Showing papers in "BMJ in 2016"

ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.

Abstract: 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.

Medical error—the third leading cause of death in the US

Abstract: 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

Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013

Abstract: 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 total physical activity were significantly associated with lower risk for all outcomes, major gains occurred at lower levels of activity (up to 3000-4000 metabolic equivalent (MET) minutes/week). For example, individuals with a total activity level of 600 MET minutes/week (the minimum recommended level) had a 2% lower risk of diabetes compared with those reporting no physical activity. An increase from 600 to 3600 MET minutes/week reduced the risk by an additional 19%. The same amount of increase yielded much smaller returns at higher levels of activity: an increase of total activity from 9000 to 12 000 MET minutes/week reduced the risk of diabetes by only 0.6%. Compared with insufficiently active individuals (total activity <600 MET minutes/week), the risk reduction for those in the highly active category (≥8000 MET minutes/week) was 14% (relative risk 0.863, 95% uncertainty interval 0.829 to 0.900) for breast cancer; 21% (0.789, 0.735 to 0.850) for colon cancer; 28% (0.722, 0.678 to 0.768) for diabetes; 25% (0.754, 0.704 to 0.809) for ischemic heart disease; and 26% (0.736, 0.659 to 0.811) for ischemic stroke. Conclusions People who achieve total physical activity levels several times higher than the current recommended minimum level have a significant reduction in the risk of the five diseases studied. More studies with detailed quantification of total physical activity will help to find more precise relative risk estimates for different levels of activity.

GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction

Abstract: #### Summary points Healthcare decision making is complex. Decision-making processes and the factors (criteria) that decision makers should consider vary for different types of decisions, including clinical recommendations, coverage decisions, and health system or public health recommendations or decisions.1 2 3 4 However, some criteria are relevant for all of these decisions, including the anticipated effects of the options being considered, the certainty of the evidence for those effects (also referred to as quality of evidence or confidence in effect estimates), and the costs and feasibility of the options. Decision makers must make judgments about each relevant factor, informed by the best evidence that is available to them. Often, the processes that decision makers use, the criteria that they consider and the evidence that they …

Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies

Abstract: 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 cardiovascular disease, with similar results when studies were stratified by whether the outcome was incidence or mortality. The relative risks for morality were 0.85 (0.80 to 0.91; I 2 =37%, n=6) for total cancer, 0.83 (0.77 to 0.90; I 2 =83%, n=11) for all causes, 0.78 (0.70 to 0.87; I 2 =0%, n=4) for respiratory disease, 0.49 (0.23 to 1.05; I 2 =85%, n=4) for diabetes, 0.74 (0.56 to 0.96; I 2 =0%, n=3) for infectious diseases, 1.15 (0.66 to 2.02; I 2 =79%, n=2) for diseases of the nervous system disease, and 0.78 (0.75 to 0.82; I 2 =0%, n=5) for all non-cardiovascular, non-cancer causes. Reductions in risk were observed up to an intake of 210-225 g/day (seven to seven and a half servings per day) for most of the outcomes. Intakes of specific types of whole grains including whole grain bread, whole grain breakfast cereals, and added bran, as well as total bread and total breakfast cereals were also associated with reduced risks of cardiovascular disease and/or all cause mortality, but there was little evidence of an association with refined grains, white rice, total rice, or total grains. Conclusions This meta-analysis provides further evidence that whole grain intake is associated with a reduced risk of coronary heart disease, cardiovascular disease, and total cancer, and mortality from all causes, respiratory diseases, infectious diseases, diabetes, and all non-cardiovascular, non-cancer causes. These findings support dietary guidelines that recommend increased intake of whole grain to reduce the risk of chronic diseases and premature mortality.

Sepsis: pathophysiology and clinical management

Abstract: 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 nosocomial infections.

Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis

Abstract: 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 A 1c (HbA 1c ) of 39-47 mmol/mol (5.7-6.4%) according to ADA criteria or 42-47 mmol/mol (6.0-6.4%) according to the National Institute for Health and Care Excellence (NICE) guideline. The relative risks of all cause mortality and cardiovascular events were calculated and reported with 95% confidence intervals. Results 53 prospective cohort studies with 1 611 339 individuals were included for analysis. The median follow-up duration was 9.5 years. Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA 1c to 39-47 mmol/mol or 42-47 mmol/mol were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality. Conclusions Prediabetes, defined as impaired glucose tolerance, impaired fasting glucose, or raised HbA 1c , was associated with an increased risk of cardiovascular disease. The health risk might be increased in people with a fasting glucose concentration as low as 5.6 mmol/L or HbA 1c of 39 mmol/mol.

Beverage purchases from stores in Mexico under the excise tax on sugar sweetened beverages: observational study.

Abstract: 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 not been implemented (counterfactual) based on pretax trends. Study answer and limitations Relative to the counterfactual in 2014, purchases of taxed beverages decreased by an average of 6% (−12 mL/capita/day), and decreased at an increasing rate up to a 12% decline by December 2014. All three socioeconomic groups reduced purchases of taxed beverages, but reductions were higher among the households of low socioeconomic status, averaging a 9% decline during 2014, and up to a 17% decrease by December 2014 compared with pretax trends. Purchases of untaxed beverages were 4% (36 mL/capita/day) higher than the counterfactual, mainly driven by an increase in purchases of bottled plain water. What this study adds The tax on sugar sweetened beverages was associated with reductions in purchases of taxed beverages and increases in purchases of untaxed beverages. Continued monitoring is needed to understand purchases longer term, potential substitutions, and health implications. Funding, competing interests, data sharing This work was supported by grants from Bloomberg Philanthropies and the Robert Wood Johnson Foundation and by the Instituto Nacional de Salud Publica and the Carolina Population Center. The authors have no competing interests. No additional data are available.

Sparse data bias: a problem hiding in plain sight.

Abstract: 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.

Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies

Abstract: 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 relative risk (8.4, 7.1 to 9.9). Chronic hypertension ranked second, both in terms of its pooled rate (16.0%, 12.6% to 19.7%) and pooled relative risk (5.1, 4.0 to 6.5) of pre-eclampsia. Pregestational diabetes (pooled rate 11.0%, 8.4% to 13.8%; pooled relative risk 3.7, 3.1 to 4.3), prepregnancy body mass index (BMI) >30 (7.1%, 6.1% to 8.2%; 2.8, 2.6 to 3.1), and use of assisted reproductive technology (6.2%, 4.7% to 7.9%; 1.8, 1.6 to 2.1) were other prominent risk factors. Conclusions There are several practical clinical risk factors that, either alone or in combination, might identify women in early pregnancy who are at “high risk” of pre-eclampsia. These data can inform the generation of a clinical prediction model for pre-eclampsia and the use of aspirin prophylaxis in pregnancy.

Health consequences of shift work and insufficient sleep

Abstract: 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 similar, they are likely to share common mechanisms. However, additional research is needed to determine whether insufficient sleep is a causal pathway for the adverse health effects associated with shift work.

BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants

Abstract: 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 (95% confidence interval 1.15 to 1.21; I 2 =95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I 2 =93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I 2 =89%, n=11) among healthy never smokers with exclusion of early follow-up, and 1.05 (1.04 to 1.07; I 2 =97%, n=198) among all participants. There was a J shaped dose-response relation in never smokers (P non-linearity Conclusion Overweight and obesity is associated with increased risk of all cause mortality and the nadir of the curve was observed at BMI 23-24 among never smokers, 22-23 among healthy never smokers, and 20-22 with longer durations of follow-up. The increased risk of mortality observed in underweight people could at least partly be caused by residual confounding from prediagnostic disease. Lack of exclusion of ever smokers, people with prevalent and preclinical disease, and early follow-up could bias the results towards a more U shaped association.

Net benefit approaches to the evaluation of prediction models, molecular markers, and diagnostic tests.

Abstract: 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 good than harm. This is in contrast to traditional measures such as sensitivity, specificity, or area under the curve, which are statistical abstractions not directly informative about clinical value. Recent years have seen an increase in practical applications of net benefit analysis to research data. This is a welcome development, since decision analytic techniques are of particular value when the purpose of a model, marker, or test is to help doctors make better clinical decisions.

Prediction models for cardiovascular disease risk in the general population: systematic review

Abstract: 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 was missing to enable the model to be used for individual risk prediction. Only 132 developed models (36%) were externally validated and only 70 (19%) by independent investigators. Model performance was heterogeneous and measures such as discrimination and calibration were reported for only 65% and 58% of the external validations, respectively. Conclusions There is an excess of models predicting incident CVD in the general population. The usefulness of most of the models remains unclear owing to methodological shortcomings, incomplete presentation, and lack of external validation and model impact studies. Rather than developing yet another similar CVD risk prediction model, in this era of large datasets, future research should focus on externally validating and comparing head-to-head promising CVD risk models that already exist, on tailoring or even combining these models to local settings, and investigating whether these models can be extended by addition of new predictors.

Blood pressure variability and cardiovascular disease: systematic review and meta-analysis

Abstract: 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 and 17 clinical trial cohorts, comprising 46 separate analyses were identified. Long term variability in blood pressure was studied in 24 papers, mid-term in four, and short-term in 15 (two studied both long term and short term variability). Results from 23 analyses were excluded from main analyses owing to high risks of confounding. Increased long term variability in systolic blood pressure was associated with risk of all cause mortality (hazard ratio 1.15, 95% confidence interval 1.09 to 1.22), cardiovascular disease mortality (1.18, 1.09 to 1.28), cardiovascular disease events (1.18, 1.07 to 1.30), coronary heart disease (1.10, 1.04 to 1.16), and stroke (1.15, 1.04 to 1.27). Increased mid-term and short term variability in daytime systolic blood pressure were also associated with all cause mortality (1.15, 1.06 to 1.26 and 1.10, 1.04 to 1.16, respectively). Conclusions Long term variability in blood pressure is associated with cardiovascular and mortality outcomes, over and above the effect of mean blood pressure. Associations are similar in magnitude to those of cholesterol measures with cardiovascular disease. Limited data for mid-term and short term variability showed similar associations. Future work should focus on the clinical implications of assessment of variability in blood pressure and avoid the common confounding pitfalls observed to date. Systematic review registration PROSPERO CRD42014015695.

Analysis of matched case-control studies

Abstract: 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.

Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis.

Abstract: 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), cardiovascular mortality (2.03, 1.79 to 2.30), major cardiovascular events (1.96, 1.53 to 2.51), stroke (2.42, 2.17 to 2.71), ischaemic stroke (2.33, 1.84 to 2.94), ischaemic heart disease (1.61, 1.38 to 1.87), sudden cardiac death (1.88, 1.36 to 2.60), heart failure (4.99, 3.04 to 8.22), chronic kidney disease (1.64, 1.41 to 1.91), and peripheral arterial disease (1.31, 1.19 to 1.45) but not haemorrhagic stroke (2.00, 0.67 to 5.96). Among the outcomes examined, the highest absolute risk increase was for heart failure. Associations between atrial fibrillation and included outcomes were broadly consistent across subgroups and in sensitivity analyses. Conclusions Atrial fibrillation is associated with an increased risk of death and an increased risk of cardiovascular and renal disease. Interventions aimed at reducing outcomes beyond stroke are warranted in patients with atrial fibrillation.

Pelvic organ prolapse.

Abstract: #### 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 posterior vaginal prolapse (that is, the rectocele), and three times more common than apical prolapse (uterine and/or post-hysterectomy vaginal vault prolapse) (fig 1⇓).10 11 However in most cases of symptomatic POP, prolapse of multiple segments of the vagina are …

GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines

Abstract: #### Summary points Clinicians regularly face situations with two or more alternative actions. Each alternative often has different advantages and disadvantages, including differences in effectiveness, adverse effects, costs and other factors …

The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines.

Abstract: 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.

Guidelines for reporting of health interventions using mobile phones: mobile health (mHealth) evidence reporting and assessment (mERA) checklist

Abstract: 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.

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.

Abstract: Objectives To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guerin (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 trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV. Conclusions Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

The impact of communicating genetic risks of disease on risk-reducing health behaviour: systematic review with meta-analysis

Abstract: 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 to 1.35, P=0.67), diet (standardised mean difference 0.12, 95% confidence interval −0.00 to 0.24, P=0.05), or physical activity (standardised mean difference −0.03, 95% confidence interval −0.13 to 0.08, P=0.62). There were also no effects on any other behaviours (alcohol use, medication use, sun protection behaviours, and attendance at screening or behavioural support programmes) or on motivation to change behaviour, and no adverse effects, such as depression and anxiety. Subgroup analyses provided no clear evidence that communication of a risk-conferring genotype affected behaviour more than communication of the absence of such a genotype. However, studies were predominantly at high or unclear risk of bias, and evidence was typically of low quality. Conclusions Expectations that communicating DNA based risk estimates changes behaviour is not supported by existing evidence. These results do not support use of genetic testing or the search for risk-conferring gene variants for common complex diseases on the basis that they motivate risk-reducing behaviour. Systematic review registration This is a revised and updated version of a Cochrane review from 2010, adding 11 studies to the seven previously identified.

Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study

Abstract: 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 naive 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 naive 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 to ischaemic stroke, NOACs were not significantly different from warfarin. During one year follow-up, rivaroxaban was associated with lower annual rates of ischaemic stroke or systemic embolism (3.0% v 3.3%, respectively) compared with warfarin: hazard ratio 0.83 (95% confidence interval 0.69 to 0.99). The hazard ratios for dabigatran and apixaban (2.8% and 4.9% annually, respectively) were non-significant compared with warfarin. The annual risk of death was significantly lower with apixaban (5.2%) and dabigatran (2.7%) (0.65, 0.56 to 0.75 and 0.63, 0.48 to 0.82, respectively) compared with warfarin (8.5%), but not with rivaroxaban (7.7%). For the combined endpoint of any bleeding, annual rates for apixaban (3.3%) and dabigatran (2.4%) were significantly lower than for warfarin (5.0%) (0.62, 0.51 to 0.74). Warfarin and rivaroxaban had comparable annual bleeding rates (5.3%). Conclusion All NOACs seem to be safe and effective alternatives to warfarin in a routine care setting. No significant difference was found between NOACs and warfarin for ischaemic stroke. The risks of death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran compared with warfarin.

PRISMA harms checklist: improving harms reporting in systematic reviews.

Abstract: 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 to improve harms reporting in reviews. These are reported in the title (“Specifically mention ‘harms’ or other related terms, or the harm of interest in the review”), synthesis of results (“Specify how zero events were handled, if relevant”), study characteristics (“Define each harm addressed, how it was ascertained (eg, patient report, active search), and over what time period”), and synthesis of results (“Describe any assessment of possible causality”). Additional guidance regarding existing PRISMA items was developed to demonstrate relevance when synthesising information about harms. Conclusion The PRISMA harms checklist identifies a minimal set of items to be reported when reviewing adverse events. This guideline extension is intended to improve harms reporting in systematic reviews, whether harms are a primary or secondary outcome.

Trends and comparison of female first authorship in high impact medical journals: observational study (1994-2014)

Abstract: 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 describe the associations of interest. Results The gender of the first author was determined for 3758 of the 3860 articles considered; 1273 (34%) were women. After adjustment, female first authorship increased significantly from 27% in 1994 to 37% in 2014 (P NEJM seemed to follow a different pattern, with female first authorship decreasing; it also seemed to decline in recent years in The BMJ but started substantially higher (approximately 40%), and The BMJ had the highest total proportion of female first authors. Compared with the mean across all six journals, first authors were significantly less likely to be female in the NEJM (adjusted odds ratio 0.68, 95% confidence interval 0.53 to 0.89) and significantly more likely to be female in The BMJ (1.30, 1.01 to 1.66) over the study period. Conclusions The representation of women among first authors of original research in high impact general medical journals was significantly higher in 2014 than 20 years ago, but it has plateaued in recent years and has declined in some journals. These results, along with the significant differences seen between journals, suggest that underrepresentation of research by women in high impact journals is still an important concern. The underlying causes need to be investigated to help to identify practices and strategies to increase women’s influence on and contributions to the evidence that will determine future healthcare policies and standards of clinical practice.

External validation of clinical prediction models using big datasets from e-health records or IPD meta-analysis: opportunities and challenges

Abstract: 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.

Inverse probability weighting.

Abstract: 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.1 Differential weighting is also used when different parts of the population are sampled with unequal probabilities of selection. Two examples of intentional unbalanced sampling are: 1. Surveys with unequal probabilities of selection —In a national survey of hypertension prevalence, certain groups with relatively rare characteristics (such as people aged ≥65 years) were oversampled to improve the precision of estimates for those groups.2 2. Two-phase prevalence studies —In the first phase of a two-phase prevalence study of mental health status, the sampled patients completed a short screening questionnaire. In the second phase, a subsample was selected for a definitive diagnostic test with oversampling of the screen-positive cases to ensure precise estimates for diagnostic prevalence.3 In such cases the ordinary unweighted sample quantities, such as means or proportions, are likely to be biased estimates of their corresponding population quantities. This “selection bias” can be eliminated by performing a weighted estimation, giving each individual’s data a …

Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses

Abstract: 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 revie ...