns, sizedistributions, and directional patterns was performed. At two sites with heavy freeway and heavy-duty-vehicle (HDV) influences and extensive size-resolved measurements, the ASM made significant errors in the diurnal pattern, concentration, and mode position of the aerosol size distribution. Observations indicated a shift in concentrations and size distributions corresponding to the afternoon development of offshore wind at the HCMS sites. The model did not reproduce the changes in particles associated with this wind shift and suffered from overprediction for particles of less than 15 nm and underprediction for particles of between 15 and 500 nm, raising doubt about the applicability of the HDV emission factors and the model's assumptions that particles were nonvolatile. The model's temporal prediction skill at individual monitoring sites was variable; the index of agreement (IOA) for hourly values at single sites ranged from 0.30 to 0.56. The model's ability to reproduce diurnal patterns in aerosol concentrations was site dependent; midday underprediction as well as underprediction for particle sizes greater than 15 nm were typical errors. Despite some problems in model skill, the number of time periods and locations evaluated as well as the extent of our qualitative and quantitative evaluations versus physical measurements well exceeded other published size-resolved modeling efforts. As a trial of a typical application, the sensitivity of the concentrations at each receptor site to LDV traffic, HDV traffic, and various road classes was evaluated. The sensitivity of overall particle numbers to all types of traffic ranged from 0.87 at the site with the heaviest traffic to 0.28 at the site with the lightest traffic, meaning that a 1% reduction in traffic could yield a reduction in particle number of 0.87% to 0.28%. Key conclusions and implications of the study are the following: 1. That variable-resolution (down to 10 m) modeling in a relatively simple framework is feasible and can support most of the applications mentioned above; 2. That model improvements will be required for some applications, especially in the areas of the HDV emission factor and the parameterization of meteorologic dispersion; 3. That particle loss from instrument transmission efficiency can be significant for particles smaller than 50 nm, and especially significant for particles smaller than 20 nm. In cases where loss corrections are not accounted for, or are inaccurate, this loss can cause disagreements in observation-model and observation-observation comparisons. 4. That LDV traffic exposures likely exceed HDV traffic exposures in some locations; 5. That variable step size and adaptive parcel width are critical to balancing computational efficiency and resolution; and 6. That the effects of roadways on air quality depend on both traffic volume and distance--in other words, low traffic volumes at close proximity need to be considered in health and planning studies just as much as do high traffic volumes at distances up to several kilometers. Future improvements to the model have been identified. They include improved emission factors; integration with the U.S. Environmental Protection Agency (EPA) Motor Vehicle Emission Simulator (MOVES) model; nesting with three-dimensional (3D) Eulerian models such as the Community Multi-scale Air Quality (CMAQ) model; increased emission dependence on acceleration, load, grade, and speed as well as evaporation and condensation of semivolatile aerosol species; and modeling of carbon dioxide (CO2) as an on-road and near-road dilution tracer. In addition, comparison with other statistically and physically based models would be highly beneficial.

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<bObjective:</b To observe how glutamine affect the skeletal muscle membrane repair in severely burned mice through promoting the mitsugumin 53 (MG53) dimerization in skeletal muscle and to explore its functional mechanism. <bMethods:</b (1) Animal experiments. A total of 179 BALB/c male mice aged 6 to 8 weeks were divided into sham injury group (<in</i=43), burn group (<in</i=73) and burn+ glutamine group (<in</i=63) according to the random number table (the same grouping method below). Mice in sham injury group were sham injured on the back, and mice in burn group and burn+ glutamine group were inflicted with 30% total body surface area full-thickness scald (hereinafter referred to as burn) on the back. Mice in burn+ glutamine group were intragastrically administered with glutamine (1 mg/kg), and the other two groups were given the same amount of amino acid solution once per day for 14 days. On post burn hour 12, 10 mice from burn group were taken for preparation of burn serum, which is used in the following cell experiments. Blood samples were collected from the hearts to prepare serum from 10 mice in sham injury group immediately after burn and from 10 mice in burn group and burn+ glutamine group on post burn day (PBD) 5, 10, and 14, respectively. And then the whole gastrocnemius muscle was harvested after the mice were sacrificed. On PBD 10, the whole flexor brevis digitorum was harvested from 6 mice in the 3 groups respectively after the mice were sacrificed. On PBD 5, 10, and 14, the whole gastrocnemius muscle tissue was harvested from another 9 mice in the 3 groups respectively after the mice were sacrificed. The mass of the whole gastrocnemius muscle of mice was weighed. The total protein content of gastrocnemius muscle of mice was detected by coomassie brilliant blue method. The repair function of myolemma of flexor brevis digitorum of mice was detected by two-photon laser fiber membrane perforating. The serum content of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) of mice was determined with radioimmunoassay. The expressions of MG53 dimer and monomer in gastrocnemius of mice were determined with non-reductive electrophoresis-Western blotting. The protein expressions of endoplasmic reticulum stress sign proteins CCAAT/enhancer binding protein homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) in gastrocnemius of mice were determined with Western blotting. (2) Cell experiments. Mice skeletal muscle precursor cells C2C12 were cultured in vitro, and cells of the second passage were selected for the experiments. The cells were divided into normal control group, burn serum group, and burn serum+ glutamine group, with 3 dishes in each group and 1×10(3) cells in each dish. Cells in normal control group were cultured with 1 mL Dulbecco's modified Eagle medium (DMEM) with fetal bovine serum of volume fraction 10%, cells in burn serum group were cultured with 1 mL DMEM with burn serum of volume fraction 10%, and cells in burn serum+ glutamine group were cultured with 1 mL DMEM with burn serum of volume fraction 10% and 4 μL glutamine with a final molar concentration of 8 mmol/L. After 24 hours of culturing, the repair function of myocyte membrane after differentiation of skeletal muscle precursor cells in mice was detected with the same method before. Another cells were grouped and cultured as before, with 3 wells in each group and 1×10(5) cells in each well. After 24 hours of culturing, the expressions of MG53 dimer and monomer and endoplasmic reticulum stress marker proteins in the cells were detected as before. Data were processed with analysis of variance of factorial design, one-way analysis of variance, least significant difference <it</i test, and Student Newman Keuls test. <bResults:</b Animal experiments. (1) Compared with those in sham injury group, the mass and total protein content of gastrocnemius muscle of mice in burn group were significantly decreased on PBD 5, 10, and 14 (<iP</i&lt;0.05). Compared with those in burn group, the mass and total protein content of gastrocnemius muscle of mice in burn+ glutamine group were significantly increased on PBD 5, 10, and 14 (<iP</i&lt;0.05). (2) Compared with that in sham injury group (0.9±0.4), the fluorescence intensity of FM1-43 in myofiber of mice in burn group (7.8±0.4) was significantly increased on PBD 10 (<it</i=7.75, <iP</i&lt;0.05). Compared with that in burn group, the fluorescence intensity of FM1-43 in myofiber of mice in burn+ glutamine group (4.0±0.4) was significantly decreased on PBD 10 (<it</i=-4.31, <iP</i&lt;0.05). (3) Compared with that in sham injury group, the serum content of TNF-α and IL-6 of mice in burn group was significantly increased on PBD 5, 10, and 14 (<iP</i&lt;0.05). Compared with that in burn group, the serum content of TNF-α and IL-6 of mice in burn+ glutamine group was significantly decreased on PBD 5, 10, and 14 (<iP</i&lt;0.05). (4) Compared with 56.97±2.82, 44.89±4.72, 42.46±1.06, 14.26±0.99, 62.36±2.74, and 29.45±0.84 in sham injury group, the expressions of MG53 dimer and monomer in gastrocnemius of mice were significantly decreased in burn group on PBD 5, 10, and 14 (6.16±0.25, 26.09±1.22, 28.86±1.53, 5.63±0.25, 26.74±0.79, 4.41±0.52, <iP</i&lt;0.05). Compared with those in burn group, the expression of MG53 dimer of gastrocnemius of mice in burn+ glutamine group was significantly increased on PBD 10 and 14 (36.79±1.44, 43.96±1.62), and the expression of MG53 monomer of gastrocnemius muscle of mice in burn+ glutamine group was significantly increased on PBD 14 (13.16±2.17, <iP</i&lt;0.05). Compared with those in sham injury group, the protein expressions of CHOP and GRP78 in gastrocnemius muscle of mice in burn group were significantly elevated on PBD 5, 10, and 14 (<iP</i&lt;0.05). Compared with those in burn group, the protein expressions of CHOP and GRP78 in gastrocnemius of mice in burn+ glutamine group were significantly reduced on PBD 5, 10 (<iP</i&lt;0.05). Cell experiments. (1) Compared with that in normal control group (1.76±0.25), the fluorescence intensity of FM1-43 in cells in burn serum group (9.46±1.22) was significantly increased after 24 hours of culturing (<it</i=12.28, <iP</i&lt;0.05). Compared with that in burn serum group, the fluorescence intensity of FM1-43 in cells in burn serum+ glutamine group (4.71±0.45) was significantly decreased after 24 hours of culturing (<it</i=-7.59, <iP</i&lt;0.05). (2) The expressions of MG53 monomer of cells were similar in normal control group, burn serum group, and burn+ glutamine group after 24 hours of culturing (<iP</i&gt;0.05). Compared with 58.5±1.8 in normal control group, the expression of MG53 dimer of cells in burn serum group was significantly decreased after 24 hours of culturing (14.1±1.4, <iP</i&lt;0.05). Compared with that in burn serum group, the expression of MG53 dimer of cells in burn serum+ glutamine group was significantly increased after 24 hours of culturing (30.9±0.6, <iP</i&lt;0.05). Compared with those in normal control group, the protein expressions of CHOP and GRP78 of cells were significantly elevated in burn serum group after 24 hours of culturing (<iP</i&lt;0.05). Compared with those in burn serum group, the protein expressions of CHOP and GRP78 of cells were significantly reduced in burn serum+ glutamine group after 24 hours of culturing (<iP</i&lt;0.05). <bConclusions:</b Glutamine can promote MG53 dimerization by alleviating endoplasmic reticulum stress in severely burned mice. Thus it can accelerate skeletal muscle membrane repair, reduce the local inflammatory reaction of skeletal muscle and consumption of skeletal muscle.

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Bone is the most common site of metastatic disease associated with breast cancer affecting more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer. To assess the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer. Randomized controlled trials were identified using the specialized register maintained by the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy. Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate. Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data. Twenty one randomized studies were included. All studies in advanced breast cancer included women with clinically evident bone metastases (osteolytic and/or mixed osteolytic/osteoblastic) by plain xray and/or radionucleotide bone scans. In nine studies that included 2189 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 17% (RR 0.83; 95% confidence interval (CI) 0.78-0.89; P &lt; 0.00001). This effect was more modest, but still highly significant if episodes of hypercalcaemia were excluded (10 studies, 2656 women, RR 0.85; 95% CI 0.79-0.91 P = 0.0001). Overall, intravenous bisphosphonates reduce the risk of developing a skeletal event by 17 % (95% CI 0.78-0.89) compared with oral bisphosphonates, which reduce the risk of developing a skeletal event by 16 % (95% CI 0.76-0.93). Of the currently available bisphosphonates, 4 mg IV zolendronate reduces the risk of developing a skeletal event by 41% (RR 0.59, 95% CI 0.42-0.82), compared with 33 % by 90 mg IV pamdronate (RR 0.77, 95% CI 0.69-0.87), 18 % by 6 mg IV ibandronate (RR 0.82, 95% CI 0.67-1.00), 14 % by 50mg oral ibandronate (RR 0.86, 95% CI 0.73-1.02) and 16 % by 1600 mg oral clodronate (RR 0.84, 95% CI 0.72-0.98). Compared with placebo or no bisphosphonate, with bisphosphonates the skeletal event rate was lower in all of 12 studies in women with clinically evident bone metastases (median reduction of 29%, range 14-48%); statistically significant reductions were reported in 10 trials (four intravenous pamidronate, two oral clodronate, one intravenous ibandronate and two oral ibandronate, a single intravenous zolendronate study). Studies of intravenous zolendronate, pamidronate and oral clodronate in women with advanced breast cancer and clinically evident bone metastases showed significant delays in the median time to a skeletal event. Event-free survival was also reported to be longer in women receiving 6 mg of ibandronate compared with controls. Compared with placebo or no bisphosphonate, with bisphosphonates significant improvements in bone pain were reported in seven studies (90 mg iv pamidronate, 4 mg iv zolendronate, 6 mg iv ibandronate, 1600 mg oral clodronate and 50 mg oral ibandronate). Eight studies tested the effect of bisphosphonates compared with placebo on patient-rated quality of life using a referenced scale. Improvements in global quality of life were reported in only the three studies of iv and oral ibandronate. Treatment with bisphosphonates does not appear to affect survival in women with advanced breast cancer. Intravenous zolendronate (4 mg) appeared to be as effective as pamidronate (90mg) when directly compared in a single randomized double-blind study, based on the risk of developing a skeletal related event, the median time to first skeletal event and skeletal morbidity rate (events per year). Updated re-evaluation of the primary data in the overall population, by multiple event analysis using the method of Anderson-Gill, showed a reduction in the risk of developing any skeletal complication (including hypercalcamia) of 20 % (zolendronate 4 mg compared with pamidronate 90 mg, RR = 0.80, 95% CI 0.66 - 0.97, p = 0.025), suggesting a possible advantage of zolendronate 4 mg compared with pamidronate 90 mg. In the three studies of bisphosphonates in 320 women with advanced breast cancer without clinically evident bone metastases, there was no significant reduction in the incidence of skeletal events (RR 0.99; 95% CI 0.67-1.47; P = 0.97). In the three studies of oral clodronate that included 1653 women with early breast cancer, there was no statistically significant evidence of reduction in the risk of developing skeletal metastases (RR 0.82; 95% CI 0.66-1.01; P = 0.07), or of visceral metastases (RR 0.95; 95% CI 0.80-1.12, p = 0.53). However there was evidence of improved survival (RR 0.82; 95% CI 0.69-0.97, p = 0.02). However there was statistically significant heterogeneity among these studies and a random effects meta-analysis emphasizes the uncertainty of this finding (RR 0.75; 95% CI 0.45 - 1.25; p = 0.19). Toxicity or adverse events were described in 18 of the 21 studies. In general, few serious adverse events were reported. Toxicity associated with bisphosphonates is generally mild and infrequent. Renal toxicity is the main issue with intravenous zolendronate and is dose (8 mg) and infusion time related (&lt; 15 minutes). With daily oral calcium (500 mg) and vitamin D (300-400IU) no significant renal impairment or hypocalcamia was observed with a 15 minute infusion of 4 mg IV zolendronate compared with 90 mg pamidronate. Monitoring of renal function with every cycle of zolendronate was undertaken in all studies and is recommended in practice. No significant renal toxicity was observed with intravenous pamidronate or ibandronate. Mild gastrointestinal toxicity is the main toxicity with oral clodronate and oral ibandronate. In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time to skeletal event. Some bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases and may improve global quality of life. The optimal timing of initiation of bisphosphonate therapy and duration of treatment is uncertain. In women with early breast cancer the effectiveness of bisphosphonates remains an open question for research.

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Aim of this paper is to allows to analyze a topic of great relevance and media interest such as the role of prophylactic mastectomy in healthy women with BRCA mutation proposing to the surgeons some useful informations for decision-making. Less than 15% of all breast cancers are associated with germline genetic mutations. The majority of hereditary breast tumors are due to mutations in BRCA1 and BRCA2 genes that are responsible for only one third of hereditary cases. The risk estimates are extremely heterogeneous with a mean cumulative lifetime breast cancer risk of approximately 72% in BRCA1 and 69% in BRCA2 by age 80. The breast cancer is often bilateral and multicentric in BRCA mutation carriers. BRCA1 carriers have earlier-onset disease, particularly before age 50 and are more likely to develop aggressive triple-negative breast cancer than BRCA2 carriers or those who are BRCA mutation negative 1. Multiple strategies are effective in managing the risk of breast cancer in these women, including surveillance, chemoprevention, bilateral salpingo-oophorectomy and risk-reducing mastectomy. More intensive surveillance, including annual mammography and breast magnetic resonance imaging screening (commonly alternated every six months) beginning at age 25 or individualized based upon the earliest age of onset in the family, have significantly improved early detection of breast cancer among patients with deleterious BRCA mutations 1. The risk-reducing benefit of chemoprevention is not as well defined; chemopreventive strategies to reduce the risk of breast cancer have focused exclusively on prevention in high-risk women and involve the use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors for breast cancer prevention. Only limited data are available regarding the preventive benefit of tamoxifene in BRCA mutations carriers 1. Risk-reducing bilateral salpingo-oophorectomy is recommended for BRCA mutation carriers by 35 to 40 or when childbearing is completed, or individualized based on age of onset of ovarian cancer in the family; bilateral salpingo-oophorectomy decreases the risk of both breast cancer and ovarian cancer in BRCA1 and BRCA2 mutation carriers and has also been associated with reduced all cause, breast cancer-specific, and ovarian cancer- specific mortality; risk-reducing bilateral salpingooophorectomy seems to offer an approximate 50% relative reduction in breast cancer risk 1. Prophylactic mastectomy provides the greatest reduction in risk of breast cancer development. In both retrospective and prospective observational studies, bilateral prophylactic mastectomy decreases the incidence of breast cancer by 90 percent or more in patients with BRCA mutation; it also is able to determine a variable gain in life expectancy compared to radiological surveillance; besides risk-reducing mastectomy allows to contain the strong anxiety and the fear of getting sick that often compromise the quality of life of BRCA mutation carriers 2. Prophylactic mastectomy could be technically performed in different ways. However, regarding the surgical technique, on the basis of current evidence, the gold standard seems to be represented by nipple-sparing mastectomy which, thanks to the preservation of the skin envelope and the nipple-areola complex, is able to optimize the oncological and aesthetic results. Nipple-sparing mastectomy provides superior cosmetic results. This procedure is usually performed through an inframmamary or radial or axillary incision where the skin is carefully dissected off the breast until all anatomic boundaries of the breast are reached and the gland in its entirety is excised. This technique does not seem to compromise the oncological/preventive efficacy compared to other types of mastectomy. In a multi-institution review of prophylactic 346 BRCA carriers undergoing either bilateral mastectomy or contralateral mastectomy with nipple- areola sparing there were no cases of breast cancer, whereas, based on models, 22 would have been expected 3. However nipple-sparing mastectomy must be carried out with technical skill and maximum attention not to leave macroscopic residues of mammary gland in particular in the axillary extension, peripheral extremities of the gland and the nipple-areola complex; it is necessary to perform an accurate dissection and a meticulous preparation of the skin flaps and of the areola-nipple complex which must be reasonably thin without however compromising its vitality. Whenever the patients opt to proceed with bilateral prophylactic mastectomy, an accurate preoperative radiological study should always be performed with mammography, ultrasound and magnetic resonance imaging to rule out the presence of suspicious breast lesions and minimize the risk of occult carcinomas by definitive histological examination. In the absence of contraindications, all patients should be candidates for breast reconstruction in order to minimize the negative physical and psychological impact of the mastectomy; the breast reconstruction should preferably be immediate, performed at the same time of the prophylactic mastectomy, by a team of dedicated plastic surgeons, or with permanent prosthesis or autologous tissues; the choice of the most appropriate reconstructive technique depends on various factors such as the physical/anatomical structure of the woman, the morphology/ degree of breast ptosis, the comorbidities but also the patient's wishes and preferences 1. However, in the discussion on the possibility of carrying out a prophylactic mastectomy, it is always necessary to consider a series of issues related to this procedure: - the possible oncological failure because risk-reducing mastectomy does not completely eliminate the risk of developing breast cancer; there is always a residual risk of about 5% to be related to the possible presence of residual glandular tissue or ectopic breast tissue 2; - the surgical morbidity with overall complication rates of 15-20% such as ischemia of the skin and/or of the areola-nipple complex, haematomas, infections, implant failure, partial/total autologous flap loss; in a considerable percentage of cases there is also the need to resort after the prophylactic mastectomy to further aesthetic/ plastic procedures to correct some imperfections or repair surgical complications 3-5; - the presence of sequelae such as the loss of sensitivity of the areola-nipple complex, possible paresthesias, painful sensations and the need for re-adaptation to a different body image 2; - the possible body image issues due to many factors, such as self-consciousness, feeling less sexually attractive and dissatisfaction with the scars 2,3. In addition to these issues we must add that most of the studies that show a gain in life expectancy thanks to prophylactic mastectomy, are based only on mathematical models and that the few prospective cohort studies often do not show a statistically significant improvement in terms of survival among women undergoing MP and intensive radiological surveillance 1,2. Therefore in consideration of the benefits but also of the problems that the prophylactic mastectomy involves, all the international guidelines highlight that this procedure must be considered, must be discussed with healthy BRCA women, however without giving an absolute recommendation to perform it 1. This discussion must take place, case by case, in specialized breast centers with a dedicated risk team. A personalized multidisciplinary path should guarantee an accurate genetic and clinical counselling, adequate psychological support and detailed information about all alternative risk management strategies. Clinical decision-making about strategies to pursue for breast cancer risk reduction should involve a tradeoff between life expectancy and quality of life. However if the patient and the medical team opt to proceed with prophylactic surgery, the cumulative evidence to date supports nipple sparing mastectomy with immediate reconstruction as an appropriate risk-reducing procedure to optimize the oncological and aesthetic results and improve quality of life.

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5-(Hydroxymethyl)-2-furfural is formed when reducing sugars such as fructose and sucrose are heated in the presence of amino acids. 5-(Hydroxymethyl)-2-furfural is ubiquitous in the human diet and occurs at concentrations greater than 1 g/kg in dried fruits, caramel products, certain types of fruit juices, and up to 6.2 g/kg in instant coffee. 5-(Hydroxymethyl)-2-furfural also occurs naturally and has been identified in honey, apple juice, citrus juices, beer, brandy, milk, breakfast cereal, baked foods, tomato products, and home cooking of sugar and carbohydrates. Industrially, 5-(hydroxymethyl)-2-furfural is used in the synthesis of dialdehydes, glycols, ethers, aminoalcohols, acetals, and phenol/furfural novolak-type resins. 5-(Hydroxymethyl)-2-furfural was nominated by the National Institute of Environmental Health Sciences for study because of extensive human exposure and the lack of adequate data characterizing its toxicity and carcinogenicity. Male and female F344/N rats and B6C3F1 mice were administered 5-(hydroxymethyl)-2-furfural (at least 99% pure) by gavage in deionized water for 3 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood erythrocytes. 3-WEEK STUDY IN RATS: core study groups of five male and five female rats were administered 0, 94, 188, 375, 750, or 1,500 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for a total of 13 doses over a 22-day period. Special study groups of five male and five female rats designated for neuropathology were administered 0 or 1,500 mg/kg on the same schedule. Except for one 1,500 mg/kg core study male rat, all rats survived to the end of the study. The final mean body weight of 1,500 mg/kg males was significantly less than that of the vehicle control group. No chemical-related histopathologic lesions were observed in core or special study animals. 3-WEEK STUDY IN MICE: groups of five male and five female mice were administered 0, 94, 188, 375, 750, or 1,500 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for a total of 13 doses over a 22-day period. Three male and three female mice administered 1,500 mg/kg died before the end of the study. Mean body weights of 1,500 mg/kg males were significantly less than those of the vehicle control group. Heart weights of 1,500 mg/kg females were significantly greater than those of the vehicle controls. No chemical-related lesions were observed. 3-MONTH STUDY IN RATS: core groups and special study groups (for clinical pathology and neuropathological evaluation) of 10 male and 10 female rats were administered 0, 94, 188, 375, 750, or 1,500 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 3 months. One male and three female rats administered 1,500 mg/kg died before the end of the study; the male died as a result of gavage trauma. Mean body weights of 750 and 1,500 mg/kg males were significantly less than those of the vehicle control group. Female rats had elongated estrous cycles; fewer 750 and 1,500 mg/kg females had regular cycles, and 375, 750, and 1,500 mg/kg females had a significantly increased probability of extended diestrus. No chemical-related lesions were observed in core or special study animals. 3-MONTH STUDY IN MICE: groups of 10 male and 10 female mice were administered 0, 47, 94, 188, 375, or 750 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 3 months. One 750 mg/kg male and one 375 mg/kg female died before the end of the study; the death of the female was attributed to ovarian teratoma. The final mean body weight of 750 mg/kg males and body weight gains of 750 mg/kg males and females were significantly less than those of the vehicle controls. The incidences of minimal to mild cytoplasmic alteration of the kidney were significantly increased in males administered 188 mg/kg or greater. 2-YEAR STUDY IN RATS: groups of 50 male and 50 female rats were administered 0, 188, 375, or 750 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 104 weeks. Survival of 188 and 750 mg/kg males was greater than that of the vehicle control group. Mean body weights of dosed groups of males and females were generally similar to those of the vehicle controls throughout the study. Incidences of olfactory epithelium degeneration were significantly increased in 750 mg/kg males and 188 and 375 mg/kg females. Incidences of olfactory epithelium respiratory metaplasia and respiratory epithelium squamous metaplasia were significantly increased in 750 mg/kg males and females. Incidences of suppurative inflammation of the nose and chronic active inflammation of the nasolacrimal duct were significantly increased in 750 mg/kg females. 2-YEAR STUDY IN MICE: groups of 50 male and 50 female mice were administered 0, 188, 375, or 750 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 104 weeks. Survival of 750 mg/kg males and females was significantly less than that of the vehicle control groups. Mean body weights of 750 mg/kg males were 14% less than those of the vehicle controls after week 26. Mean body weights of 375 and 750 mg/kg females were 9% and 30% less, respectively, than those of the vehicle controls after week 36. Beginning in month 8 and continuing until the end of the study, 750 mg/kg males and females exhibited clinical signs indicative of neurological effects of 5-(hydroxymethyl)-2-furfural administration. These signs included decreased exploratory behavior, piloerection, salivation, Straub tail, catatonia, excitation, dyspnea, clonic-tonic seizures, and unconsciousness. Because of the reduced survival of this group and the presence of the treatment-related clinical signs, groups of mice that received 750 mg/kg were not included in the evaluation of carcinogenic potential. The incidences of hepatocellular adenoma were significantly increased in 188 and 375 mg/kg females. In the nose, the incidences of olfactory epithelium metaplasia, degeneration, and hyaline droplet accumulation; chronic active inflammation; respiratory epithelium hyaline droplet accumulation; and hyperplasia, dilatation, and chronic active inflammation of the glands were significantly increased in 375 and 750 mg/kg males and females. Incidences of olfactory epithelium hyperplasia were significantly increased in 375 and 750 mg/kg females. GENETIC TOXICOLOGY 5-(Hydroxymethyl)-2-furfural was tested in two independent bacterial mutagenicity assays. In the first study, the chemical was weakly mutagenic in Salmonella typhimurium strain TA100 in the absence of exogenous metabolic activation; no mutagenic activity was detected in TA100 with activation or in strains TA97, TA98, TA102, or TA1535, with or without activation. In the second study, no mutagenicity was detected, with or without activation, in TA98 or TA100 or Escherichia coli WP2 uvrA/pKM101. No increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood of male or female mice administered 5-(hydroxymethyl)-2-furfural by gavage for 3 months. under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 5-(hydroxymethyl)-2-furfural in male or female F344/N rats administered 188, 375, or 750 mg/kg. There was no evidence of carcinogenic activity of 5-(hydroxymethyl)-2-furfural in male B6C3F1 mice administered 188 or 375 mg/kg. There was some evidence of carcinogenic activity of 5-(hydroxymethyl)-2-furfural in female B6C3F1 mice based on increased incidences of hepatocellular adenoma in the 188 and 375 mg/kg groups. Administration of 5-(hydroxymethyl)-2-furfural was associated with increased incidences of lesions of the olfactory and respiratory epithelium of the nose in male and female rats and mice.

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The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials. This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy. Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis. All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7. PRIMARY ENDPOINT: In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay &gt; 4 days, development of acute kidney injury ( &gt; 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to &gt; 30% in 48 hours and lymphocyte count drop&gt; 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts. Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm. This is an open label study with no blinding. The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations. Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1<supst</sup 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1<supst</sup 2021. Trial registration: ClincalTrials.gov : NCT04508985 , date of registration: August 11<supth</sup , 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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To examine the effectiveness and cost-effectiveness of hyperbaric oxygen therapy (HBOT) to treat people with diabetes mellitus (DM) and non-healing ulcers. This policy appraisal systematically reviews the published literature in the above patient population, and applies the results and conclusions of the review to current health care practices in Ontario, Canada. Although HBOT is an insured service in Ontario, the costs for the technical provision of this technology are not covered publicly outside the hospital setting. Moreover, access to this treatment is limited, because many hospitals do not offer it, or are not expanding capacity to meet the demand. Diabetes mellitus is a chronic disease characterized by an increase in blood sugar that can lead to many severe conditions such as vision, cardiac, and vascular disorders. The prevalence of DM is difficult to estimate, because some people who have the condition are undiagnosed or may not be captured through data that reflect access to the health care system. The Canadian Diabetic Association estimates there are about 2 million people in Canada with diabetes (almost 7% of the population). According to recent data, the prevalence of DM increased from 4.72% of the population aged 20 years and over in 1995, to 6.19% of the population aged 20 years and over in 1999, or about 680,900 people in 1999. Prevalence estimates expanded to 700,000 in 2003. About 10% to 15% of people with DM develop a foot wound in their lifetimes because of underlying peripheral neuropathy and peripheral vascular disease. This equals between 70,000 and 105,000 people in Ontario, based on the DM prevalence estimate of 700,000 people. Without early treatment, a foot ulcer may fester until it becomes infected and chronic. Chronic wounds are difficult to heal, despite medical and nursing care, and may lead to impaired quality of life and functioning, amputation, or even death. Hyperbaric oxygen therapy has been in use for about 40 years. It is thought to aid wound healing by supplying oxygen to the wound. According to the Hyperbaric Oxygen Therapy Association, HBOT acts as a bactericidal, stops toxin production, and promotes tissue growth to heal difficult wounds. During the procedure, a patient is placed in a compression chamber with increased pressure between 2.0 and 2.5 atmospheres absolute for 60 to 120 minutes, once or twice daily. In the chamber, the patient inhales 100% oxygen. Treatment usually runs for 15 to 20 sessions. Noted complications are rare but may include claustrophobia; ear, sinus, or lung damage due to pressure; temporary worsening of short sightedness; and oxygen poisoning. Careful monitoring during the treatment sessions and follow-up by a trained health care provider is recommended. The aims of this health technology policy appraisal were to assess the effectiveness, safety, and cost-effectiveness of HBOT, either alone, or as an adjunct, compared with the standard treatments for non-healing foot or leg ulcers in patients with DM. The following questions were asked: Alone or as an adjunct therapy, is HBOT more effective than other therapies for non-healing foot or leg ulcers in patients with DM?If HBOT is effective, what is the incremental benefit over and above currently used strategies?When is the best time in a wound treatment strategy to use HBOT?What is the best treatment algorithm with HBOT?The Medical Advisory Secretariat searched for health technology assessments in the published and grey literature. The search yielded 4 reports, which were published from 2000 to 2005. The most recent from the Cochrane Collaboration had a literature review and analysis of randomized control trials to 2003. As an update to this review, as per the standard Medical Advisory Secretariat systematic review strategy, the abstracts of peer-reviewed publications were identified using Ovid MEDLINE, EMBASE, MEDLINE in-process and not-yet-indexed citations, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, and INAHTA using key words and searching from January 1, 2003 to 2004. The criteria for inclusion were as follows: Patients with diabetesLive human studyEnglish-language studyHBOT as adjunctive therapy or aloneRandomized control trialThe number of excluded studies included the following: 2 animal studies13 focus on condition other than DM8 review/protocol for HBOT use3 HBOT not focus of report2 health technology assessments (2)1 non-RCTOutcomes of interest were wound healing and prevention of amputation. The search yielded 29 articles published between 2003 and 2004. All 29 of these were excluded, as shown beside the exclusion criteria above. Therefore, this health technology policy assessment focused exclusively on the most recently published health technology assessments and systematic reviews. Four health technology assessments and reviews were found. Cochrane Collaboration researchers published the most recent review in 2005. They included only randomized controlled trials and conducted a meta-analysis to examine wound healing and amputation outcomes. They found that, based on findings from 118 patients in 3 studies, HBOT may help to prevent major amputation (relative risk, 0.31; 95% confidence interval [CI], 0.13-0.71) with a number needed to treat (NNT) of 4 (95% CI, 3-11). They noted, however, that the point estimates derived from trials were not well reported, and had varying populations with respect to wound severity, HBOT regimens, and outcome measures. These noted limitations rendered the comparison of results from the trials difficult. Further, they suggested that the evidence was not strong enough to suggest a benefit for wound healing in general or for prevention of minor amputations. The Medical Advisory Secretariat also evaluated the studies that the Cochrane Collaboration used in their analysis, and agreed with their evaluation that the quality of the evidence was low for major and minor amputations, but low to moderate for wound healing, suggesting that the results from new and well-conducted studies would likely change the estimates calculated by Cochrane and others. In 2003, the Ontario Health Technology Advisory Committee recommended a more coordinated strategy for wound care in Ontario to the Ministry of Health and Long-term Care. This strategy has begun at the community care and long-term care institution levels, but is pending in other areas of the health care system. There are about 700,000 people in Ontario with diabetes; of these, 10% to 15% may have a foot ulcer sometime in their lifetimes. Foot ulcers are treatable, however, when they are identified, diagnosed and treated early according to best practice guidelines. Routine follow-up for people with diabetes who may be at risk for neuropathy and/or peripheral vascular disease may prevent subsequent foot ulcers. There are 4 chambers that provide HBOT in Ontario. Fewer than 20 people with DM received HBOT in 2003. The quality of the evidence assessing the effectiveness of HBOT as an adjunct to standard therapy for people with non-healing diabetic foot ulcers is low, and the results are inconsistent. The results of a recent meta-analysis that found benefit of HBOT to prevent amputation are therefore uncertain. Future well-conducted studies may change the currently published estimates of effectiveness for wound healing and prevention of amputation using HBOT in the treatment of non-healing diabetic foot ulcers. Although HBOT is an insured service in Ontario, a well conducted, randomized controlled trial that has wound healing and amputation as the primary end-points is needed before this technology is used widely among patients with foot wounds due to diabetes.

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The purpose of this review was to determine the effectiveness and adverse effects of arthroscopic lavage and debridement, with or without lavage, in the treatment of symptoms of osteoarthritis (OA) of the knee, and to conduct an economic analysis if evidence for effectiveness can be established. QUESTIONS ASKED: Does arthroscopic lavage improve motor function and pain associated with OA of the knee?Does arthroscopic debridement improve motor function and pain associated with OA of the knee?If evidence for effectiveness can be established, what is the duration of effect?What are the adverse effects of these procedures?What are the economic considerations if evidence for effectiveness can be established? Osteoarthritis, the most common rheumatologic musculoskeletal disorder, affects about 10% of the Canadian adult population. Although the natural history of OA is not known, it is a degenerative condition that affects the bone cartilage in the joint. It can be diagnosed at earlier ages, particularly within the sports injuries population, though the prevalence of non-injury-related OA increases with increasing age and varies with gender, with women being twice as likely as men to be diagnosed with this condition. Thus, with an aging population, the impact of OA on the health care system is expected to be considerable. Treatments for OA of the knee include conservative or nonpharmacological therapy, like physiotherapy, weight management and exercise; and more generally, intra-articular injections, arthroscopic surgery and knee replacement surgery. Whereas knee replacement surgery is considered an end-of-line intervention, the less invasive surgical procedures of lavage or debridement may be recommended for earlier and more severe disease. Both arthroscopic lavage and debridement are generally indicated in patients with knee joint pain, with or without mechanical problems, that are refractory to medical therapy. The clinical utility of these procedures is unclear, hence, the assessment of their effectiveness in this review. LAVAGE AND DEBRIDEMENT: Arthroscopic lavage involves the visually guided introduction of saline solution into the knee joint and removal of fluid, with the intent of extracting any excess fluids and loose bodies that may be in the knee joint. Debridement, in comparison, may include the introduction of saline into the joint, in addition to the smoothening of bone surface without any further intervention (less invasive forms of debridement), or the addition of more invasive procedures such as abrasion, partial or full meniscectomy, synovectomy, or osteotomy (referred to as debridement in combination with meniscectomy or other procedures). The focus of this health technology assessment is on the effectiveness of lavage, and debridement (with or without meniscal tear resection). THE MEDICAL ADVISORY SECRETARIAT FOLLOWED ITS STANDARD PROCEDURES AND SEARCHED THESE ELECTRONIC DATABASES: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment. THE KEYWORDS SEARCHED WERE: arthroscopy, debridement, lavage, wound irrigation, or curettage; arthritis, rheumatoid, osteoarthritis; osteoarthritis, knee; knee or knee joint. TIME FRAME: Only 2 previous health technology assessments were identified, one of which was an update of the other, and included 3 of 4 randomized controlled trials (RCTs) from the first report. Therefore, the search period for inclusion of studies in this assessment was January 1, 1995 to April 24, 2005. EXCLUDED WERE: case reports, comments, editorials, and letters. Identified were 335 references, including previously published health technology assessments, and 5 articles located through a manual search of references from published articles and health technology assessments. These were examined against the criteria, as described below, which resulted in the inclusion of 1 health technology assessment and its corresponding update, and 4 articles (2 RCTs and 2 level 4 studies) for arthroscopic lavage and 8 papers (2 RCTs and 6 level 4 studies) for arthroscopic debridement. English-language articles from PubMed, EMBASE, Cochrane Systematic Reviews, and health technology assessments from January 1, 1995 onwardStudies on OA of the knee with a focus on the outcomes of motor function and painStudies of arthroscopic procedures onlyStudies in which meniscal tear resection/meniscectomy (partial or full) has been conducted in conjunction with lavage or debridement. Studies that focus on inflammatory OA, joint tuberculosis, septic joints, psoriatic joints (e.g., psoriatic knee joint synovitis), synovitis, chondropathy of the knee and gonarthrosis (which includes varotic gonarthrosis)Studies that focus on rheumatoid arthritisStudies that focus on meniscal tears from an acute injury (e.g., sports injury)Studies that are based on lavage or debridement for microfracture of the kneeStudies in which other surgical procedures (e.g., high tibial osteotomy, synovectomy, have been conducted in addition to lavage/debridement)Studies based on malalignment of the knee (e.g., varus/valgus arthritic conditions).Studies that compare lavage to lavage plus drug therapyStudies on procedures that are not arthroscopic (i.e., visually guided) (e.g., nonarthroscopic lavage)Studies of OA in children. Arthroscopic lavage or debridement, with or without meniscectomy, for the treatment of motor function symptoms and pain associated with OA of the knee. Studies in which there was a comparison group of either diseased or healthy subjects or one in which subjects were their own control were included. Comparisons to other treatments included placebo (or sham) arthroscopy. Sham arthroscopy involved making small incisions and manipulating the knee, without the insertion of instruments. IN EARLY OA OF THE KNEE WITH PAIN REFRACTORY TO MEDICAL TREATMENT, THERE IS LEVEL 1B EVIDENCE THAT: Arthroscopic lavage gives rise to a statistically significant, but not clinically meaningful effect in improving pain (WOMAC pain and VAS pain) up to 12 months following surgery. The effect on joint function (WOMAC function) and the primary outcome (WOMAC aggregate) was neither statistically nor clinically significant. IN MODERATE OR SEVERE OA OF THE KNEE WITH PAIN REFRACTORY TO MEDICAL TREATMENT, THERE IS: Level 1b evidence that the effect on pain and function of arthroscopic lavage (10 L saline) and debridement (with 10 L saline lavage) is not statistically significant up to 24 months following surgery.Level 2 evidence that arthroscopic debridement (with 3 L saline lavage) is effective in the control of pain in severe OA of the medial femoral condyle for up to 5 years.For debridement in combination with meniscectomy, there is level 4 evidence that the procedure, as appropriate, might be effective in earlier stages, unicompartmental disease, shorter symptom duration, sudden onset of mechanical symptoms, and preoperative full range of motion. However, as these findings are derived from very poor quality evidence, the identification of subsets of patients that may benefit from this procedure requires further testing.In patients with pain due to a meniscal tear, of the medial compartment in particular, repair of the meniscus results in better pain control at 2 years following surgery than if the pain is attributable to other causes. There is insufficient evidence to comment on the effectiveness of lateral meniscus repair on pain control. Arthroscopic debridement of the knee has thus far only been found to be effective for medial compartmental OA. All other indications should be reviewed with a view to reducing arthroscopic debridement as an effective therapy. Arthroscopic lavage of the knee is not indicated for any stage of OA. There is very poor quality evidence on the effectiveness of debridement with partial meniscectomy in the case of meniscal tears in OA of the knee.

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This thesis describes the different aspects of otitis media (OM) in the population of Greenland viewed in a historical and modern clinical perspective. Chapter 1 outlines the addressed problems and aims while chapters 2 and 3 deal with historical studies and an evaluation of the present knowledge based on the literature. Physical anthropological studies, using skeletal samples of adult Eskimo crania from before and after the colonization of Greenland in 1721 and information about modern living Eskimos (Inuit), have shown that OM sequelae of the temporal bones were significantly less common in pre-colonization Eskimos and that the mean area size of the pneumatized cell system in the temporal bone was significantly larger in pre-colonization Eskimos. These findings indicated an increase in OM after the colonization most likely caused by the social, cultural, habitary, and dietary changes due to increased contact with the outside world. Historical reports after the colonization confirm a high prevalence of OM especially in children. Modern epidemiological studies from the 1960's to 1980's in the Arctic region of Alaska, Canada, and Greenland along with reports from visiting consultant otologists in Greenland almost uniformly mention prevalent OM problems in children as well as in adults. The aim was therefore to further describe the epidemiological pattern of the different OM disease entities (acute OM (AOM), chronic OM (COM), COM with suppuration (CSOM), secretory OM (SOM), and cholesteatoma) and investigate the potentially associated risk factors in especially Greenlandic children because these diseases are primarily established and problematical in childhood. Chapter 4 describes the definitions used in the thesis and chapter 5 describes the studies included. Section 5.1 describes a study of cholesteatoma in Greenlanders. The study revealed an almost similar incidence of hospital treated children with cholesteatoma (6.6 per 100,000) as seen in comparable studies from other parts of the world. Furthermore, childhood cholesteatomas were the most aggressive. The frequency of residuals or recurrences after otosurgical treatment was high with a trend for better results when using the extensive canal wall-down procedure. It could be concluded that these patients urgently need close follow-up for at least five years postoperatively, if not lifelong. Section 5.2 describes a hearing screening survey of 167 school children using school registration charts. A high prevalence of hearing loss (HL) was found. A total of 43% of the children had hearing thresholds exceeding 20 dB at one or more frequencies between 250-8000 Hz in one or both ears, and 19% had the same type of HL in the frequencies 500-2000 Hz. HL was significantly associated with episodes of OM. These findings were in accordance with reports from Alaska and Canada. It is therefore concluded that a hearing screening programme of school children is important and that OM seems to have an impact on hearing in school children in Greenland. In section 5.3 an epidemiological survey is described concerning the prevalence of the different OM disease entities. The survey was carried out in Nuuk and Sisimiut and involved 740 children aged 3, 4, 5, and 8 years. A total of 591 children participated and selection bias was not found when controlling for age, sex, and episodes of AOM. The survey revealed that 52% of children in Nuuk and 54% in Sisimiut had some kind of pathological affection of their middle ear. COM and CSOM were found in 9%, but more prevalent among children in Sisimiut (12%) than in Nuuk (7%). Middle ear effusion (MEE) diagnosed by tympanometry was found in 23% in Nuuk and 28% in Sisimiut while simple tubal dysfunction (STD) was found in 13% and 8%, respectively. MEE and STD were associated with young age. Sequelae of OM was apparent in 11% in both towns. When comparing the results with a 10-year-older, almost similar survey of 142 children, it was evident that the OM situation had not changed in the period between the studies. The survey underlines the need for increased focus on the different OM entities in Greenlandic children. Section 5.4 deals with microbiological aspects. The nasopharyngeal microflora and ear discharge microflora of potential pathogens were evaluated in 54 children with AOM and in 201 control children without AOM. Very high carriage rates expressed qualitatively and semiquantitatively of potentially pathogenio bacteria were found in the nasopharynx of children with AOM (98%) but also in that of the control children (91%) and even in children denoted as being very healthy (94%). However, the same bacterial species were cultured from the nasopharynx and ear discharge as in comparable studies world-wide. Only S. pneumoniae was carried significantly more often in the nasopharynx of AOM children compared with age matched control children. Chlamydiae, M. pneumoniae, adenovirus, respiratory syncytial virus, parainfluenza- type 1, 2, and 3 virus, and influenza- type A and B virus were not major pathogens. In contrast, entero- and rhinoviruses were detected significantly more frequent in nasopharyngeal specimens from AOM children (59%) compared with age matched controls (33%) and also in 29% of the examined ear discharge specimens. It is therefore concluded that the potentially pathogenic bacterial load is early and massive. This alone or in interplay with entero- and rhinovirus infection and occasionally with other viruses may play an important role in the high prevalence of OM among children in Greenland. Section 5.5 deals with an examination of potential risk factors for AOM, recurrent AOM (rAOM), and COM in the same 591 children as studied in section 5.3. Early age at first AOM episode was associated with rAOM episodes (&gt; or = 5 episodes since birth). Thus, the relative risk of developing rAOM was eight times higher if the first episode of AOM occurred before 7 months of age than after 24 months of age. Furthermore, compared with studies elsewhere in the world, a high proportion (40%) of the children in this survey had their first AOM episode during their first year of life and 41% of these children developed rAOM. It was also found that children had an increased risk of AOM, rAOM, or COM when both parents were born in Greenland, when parents also have had OM, when living in very crowded households, and when having experienced a long period of exclusive breast feeding, or when recalling of breast feeding was not possible. Gender, type, and size of housing, insulation standard of housing, daycare, exposure to passive cigarette smoking, and dietary habits were not associated with AOM, rAOM, or COM in the surveyed children. It is concluded that early onset of AOM occurs frequently in Greenlandic children and that a high proportion of these children develop rAOM. The study confirms that AOM is a highly multifactorial disease determined by a number of genetic and environmental factors. Finally, section 5.6 is a hypothesis generating study attempting to explain the high prevalence of early episodes of AOM in community-based children in Nuuk. The hypothesis is based on a possible association between findings of mannose-binding lectin genotypes, early Epstein-Barr virus infections and episodes of AOM, rAOM, or nasopharyngeal colonization with potentially pathogenic bacteria. However, the study does not support any of this hypothesis. In chapter 6, future studies are suggested and chapter 7 presents concluding remarks.

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Allyl glycidyl ether is used as a resin intermediate and as a stabilizer of chlorinated compounds, vinyl resins, and rubber. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of Osborne-Mendel rats and B6C3F1 of each sex to allyl gylcidyl ether (greater than 97% pure) by inhalation for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Studies of reproductive effects were conducted in rats and mice exposed to allyl glycidyl ether for 8 weeks. Two-Week Studies: Exposure concentrations ranged up to 500 ppm in rats and 100 ppm in mice. All rats that were exposed to 500 ppm died; no deaths occurred at the next lower (200 ppm) exposure concentration. All male mice and 3/5 female mice exposed to 100 ppm and 2/5 male mice and 1/5 female mice exposed to 50 ppm died. Compound-related lesions in rats and mice included acute inflammation of the nasal passage and major airways. Eight-Week Studies of Reproductive Effects: Rats were exposed to 0-200 ppm allyl glycidyl ether, and mice were exposed to 0-30 ppm, 6 hours per day, 5 days per week for 8 weeks. The mating performance of exposed male rats was markedly reduced; however, sperm motility and number were not affected. No deficiencies were seen in the reproductive performance of exposed female rats or male or female mice. Thirteen-Week Studies: Exposure concentrations ranged up to 200 ppm for rats and 30 ppm for mice. All rats lived to the end of the studies. The final mean body weights of male rats exposed to 10-200 ppm were 7%-24% lower than that of controls. Clinical signs attributable to irritation of the upper respiratory tract and eyes were seen in exposed animals. Histologic lesions included squamous metaplasia of the nasal passage in all exposure groups (4 ppm, lowest concentration) and involved both the respiratory epithelium and the olfactory epithelium. The lesions were more severe anteriorly and dorsally and with increasing concentration. At 30 ppm and higher, erosion was seen in the nasal passage and squamous metaplasia was seen in the upper airways. There were no compound-related deaths in mice. The final mean body weights of mice exposed to 30 ppm were 12% lower than those of controls for both males and females. Mice exposed to 10 or 30 ppm allyl glycidyl ether had squamous metaplasia of the nasal passage, involving both the respiratory epithelium and the olfactory epithelium, which tended to be more severe in the anterior and dorsal portions of the nasal passage. In mice exposed to 30 ppm, epithelial erosions were also found. Body Weights and Survival in the Two-Year Studies: Two-year studies were conducted by exposing groups of 50 Osborne-Mendel rats and B6C3F1 mice of each sex to 0, 5, or 10 ppm allyl glycidyl ether by inhalation for 6 hours per day, 5 days per week for 102 or 103 weeks. Mean body weights of the exposed rats were within 8% of those of controls throughout the studies. Mean body weights of mice exposed to 5 or 10 ppm were 5%-20% lower than those of controls. Deaths were seen in all groups of male rats beginning at 1 year of age (final survival-- control, 12/50; 5 ppm, 11/50; 10 ppm, 8/50). Survival of female rats was not exposure related (24/50; 30/50; 25/50). Exposed mice had slightly increased survival (male mice: 38/50; 39/50; 46/50; female mice: 33/50; 42/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In male rats exposed to 10 ppm allyl glycidyl ether, three apparently unrelated neoplasms of the nasal passage were found. Two neoplasms, a papillary adenoma and a squamous cell carcinoma, appeared to arise from different cell types in the respiratory epithelium. One poorly differentiated adenocarcinoma in the olfactory region was also found. One papillary adenoma of respiratory epithelial origin was found in a female rat exposed to 5 ppm. Exposure-related nonneoplastic lesions of the nasal passages in rats included inflammation, squamous metaplasiin rats included inflammation, squamous metaplasia, respiratory metaplasia (replacement of olfactory epithelium by ciliated epithelium), hyperplasia of the respiratory epithelium, and degeneration of the olfactory epithelium. In male mice exposed to 10 ppm allyl glycidyl ether, a hemangioma and three papillary adenomas were present in the nasal passage. In female mice exposed to 10 ppm, a hemangioma and an adenoma were found in the nasal passage. Nonneoplastic lesions of the nasal passages in mice included inflammation, squamous metaplasia, hyperplasia, basal cell hyperplasia, dysplasia of the respiratory epithelium, and metaplasia of the olfactory epithelium. In male mice, there was an exposure-related decrease in the incidences of hepatocellular neoplasms; in female mice, there was a decrease in the incidences of pituitary gland adenomas. Genetic Toxicology: Allyl glycidyl ether was mutagenic in S. typhimurium strains TA100 and TA1535 with and without exogenous metabolic activation; no mutagenic activity was observed in strains TA98 or TA1537. Allyl glycidyl ether induced sister chromatid exchanges and chromosomal aberrations in CHO cells both in the presence and the absence of metabolic activation. A significant increase in sex-linked recessive lethal mutations was recorded in the germ cells of male D. melanogaster fed a sucrose solution containing allyl glycidyl ether, but no increase in reciprocal translocations occurred in these cells. Conclusions: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of allyl glycidyl ether for male Osborne-Mendel rats, based on the presence of one papillary adenoma of respiratory epithelial origin, one squamous cell carcinoma of respiratory epithelial origin, and one poorly differentiated adenocarcinoma of olfactory epithelial origin, all occurring in the nasal passage of males exposed to 10 ppm. There was no evidence of carcinogenic activity of allyl glycidyl ether for female rats. One papillary adenoma of the respiratory epithelium was present in a female rat exposed to 5 ppm. There was some evidence of carcinogenic activity of allyl glycidyl ether for male B6C3F1 mice, based on the presence of three adenomas of the respiratory epithelium, dysplasia in four males, and focal basal cell hyperplasia of the respiratory epithelium in seven males in the nasal passage of mice exposed to 10 ppm. There was equivocal evidence of carcinogenic activity of allyl glycidyl ether for female mice, based on the presence of one adenoma of the respiratory epithelium and focal basal cell hyperplasia of the respiratory epithelium in seven females exposed to 10 ppm. The sensitivity of the assay to detect potential carcinogenicity may have been reduced in male rats because of poor survival in all groups. In exposed mice, body weights were decreased 10&amp;percnt; or more, mortality was decreased, and there were lower incidences of liver neoplasms (males) and pituitary gland adenomas (females) compared with controls. Significant exposure-related nonneoplastic lesions were restricted to the nasal passage in both rats and mice and induced inflammation, metaplasia, respiratory epithelial hyperplasia, and olfactory epithelial degeneration. Basal cell hyperplasia and dysplasia of the respiratory epithelium of the nasal passage were found only in the mice. Synonyms: allyl 2,3-epoxypropyl ether; 1-allyloxy-2,3-epoxypropane; 1,2-epoxy-3-allyloxypropane; glycidyl allyl ether; ((2-propenyloxy)methyl)oxirane; 1-(allyloxy)-2,3-epoxypropane

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This thesis is based on ten published articles. The experimental work was carried out at the Faculty of Health Sciences, University of Copenhagen. The aim was to investigate and describe a number of basic mechanical and physiological mechanisms behind human walking. The methodologies used were biomechanical movement analysis and electrophysiology. The walking experiments were carried out in a gait lab, where the subjects were video recorded while they walked across two force platforms, which measured the ground reaction forces. Net joint moments about the hip-, knee- and ankle joint were calculated by combining the movement data and the external reaction forces (inverse dynamics). Muscle activity and sensory input to the spinal cord were measured by electromyography (EMG) and electrical stimulation of peripheral nerves. The results showed that the gait pattern varies to a great degree between individuals. Some people choose to exert the highest forces about the ankle joint while others prefer to use the knee joint. By use of a cluster analysis, fifteen healthy subjects could be divided into two groups. The extensor moment about the knee joint was the main factor for separating the two gait patterns, but the group with the highest extensor moments about the knee joint also walked with more flexed knee joints, higher EMG activity in the quadriceps muscle and higher bone-on-bone forces. This may lead to development of osteoarthritis over the years. Walking on high-heeled shoes reduced the ankle joint moment significantly either because of reduced muscle fiber length and/or increased co-contraction about the joint. On the contrary, the extensor moment about the knee joint was almost doubled in the high-heeled condition compared to bare footed walking at the same velocity. Also the EMG activity increased in the leg muscles. This could be an explanation pertaining to the higher incidence of osteoarthritis in women than in men. Patients with a drop-foot cannot put the foot to the ground with the heel first. Moreover, they have to increase flexion of the hip joint during the swing phase because the foot hangs in a plantar flexed position. It was shown that the ankle joint plantar flexor moment increased in the healthy leg and that the knee joint extensor moment increased significantly in both the affected and the healthy leg. The latter is most likely due to the patients trying to avoid an asymmetrical gait pattern. It is recommended to use an orthosis with drop-foot patients in order to keep the ankle joint dorsiflexed prior to touchdown, otherwise bone-on-bone forces in both knee joints will increase and probably lead to osteoarthritis. The hip joint moment varies less between individuals. However, both during walking and running an unexplained hip joint flexor moment is present during the last half of the stance phase. The moment appears to oppose the speed of progression and it has been suggested that it serves to balance the upper body. This was investigated in a group of healthy subjects who were asked to walk with their upper body in a reclined, inclined and normal position, respectively. It was shown that the hip joint flexor moment was similar in the reclined and the normal position but lower when walking in the inclined position and it can be concluded that the upper body is not balanced by hip joint flexor muscles but rather by accelerations of the pelvis and activity in abdominal and back muscles. These experiments also showed that the trailing leg is brought forward during the swing phase without activity in the flexor muscles about the hip joint. This was verified by the absence of EMG activity in the iliacus muscle measured by intramuscular wire electrodes. Instead the strong ligaments restricting hip joint extension are stretched during the first half of the swing phase thereby storing elastic energy, which is released during the last half of the stance phase and accelerating the leg into the swing phase. This is considered an important energy conserving feature of human walking. The gating of sensory input to the spinal cord during walking and running was investigated by use of the Hoffmann (H) reflex in m. soleus and m. gastrocnemius medialis. This reflex expresses the central component of the stretch reflex, i.e. the transmission from Ia afferents to α-motoneurones in the spinal cord. The soleus H-reflex was shown to be strongly modulated during the gait cycle. In general, it was facilitated in the stance phase and suppressed in the swing phase. However, as it was the case with the biomechanical parameters, inter-individual H-reflex modulations were found and they were highly reproducible between days. One group of subjects had an almost completely suppressed H-reflex during the entire swing phase, while another group showed a gradually increasing reflex excitability during the swing phase. This group also walked with a lower extensor moment about the knee joint and higher plantar flexor moment about the ankle joint and it is speculated that this gait pattern highly relies on reflexes to deal with unexpected perturbations. The subjects with the suppressed reflex during the swing phase also showed a higher EMG activity in the anterior tibial muscle, so it is likely that the suppression of the H-reflex was at least partly due to reciprocal antagonist inhibition. All subjects showed complete suppression of the H-reflex at toeoff. This seems necessary to avoid a stretch reflex being elicited in the soleus muscle as the ankle joint undergoes a fast dorsiflexion just after toeoff. The reflex modulation is clearly an integrated part of the human gait pattern and is absolutely necessary for normal gait function with smoothe movements. Furthermore, it is anticipated that the afferent input from the muscle spindles is used to drive the motor output from the α-motoneurones together with descending activity from the motor cortex. During running the H-reflex increased in both the soleus and the gastrocnemius already before heel strike and before the onset of EMG activity in the same two muscles and with a relatively high activity in the anterior tibial muscle, but this was most pronounced in the soleus. The H-reflex was always higher in the soleus also when expressed as percentage of the maximal M-wave. This is due to the difference in muscle fiber type distribution between the two muscles. The H-reflex increased from walking to running in both muscles and further with increasing running speed. Unexpectedly, there were no signs of the faster gastrocnemius becoming more important at higher running speed. During walking it is not possible to observe a stretch reflex in the form of a synchronized activation of a large number of muscle fibers as this would disturb the movement pattern. It is rather likely that the input from Ia afferents directly contributes to activate the α-motoneurones. However, during running the stance phase is much shorter, which enables the possibility of a stretch reflex to contribute to a strong contraction during push-off. EMG peaks in the soleus with an appropriate latency were observed in the soleus during running. This was not the case with the gastrocnemius and the explanation is most likely that the gastrocnemius is biarticular and not stretched to any great extent during running.

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Accurate rapid diagnostic tests for SARS-CoV-2 infection could contribute to clinical and public health strategies to manage the COVID-19 pandemic. Point-of-care antigen and molecular tests to detect current infection could increase access to testing and early confirmation of cases, and expediate clinical and public health management decisions that may reduce transmission. To assess the diagnostic accuracy of point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. Electronic searches of the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 30 Sept 2020. We checked repositories of COVID-19 publications and included independent evaluations from national reference laboratories, the Foundation for Innovative New Diagnostics and the Diagnostics Global Health website to 16 Nov 2020. We did not apply language restrictions. We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen or molecular tests suitable for a point-of-care setting (minimal equipment, sample preparation, and biosafety requirements, with results within two hours of sample collection). We included all reference standards that define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction (RT-PCR) tests and established diagnostic criteria). Studies were screened independently in duplicate with disagreements resolved by discussion with a third author. Study characteristics were extracted by one author and checked by a second; extraction of study results and assessments of risk of bias and applicability (made using the QUADAS-2 tool) were undertaken independently in duplicate. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and pooled data using the bivariate model separately for antigen and molecular-based tests. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. Seventy-eight study cohorts were included (described in 64 study reports, including 20 pre-prints), reporting results for 24,087 samples (7,415 with confirmed SARS-CoV-2). Studies were mainly from Europe (n = 39) or North America (n = 20), and evaluated 16 antigen and five molecular assays. We considered risk of bias to be high in 29 (50%) studies because of participant selection; in 66 (85%) because of weaknesses in the reference standard for absence of infection; and in 29 (45%) for participant flow and timing. Studies of antigen tests were of a higher methodological quality compared to studies of molecular tests, particularly regarding the risk of bias for participant selection and the index test. Characteristics of participants in 35 (45%) studies differed from those in whom the test was intended to be used and the delivery of the index test in 39 (50%) studies differed from the way in which the test was intended to be used. Nearly all studies (97%) defined the presence or absence of SARS-CoV-2 based on a single RT-PCR result, and none included participants meeting case definitions for probable COVID-19. Antigen tests Forty-eight studies reported 58 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies. There were differences between symptomatic (72.0%, 95% CI 63.7% to 79.0%; 37 evaluations; 15530 samples, 4410 cases) and asymptomatic participants (58.1%, 95% CI 40.2% to 74.1%; 12 evaluations; 1581 samples, 295 cases). Average sensitivity was higher in the first week after symptom onset (78.3%, 95% CI 71.1% to 84.1%; 26 evaluations; 5769 samples, 2320 cases) than in the second week of symptoms (51.0%, 95% CI 40.8% to 61.0%; 22 evaluations; 935 samples, 692 cases). Sensitivity was high in those with cycle threshold (Ct) values on PCR ≤25 (94.5%, 95% CI 91.0% to 96.7%; 36 evaluations; 2613 cases) compared to those with Ct values &gt;25 (40.7%, 95% CI 31.8% to 50.3%; 36 evaluations; 2632 cases). Sensitivity varied between brands. Using data from instructions for use (IFU) compliant evaluations in symptomatic participants, summary sensitivities ranged from 34.1% (95% CI 29.7% to 38.8%; Coris Bioconcept) to 88.1% (95% CI 84.2% to 91.1%; SD Biosensor STANDARD Q). Average specificities were high in symptomatic and asymptomatic participants, and for most brands (overall summary specificity 99.6%, 95% CI 99.0% to 99.8%). At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed. At 0.5% prevalence applying the same tests in asymptomatic people would result in PPVs of 11% to 28% meaning that between 7 in 10 and 9 in 10 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. No studies assessed the accuracy of repeated lateral flow testing or self-testing. Rapid molecular assays Thirty studies reported 33 evaluations of five different rapid molecular tests. Sensitivities varied according to test brand. Most of the data relate to the ID NOW and Xpert Xpress assays. Using data from evaluations following the manufacturer's instructions for use, the average sensitivity of ID NOW was 73.0% (95% CI 66.8% to 78.4%) and average specificity 99.7% (95% CI 98.7% to 99.9%; 4 evaluations; 812 samples, 222 cases). For Xpert Xpress, the average sensitivity was 100% (95% CI 88.1% to 100%) and average specificity 97.2% (95% CI 89.4% to 99.3%; 2 evaluations; 100 samples, 29 cases). Insufficient data were available to investigate the effect of symptom status or time after symptom onset. Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. The assays shown to meet appropriate criteria, such as WHO's priority target product profiles for COVID-19 diagnostics ('acceptable' sensitivity ≥ 80% and specificity ≥ 97%), can be considered as a replacement for laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. Positive predictive values suggest that confirmatory testing of those with positive results may be considered in low prevalence settings. Due to the variable sensitivity of antigen tests, people who test negative may still be infected. Evidence for testing in asymptomatic cohorts was limited. Test accuracy studies cannot adequately assess the ability of antigen tests to differentiate those who are infectious and require isolation from those who pose no risk, as there is no reference standard for infectiousness. A small number of molecular tests showed high accuracy and may be suitable alternatives to RT-PCR. However, further evaluations of the tests in settings as they are intended to be used are required to fully establish performance in practice. Several important studies in asymptomatic individuals have been reported since the close of our search and will be incorporated at the next update of this review. Comparative studies of antigen tests in their intended use settings and according to test operator (including self-testing) are required.

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RESUMEN: En los últimos quince años diez paises han inaugurado programas nacionales de planeamiento familiar: India, Pakistán, Corea del Sur, Taiwan, Turquía, Malasia, Ceilán, Túez, la República Arabe Unida, y Marruecos. Otros paises, incluyendo Tailandia, Hong Kong, Singapur, Kenya, Barbados, Trinidad y los Estados Unidos, apoyan y/o estimulan actividades de planeamiento familiar. En la mayor parte de los casos la razón fundamental del programa ha sido que si la tasa de crecimiento poblacional disminuyera, aumentaría la tasa de crecimiento económico.Las metas de largo alcance, expresadas típicamente en términos de reducir las tasa.de de natalidad o de crecimiento, tienen su ejemplo en el propósito de Pakistán de reducir su tasa de crecimiento a 26 para 1970; el de Corea de reducir su tasa de natalidad a 20 para 1971; y el de India de reducir su tasa de natalidad a 25 para 1973.Los objectivos intermedios, que cubren diversos aspectos del pro grama, incluyen metas específicas para un determinado mes a año, considerando personal, la adquisición de anticonceptivos, y el número de usarios por método. Las metas específicas anuales de aceptantes de dispositivos intrauterinos (IUD), para Taiwán, Corea, Túnez, Pakistán e India, son comunes, tanto por la naturaleza del artefacto, como por la facilidad de medición de los que continúan utilizándolos. El programa de evaluación en Taiwán, que trata de medir por diversos medios los efectos inmediatos, mediatos y de largo plazo del programa de planeamiento familiar sirve de modelo. El propósito de la evaiuación de un programa de planeamiento familiar es contribuir a la efectividad y eficiencia del programa, midiendo y analizando su progreso. Las áreas a medir pueden ser clasificadas como- (1) conocimiento acerca de; (2) actitudes hacia; (3) práctica de control de natalidad; y (4) nivel de fecundidad.Un buen sistema de evaluación debería incluir: A. Un buen conjunto de estadísticas de servicio presentadas en formularios estandarizados, en las siguienies formas: 1. Informes nensuales por áreas administrativas, sobre los actuales servicios de planeamiento familiar proporcionados en la actualidad, de carácter permanente o de larga duración (al presente, esterilización y IUD de acuerdo a las siguientes características del receptor: residencia, edad, paridad (número de hijos vivos por sexo), y donde se enteró del programa, si es posible "clase";(probablemente educación de la madre, pero posiblemente ocupación del esposo, ingreso, o equivalente); prácticas anticonceptivas anteriores; intervalo; y deseo de tener más hijos. En un programa grande estos datos pueden obtenerse en base a una muestra. 2. Informes mensuales sobre la distribución de suministros anticonceptivos (condones, píldoras, sustancias efervescentes, etc.), los primeros suministros deben ir acompañados de un registro de las características del recipiente, como anteriormente; los suministros subsecuentes se regietrarán sólo en volumen bruto. Esto también se aplicará al ritmo, donde éste método se enseñe a un número considerable de mujeres. 3. Informes regulares sobre las actividades de planeamiento familiar de médicos privados, como una estimación del efecto catalítico del programa del gobierno sobre ci sector privado. 4. Datos generates mensuales, ppr áreas admirtistrativas importantes, sabre: visitas domiciliarias, reuniones, cuñas radiates y televisadas, avisos en los periódicos y personal que trabaja. 5. Para propósitos de seguimiento una entrevi eta de campo cada 6 a 12 meses a cada N mujer de las listas para (1) y (2) arriba, en un total de 300 o 400, para conocer las tasas de continuación y las razones de abandono (ej: desea otro hijo, insatisfecha can ci método, otras). Las mue.stras podrían ser de 300 cada una, con una supuesta experiencia de 6, 12, 18 y 24 meses. B. Un buen conjunto de datos sobre costa (datos sobre cotos actulaes atribuíbles directamente al programa de planeamiento familiar) fraccionados par áreas principales y cinco a seis categorías de costos importantes tales coma: adminietración, personal de campo, publicidad, suministros, etc. C. Un buen conjunto de dates globales sobre la distribución de los suministros comerciales que puedan llegar tan cerca como sea posible del último consumidor, to cual significa probablemente obtener información de los mayoristas. D. Una encuesta de conocimientos, actitudes y prácticas (KAP) para una evaluación general cada dos años. Las preguntas básicas (además de las antes mencionadas y estatus marital y étnico cuando sea pertinente) son: actitud hacia e interés por la anticoncepción, número de niños por sexo, deseo de tener más hijos, prácticas anticonceptivas, experiencia sobre abortos, tal vez historia de embarazo (especialmente si esta producirá una tasa de fecundidad válida), aprobación del programa gubernamental (para uso politico), y si está actualmente embarazada (la única y mejor pregunta cuya respuesta habla del efecto sobre la tasa de natalidad). Administrativamente, la responsabilidad por la evalucion debe estar cerca al director, se debe tomar provisiones para obtener informes regulares (meneulaes) y especiales dirigidos a preguntar sobre política. El corolario es que el jefe de evaluación debe tener la confianza del director y debe estar al día en cuanto a las decisiones sabre la politics a seguir. Su trabajo consiste en extractar los aspectos principales que funcionan bien y los no operantes. En cuanto a costos, la evaluación debe hacerse sobre no más del 10 par ciento del costa del programa en paises pequeños (de menos de 30 milliones) y sabre no más del 5 per ciento en paises más grandes.Para medir en que forma el programa satisface el criterio final-la magnitud en que cambia la fecundidad-se debe realizar un trabajo más elaborado en el centro (Universidades, Consejos de población, etc.) para desarrollar una forma (a formas) segura de traducir las estadísticas de servicio en práticas y tal vez aún datos sobre suministro comercial en datos sabre tasas de natalidad. Esto incluye, par ejemplo, los esfuerzos para consolidar observaciones coma "cinco años-mujer de usa de IUD, a 400 condones equivalen a la prevención de un nacimiento," y esfuerzos como los de Pakistán de calcular tasas coma "años de protección de una pareja contra el embarazo."In the belief that a decrease in the rate of population growth will increase economic development, more than ten countries have inaugurated family planning programs in the past fifteen years. To provide a model for measuring the immediate, intermediate, and long-term effects of any such program, the authors use the Taiwan evaluation.The model suggests that a good system of evaluation should include monthly statistics on (1) participants, who are grouped by characteristics; (2) the distribution of supplies, reported at first by the characteristics of recipients, but after by gross volume only; (3) family planning activities of private physicians to measure the catalytic effect on the private sector; (4) new contacts and amount of advertising in mass media; (5) costs broken down by areas and by cost categories; and (6) distribution of commercial supplies. In addition, the program should conduct 300-400 interviews every 6-12 months to learn the rates of continuation and the rates and reasons for discontinuation. Finally, a KAP survey should be conducted every two years.The administration of the evaluation should be close to the director for policy decisions and for the ultimate work of evaluation-the finding of new ways to measure the main goal of change in fertility by the translation of statistics on Services provided and commercial supplies into birth rate data.

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N-Phenyl- 2- naphthylamine, formerly used as a antioxidant in the rubber industry, was selected for toxicology and carcinogenesis studies because at the time of nomination (1976) it had a large annual production and widespread human exposure. Additional reasons for selection included it structural similarity and possible metabolism to the known human urinary bladder carcinogen, 2-naphthylamine. Toxicology and carcinogenesis studies were conducted by feeding diets containing N-phenyl-2-naphthylamine (approximately 98% pure and containing less than 1 ppm 2-naphthylamine) at various concentrations to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In 14-day studies, 3/5 male and 4/5 female rats that received 50,000 ppm N-phenyl-2-naphthylamine died before the end of the studies. Final mean body weights of rats that received 12,500 ppm or more were considerably lower (18%-57%) than those of the controls. Arched backs, rough coats, and diarrhea were observed for males that received 12,500 ppm or more and for females that received 25,000 or 50,000 ppm. All mice were alive at the end of the studies, and no compound-related clinical signs of toxicity were observed in mice given feed containing up to 20,000 ppm. In 13-week studies, deaths occurred in 4/10 male and 9/10 female rats that received the highest dose (40,000 ppm) of N-phenyl-2-naphthylamine. Final mean body weights of rats that received 5,000-40,000 ppm were 9%-60% lower than those of the controls. The liver weight to body weight ratios increased with increasing dose, with the ratios for male rats at 10,000 ppm or more and for female rats at 5,000 ppm being greater (P&lt;0.05) than those of controls. A compound-related nephropathy occurred in rats and was characterized by renal tubular epithelial degeneration and hyperplasia. Other effects in rats included hematopoietic hypoplasia or atrophy of the femoral bone marrow, testicular hypospermatogenesis, lymphoid degeneration of the thymus, and lymphoid depletion of the spleen. In mice, 2/10 males and 7/10 females that received 40,000 ppm died before the end of the 13-week studies. The final mean body weights of mice that received 10,000, 20,000, or 40,000 ppm were 9%-32% lower than those of the controls. The liver weight to body weight ratios for mice increased with increasing dose. Those for male mice at 10,000 ppm or more and for female mice at 20,000 ppm or more were greater (P&lt;0.05) than those for the controls. Nephropathywas observed at increased incidences and severity in dosed mice. Because of kidney lesions, liver enlargement, lower weight gain, and increased mortality in the shorter term studies, dietary concentrations of N-phenyl-2-naphthylamine selected for the 2-year studies in rats and mice were 0, 2,5000, and 5,000 ppm. Body Weight and Survival in the Two-Year Studies: The mean body weights of dosed rats were lower than those of the controls throughout the studies (12% and 16% lower for dosed males and 15% and 31% lower for dosed females at the end of the studies). The average daily feed consumption for rats was 94%-87% that of the controls for dosed males and 88% that of the controls for dosed females. The estimated average amount of N-phenyl-2-naphthylamine consumed per day was 100 mg/kg and 225 mg/kg for male rats and 120 mg/kg and 260 mg/kg for female rats. The survival of the high dose group of male rats was greater (P&lt;0.05) than that of the controls after week 101 (male: control, 24/50; low dose, 28/50; high dose, 34/50; female: 26/50; 44/50; 38/50). Final mean body weights of high dose male and female mice were lower (male, 9%; female, 23%) than those of the controls. The estimated average daily feed consumption by dosed mice was within 10% that of the controls. The average amount of N-phenyl-2-naphthylamine consumed per day was approximately 500 or 1,000 mg/kg for male mice and 450 or 900 mg/kg for female mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; male mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; low dose, 36/50; high dose, 28/50; female: 36/50; 30/50; 35/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: As in the 13-week studies, the kidney was the principal target for toxic effects of N-phenyl-2-naphthylamine. Mineralization of the kidney, necrosis of the renal papilla, and epithelial hyperplasia and calculi of the kidney pelvis were observed at increased incidences in high dose female rats. Hydronephrosis, atrophy, fibrosis, and chronic focal inflammation of the kidney were observed at increased incidences in high dose female rats. Cysts and acute suppurative inflammation of the kidney were observed at increased incidences in dosed male and high dose female rats. No compound-related renal neoplasms were observed in rats. Nuclear enlargement of renal tubular epithelial cells and nephropathy were observed at increased incidences in high dose female mice. Atypical tubular cell hyperplasia occurred in two high dose female mice. A tubular cell adenoma was found in one high dose female mouse, and a tubular cell adenocarcinoma was found in another high dose female mouse. No renal neoplasms were observed in dosed male mice. Neoplasms of several organs occurred in rats with negative trends and/or at significantly lower incidences in high dose groups. These included thyroid gland C-cell neoplasms in males and females and mammary gland fibroadenomas, pituitary gland adenomas, and mononuclear cell leukemia in females. The lack of carcinogenicity in rats may be related to an inability to metabolize this compound to the known animal and human carcinogen 2-napththylamine. Genetic Toxicity: N-Phenyl-2-naphthylamine was not mutagenic in the Salmonella typhimurium/microsome assay with strains TA97, TA98, TA100, or TA1535 with or without induced hamster or rat liver S9. The chemical did not induce chromosomal aberrations in cultured Chinese hamster ovary (CHO) cells with or without metabolic activation. No increase in sister chromatid exchanges (SCEs) was observed in the absence of metabolic activation; in the presence of rat liver S9, the SCE results were judged to be equivocal. Data Audit: The data, documents, and pathology materials from the 2-year studies of N-phenyl-2-naphthylamine were audited at the NTP Archives. The audit findings show thatthe conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity for male or female F344/N rats fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. Decreased incidences of several neoplasms were observed in dosed rats: thyroid gland C-cell neoplasms in males and females and mononuclear cell leukemia, pituitary gland adenomas, and mammary gland fibroadenomas in females. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. There was equivocal evidence of carcinogenic activity of N-phenyl-2-naphthylamine for female B6C3F1 mice as indicated by the occurrence of two rare kidney neoplasms. Chemical-related nonneoplastic lesions (nephropathy, karyomegaly, and hyperplasia) occurred in the kidney of rats and mice. Synonyms: N-(2-naphthyl)aniline; 2-naphthylphenylamine; b-naphthylphenylamine; 2-phenylaminonaphthalene; phenyl-b-naphthylamine; N-phenyl-b-naphthylamine Trade Names: Aceto PBN; Agerite Powder: Antioxidant 116; Neosone D; Neozon D; Nilox PBNA; Nonox D; PBNA; Stabilizator AR

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In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER: An Evidence-Based and Economic AnalysisEpidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based and Economic AnalysisK-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis. The objective of this systematic review is to determine the predictive value of KRAS testing in the treatment of metastatic colorectal cancer (mCRC) with two anti-EGFR agents, cetuximab and panitumumab. Economic analyses are also being conducted to evaluate the cost-effectiveness of KRAS testing. CONDITION AND TARGET POPULATION Metastatic colorectal cancer (mCRC) is usually defined as stage IV disease according to the American Joint Committee on Cancer tumour node metastasis (TNM) system or stage D in the Duke's classification system. Patients with advanced colorectal cancer (mCRC) either present with metastatic disease or develop it through disease progression. KRAS (Kristen-RAS, a member of the rat sarcoma virus (ras) gene family of oncogenes) is frequently mutated in epithelial cancers such as colorectal cancer, with mutations occurring in mutational hotspots (codons 12 and 13) of the KRAS protein. Involved in EGFR-mediated signalling of cellular processes such as cell proliferation, resistance to apoptosis, enhanced cell motility and neoangiogenesis, a mutation in the KRAS gene is believed to be involved in cancer pathogenesis. Such a mutation is also hypothesized to be involved in resistance to targeted anti-EGFR (epidermal growth factor receptor with tyrosine kinase activity) treatments such as cetuximab and panitumumab, hence, the important in evaluating the evidence on the predictive value of KRAS testing in this context. KRAS MUTATION TESTING IN ADVANCED COLORECTAL CANCER: Both cetuximab and panitumumab are indicated by Health Canada in the treatment of patients with metastatic colorectal cancer whose tumours are WT for the KRAS gene. Cetuximab may be offered as monotherapy in patients intolerant to irinotecan-based chemotherapy or in patients who have failed both irinotecan and oxaliplatin-based regimens and who received a fluoropyrimidine. It can also be administered in combination with irinotecan in patients refractory to other irinotecan-based chemotherapy regimens. Panitumumab is only indicated as a single agent after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. In Ontario, patients with advanced colorectal cancer who are refractory to chemotherapy may be offered the targeted anti-EGFR treatments cetuximab or panitumumab. Eligibility for these treatments is based on the KRAS status of their tumour, derived from tissue collected from surgical or biopsy specimens. It is believed that KRAS status is not affected by treatments, therefore, for patients for whom surgical tissue is available for KRAS testing, additional biopsies prior to treatment with these targeted agents is not necessary. For patients that have not undergone surgery or for whom surgical tissue is not available, a biopsy of either the primary or metastatic site is required to determine their KRAS status. This is possible as status at the metastatic and primary tumour sites is considered to be similar. To determine if there is predictive value of KRAS testing in guiding treatment decisions with anti-EGFR targeted therapies in advanced colorectal cancer patients refractory to chemotherapy. The Medical Advisory Secretariat followed its standard procedures and on May 18, 2010, searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process &amp; Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included colorectal cancer, cetuximab, panitumumab, and KRAS testing. The search was further restricted to English-language articles published between January 1, 2009 and May 18, 2010 resulting in 1335 articles for review. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters. Studies published from January 1, 2005 to December 31, 2008 were identified in a health technology assessment conducted by the Agency for Healthcare Research and Quality (AHRQ), published in 2010. In total, 14 observational studies were identified for inclusion in this EBA: 4 for cetuximab monotherapy, 7 for the cetuximab-irinotecan combination therapy, and 3 to be included in the review for panitumumab monotherapy English-language articles, and English or French-language HTAs published from January 2005 to May 2010, inclusive.Randomized controlled trials (RCTs) or observational studies, including single arm treatment studies that include KRAS testing.Studies with data on main outcomes of interest, overall and progression-free survival.Studies of third line treatment with cetuximab or panitumumab in patients with advanced colorectal cancer refractory to chemotherapy.For the cetuximab-irinotecan evaluation, studies in which at least 70% of patients in the study received this combination therapy. Studies whose entire sample was included in subsequent publications which have been included in this EBA.Studies in pediatric populations.Case reports, comments, editorials, or letters. Overall survival (OS), medianProgression-free-survival (PFS), median.Response rates.Adverse event rates.Quality of life (QOL). SUMMARY OF FINDINGS OF SYSTEMATIC REVIEW: CETUXIMAB OR PANITUMUMAB MONOTHERAPY: Based on moderate GRADE observational evidence, there is improvement in PFS and OS favouring patients without the KRAS mutation (KRAS wildtype, or KRAS WT) compared to those with the mutation. CETUXIMAB-IRINOTECAN COMBINATION THERAPY: There is low GRADE evidence that testing for KRAS may optimize survival benefits in patients without the KRAS mutation (KRAS wildtype, or KRAS WT) compared to those with the mutation. However, cetuximab-irinotecan combination treatments based on KRAS status discount any effect of cetuximab in possibly reversing resistance to irinotecan in patients with the mutation, as observed effects were lower than for patients without the mutation. Clinical experts have raised concerns about the biological plausibility of this observation and this conclusion would, therefore, be regarded as hypothesis generating. Cost-effectiveness and budget impact analyses were conducted incorporating estimates of effectiveness from this systematic review. Evaluation of relative cost-effectiveness, based on a decision-analytic cost-utility analysis, assessed testing for KRAS genetic mutations versus no testing in the context of treatment with cetuximab monotherapy, panitumumab monotherapy, cetuximab in combination with irinotecan, and best supportive care. Of importance to note is that the cost-effectiveness analysis focused on the impact of testing for KRAS mutations compared to no testing in the context of different treatment options, and does not assess the cost-effectiveness of the drug treatments alone. KRAS status is predictive of outcomes in cetuximab and panitumumab monotherapy, and in cetuximab-irinotecan combination therapy. While KRAS testing is cost-effective for all strategies considered, it is not equally cost-effective for all treatment options.

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Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&amp;D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in effect, gave OSI a royalty-free, cashless license to the drug. In November 2001, OSI announced a partnership deal with HopeLink Corporation, a healthcare information technology company with an Internet-based Clinical Trial Service. The partnership will enable OSI to heighten awareness of its clinical trials and shorten patient accrual times. It will initially involve the presentation of the OSI phase III pancreatic and refractory NSCLC trials via Hopelink's Syndicated Network. In addition to this the two companies have also agreed to develop additional products and service together that will increase the efficiency of the clinical trial process, increase awareness of clinical trials, and enhance patient accrual techniques. OSI has also entered into an agreement with Therradex, a contract research organisation (CRO) to monitor phase II trials for erlotinib in NSCLC, ovarian and head and neck cancer. In addition, OSI entered into an agreement in 2001 with the US NCI. The NCI is conducting trials in a variety of different cancers. A phase III front-line NSCLC trial (TRIBUTE) of erlotinib in combination with carboplatin and paclitaxel was initiated in July 2001. The multicentre study is being conducted by Genentech in 1000 patients in the US, and will determine whether the addition of erlotinib to carboplatin chemotherapy is able to improve the duration of patient survival. Enrolment for this trial was completed in July 2002. An independent Data Monitoring Committee (DMC) has since reviewed the data from the trial and concluded that there are no safety or efficacy concerns that would warrant stopping the trial. However, the DMC did recommend stopping erlotinib at the time of disease progression or at the start of second-line therapy. A front-line phase III study of erlotinib in NSCLC (TALENT) in combination with gemcitabine and cisplatin chemotherapy was initiated by Roche in Europe in November 2001. Enrolment into this study was completed in September 2002, with approximately 1200 patients. Roche has confirmed that the study woulde has confirmed that the study would be included in the alliance's potential regulatory submission for front-line therapy in chemotherapy-naive patients in the US. Data from the trial is expected in the second half of 2003. OSI has opened two additional phase Ib studies to examine the potential of erlotinib in combination with carboplatin and paclitaxel in one study and gemcitabine and cisplatin in the other. A phase I study of erlotinib is also being conducted in patients with lung cancer in Japan. OSI received fast-track status from the US FDA in September 2002 for erlotinib as a second- or third-line treatment for patients with incurable stage IIIB/IV NSCLC who have failed to respond to standard therapy for advanced metastatic disease. Fast-track status was also granted to erlotinib in May 2002 for the treatment of chemotherapy-naive stage III/IV NSCLC. There are important differences between phase III studies of erlotinib and AstraZeneca's direct competitor drug gefitinib, which recently returned disappointing results in a frontline NSCLC trial with combination chemotherapy. In assessing the survival benefit of erlotinib with chemotherapy, the dose employed of 150 mg/day is the maximum tolerated dose (MTD), whereas the gefitinib trials were conducted at relatively lower doses than the MTD determined in earlier phase I studies. OSI is also investigating the survival benefit of erlotinib in a phase III study in refractory NSCLC patients, a key registration study. Patient size of the NSCLC trial was increased from 330 to 700 as OSI shifted emphasis from its pancreatic cancer trials. Phase II development for this indication was initiated based on data from a phase I trial, which had completed patient enrolment by April 2003. OSI and the US NCI signed a collaborative research agreement in 2001. The NCI is developing erlotinib through its CTEP programme for multiple tumour types including epithelial malignancies, gastrointestinal and genitourinary tracts, gynaecological malignancies and brain tumours. OSI supplies erlotinib for the trial, but the NCI provides the funding and manages the trials. A series of approximately ten phase Ib trials are already underway or were set to start in the US in 2001 to determine safety, tolerance and pharmacokinetic parameters of erlotinib in combination with a number of commonly used chemotherapeutic agents. The Wall Street Journal reported on 25 February 2002, that analysts at Robert Stephens, New York, USA, have forecast Tarceva to reach annual sales of &gt;$US1 billion. Other analysts, at Merrill Lynch &amp; Co., have predicted that products belonging to the same class as Tarceva could reach combined worldwide sales of $US6 billion to $US10 billion annually. In an earlier report by the Financial Times on 10 May 2001, it was stated that approximately 12 new anticancer agents are expected to be approved by the FDA through to the end of 2002. These agents, of which Tarceva is one, were said to have the potential to generate total sales of $US2.6 billion. Goldman Sachs have forecast Tarceva to reach peak sales of $US250 million for the indication of head and neck cancer alone. Previously in January 2001, the Financial Times claimed that OSI Pharmaceuticals, one of the development partners for Tarceva, stood to gain $US187 million pending regulatory approval. Genentech and Roche were each said to be buying $US35 million worth of OSI's stock and paying upfront fees. Tarceva is facing competition by two similar compounds, developed by AstraZeneca and ImClone, respectively.

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Patients with rheumatoid arthritis have an increased risk for cardiovascular disease. Because of accelerated atherosclerosis and changes in left ventricular (LV) geometry, circumferential and longitudinal (C&amp;L) LV systolic dysfunction (LVSD) may be impaired in these patients despite preserved LV ejection fraction. The aim of this study was to determine the prevalence of and factors associated with combined C&amp;L LVSD in patients with rheumatoid arthritis. One hundred ninety-eight outpatients with rheumatoid arthritis without overt cardiac disease were prospectively analyzed from January through June 2014 and compared with 198 matched control subjects. C&amp;L systolic function was evaluated by stress-corrected midwall shortening (sc-MS) and tissue Doppler mitral annular peak systolic velocity (S'). Combined C&amp;L LVSD was defined if sc-MS was &lt;86.5% and S' was &lt;9.0 cm/sec (the 10th percentiles of sc-MS and S' derived in 132 healthy subjects). Combined C&amp;L LVSD was detected in 56 patients (28%) and was associated with LV mass (odds ratio, 1.03; 95% CI, 1.01-1.06; P = .04) and concentric LV geometry (odds ratio, 2.76; 95% CI, 1.07-7.15; P = .03). By multiple logistic regression analysis, rheumatoid arthritis emerged as an independent predictor of combined C&amp;L LVSD (odds ratio, 2.57; 95% CI, 1.06-6.25). The relationship between sc-MS and S' was statistically significant in the subgroup of 142 patients without combined C&amp;L LVSD (r = 0.40, F &lt; 0.001), having the best fitting by a linear function (sc-MS = 58.1 + 3.34 × peak S'; r(2) = 0.19, P &lt; .0001), absent in patients with combined C&amp;L LVSD. Combined C&amp;L LVSD is detectable in about one fourth of patients with asymptomatic rheumatoid arthritis and is associated with LV concentric remodeling and hypertrophy. Rheumatoid arthritis predicts this worrisome condition, which may explain the increased risk for cardiovascular events in these patients. The aim of this "notice of clarification" is to analyze in brief the similarities and to underline the differences between the current article (defined as "paper J") and a separate article entitled "Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis" (defined as "paper E"), which was written several months before paper J, and recently accepted for publication by the journal "Echocardiography" (Cioffi et al. http://dx.doi.org/10.1111/echo.13186). We wish to explain more clearly how the manuscript described in "paper J" relates to the "paper E" and the context in which it ought to be considered. Data in both papers were derived from the same prospective database, so that it would appear questionable if the number of the enrolled patients and/or their clinical/laboratory/echocardiographic characteristics were different. Accordingly, both papers reported that 198 patients with rheumatoid arthritis (RA) were considered and their characteristics were identical, due to the fact that they were the same subjects (this circumstance is common and mandatory among all studies in which the patients were recruited from the same database). These are the similarities between the papers. In paper E, which was written several months before paper J, we focused on the prevalence and factors associated with impaired circumferential left ventricular (LV) systolic function measured as mid-wall shortening (corrected for circumferential end-systolic stress). We found that 110 patients (56% of the whole population) demonstrated this feature. Thus, these 110 patients were the object of the study described in paper E, in which we specifically analyzed the factors associated with the impairment of stress-corrected mid-wall shortening (sc-MS). The conclusions of that paper were: (i) subclinical LV systolic dysfunction (LVSD) is detectable in more than half RA population without overt cardiac disease as measured by sc-MS, (ii) RA per se is associated with LVSD, and (iii) in RA patients only LV relative wall thickness was associated with impaired sc-MS based upon multivariate logistic regression analysis. Differently, in the paper J, we focused on the prevalence and factors associated with combined impairment of circumferential and longitudinal shortening (C&amp;L) in 198 asymptomatic patients with RA. We found that 56 patients (28% of the whole population) presented this feature. Thus, these 56 patients were analyzed in detail in this study, as well as the factors associated with the combined impairment of C&amp;L shortening. In paper J, we evaluated sc-MS as an indicator of circumferential systolic LV shortening, and we also determined the average of tissue Doppler measures of maximal systolic mitral annular velocity at four different sampling sites ( S') as an indicator of longitudinal LV systolic shortening. This approach clearly demonstrates that in paper J, we analyzed data deriving from the tissue Doppler analysis, which were not taken into any consideration in paper E. The investigation described in paper J made evident several original and clinically relevant findings. In patients with RA: (i) the condition of combined C&amp;L left ventricular systolic dysfunction (LVSD) is frequent; (ii) these patients have comparable clinical and laboratory characteristics with those without combined C&amp;L LVSD, but exhibit remarkable concentric LV geometry and increased LV mass, a phenotype that can be consider a model of compensated asymptomatic chronic heart failure; (iii) RA is an independent factor associated with combined C&amp;L LVSD; (iv) no relationship between indexes of circumferential and longitudinal function exists in patients with combined C&amp;L LVSD, while it is statistically significant and positive when the subgroup of patients without combined C&amp;L LVSD is considered, having the best fitting by a linear function. All these findings are unique to the paper J and are not presented (they could not have been) in paper E. It appears clear that, starting from the same 198 patients included in the database, different sub-groups of patients were selected and analyzed in the two papers (they had different echocardiographic characteristics) and, consequently, different factors emerged by the statistical analyses as covariates associated with the different phenotypes of LVSD considered. Importantly, both papers E and J had a very long gestation because all reviewers for the different journals found several and important issues that merited to be addressed: a lot of changes were proposed and much additional information was required, particularly by the reviewers of paper E. Considering this context, it emerges that although paper E was written well before paper J, the two manuscripts were accepted at the same time (we received the letters of acceptance within a couple of weeks). Thus, the uncertainty about the fate of both manuscripts made it very difficult (if not impossible) to cite either of them in the other one and, afterward, we just did not think about this point anymore. Of note, the idea to combine in the analysis longitudinal function came therefore well after the starting process of revision of the paper E and was, in some way inspired by a reviewer's comment. That is why we did not put both findings in the same paper. We think that our explanations provide the broad audience of your journal a perspective of transparency and our respect for the readers' right to understand how the work described in the paper J relates to other work by our research group. Giovanni Cioffi On behalf of all co-authors Ombretta Viapiana, Federica Ognibeni, Andrea Dalbeni, Davide Gatti, Carmine Mazzone, Giorgio Faganello, Andrea Di Lenarda, Silvano Adami, and Maurizio Rossini.

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The objectives of this consensus conference were to evaluate the evidence for the efficacy and safety of perioperative drugs, technologies, and techniques in reducing allogeneic blood transfusion for adults undergoing cardiac surgery and to develop evidence-based recommendations for comprehensive perioperative blood management in cardiac surgery, with emphasis on minimally invasive cardiac surgery. The consensus panel short-listed the potential topics for review from a comprehensive list of potential drugs, devices, technologies, and techniques. The process of short-listing was based on the need to prioritize and focus on the areas of highest importance to surgeons, anesthesiologists, perfusionists, hematologists, and allied health care involved in the management of patients who undergo cardiac surgery whether through the conventional or minimally invasive approach. MEDLINE, Cochrane Library, and Embase databases were searched from their date of inception to May 2011, and supplemental hand searches were also performed. Detailed methodology and search strategies are outlined in each of the subsequently published systematic reviews. In general, all relevant synonyms for drugs (antifibrinolytic, aprotinin, [Latin Small Letter Open E]-aminocaproic acid, tranexamic acid [TA], desmopressin, anticoagulants, heparin, antiplatelets, anti-Xa agents, adenosine diphosphate inhibitors, acetylsalicylic acid [ASA], factor VIIa [FVIIa]), technologies (cell salvage, miniaturized cardiopulmonary bypass (CPB) circuits, biocompatible circuits, ultrafiltration), and techniques (transfusion thresholds, minimally invasive cardiac or aortic surgery) were searched and combined with terms for blood, red blood cells, fresh-frozen plasma, platelets, transfusion, and allogeneic exposure. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation. Database search identified more than 6900 articles, with 4423 full-text randomized controlled trials assessed for eligibility, and the final 125 systematic reviews and meta-analyses were used in the consensus conference. The results of the consensus conference, including the evidence-based statements and the recommendations, are outlined in the text, with references given for the relevant evidence that formed the basis for the statements and recommendations. RECOMMENDATIONS FOR ANTIFIBRINOLYTICS: The lysine analogs ?-aminocaproic acid (Amicar) and tranexamic acid (TA) reduce exposure to allogeneic blood inpatients undergoing on-pump cardiac surgery. These agents are recommended to be used routinely as part of a blood conservation strategy especially in patients at risk of undergoing onpump cardiac surgery (Class I, Level A). It is important not to exceed maximum TA total dosages (50Y100mg/kg) because of potential neurotoxicity in the elderly and open-heart procedures (Class IIb, Level C). Aprotinin is not recommended in adult cardiac surgery until further studies on its safety profile have been performed (Class III, Level A). RECOMMENDATIONS FOR TA IN OFF-PUMP CORONARY ARTERY BYPASS: Tranexamic acid may be recommended as part of a blood conservation strategy in high risk patients undergoing off-pump coronary artery bypass (OPCAB) surgery (Class I, Level A).Tranexamic acid dosing in OPCAB surgery needs further study particularly with regard to possible neurotoxicity such as seizures.In addition, the benefit-risk ratio in OPCAB needs further eludication because of the lower inherent risk for bleeding in this group (Class IIb, Level C). RECOMMENDATIONS FOR DDAVP: DDAVP can be considered for prophylaxis in coronary artery bypass grafting (CABG) surgery, in particular, for patients onASA within 7 days or prolonged CPB more than 140 minutes (Class IIa, Level A). Caution should be used with the DDAVP infusion rate to avoid significant systemic hypotension (Class I, Level A). RECOMMENDATIONS FOR TOPICAL HEMOSTATICS: The routine use of topical antifibrinolytics in cardiac surgery isnot recommended (Class IIa, Level A). Topical fibrin sealants may be considered in clinical situations where conventional approaches of surgical and medical improvement of hemostasis are not effective, that is, with bleeding problems more local than generalized, bearing in mind the blackbox warning of bovine thrombin by the US Food and Drug Administration (Class IIb, Level C).Recommendations for FVIIa:Prophylactic use of FVIIa cannot be recommended because of a significant increase in the risk of thromboembolic events and stroke (Class IIa, Level A).Factor VIIa may be considered in clinical situations where conventional approaches of surgical and pharmacologic hemostasis have failed and uncontrollable hemorrhage poses a high risk of severe and life-threatening outcomes (Class IIb, Level B). RECOMMENDATIONS FOR ERYTHROPOIETIN PLUS IRON: It is reasonable to administer erythropoietin preoperatively to increase red blood cell mass in patients who are anemic or refuse blood products (such as for Jehovah’s Witness faith) or who are likely to have postoperative anemia (Class IIa, Level A). RECOMMENDATIONS FOR ANTIPLATELETS BEFORE CARDIAC SURGERY: Acetylsalicylic acid may be continued until surgery (Class IIa,Level B) For stable elective CABG procedures with no drug-elutingstent, stop clopidogrel 5 days before surgery (Class I, Level A).h For stable elective CABG procedures with drug-eluting stents less than 1 year old, consider continuing clopidogrel or heparin as abridge to surgery (Class IIb, Level C).h Direct-acting P2Y12 receptor antagonists may be a better alternative than clopidogrel in acute coronary syndrome patients undergoing CABG surgery (Class IIa, Level B). RECOMMENDATIONS FOR ANTIPLATELETS AFTER CARDIAC SURGERY: In stable CABG surgery (nonYacute coronary syndrome patients), the routine use of postoperative clopidogrel with ASAis not warranted (Class IIb, Level B). RECOMMENDATIONS FOR ACUTE NORMOVOLEMIC HEMODILUTION: Acute normovolemic hemodilution can be considered in selected patients with adequate preoperative hemoglobin to reduce post-CPB bleeding (Class IIa, Level A).The routine use of acute normovolemic hemodilution is not recommended (Class IIb, Level B). RECOMMENDATIONS FOR RETROGRADE AUTOLOGOUS PRIMING: Retrograde autologous priming is recommended as a blood conservation modality to reduce allogeneic blood transfusion for onpump cardiac surgery (Class I, Level A). RECOMMENDATIONS FOR CELL SALVAGE: Routine use of cell salvage is recommended in operations where an increased blood loss is expected (Class 1, Level A). Cell salvage should be used throughout the entire operation and not merely as a replacement for CPB cardiotomy suction (Class IIa, Level A). BIOCOMPATIBLE CPB CIRCUITS: The routine use of biocompatible coated CPB circuitry may be considered as part of a multimodal blood conservation program. However, the heterogeneity of surface-modified products, anticoagulation management, and CPB technique does not significantly impact surgical blood loss and transfusion needs (Class IIb,Level A). RECOMMENDATIONS FOR MINIATURIZED EXTRACORPOREAL CARDIOPULMONARY CIRCUIT VERSUS CONVENTIONAL EXTRACORPOREAL CARDIOPULMONARY CIRCUIT: Miniaturized extracorporeal cardiopulmonary circuit can be considered as a blood conservation technique to reduce allogeneic blood exposure (Class IIa, Level A); however, issues related to heparinization management and biocompatible coatings remain to be clarified. RECOMMENDATIONS FOR ULTRAFILTRATION (CONTINUOUS OR MODIFIED):h Ultrafiltration may be considered for blood conservation (Class IIb, Level A); however, the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR PLATELET PLASMAPHERESIS:It is reasonable to recommend platelet plasmapheresis for blood management in cardiac surgery (Class IIa, Level A), although the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR POINT-OF-CARE MONITORING:The evidence is too premature to recommend point-of-caretechnology for routine use because its use has not been shown to impact clinical outcome (Class IIb, Level A). RECOMMENDATIONS FOR SURGICAL TECHNIQUES FOR OPCAB, MINIMALLY INVASIVE STERNOTOMY FOR AORTIC VALVE SURGERY, MINIMALLY INVASIVE STERNOTOMY FOR MITRAL VALVE SURGERY, AND TRANSCATHETHER AORTIC VALVE IMPLANTATION: Although these minimally invasive procedures are not primarily selected for the purpose of blood management, the reduced allogeneic blood exposure should be considered in the balance of benefits and risks when selecting the appropriate surgery for patients.

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