The 100 most-cited articles in BMJ, 2016

Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.

The Consolidated Standards of Reporting Trials (CONSORT) statement is a guideline designed to improve the transparency and quality of the reporting of randomised controlled trials (RCTs). In this article we present an extension to that statement for randomised pilot and feasibility trials conducted in advance of a future definitive RCT. The checklist applies to any randomised study in which a future definitive RCT, or part of it, is conducted on a smaller scale, regardless of its design (eg, cluster, factorial, crossover) or the terms used by authors to describe the study (eg, pilot, feasibility, trial, study). The extension does not directly apply to internal pilot studies built into the design of a main trial, non-randomised pilot and feasibility studies, or phase II studies, but these studies all have some similarities to randomised pilot and feasibility studies and so many of the principles might also apply. The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in…

Medical error is not included on death certificates or in rankings of cause of death. Martin Makary and Michael Daniel assess its contribution to mortality and call for better reporting

Templates used for EtD frameworks are adapted for specific types of decisions.The one shown here is for a clinical recommendation from a population perspective.

OBJECTIVE: To quantify the dose-response associations between total physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events. DESIGN: Systematic review and Bayesian dose-response meta-analysis. DATA SOURCES: PubMed and Embase from 1980 to 27 February 2016, and references from relevant systematic reviews. Data from the Study on Global AGEing and Adult Health conducted in China, Ghana, India, Mexico, Russia, and South Africa from 2007 to 2010 and the US National Health and Nutrition Examination Surveys from 1999 to 2011 were used to map domain specific physical activity (reported in included studies) to total activity. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective cohort studies examining the associations between physical activity (any domain) and at least one of the five diseases studied. RESULTS: 174 articles were identified: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke (some articles included multiple outcomes). Although higher levels of…

Sepsis, severe sepsis, and septic shock represent increasingly severe systemic inflammatory responses to infection. Sepsis is common in the aging population, and it disproportionately affects patients with cancer and underlying immunosuppression. In its most severe form, sepsis causes multiple organ dysfunction that can produce a state of chronic critical illness characterized by severe immune dysfunction and catabolism. Much has been learnt about the pathogenesis of sepsis at the molecular, cell, and intact organ level. Despite uncertainties in hemodynamic management and several treatments that have failed in clinical trials, investigational therapies increasingly target sepsis induced organ and immune dysfunction. Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients. These improvements include lung protective ventilation, more judicious use of blood products, and strategies to reduce…

This review summarises the literature on shift work and its relation to insufficient sleep, chronic diseases, and accidents. It is based on 38 meta-analyses and 24 systematic reviews, with additional narrative reviews and articles used for outlining possible mechanisms by which shift work may cause accidents and adverse health. Evidence shows that the effect of shift work on sleep mainly concerns acute sleep loss in connection with night shifts and early morning shifts. A link also exists between shift work and accidents, type 2 diabetes (relative risk range 1.09-1.40), weight gain, coronary heart disease (relative risk 1.23), stroke (relative risk 1.05), and cancer (relative risk range 1.01-1.32), although the original studies showed mixed results. The relations of shift work to cardiometabolic diseases and accidents mimic those with insufficient sleep. Laboratory studies indicate that cardiometabolic stress and cognitive impairments are increased by shift work, as well as by sleep loss. Given that the health and safety consequences of shift work and insufficient sleep are very…

Many decisions in medicine involve trade-offs, such as between diagnosing patients with disease versus unnecessary additional testing for those who are healthy. Net benefit is an increasingly reported decision analytic measure that puts benefits and harms on the same scale. This is achieved by specifying an exchange rate, a clinical judgment of the relative value of benefits (such as detecting a cancer) and harms (such as unnecessary biopsy) associated with models, markers, and tests. The exchange rate can be derived by asking simple questions, such as the maximum number of patients a doctor would recommend for biopsy to find one cancer. As the answers to these sorts of questions are subjective, it is possible to plot net benefit for a range of reasonable exchange rates in a “decision curve.” For clinical prediction models, the exchange rate is related to the probability threshold to determine whether a patient is classified as being positive or negative for a disease. Net benefit is useful for determining whether basing clinical decisions on a model, marker, or test would do more…

Objectives To evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality. Design Meta-analysis of prospective cohort studies. Data sources Electronic databases (PubMed, Embase, and Google Scholar). Selection criteria Prospective cohort studies from general populations were included for meta-analysis if they reported adjusted relative risks with 95% confidence intervals for associations between the risk of composite cardiovascular disease, coronary heart disease, stroke, all cause mortality, and prediabetes. Review methods Two authors independently reviewed and selected eligible studies, based on predetermined selection criteria. Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47…

OBJECTIVE: To quantify the dose-response relation between consumption of whole grain and specific types of grains and the risk of cardiovascular disease, total cancer, and all cause and cause specific mortality. DATA SOURCES: PubMed and Embase searched up to 3 April 2016. STUDY SELECTION: Prospective studies reporting adjusted relative risk estimates for the association between intake of whole grains or specific types of grains and cardiovascular disease, total cancer, all cause or cause specific mortality. DATA SYNTHESIS: Summary relative risks and 95% confidence intervals calculated with a random effects model. RESULTS: 45 studies (64 publications) were included. The summary relative risks per 90 g/day increase in whole grain intake (90 g is equivalent to three servings-for example, two slices of bread and one bowl of cereal or one and a half pieces of pita bread made from whole grains) was 0.81 (95% confidence interval 0.75 to 0.87; I(2)=9%, n=7 studies) for coronary heart disease, 0.88 (0.75 to 1.03; I(2)=56%, n=6) for stroke, and 0.78 (0.73 to 0.85; I(2)=40%, n=10) for…

OBJECTIVE: To develop a practical evidence based list of clinical risk factors that can be assessed by a clinician at ≤ 16 weeks' gestation to estimate a woman's risk of pre-eclampsia. DESIGN: Systematic review and meta-analysis of cohort studies. DATA SOURCES: PubMed and Embase databases, 2000-15. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Cohort studies with ≥ 1000 participants that evaluated the risk of pre-eclampsia in relation to a common and generally accepted clinical risk factor assessed at ≤ 16 weeks' gestation. DATA EXTRACTION: Two independent reviewers extracted data from included studies. A pooled event rate and pooled relative risk for pre-eclampsia were calculated for each of 14 risk factors. RESULTS: There were 25,356,688 pregnancies among 92 studies. The pooled relative risk for each risk factor significantly exceeded 1.0, except for prior intrauterine growth restriction. Women with antiphospholipid antibody syndrome had the highest pooled rate of pre-eclampsia (17.3%, 95% confidence interval 6.8% to 31.4%). Those with prior pre-eclampsia had the greatest pooled…

OBJECTIVE: To conduct a systematic review and meta-analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose-response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease. DATA SOURCES: PubMed and Embase databases searched up to 23 September 2015. STUDY SELECTION: Cohort studies that reported adjusted risk estimates for at least three categories of BMI in relation to all cause mortality. DATA SYNTHESIS: Summary relative risks were calculated with random effects models. Non-linear associations were explored with fractional polynomial models. RESULTS: 230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738 144 deaths and >9 976 077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3 744 722 deaths among 30 233 329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18…

OBJECTIVE: To provide an overview of prediction models for risk of cardiovascular disease (CVD) in the general population. DESIGN: Systematic review. DATA SOURCES: Medline and Embase until June 2013. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Studies describing the development or external validation of a multivariable model for predicting CVD risk in the general population. RESULTS: 9965 references were screened, of which 212 articles were included in the review, describing the development of 363 prediction models and 473 external validations. Most models were developed in Europe (n=167, 46%), predicted risk of fatal or non-fatal coronary heart disease (n=118, 33%) over a 10 year period (n=209, 58%). The most common predictors were smoking (n=325, 90%) and age (n=321, 88%), and most models were sex specific (n=250, 69%). Substantial heterogeneity in predictor and outcome definitions was observed between models, and important clinical and methodological information were often missing. The prediction horizon was not specified for 49 models (13%), and for 92 (25%) crucial information…

Effects of treatment or other exposure on outcome events are commonly measured by ratios of risks, rates, or odds. Adjusted versions of these measures are usually estimated by maximum likelihood regression (eg, logistic, Poisson, or Cox modelling). But resulting estimates of effect measures can have serious bias when the data lack adequate case numbers for some combination of exposure and outcome levels. This bias can occur even in quite large datasets and is hence often termed sparse data bias. The bias can arise or be worsened by regression adjustment for potentially confounding variables; in the extreme, the resulting estimates could be impossibly huge or even infinite values that are meaningless artefacts of data sparsity. Such estimate inflation might be obvious in light of background information, but is rarely noted let alone accounted for in research reports. We outline simple methods for detecting and dealing with the problem focusing especially on penalised estimation, which can be easily performed with common software packages.

OBJECTIVE: To quantify the association between atrial fibrillation and cardiovascular disease, renal disease, and death. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline and Embase. ELIGIBILITY CRITERIA: Cohort studies examining the association between atrial fibrillation and cardiovascular disease, renal disease, and death. Two reviewers independently extracted study characteristics and the relative risk of outcomes associated with atrial fibrillation: specifically, all cause mortality, cardiovascular mortality, major cardiovascular events, any stroke, ischaemic stroke, haemorrhagic stroke, ischaemic heart disease, sudden cardiac death, congestive heart failure, chronic kidney disease, and peripheral arterial disease. Estimates were pooled with inverse variance weighted random effects meta-analysis. RESULTS: 104 eligible cohort studies involving 9 686 513 participants (587 867 with atrial fibrillation) were identified. Atrial fibrillation was associated with an increased risk of all cause mortality (relative risk 1.46, 95% confidence interval 1.39 to 1.54),…

OBJECTIVE: To systematically review studies quantifying the associations of long term (clinic), mid-term (home), and short term (ambulatory) variability in blood pressure, independent of mean blood pressure, with cardiovascular disease events and mortality. DATA SOURCES: Medline, Embase, Cinahl, and Web of Science, searched to 15 February 2016 for full text articles in English. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Prospective cohort studies or clinical trials in adults, except those in patients receiving haemodialysis, where the condition may directly impact blood pressure variability. Standardised hazard ratios were extracted and, if there was little risk of confounding, combined using random effects meta-analysis in main analyses. Outcomes included all cause and cardiovascular disease mortality and cardiovascular disease events. Measures of variability included standard deviation, coefficient of variation, variation independent of mean, and average real variability, but not night dipping or day-night variation. RESULTS: 41 papers representing 19 observational cohort studies…

STUDY QUESTION: What has been the effect on purchases of beverages from stores in Mexico one year after implementation of the excise tax on sugar sweetened beverages? METHODS: In this observational study the authors used data on the purchase of beverages in Mexico from January 2012 to December 2014 from an unbalanced panel of 6253 households providing 205 112 observations in 53 cities with more than 50 000 inhabitants. To test whether the post-tax trend in purchases was significantly different from the pretax trend, the authors used a difference in difference fixed effects model, which adjusts for both macroeconomic variables that can affect the purchase of beverages over time, and pre-existing trends. The variables used in the analysis included demographic information on household composition (age and sex of household members) and socioeconomic status (low, middle, and high). The authors compared the predicted volumes (mL/capita/day) of taxed and untaxed beverages purchased in 2014-the observed post-tax period-with the estimated volumes that would have been purchased if the tax had…

Funding: Work on this article has been partially funded by the European Commission FP7 Program (grant agreement 258583) as part of the DECIDE project. Sole responsibility lies with the authors; the European Commission is not responsible for any use that may be made of the information contained therein.

AGREE II is a widely used standard for assessing the methodological quality of practice guidelines. This article describes the development of the AGREE Reporting Checklist, which was designed to improve the quality of practice guideline reporting and aligns with AGREE II in its structure and content.

There are two common misconceptions about case-control studies: that matching in itself eliminates (controls) confounding by the matching factors, and that if matching has been performed, then a “matched analysis” is required. However, matching in a case-control study does not control for confounding by the matching factors; in fact it can introduce confounding by the matching factors even when it did not exist in the source population. Thus, a matched design may require controlling for the matching factors in the analysis. However, it is not the case that a matched design requires a matched analysis. Provided that there are no problems of sparse data, control for the matching factors can be obtained, with no loss of validity and a possible increase in precision, using a “standard” (unconditional) analysis, and a “matched” (conditional) analysis may not be required or appropriate.

To improve the completeness of reporting of mobile health (mHealth) interventions, the WHO mHealth Technical Evidence Review Group developed the mHealth evidence reporting and assessment (mERA) checklist. The development process for mERA consisted of convening an expert group to recommend an appropriate approach, convening a global expert review panel for checklist development, and pilot testing the checklist. The guiding principle for the development of these criteria was to identify a minimum set of information needed to define what the mHealth intervention is (content), where it is being implemented (context), and how it was implemented (technical features), to support replication of the intervention. This paper presents the resulting 16 item checklist and a detailed explanation and elaboration for each item, with illustrative reporting examples. Through widespread adoption, we expect that the use of these guidelines will standardise the quality of mHealth evidence reporting, and indirectly improve the quality of mHealth evidence.

OBJECTIVES: To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A. DESIGN: Systematic review, including assessment of risk of bias, and meta-analyses of similar studies. STUDY ELIGIBILITY CRITERIA: Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5. DATA SOURCES: Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified. RESULTS: Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical…

Access to big datasets from e-health records and individual participant data (IPD) meta-analysis is signalling a new advent of external validation studies for clinical prediction models. In this article, the authors illustrate novel opportunities for external validation in big, combined datasets, while drawing attention to methodological challenges and reporting issues.

Lumbar spinal stenosis (LSS) affects more than 200,000 adults in the United States, resulting in substantial pain and disability. It is the most common reason for spinal surgery in patients over 65 years. Lumbar spinal stenosis is a clinical syndrome of pain in the buttocks or lower extremities, with or without back pain. It is associated with reduced space available for the neural and vascular elements of the lumbar spine. The condition is often exacerbated by standing, walking, or lumbar extension and relieved by forward flexion, sitting, or recumbency. Clinical care and research into lumbar spinal stenosis is complicated by the heterogeneity of the condition, the lack of standard criteria for diagnosis and inclusion in studies, and high rates of anatomic stenosis on imaging studies in older people who are completely asymptomatic. The options for non-surgical management include drugs, physiotherapy, spinal injections, lifestyle modification, and multidisciplinary rehabilitation. However, few high quality randomized trials have looked at conservative management. A systematic review…

INTRODUCTION: For any health intervention, accurate knowledge of both benefits and harms is needed. Systematic reviews often compound poor reporting of harms in primary studies by failing to report harms or doing so inadequately. While the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) helps systematic review authors ensure complete and transparent reporting, it is focused mainly on efficacy. Thus, a PRISMA harms checklist has been developed to improve harms reporting in systematic reviews, promoting a more balanced assessment of benefits and harms. METHODS: A development strategy, endorsed by the EQUATOR Network and existing reporting guidelines (including the PRISMA statement, PRISMA for abstracts, and PRISMA for protocols), was used. After the development of a draft checklist of items, a modified Delphi process was initiated. The Delphi consisted of three rounds of electronic feedback followed by an in-person meeting. RESULTS: The PRISMA harms checklist contains four essential reporting elements to be added to the original PRISMA statement…

The self controlled case series (SCCS) method is an epidemiological study design for which individuals act as their own control—ie, comparisons are made within individuals. Hence, only individuals who have experienced an event are included and all time invariant confounding is eliminated. The temporal association between a transient exposure and an event is estimated. SCCS was originally developed for evaluation of vaccine safety, but has since been applied in a range of settings where exact information on the size of the population at risk is lacking or identification of an appropriate comparison group is difficult—eg, for studies of adverse effects of drug treatments. We provide an overview of the SCCS method, with examples of its use, discuss limitations, assumptions, and potential biases that can arise where assumptions are not met, and provide solutions and examples of good practice.

OBJECTIVE: To assess the effect of treatment for cervical intraepithelial neoplasia (CIN) on obstetric outcomes and to correlate this with cone depth and comparison group used. DESIGN: Systematic review and meta-analysis. DATA SOURCES: CENTRAL, Medline, Embase from 1948 to April 2016 were searched for studies assessing obstetric outcomes in women with or without previous local cervical treatment. DATA EXTRACTION AND SYNTHESIS: Independent reviewers extracted the data and performed quality assessment using the Newcastle-Ottawa criteria. Studies were classified according to method and obstetric endpoint. Pooled risk ratios were calculated with a random effect model and inverse variance. Heterogeneity between studies was assessed with I(2) statistics. MAIN OUTCOME MEASURES: Obstetric outcomes comprised preterm birth (including spontaneous and threatened), premature rupture of the membranes, chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage, and cervical stenosis. Neonatal outcomes comprised low birth…

OBJECTIVE: To assess the impact of communicating DNA based disease risk estimates on risk-reducing health behaviours and motivation to engage in such behaviours. DESIGN: Systematic review with meta-analysis, using Cochrane methods. DATA SOURCES: Medline, Embase, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials up to 25 February 2015. Backward and forward citation searches were also conducted. STUDY SELECTION: Randomised and quasi-randomised controlled trials involving adults in which one group received personalised DNA based estimates of disease risk for conditions where risk could be reduced by behaviour change. Eligible studies included a measure of risk-reducing behaviour. RESULTS: We examined 10,515 abstracts and included 18 studies that reported on seven behavioural outcomes, including smoking cessation (six studies; n=2663), diet (seven studies; n=1784), and physical activity (six studies; n=1704). Meta-analysis revealed no significant effects of communicating DNA based risk estimates on smoking cessation (odds ratio 0.92, 95% confidence interval 0.63…

OBJECTIVE: To examine changes in representation of women among first authors of original research published in high impact general medical journals from 1994 to 2014 and investigate differences between journals. DESIGN: Observational study. STUDY SAMPLE: All original research articles published in Annals of Internal Medicine, Archives of Internal Medicine, The BMJ, JAMA, The Lancet, and the New England Journal of Medicine (NEJM) for one issue every alternate month from February 1994 to June 2014. MAIN EXPOSURES: Time and journal of publication. MAIN OUTCOME MEASURES: Prevalence of female first authorship and its adjusted association with time of publication and journal, assessed using a multivariable logistic regression model that accounted for number of authors, study type and specialty/topic, continent where the study was conducted, and the interactions between journal and time of publication, study type, and continent. Estimates from this model were used to calculate adjusted odds ratios against the mean across the six journals, with 95% confidence intervals and P values to…

OBJECTIVE: To determine whether atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men. DESIGN: Meta-analysis of cohort studies. DATA SOURCES: Studies published between January 1966 and March 2015, identified through a systematic search of Medline and Embase and review of references. ELIGIBILITY FOR SELECTING STUDIES: Cohort studies with a minimum of 50 participants with and 50 without atrial fibrillation that reported sex specific associations between atrial fibrillation and all cause mortality, cardiovascular mortality, stroke, cardiac events (cardiac death and non-fatal myocardial infarction), and heart failure. DATA EXTRACTION: Two independent reviewers extracted study characteristics and maximally adjusted sex specific relative risks. Inverse variance weighted random effects meta-analysis was used to pool sex specific relative risks and their ratio. RESULTS: 30 studies with 4,371,714 participants were identified. Atrial fibrillation was associated with a higher risk of all cause mortality in women (ratio of relative risks…

OBJECTIVE: To determine whether government efforts in reducing inequalities in health in European countries have actually made a difference to mortality inequalities by socioeconomic group. DESIGN: Register based study. DATA SOURCE: Mortality data by level of education and occupational class in the period 1990-2010, usually collected in a census linked longitudinal study design. We compared changes in mortality between the lowest and highest socioeconomic groups, and calculated their effect on absolute and relative inequalities in mortality (measured as rate differences and rate ratios, respectively). SETTING: All European countries for which data on socioeconomic inequalities in mortality were available for the approximate period between years 1990 and 2010. These included Finland, Norway, Sweden, Scotland, England and Wales (data applied to both together), France, Switzerland, Spain (Barcelona), Italy (Turin), Slovenia, and Lithuania. RESULTS: Substantial mortality declines occurred in lower socioeconomic groups in most European countries covered by this study. Relative…

OBJECTIVE: To study the effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (novel oral anticoagulants, NOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin in anticoagulant naïve patients with atrial fibrillation. DESIGN: Observational nationwide cohort study. SETTING: Three Danish nationwide databases, August 2011 to October 2015. PARTICIPANTS: 61 678 patients with non-valvular atrial fibrillation who were naïve to oral anticoagulants and had no previous indication for valvular atrial fibrillation or venous thromboembolism. The study population was distributed according to treatment type: warfarin (n=35 436, 57%), dabigatran 150 mg (n=12 701, 21%), rivaroxaban 20 mg (n=7192, 12%), and apixaban 5 mg (n=6349, 10%). MAIN OUTCOME MEASURES: Effectiveness outcomes defined a priori were ischaemic stroke; a composite of ischaemic stroke or systemic embolism; death; and a composite of ischaemic stroke, systemic embolism, or death. Safety outcomes were any bleeding, intracranial bleeding, and major bleeding. RESULTS: When the analysis was restricted…

Statistical analysis usually treats all observations as equally important.In some circumstances, however, it is appropriate to vary the weight given to different observations.Well known examples are in meta-analysis, where the inverse variance (precision) weight given to each contributing study varies, and in the analysis of clustered data.

Updating of systematic reviews is generally more efficient than starting all over again when new evidence emerges, but to date there has been no clear guidance on how to do this. This guidance helps authors of systematic reviews, commissioners, and editors decide when to update a systematic review, and then how to go about updating the review.

OBJECTIVES: To systematically review studies investigating the prevalence of antibiotic resistance in urinary tract infections caused by Escherichia coli in children and, when appropriate, to meta-analyse the relation between previous antibiotics prescribed in primary care and resistance. DESIGN AND DATA ANALYSIS: Systematic review and meta-analysis. Pooled percentage prevalence of resistance to the most commonly used antibiotics in children in primary care, stratified by the OECD (Organisation for Economic Co-operation and Development) status of the study country. Random effects meta-analysis was used to quantify the association between previous exposure to antibiotics in primary care and resistance. DATA SOURCES: Observational and experimental studies identified through Medline, Embase, Cochrane, and ISI Web of Knowledge databases, searched for articles published up to October 2015. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were eligible if they investigated and reported resistance in community acquired urinary tract infection in children and young people aged 0-17.…

OBJECTIVES: To assess the association between maternal glucose concentrations and adverse perinatal outcomes in women without gestational or existing diabetes and to determine whether clear thresholds for identifying women at risk of perinatal outcomes can be identified. DESIGN: Systematic review and meta-analysis of prospective cohort studies and control arms of randomised trials. DATA SOURCES: Databases including Medline and Embase were searched up to October 2014 and combined with individual participant data from two additional birth cohorts. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies including pregnant women with oral glucose tolerance (OGTT) or challenge (OGCT) test results, with data on at least one adverse perinatal outcome. APPRAISAL AND DATA EXTRACTION: Glucose test results were extracted for OGCT (50 g) and OGTT (75 g and 100 g) at fasting and one and two hour post-load timings. Data were extracted on induction of labour; caesarean and instrumental delivery; pregnancy induced hypertension; pre-eclampsia; macrosomia; large for gestational age; preterm birth; birth…

Resistance of the Enterobacteriaceae to antibiotics, especially of the β lactam type, is increasingly dominated by the mobilization of continuously expressed single genes that encode efficient drug modifying enzymes. Strong and ubiquitous selection pressure has seemingly been accompanied by a shift from "natural" resistance, such as inducible chromosomal enzymes, membrane impermeability, and drug efflux, to the modern paradigm of mobile gene pools that largely determine the epidemiology of modern antibiotic resistance. In this way, antibiotic resistance is more available than ever before to organisms such as Escherichia coli and Klebsiella pneumoniae that are important causes of major sepsis. Modulation of the phenotype by host bacteria makes gene transmission less obvious and may in part explain why tracking and control of carbapenem resistance has been particularly problematic in the Enterobacteriaceae. This review discusses the underlying principles and clinical implications of the mobility and fixation of resistance genes and the exploitable opportunities and potential threats…

Seventy six senior academics from 11 countries invite The BMJ’s editors to reconsider their policy of rejecting qualitative research on the grounds of low priority. They challenge the journal to develop a proactive, scholarly, and pluralist approach to research that aligns with its stated mission

OBJECTIVE: To report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic. DESIGN: Retrospective study with a case series. SETTING: Association for Assistance of Disabled Children (AACD), Pernambuco state, Brazil. PARTICIPANTS: 23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. MAIN OUTCOME MEASURES: Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. RESULTS: Six of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus--the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI.…

OBJECTIVE: To assess the effect of antihypertensive treatment on mortality and cardiovascular morbidity in people with diabetes mellitus, at different blood pressure levels. DESIGN: Systematic review and meta-analyses of randomised controlled trials. DATA SOURCES: CENTRAL, Medline, Embase, and BIOSIS were searched using highly sensitive search strategies. When data required according to the protocol were missing but trials were potentially eligible, we contacted researchers, pharmaceutical companies, and authorities. ELIGIBILITY CRITERIA: Randomised controlled trials including 100 or more people with diabetes mellitus, treated for 12 months or more, comparing any antihypertensive agent against placebo, two agents against one, or different blood pressure targets. RESULTS: 49 trials, including 73,738 participants, were included in the meta-analyses. Most of the participants had type 2 diabetes. If baseline systolic blood pressure was greater than 150 mm Hg, antihypertensive treatment reduced the risk of all cause mortality (relative risk 0.89, 95% confidence interval 0.80 to 0.99),…

OBJECTIVE: To determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status. DESIGN: Mendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non-genetic factors. SETTING: UK Biobank. PARTICIPANTS: 119,669 men and women of British ancestry, aged between 37 and 73 years. MAIN OUTCOME MEASURES: Age completed full time education, degree level education, job class, annual household income, and Townsend deprivation index. RESULTS: In the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a £210…

OBJECTIVE: To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic review and meta-analysis. DESIGN: The MCE (1968-73) is a double blind randomized controlled trial designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduces coronary heart disease and death by lowering serum cholesterol. Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators. Further, a systematic review and meta-analyses of randomized controlled trials that lowered serum cholesterol by providing vegetable oil rich in linoleic acid in place of saturated fat without confounding by concomitant interventions was conducted. SETTING: One nursing home and six state mental hospitals in Minnesota, United States. PARTICIPANTS: Unpublished documents with completed analyses for the randomized cohort of 9423…

OBJECTIVES: To determine whether late mortality after sepsis is driven predominantly by pre-existing comorbid disease or is the result of sepsis itself. DEIGN: Observational cohort study. SETTING: US Health and Retirement Study. PARTICIPANTS: 960 patients aged ≥65 (1998-2010) with fee-for-service Medicare coverage who were admitted to hospital with sepsis. Patients were matched to 777 adults not currently in hospital, 788 patients admitted with non-sepsis infection, and 504 patients admitted with acute sterile inflammatory conditions. MAIN OUTCOME MEASURES: Late (31 days to two years) mortality and odds of death at various intervals. RESULTS: Sepsis was associated with a 22.1% (95% confidence interval 17.5% to 26.7%) absolute increase in late mortality relative to adults not in hospital, a 10.4% (5.4% to 15.4%) absolute increase relative to patients admitted with non-sepsis infection, and a 16.2% (10.2% to 22.2%) absolute increase relative to patients admitted with sterile inflammatory conditions (P<0.001 for each comparison). Mortality remained higher for at least two years…

The lung is a common site of complications of systemic connective tissue disease (CTD), and lung involvement can present in several ways. Interstitial lung disease (ILD) and pulmonary hypertension are the most common lung manifestations in CTD. Although it is generally thought that interstitial lung disease develops later on in CTD it is often the initial presentation ("lung dominant" CTD). ILD can be present in most types of CTD, including rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD, such as idiopathic pulmonary fibrosis. Pulmonary hypertension (PH) can present as a primary vasculopathy in pulmonary arterial hypertension or in association with ILD (PH-ILD). Therefore, detailed history, physical examination, targeted serologic testing, and, occasionally, lung biopsy are needed to diagnose CTD-ILD,…

OBJECTIVE: To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors.Design Systematic review and meta-analysis. MAIN OUTCOME MEASURES: Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia. DATA SOURCES: Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly's website. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms. DATA EXTRACTION AND ANALYSIS: Two researchers extracted data independently; the outcomes were meta-analysed by Peto's exact method (fixed effect model). RESULTS: We included 70 trials (64,381 pages of clinical study reports) with 18,526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in…

Jansen and colleagues explore the role of shared decision making in tackling inappropriate polypharmacy in older adults

OBJECTIVE: To determine if exercise therapy is superior to arthroscopic partial meniscectomy for knee function in middle aged patients with degenerative meniscal tears. DESIGN: Randomised controlled superiority trial. SETTING: Orthopaedic departments at two public hospitals and two physiotherapy clinics in Norway. PARTICIPANTS: 140 adults, mean age 49.5 years (range 35.7-59.9), with degenerative medial meniscal tear verified by magnetic resonance imaging. 96% had no definitive radiographic evidence of osteoarthritis. INTERVENTIONS: 12 week supervised exercise therapy alone or arthroscopic partial meniscectomy alone. MAIN OUTCOME MEASURES: ), defined a priori as the mean score for four of five KOOS subscale scores (pain, other symptoms, function in sport and recreation, and knee related quality of life) from baseline to two year follow-up and change in thigh muscle strength from baseline to three months. RESULTS: at two years (0.9 points, 95% confidence interval -4.3 to 6.1; P=0.72). At three months, muscle strength had improved in the exercise group (P≤0.004). No serious adverse…

OBJECTIVE: To determine whether a treatment strategy based on structured ultrasound assessment would lead to improved outcomes in rheumatoid arthritis, compared with a conventional strategy. DESIGN: Multicentre, open label, two arm, parallel group, randomised controlled strategy trial. SETTING: Ten rheumatology departments and one specialist centre in Norway, from September 2010 to September 2015. PARTICIPANTS: 238 patients were recruited between September 2010 and April 2013, of which 230 (141 (61%) female) received the allocated intervention and were analysed for the primary outcome. The main inclusion criteria were age 18-75 years, fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis, disease modifying anti-rheumatic drug naivety with indication for disease modifying drug therapy, and time from first patient reported swollen joint less than two years. Patients with abnormal kidney or liver function or major comorbidities were excluded. INTERVENTIONS: 122 patients were randomised to an…

Objectives To investigate the association between long term intake of individual saturated fatty acids (SFAs) and the risk of coronary heart disease, in two large cohort studies. Design Prospective, longitudinal cohort study. Setting Health professionals in the United States. Participants 73 147 women in the Nurses’ Health Study (1984-2012) and 42 635 men in the Health Professionals Follow-up Study (1986-2010), who were free of major chronic diseases at baseline. Main outcome measure Incidence of coronary heart disease (n=7035) was self-reported, and related deaths were identified by searching National Death Index or through report of next of kin or postal authority. Cases were confirmed by medical records review. Results Mean intake of SFAs accounted for 9.0-11.3% energy intake over time, and was mainly composed of lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), and stearic acid (18:0; 8.8-10.7% energy). Intake of 12:0, 14:0, 16:0 and 18:0 were highly correlated, with Spearman correlation coefficients between 0.38 and 0.93 (all P<0.001). Comparing the highest to the…

OBJECTIVES: To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs. DESIGN: Nested case-control study. SETTING: Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom). PARTICIPANTS: Adult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry). MAIN OUTCOME MEASURE: Association between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed. RESULTS: Current use of any NSAID (use in preceding 14 days) was found to be associated with a…

OBJECTIVE: To evaluate the association between migraine and incident cardiovascular disease and cardiovascular mortality in women. DESIGN: Prospective cohort study among Nurses' Health Study II participants, with follow-up from 1989 and through June 2011. SETTING: Cohort of female nurses in United States. PARTICIPANTS: 115 541 women aged 25-42 years at baseline and free of angina and cardiovascular disease. Cumulative follow-up rates were more than 90%. MAIN OUTCOME MEASURES: The primary outcome of the study was major cardiovascular disease, a combined endpoint of myocardial infarction, stroke, or fatal cardiovascular disease. Secondary outcome measures included individual endpoints of myocardial infarction, stroke, angina/coronary revascularization procedures, and cardiovascular mortality. RESULTS: 17 531 (15.2%) women reported a physician's diagnosis of migraine. Over 20 years of follow-up, 1329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjustment for potential confounding factors, migraine was associated with an increased…

OBJECTIVE: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases (until December 2015). REVIEW METHODS: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation. RESULTS: 32 studies (29 685 dichorionic, 5486…

OBJECTIVE: To determine the association between exposure to radiotherapy for the treatment of prostate cancer and subsequent second malignancies (second primary cancers). DESIGN: Systematic review and meta-analysis of observational studies. DATA SOURCES: Medline and Embase up to 6 April 2015 with no restrictions on year or language. STUDY SELECTION: Comparative studies assessing the risk of second malignancies in patients exposed or unexposed to radiotherapy in the course of treatment for prostate cancer were selected by two reviewers independently with any disagreement resolved by consensus. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted study characteristics and outcomes. Risk of bias was assessed with the Newcastle-Ottawa scale. Outcomes were synthesized with random effects models and Mantel-Haenszel weighting. Unadjusted odds ratios and multivariable adjusted hazard ratios, when available, were pooled. MAIN OUTCOME MEASURES: Second cancers of the bladder, colorectal tract, rectum, lung, and hematologic system. RESULTS: Of 3056 references retrieved, 21…

OBJECTIVE: To systematically identify, critically appraise, and synthesise empirical studies about the impact of the 2008 financial crisis in Europe on health outcomes. DESIGN: Systematic literature review. DATA SOURCES: Structural searches of key databases, healthcare journals, and organisation based websites. REVIEW METHODS: Empirical studies reporting on the impact of the financial crisis on health outcomes in Europe, published from January 2008 to December 2015, were included. All selected studies were assessed for risk of bias. Owing to the heterogeneity of studies in terms of study design and analysis and the use of overlapping datasets across studies, studies were analysed thematically per outcome, and the evidence was synthesised on different health outcomes without formal meta-analysis. RESULTS: 41 studies met the inclusion criteria, and focused on suicide, mental health, self rated health, mortality, and other health outcomes. Of those studies, 30 (73%) were deemed to be at high risk of bias, nine (22%) at moderate risk of bias, and only two (5%) at low risk of bias,…

The number of people living into older age (≥65 years) is rising rapidly. Older people are more likely to fall and this has adverse consequences for their quality of life and that of their families. Falls also pose a substantial financial burden on healthcare systems . Extensive research from systematic reviews and meta-analyses has established effective approaches for reducing falls among older people, although uncertainties and controversy remain. The evidence suggests that exercise based and tailored interventions are the most effective way to reduce falls and associated healthcare costs among older people in the community. This review integrates current knowledge on assessment and management strategies to prevent falls in older people living in the community. It summarizes known risk factors for falls in this population and presents assessment strategies that can be used to assess the risk of falls. It discusses the management of risks and interventions to reduce falls among older people in the community, as well as future directions and promising approaches. A fall is an event…

OBJECTIVE: To develop a prediction model to estimate the chances of a live birth over multiple complete cycles of in vitro fertilisation (IVF) based on a couple's specific characteristics and treatment information. DESIGN: Population based cohort study. SETTING: All licensed IVF clinics in the UK. National data from the Human Fertilisation and Embryology Authority register. PARTICIPANTS: All 253 417 women who started IVF (including intracytoplasmic sperm injection) treatment in the UK from 1999 to 2008 using their own eggs and partner's sperm. MAIN OUTCOME MEASURE: Two clinical prediction models were developed to estimate the individualised cumulative chance of a first live birth over a maximum of six complete cycles of IVF-one model using information available before starting treatment and the other based on additional information collected during the first IVF attempt. A complete cycle is defined as all fresh and frozen-thawed embryo transfers arising from one episode of ovarian stimulation. RESULTS: After exclusions, 113 873 women with 184 269 complete cycles were included, of…

The spectrum effect describes the variation between settings in performance of tests used to predict, screen for, and diagnose disease. In particular, the predictive use of a test may be different when it is applied in a general population rather than in the study sample in which it was first developed. This article discusses the impact of the spectrum effect on measures of test performance, and its implications for the development, evaluation, application, and implementation of such tests.

OBJECTIVE: To compare patient outcomes of restrictive versus liberal blood transfusion strategies in patients with cardiovascular disease not undergoing cardiac surgery. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Randomised controlled trials involving a threshold for red blood cell transfusion in hospital. We searched (to 2 November 2015) CENTRAL, Medline, Embase, CINAHL, PubMed, LILACS, NHSBT Transfusion Evidence Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ISRCTN Register, and EU Clinical Trials Register. Authors were contacted for data whenever possible. TRIAL SELECTION: Published and unpublished randomised controlled trials comparing a restrictive with liberal transfusion threshold and that included patients with cardiovascular disease. DATA EXTRACTION AND SYNTHESIS: Data extraction was completed in duplicate. Risk of bias was assessed using Cochrane methods. Relative risk ratios with 95% confidence intervals were presented in all meta-analyses. Mantel-Haenszel random effects models were used to pool risk ratios. MAIN OUTCOME…

OBJECTIVE: To investigate whether screening for thyroid cancer led to the current "epidemic" in South Korea. DESIGN: Review of the medical records of nationally representative samples of patients with a diagnosis of thyroid cancer in 1999, 2005, and 2008. SETTING: Sample cases were randomly selected from South Korea's nationwide cancer registry, using a systematic sampling method after stratification by region. PARTICIPANTS: 5796 patients with thyroid cancer were included (891 in 1999, 2355 in 2005, and 2550 in 2008). MAIN OUTCOME MEASURES: The primary outcome was age standardised incidence of thyroid cancer and the changes in incidence between 1999 and 2008 according to the methods used to detect tumours (screen detection versus clinical detection versus unspecified). RESULTS: Between 1999 and 2008, the incidence of thyroid cancer increased 6.4-fold (95% confidence interval 4.9-fold to 8.4-fold), from 6.4 (95% confidence interval 6.2 to 6.6) per 100 000 population to 40.7 (40.2 to 41.2) per 100 000 population. Of the increase, 94.4% (34.4 per 100 000 population) were for tumours…

OBJECTIVE: To determine whether refugees are at elevated risk of schizophrenia and other non-affective psychotic disorders, relative to non-refugee migrants from similar regions of origin and the Swedish-born population. DESIGN: Cohort study of people living in Sweden, born after 1 January 1984 and followed from their 14th birthday or arrival in Sweden, if later, until diagnosis of a non-affective psychotic disorder, emigration, death, or 31 December 2011. SETTING: Linked Swedish national register data. PARTICIPANTS: 1,347,790 people, including people born in Sweden to two Swedish-born parents (1,191,004; 88.4%), refugees (24,123; 1.8%), and non-refugee migrants (132,663; 9.8%) from four major refugee generating regions: the Middle East and north Africa, sub-Saharan Africa, Asia, and Eastern Europe and Russia. MAIN OUTCOME MEASURES: Cox regression analysis was used to estimate adjusted hazard ratios for non-affective psychotic disorders by refugee status and region of origin, controlling for age at risk, sex, disposable income, and population density. RESULTS: 3704 cases of…

#### What you need to know For those with multimorbidity Most people with a chronic condition have one or more other chronic conditions, and multimorbidity is the norm in older people (see infographic 1 and box1).1 Multimorbidity matters because it is associated with reduced quality of life, higher mortality, polypharmacy and higher rates of adverse drug events, and high use of unplanned health care.2 3 4 5 Those with multimorbidity frequently receive care from both primary care and multiple specialists, who may not be communicating effectively with each other.6 7 Clinicians express uncertainty about the balance of benefit and harm of treatments in people with multimorbidity because evidence is largely based on trials of interventions for single conditions, from which people with multimorbidity are often excluded.8 9 Guidelines derived from such trials may lead to burdensome levels of treatment or unfeasible patterns of healthcare use .10 #### Box 1: What is multimorbidity? Multimorbidityis the presence of two or more long term health conditions, which can include: There is…

OBJECTIVES: To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes. DESIGN: Systematic review and meta-analysis of randomised and observational studies. DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts. ELIGIBILITY CRITERIA: Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure. DATA COLLECTION AND ANALYSIS: Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE…

STUDY QUESTION: What is the association between clarithromycin use and cardiovascular outcomes? METHODS: In this population based study the authors compared cardiovascular outcomes in adults aged 18 or more receiving oral clarithromycin or amoxicillin during 2005-09 in Hong Kong. Based on age within five years, sex, and calendar year at use, each clarithromycin user was matched to one or two amoxicillin users. The cohort analysis included patients who received clarithromycin (n=108,988) or amoxicillin (n=217,793). The self controlled case series and case crossover analysis included those who received Helicobacter pylori eradication treatment containing clarithromycin. The primary outcome was myocardial infarction. Secondary outcomes were all cause, cardiac, or non-cardiac mortality, arrhythmia, and stroke. STUDY ANSWER AND LIMITATIONS: The propensity score adjusted rate ratio of myocardial infarction 14 days after the start of antibiotic treatment was 3.66 (95% confidence interval 2.82 to 4.76) comparing clarithromycin use (132 events, rate 44.4 per 1000 person years) with…

OBJECTIVE: To determine whether pioglitazone compared with other antidiabetic drugs is associated with an increased risk of bladder cancer in people with type 2 diabetes. DESIGN: Population based cohort study. SETTING: General practices contributing data to the United Kingdom Clinical Practice Research Datalink. PARTICIPANTS: A cohort of 145,806 patients newly treated with antidiabetic drugs between 1 January 2000 and 31 July 2013, with follow-up until 31 July 2014. MAIN OUTCOME MEASURES: The use of pioglitazone was treated as a time varying variable, with use lagged by one year for latency purposes. Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident bladder cancer associated with pioglitazone overall and by both cumulative duration of use and cumulative dose. Similar analyses were conducted for rosiglitazone, a thiazolidinedione not previously associated with an increased risk of bladder cancer. RESULTS: The cohort generated 689,616 person years of follow-up, during which 622 patients were newly diagnosed as having…

OBJECTIVE: To determine whether higher cumulative use of benzodiazepines is associated with a higher risk of dementia or more rapid cognitive decline. DESIGN: Prospective population based cohort. SETTING: Integrated healthcare delivery system, Seattle, Washington. PARTICIPANTS: 3434 participants aged ≥ 65 without dementia at study entry. There were two rounds of recruitment (1994-96 and 2000-03) followed by continuous enrollment beginning in 2004. MAIN OUTCOMES MEASURES: The cognitive abilities screening instrument (CASI) was administered every two years to screen for dementia and was used to examine cognitive trajectory. Incident dementia and Alzheimer's disease were determined with standard diagnostic criteria. Benzodiazepine exposure was defined from computerized pharmacy data and consisted of the total standardized daily doses (TSDDs) dispensed over a 10 year period (a rolling window that moved forward in time during follow-up). The most recent year was excluded because of possible use for prodromal symptoms. Multivariable Cox proportional hazard models were used to examine time…

OBJECTIVES: To estimate how far changes in the prevalence of electronic cigarette (e-cigarette) use in England have been associated with changes in quit success, quit attempts, and use of licensed medication and behavioural support in quit attempts. DESIGN: Time series analysis of population trends. PARTICIPANTS: Participants came from the Smoking Toolkit Study, which involves repeated, cross sectional household surveys of individuals aged 16 years and older in England. Data were aggregated on about 1200 smokers quarterly between 2006 and 2015. Monitoring data were also used from the national behavioural support programme; during the study, 8 029 012 quit dates were set with this programme. SETTING: England. MAIN OUTCOME MEASURES: Prevalence of e-cigarette use in current smokers and during a quit attempt were used to predict quit success. Prevalence of e-cigarette use in current smokers was used to predict rate of quit attempts. Percentage of quit attempts involving e-cigarette use was also used to predict quit attempts involving use of prescription treatments, nicotine replacement…

OBJECTIVE: To determine rates of publication and reporting of results within two years for all completed clinical trials registered in ClinicalTrials.gov across leading academic medical centers in the United States. DESIGN: Cross sectional analysis. SETTING: Academic medical centers in the United States. PARTICIPANTS: Academic medical centers with 40 or more completed interventional trials registered on ClinicalTrials.gov. METHODS: Using the Aggregate Analysis of ClinicalTrials.gov database and manual review, we identified all interventional clinical trials registered on ClinicalTrials.gov with a primary completion date between October 2007 and September 2010 and with a lead investigator affiliated with an academic medical center. MAIN OUTCOME MEASURES: The proportion of trials that disseminated results, defined as publication or reporting of results on ClinicalTrials.gov, overall and within 24 months of study completion. RESULTS: We identified 4347 interventional clinical trials across 51 academic medical centers. Among the trials, 1005 (23%) enrolled more than 100 patients, 1216…

OBJECTIVE: To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question. DESIGN: Meta-epidemiological survey. DATA SOURCES: PubMed searched up to November 2014. METHODS: Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more…

OBJECTIVE: To quantify how a period of intense media coverage of controversy over the risk:benefit balance of statins affected their use. DESIGN: Interrupted time series analysis of prospectively collected electronic data from primary care. SETTING: Clinical Practice Research Datalink (CPRD) in the United Kingdom. PARTICIPANTS: Patients newly eligible for or currently taking statins for primary and secondary cardiovascular disease prevention in each month in January 2011-March 2015. MAIN OUTCOME MEASURES: Adjusted odds ratios for starting/stopping taking statins after the media coverage (October 2013-March 2014). RESULTS: There was no evidence that the period of high media coverage was associated with changes in statin initiation among patients with a high recorded risk score for cardiovascular disease (primary prevention) or a recent cardiovascular event (secondary prevention) (odds ratio 0.99 (95% confidence interval 0.87 to 1.13; P=0.92) and 1.04 (0.92 to 1.18; P=0.54), respectively), though there was a decrease in the overall proportion of patients with a recorded risk score.…

Martin Roland and Bruce Guthrie assess the successes and failures of the pay-for-performance scheme and what its future should be In 2004 the UK National Health Service introduced the largest health related pay-for- performance scheme in the world—the Quality and Outcomes Framework (QOF).1 However Scotland is now abandoning the scheme, and growing disenchantment in England is likely to lead to major changes. What have we learnt, and what should happen to QOF in future? In the late 1990s, general practitioners’ pay had fallen substantially behind that of specialists, and morale and recruitment in general practice were poor. The government and the British Medical Association (BMA) privately agreed that a large pay rise was needed. Money was available because in 2000 the government had committed to increasing NHS spending to mid-European levels as a percentage of gross domestic product. However, the profession had to give something in return, and the BMA dropped its longstanding opposition to “quality payments” and started to negotiate a pay-for-performance scheme that would…

#### What you need to know A woman’s lifetime risk of surgery for pelvic organ prolapse (POP) is 12-19% with over 300 000 prolapse surgeries performed annually in the US alone.1 2 3 POP accounts for about 15-18% of hysterectomies, and uterovaginal prolapse is the most common indication for hysterectomy in postmenopausal women.4 About one in 12 women living in the community in the UK report symptoms of pelvic organ prolapse.5 POP is the downward decent of the female pelvic organs (vagina, uterus, bladder, and/or rectum) into or through the vagina. This review provides an evidence based update on the epidemiology, evaluation, and management of this condition. Loss of vaginal or uterine support is seen in up to 30-76% of women presenting for routine gynaecology care, with 3-6% of those with descent beyond the vaginal opening (that is, level of the hymen).6 7 8 One population based study found that about 3% of 1961 adult women surveyed reported symptomatic vaginal bulging.9 Prolapse of the anterior vaginal wall, or cystocele, is the most common form of POP, detected twice as often as…

#### What you need to know There has been a lack of national guidance and care pathways for primary care on when to offer testing for NAFLD. Investigation and referral of suspected NAFLD vary widely. There is currently no licensed treatment for NAFLD, and most people are managed by their general practitioner with a focus on lifestyle advice such as weight loss. Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease from fatty liver to non-alcoholic steatohepatitis, fibrosis, and cirrhosis. At the least advanced end of the spectrum, non-alcoholic fatty liver (NAFL) is an excess of fat in the liver (steatosis) present in 20-30% of the general population and is largely asymptomatic.1 2 3 4 Currently, diagnosis of NAFLD is most commonly made through incidental findings, such as ultrasonography for investigation of persistently abnormal liver function tests, when other suspected causes have been ruled out. In around 5-6% of patients with NAFL only the condition progresses to non-alcoholic steatohepatitis (NASH), fibrosis, or cirrhosis (see fig 1⇓).5 In this small group there…

OBJECTIVE: To estimate the effect of playing Pokémon GO on the number of steps taken daily up to six weeks after installation of the game. DESIGN: Cohort study using online survey data. PARTICIPANTS: Survey participants of Amazon Mechanical Turk (n=1182) residing in the United States, aged 18 to 35 years and using iPhone 6 series smartphones. MAIN OUTCOME MEASURES: Number of daily steps taken each of the four weeks before and six weeks after installation of Pokémon GO, automatically recorded in the "Health" application of the iPhone 6 series smartphones and reported by the participants. A difference in difference regression model was used to estimate the change in daily steps in players of Pokémon GO compared with non-players. RESULTS: 560 (47.4%) of the survey participants reported playing Pokémon GO and walked on average 4256 steps (SD 2697) each day in the four weeks before installation of the game. The difference in difference analysis showed that the daily average steps for Pokémon GO players during the first week of installation increased by 955 additional steps (95%…

OBJECTIVE: To describe the clinical, radiological, and electromyographic features in a series of children with joint contractures (arthrogryposis) associated with congenital infection presumably caused by Zika virus. DESIGN: Retrospective case series study. SETTING: Association for Assistance of Disabled Children, Pernambuco state, Brazil. PARTICIPANTS: Seven children with arthrogryposis and a diagnosis of congenital infection presumably caused by Zika virus during the Brazilian microcephaly epidemic. MAIN OUTCOME MEASURES: Main clinical, radiological, and electromyographic findings, and likely correlation between clinical and primary neurological abnormalities. RESULTS: The brain images of all seven children were characteristic of congenital infection and arthrogryposis. Two children tested positive for IgM to Zika virus in the cerebrospinal fluid. Arthrogryposis was present in the arms and legs of six children (86%) and the legs of one child (14%). Hip radiographs showed bilateral dislocation in seven children, subluxation of the knee associated with genu valgus in three children…

OBJECTIVE: To determine whether feeding infants with hydrolysed formula reduces their risk of allergic or autoimmune disease. DESIGN: Systematic review and meta-analysis, as part of a series of systematic reviews commissioned by the UK Food Standards Agency to inform guidelines on infant feeding. Two authors selected studies by consensus, independently extracted data, and assessed the quality of included studies using the Cochrane risk of bias tool. DATA SOURCES: Medline, Embase, Web of Science, CENTRAL, and LILACS searched between January 1946 and April 2015. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective intervention trials of hydrolysed cows' milk formula compared with another hydrolysed formula, human breast milk, or a standard cows' milk formula, which reported on allergic or autoimmune disease or allergic sensitisation. RESULTS: 37 eligible intervention trials of hydrolysed formula were identified, including over 19,000 participants. There was evidence of conflict of interest and high or unclear risk of bias in most studies of allergic outcomes and evidence of…

High profile device failures have highlighted the inadequacies of current regulation. Art Sedrakyan and colleagues call for a move to a graduated model of approval and suggest a framework to achieve this goal

Eugene Nelson and colleagues call for registries of care data to be transformed into patient centred interactive learning systems

OBJECTIVE: To assess the risk of pulmonary embolism, ischaemic stroke, and myocardial infarction associated with combined oral contraceptives according to dose of oestrogen (ethinylestradiol) and progestogen. DESIGN: Observational cohort study. SETTING: Data from the French national health insurance database linked with data from the French national hospital discharge database. PARTICIPANTS: 4 945 088 women aged 15-49 years, living in France, with at least one reimbursement for oral contraceptives and no previous hospital admission for cancer, pulmonary embolism, ischaemic stroke, or myocardial infarction, between July 2010 and September 2012. MAIN OUTCOME MEASURES: Relative and absolute risks of first pulmonary embolism, ischaemic stroke, and myocardial infarction. RESULTS: The cohort generated 5 443 916 women years of oral contraceptive use, and 3253 events were observed: 1800 pulmonary embolisms (33 per 100 000 women years), 1046 ischaemic strokes (19 per 100 000 women years), and 407 myocardial infarctions (7 per 100 000 women years). After adjustment for progestogen and risk…

STUDY QUESTION: What is the long term efficacy of betahistine dihydrochloride on the incidence of vertigo attacks in patients with Meniere's disease, compared with placebo? METHODS: The BEMED trial is a multicentre, double blind, randomised, placebo controlled, three arm, parallel group, phase III, dose defining superiority trial conducted in 14 German tertiary referral centres (for neurology or ear, nose, and throat). Adults aged 21-80 years (mean age 56 years) with definite unilateral or bilateral Meniere's disease were recruited from March 2008 to November 2012. Participants received placebo (n=74), low dose betahistine (2 × 24 mg daily, (n=73)), or high dose betahistine (3 × 48 mg daily, (n=74)) over nine months. The primary outcome was the number of attacks per 30 days, based on patients' diaries during a three month assessment period at months seven to nine. An internet based randomisation schedule performed a concealed 1:1:1 allocation, stratified by study site. Secondary outcomes included the duration and severity of attacks, change in quality of life scores, and several…

OBJECTIVE: To investigate whether bariatric surgery increases the risk of fracture. DESIGN: Retrospective nested case-control study. SETTING: Patients who underwent bariatric surgery in the province of Quebec, Canada, between 2001 and 2014, selected using healthcare administrative databases. PARTICIPANTS: 12 676 patients who underwent bariatric surgery, age and sex matched with 38 028 obese and 126 760 non-obese controls. MAIN OUTCOME MEASURES: Incidence and sites of fracture in patients who had undergone bariatric surgery compared with obese and non-obese controls. Fracture risk was also compared before and after surgery (index date) within each group and by type of surgery from 2006 to 2014. Multivariate conditional Poisson regression models were adjusted for fracture history, number of comorbidities, sociomaterial deprivation, and area of residence. RESULTS: Before surgery, patients undergoing bariatric surgery (9169 (72.3%) women; mean age 42 (SD 11) years) were more likely to fracture (1326; 10.5%) than were obese (3065; 8.1%) or non-obese (8329; 6.6%) controls. A mean of 4.4…

OBJECTIVES: To evaluate the efficacy and safety of endovascular treatment, particularly adjunctive intra-arterial mechanical thrombectomy, in patients with ischaemic stroke. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SciELO, LILACS, and clinical trial registries from inception to December 2015. Reference lists were crosschecked. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials in adults aged 18 or more with ischaemic stroke comparing endovascular treatment, including thrombectomy, with medical care alone, including intravenous recombinant tissue plasminogen activator (rt-PA). Trial endpoints were functional outcome (modified Rankin scale scores of ≤2) and mortality at 90 days after onset of symptoms. No language or time restrictions applied. RESULTS: 10 randomised controlled trials (n=2925) were included. In pooled analysis endovascular treatment, including thrombectomy, was associated with a higher proportion of patients experiencing good (modified Rankin scale…

Objective To evaluate the effectiveness of antenatal corticosteroids given at ≥34 weeks’ gestation. Design Systematic review with meta-analysis. Data sources Electronic databases were searched from their inception to February 2016. Eligibility criteria for study selection Randomized clinical trials comparing antenatal corticosteroids with placebo or no treatment in women with a singleton pregnancy at ≥34 weeks’ gestation. Trials on antenatal steroids in women expected to deliver late preterm (340-366 weeks) and trials given before planned cesarean delivery at term (≥37 weeks) were included. Data synthesis The primary outcome was the incidence of severe respiratory distress syndrome (RDS). The summary measures were reported as relative risks or mean differences with 95% confidence intervals. Results Six trials, including 5698 singleton pregnancies, were analyzed. Three included 3200 women at 340-366 weeks’ gestation and at risk of imminent premature delivery at the time of hospital admission. The three other trials included 2498 women undergoing planned cesarean delivery at ≥37…

OBJECTIVE: To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate. DESIGN: Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis. DATA SOURCES: Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews. STUDY SELECTION CRITERIA: Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest. MAIN OUTCOMES: American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two…

OBJECTIVE: To examine whether dietary intake of specific flavonoid subclasses (including flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and flavonoid polymers) is associated with weight change over time. DESIGN: Three prospective cohort studies. SETTING: Health professionals in the United States. PARTICIPANTS: 124,086 men and women participating in the Health Professionals Follow-up Study (HPFS), Nurses' Health Study (NHS), and Nurses' Health Study II (NHS II). MAIN OUTCOME MEASURE: Self reported change in weight over multiple four year time intervals between 1986 and 2011. RESULTS: Increased consumption of most flavonoid subclasses, including flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers, was inversely associated with weight change over four year time intervals, after adjustment for simultaneous changes in other lifestyle factors including other aspects of diet, smoking status, and physical activity. In the pooled results, the greatest magnitude of association was observed for anthocyanins (-0.23 (95% confidence interval -0.30 to -0.15) lbs per…

OBJECTIVE: To examine the association between adherence to the Japanese Food Guide Spinning Top and total and cause specific mortality. DESIGN: Large scale population based prospective cohort study in Japan with follow-up for a median of 15 years. SETTING: 11 public health centre areas across Japan. PARTICIPANTS: 36,624 men and 42,970 women aged 45-75 who had no history of cancer, stroke, ischaemic heart disease, or chronic liver disease. MAIN OUTCOME MEASURES: Deaths and causes of death identified with the residential registry and death certificates. RESULTS: Higher scores on the food guide (better adherence) were associated with lower total mortality; the multivariable adjusted hazard ratios (95% confidence interval) of total mortality for the lowest through highest scores were 1.00, 0.92 (0.87 to 0.97), 0.88 (0.83 to 0.93), and 0.85 (0.79 to 0.91) (P<0.001 for trend) and the multivariable adjusted hazard ratio associated with a 10 point increase in food guide scores was 0.93 (0.91 to 0.95; P<0.001 for trend). This score was inversely associated with mortality from cardiovascular…

OBJECTIVE: To assess the association between early and prolonged β blocker treatment and mortality after acute myocardial infarction. DESIGN: Multicentre prospective cohort study. SETTING: Nationwide French registry of Acute ST- and non-ST-elevation Myocardial Infarction (FAST-MI) (at 223 centres) at the end of 2005. PARTICIPANTS: 2679 consecutive patients with acute myocardial infarction and without heart failure or left ventricular dysfunction. MAIN OUTCOME MEASURES: Mortality was assessed at 30 days in relation to early use of β blockers (≤48 hours of admission), at one year in relation to discharge prescription, and at five years in relation to one year use. RESULTS: β blockers were used early in 77% (2050/2679) of patients, were prescribed at discharge in 80% (1783/2217), and were still being used in 89% (1230/1383) of those alive at one year. Thirty day mortality was lower in patients taking early β blockers (adjusted hazard ratio 0.46, 95% confidence interval 0.26 to 0.82), whereas the hazard ratio for one year mortality associated with β blockers at discharge was 0.77 (0.46…

Despite advances in cardiac therapy, heart failure (HF) remains a progressive, highly symptomatic, and deadly disease that places great demands on patients, caregivers, and healthcare systems. Palliative care is a multidisciplinary approach to care that focuses on communication, shared decision making, and advance care planning; provides relief from pain and other distressing symptoms; integrates psychological and spiritual aspects of care; and offers a support system to help families cope during illness and bereavement. Palliative care has applications across the stages of heart failure, including early in the course of illness, often in conjunction with other therapies that are intended to prolong life. However, the incorporation of palliative care into the management of heart failure has been suboptimal for several reasons: uncertainty in the disease trajectory, failure to reward communication between healthcare providers and patients, siloed care, lack of knowledge, overlay of comorbidity and frailty, life saving devices with complex trade-offs, and a limited evidence base. This…

OBJECTIVE: To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation. DESIGN: Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation)-a multicentre, double blind, double dummy trial that started in 2006 and ended in 2011. PARTICIPANTS: 18 201 ARISTOTLE trial participants. INTERVENTIONS: In the ARISTOTLE trial, patients were randomised to either 5 mg apixaban twice daily (n=9120) or warfarin (target international normalised ratio range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into groups according to the number of concomitant drug treatments used at baseline (0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years. MAIN OUTCOME MEASURES: Clinical outcomes and treatment effects of apixaban versus warfarin (adjusted for age, sex, and country). RESULTS: Each patient used a median of six drugs (interquartile range 5-9); polypharmacy (≥5 drugs) was seen in 13 932…

OBJECTIVE: To evaluate the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents in people with diabetes. DESIGN: Meta-analysis. DATA SOURCES AND STUDY SELECTION: PubMed, Embase, and the Cochrane central register of controlled trials databases for randomized trials of RAS blockers versus other antihypertensive agents in people with diabetes mellitus. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, and end stage renal disease. RESULTS: The search yielded 19 randomized controlled trials that enrolled 25,414 participants with diabetes for a total of 95,910 patient years of follow-up. When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% confidence interval 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77…

OBJECTIVE: To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk. DESIGN: Population based case-control study SETTING: 370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality. PARTICIPANTS: 19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013. EXPOSURE OF INTEREST: Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was subdivided into duration of more or less than six months. MAIN OUTCOME MEASURE: Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for…

OBJECTIVE: To describe patterns in maternal gestational weight gain (GWG) in healthy pregnancies with good maternal and perinatal outcomes. DESIGN: Prospective longitudinal observational study. SETTING: Eight geographically diverse urban regions in Brazil, China, India, Italy, Kenya, Oman, United Kingdom, and United States, April 2009 to March 2014. PARTICIPANTS: Healthy, well nourished, and educated women enrolled in the Fetal Growth Longitudinal Study component of the INTERGROWTH-21(st) Project, who had a body mass index (BMI) of 18.50-24.99 in the first trimester of pregnancy. MAIN OUTCOME MEASURES: Maternal weight measured with standardised methods and identical equipment every five weeks (plus/minus one week) from the first antenatal visit (<14 weeks' gestation) to delivery. After confirmation that data from the study sites could be pooled, a multilevel, linear regression analysis accounting for repeated measures, adjusted for gestational age, was applied to produce the GWG values. RESULTS: 13,108 pregnant women at <14 weeks' gestation were screened, and 4607 met the…

OBJECTIVES: To evaluate the implementation of four high evidence practices for the care of very preterm infants to assess their use and impact in routine clinical practice and whether they constitute a driver for reducing mortality and neonatal morbidity. DESIGN: Prospective multinational population based observational study. SETTING: 19 regions from 11 European countries covering 850 000 annual births participating in the EPICE (Effective Perinatal Intensive Care in Europe for very preterm births) project. PARTICIPANTS: 7336 infants born between 24+0 and 31+6 weeks' gestation in 2011/12 without serious congenital anomalies and surviving to neonatal admission. MAIN OUTCOME MEASURES: Combined use of four evidence based practices for infants born before 28 weeks' gestation using an "all or none" approach: delivery in a maternity unit with appropriate level of neonatal care; administration of antenatal corticosteroids; prevention of hypothermia (temperature on admission to neonatal unit ≥36°C); surfactant used within two hours of birth or early nasal continuous positive airway…

Geva Greenfield and colleagues ask whether it is time to reconsider the role of the GP as gatekeeper to specialist services, and call for more evidence to guide future policy

Multiple sclerosis (MS) is a common, disabling, putatively autoimmune neurological disease with worldwide distribution. It typically begins as a relapsing disorder that later evolves to a secondary progressive phase. Inflammatory and neurodegenerative mechanisms seem to operate in both phases, but their relative contributions and interactions are incompletely understood. Disease modifying therapies (DMTs) approved for relapsing multiple sclerosis interfere with a variety of immunological mechanisms to reduce rates of relapse, accumulation of disease burden measured by magnetic resonance imaging (MRI), and decline in neurological function over the two to three year duration of typical randomized controlled trials. Benefits of longer duration of therapy on disability are less clear, as data beyond three years are largely limited to observational studies. However, current DMTs do not slow accrual of disability once progressive multiple sclerosis is established. This review summarizes the evidence about the use of approved DMTs and examines how to individualize treatment despite the…

Chronic insomnia is a common condition that affects people worldwide and has negative effects on patients' health and wellbeing. The treatment of insomnia can be complex and time consuming for patients and providers. Although behavioral interventions are the first line therapy, there are barriers to access for these treatments. However, in recent years, alternative ways of providing these behavioral therapies that make them more widely available have been investigated. Drugs also play an important role in the treatment of insomnia and new drugs have been introduced as options for treating patients with sleep initiation and sleep maintenance insomnia. In this review, we will discuss advances in the past six years in both non-pharmacologic and pharmacologic treatments for patients with chronic insomnia. We will also review the controversies surrounding some of the current drug treatments, as well as the role that technology and personal activity monitoring devices may play in treating insomnia.

OBJECTIVES: To estimate differences in annual income of physicians in the United States by race and sex adjusted for characteristics of physicians and practices. DESIGN: Cross sectional survey study. SETTING: Nationally representative samples of US physicians. PARTICIPANTS: The 2000-13 American Community Survey (ACS) included 43 213 white male, 1698 black male, 15 164 white female, and 1252 black female physicians. The 2000-08 Center for Studying Health System Change (HSC) physician surveys included 12 843 white male, 518 black male, 3880 white female, and 342 black female physicians. MAIN OUTCOME MEASURES: Annual income adjusted for age, hours worked, time period, and state of residence (from ACS data). Income was adjusted for age, specialty, hours worked, time period, years in practice, practice type, and percentage of revenue from Medicare/Medicaid (from HSC physician surveys). RESULTS: White male physicians had a higher median annual income than black male physicians, whereas race was not consistently associated with median income among female physicians. For example, in 2010-13…

The World Health Organisation estimates that approximately one billion people are infected and up to 500 000 people die from influenza each year. 1 The greatest burden of illness usually occurs among children, while the highest burden of severe disease (in terms of hospitalisation and death) occurs in those with underlying medical conditions, infants and young children, and elderly people. 2 Current circulating influenza strains in humans include influenza A(H1N1)pdm09, influenza A(H3N2), and both influenza B viruses (B/Victoria and B/Yamagata).3 4 This article provides non-specialists with information on how to diagnose, manage, and prevent flu.

The prevalence of kidney stones is increasing in industrialized nations, resulting in a corresponding rise in economic burden. Nephrolithiasis is now recognized as both a chronic and systemic condition, which further underscores the impact of the disease. Diet and environment play an important role in stone disease, presumably by modulating urine composition. Dietary modification as a preventive treatment to decrease lithogenic risk factors and prevent stone recurrence has gained interest because of its potential to be safer and more economical than drug treatment. However, not all abnormalities are likely to be amenable to dietary therapy, and in some cases drugs are necessary to reduce the risk of stone formation. Unfortunately, no new drugs have been developed for stone prevention since the 1980s when potassium citrate was introduced, perhaps because the long observation period needed to demonstrate efficacy discourages investigators from embarking on clinical trials. Nonetheless, effective established treatment regimens are currently available for stone prevention.