Objective To assess the magnitude and duration of any hypothesised protective effect of household exposure to a child with varicella on the relative incidence of herpes zoster in adults. Design Self controlled case series. Setting UK general practices contributing to Clinical Practice Research Datalink. Participants 9604 adults (≥18 years) with a diagnosis of herpes zoster (in primary care or hospital records) between 1997 and 2018, who during their observation period lived with a child (<18 years) with a diagnosis of varicella. Main outcome measures Relative incidence of herpes zoster in the 20 years after exposure to a child with varicella in the household compared with baseline time (all other time, excluding the 60 days before exposure). Results 6584 of the 9604 adults with herpes zoster (68.6%) were women. Median age of exposure to a child with varicella was 38.3 years (interquartile range 32.3-48.8 years) and median observation period was 14.7 (11.1-17.7) years. 4116 adults developed zoster in the baseline period, 433 in the 60 days before exposure and 5055 in the risk period. After adjustment for age, calendar time, and season, strong evidence suggested that in the two years after household exposure to a child with varicella, adults were 33% less likely to develop zoster (incidence ratio 0.67, 95% confidence interval 0.62 to 0.73) compared with baseline time. In the 10-20 years after exposure, adults were 27% less likely to develop herpes zoster (0.73, 0.62 to 0.87) compared with baseline time. A stronger boosting effect was observed among men than among women after exposure to varicella. Conclusions The relative incidence of zoster was lower in the periods after exposure to a household contact with varicella, with modest but long lasting protective effects observed. This study suggests that exogenous boosting provides some protection from the risk of herpes zoster, but not complete immunity, as assumed by previous cost effectiveness estimates of varicella immunisation.

Objective To investigate pharmaceutical or medical device industry funding of patient groups. Design Systematic review with meta-analysis. Data sources Ovid Medline, Embase, Web of Science, Scopus, and Google Scholar from inception to January 2018; reference lists of eligible studies and experts in the field. Eligibility criteria for selecting studies Observational studies including cross sectional, cohort, case-control, interrupted time series, and before-after studies of patient groups reporting at least one of the following outcomes: prevalence of industry funding; proportion of industry funded patient groups that disclosed information about this funding; and association between industry funding and organisational positions on health and policy issues. Studies were included irrespective of language or publication type. Review methods Reviewers carried out duplicate independent data extraction and assessment of study quality. An amended version of the checklist for prevalence studies developed by the Joanna Briggs Institute was used to assess study quality. A DerSimonian-Laird estimate of single proportions with Freeman-Tukey arcsine transformation was used for meta-analyses of prevalence. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to assess the quality of the evidence for each outcome. Results 26 cross sectional studies met the inclusion criteria. Of these, 15 studies estimated the prevalence of industry funding, which ranged from 20% (12/61) to 83% (86/104). Among patient organisations that received industry funding, 27% (175/642; 95% confidence interval 24% to 31%) disclosed this information on their websites. In submissions to consultations, two studies showed very different disclosure rates (0% and 91%), which appeared to reflect differences in the relevant government agency’s disclosure requirements. Prevalence estimates of organisational policies that govern corporate sponsorship ranged from 2% (2/125) to 64% (175/274). Four studies analysed the relationship between industry funding and organisational positions on a range of highly controversial issues. Industry funded groups generally supported sponsors’ interests. Conclusion In general, industry funding of patient groups seems to be common, with prevalence estimates ranging from 20% to 83%. Few patient groups have policies that govern corporate sponsorship. Transparency about corporate funding is also inadequate. Among the few studies that examined associations between industry funding and organisational positions, industry funded groups tended to have positions favourable to the sponsor. Patient groups have an important role in advocacy, education, and research, therefore strategies are needed to prevent biases that could favour the interests of sponsors above those of the public. Systematic review registration PROSPERO CRD42017079265.

Objectives To study the impact of blinding on estimated treatment effects, and their variation between trials; differentiating between blinding of patients, healthcare providers, and observers; detection bias and performance bias; and types of outcome (the MetaBLIND study). Design Meta-epidemiological study. Data source Cochrane Database of Systematic Reviews (2013-14). Eligibility criteria for selecting studies Meta-analyses with both blinded and non-blinded trials on any topic. Review methods Blinding status was retrieved from trial publications and authors, and results retrieved automatically from the Cochrane Database of Systematic Reviews. Bayesian hierarchical models estimated the average ratio of odds ratios (ROR), and estimated the increases in heterogeneity between trials, for non-blinded trials (or of unclear status) versus blinded trials. Secondary analyses adjusted for adequacy of concealment of allocation, attrition, and trial size, and explored the association between outcome subjectivity (high, moderate, low) and average bias. An ROR lower than 1 indicated exaggerated effect estimates in trials without blinding. Results The study included 142 meta-analyses (1153 trials). The ROR for lack of blinding of patients was 0.91 (95% credible interval 0.61 to 1.34) in 18 meta-analyses with patient reported outcomes, and 0.98 (0.69 to 1.39) in 14 meta-analyses with outcomes reported by blinded observers. The ROR for lack of blinding of healthcare providers was 1.01 (0.84 to 1.19) in 29 meta-analyses with healthcare provider decision outcomes (eg, readmissions), and 0.97 (0.64 to 1.45) in 13 meta-analyses with outcomes reported by blinded patients or observers. The ROR for lack of blinding of observers was 1.01 (0.86 to 1.18) in 46 meta-analyses with subjective observer reported outcomes, with no clear impact of degree of subjectivity. Information was insufficient to determine whether lack of blinding was associated with increased heterogeneity between trials. The ROR for trials not reported as double blind versus those that were double blind was 1.02 (0.90 to 1.13) in 74 meta-analyses. Conclusion No evidence was found for an average difference in estimated treatment effect between trials with and without blinded patients, healthcare providers, or outcome assessors. These results could reflect that blinding is less important than often believed or meta-epidemiological study limitations, such as residual confounding or imprecision. At this stage, replication of this study is suggested and blinding should remain a methodological safeguard in trials.

Objective To investigate the impact of modifications to contemporary cancer protocols, which minimize exposures to cardiotoxic treatments and preserve long term health, on serious cardiac outcomes among adult survivors of childhood cancer. Design Retrospective cohort study. Setting 27 institutions participating in the Childhood Cancer Survivor Study. Participants 23 462 five year survivors (6193 (26.4%) treated in the 1970s, 9363 (39.9%) treated in the 1980s, and 7906 (33.6%) treated in the 1990s) of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas diagnosed prior to age 21 years between 1 January 1970 and 31 December 1999. Median age at diagnosis was 6.1 years (range 0-20.9) and 27.7 years (8.2-58.3) at last follow-up. A comparison group of 5057 siblings of cancer survivors were also included. Main outcome measures Cumulative incidence and 95% confidence intervals of reported heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias by treatment decade. Events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Multivariable subdistribution hazard models were used to estimate hazard ratios by decade, and mediation analysis examined risks with and without exposure to cardiotoxic treatments. Results The 20 year cumulative incidence of heart failure (0.69% for those treated in the 1970s, 0.74% for those treated in the 1980s, 0.54% for those treated in the 1990s) and coronary artery disease (0.38%, 0.24%, 0.19%, respectively), decreased in more recent eras (P<0.01), though not for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%), or arrhythmias (0.08%, 0.09%, 0.13%). Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly for coronary artery disease (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92 and 0.53, 0.36 to 0.77, respectively). The overall risk of coronary artery disease was attenuated by adjustment for cardiac radiation (0.90, 0.78 to 1.05), particularly among survivors of Hodgkin lymphoma (unadjusted for radiation: 0.77, 0.66 to 0.89; adjusted for radiation: 0.87, 0.69 to 1.10). Conclusions Historical reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer. Additional follow-up is needed to investigate risk reductions for other cardiac outcomes. Trial registration ClinicalTrials.gov NCT01120353.

In systematic reviews that lack data amenable to meta-analysis, alternative synthesis methods are commonly used, but these methods are rarely reported. This lack of transparency in the methods can cast doubt on the validity of the review findings. The Synthesis Without Meta-analysis (SWiM) guideline has been developed to guide clear reporting in reviews of interventions in which alternative synthesis methods to meta-analysis of effect estimates are used. This article describes the development of the SWiM guideline for the synthesis of quantitative data of intervention effects and presents the nine SWiM reporting items with accompanying explanations and examples. ### Summary points Decision makers consider systematic reviews to be an essential source of evidence.1 Complete and transparent reporting of the methods and results of reviews allows users to assess the validity of review findings. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA; http://www.prisma-statement.org/) statement, consisting of a 27 item checklist, was developed to facilitate improved reporting of systematic reviews.2 Extensions are …

Objectives To determine whether patients discharged after hospital admissions for conditions covered by national readmission programs who received care in emergency departments or observation units but were not readmitted within 30 days had an increased risk of death and to evaluate temporal trends in post-discharge acute care utilization in inpatient units, emergency departments, and observation units for these patients. Design Retrospective cohort study. Setting Medicare claims data for 2008-16 in the United States. Participants Patients aged 65 or older admitted to hospital with heart failure, acute myocardial infarction, or pneumonia—conditions included in the US Hospital Readmissions Reduction Program. Main outcome measures Post-discharge 30 day mortality according to patients’ 30 day acute care utilization; acute care utilization in inpatient and observation units and the emergency department during the 30 day and 31-90 day post-discharge period. Results 3 772 924 hospital admissions for heart failure, 1 570 113 for acute myocardial infarction, and 3 131 162 for pneumonia occurred. The overall post-discharge 30 day mortality was 8.7% for heart failure, 7.3% for acute myocardial infarction, and 8.4% for pneumonia. Risk adjusted mortality increased annually by 0.05% (95% confidence interval 0.02% to 0.08%) for heart failure, decreased by 0.06% (−0.09% to −0.04%) for acute myocardial infarction, and did not significantly change for pneumonia. Specifically, mortality increased for patients with heart failure who did not utilize any post-discharge acute care, increasing at a rate of 0.08% (0.05% to 0.12%) per year, exceeding the overall absolute annual increase in post-discharge mortality in heart failure, without an increase in mortality in observation units or the emergency department. Concurrent with a reduction in 30 day readmission rates, stays for observation and visits to the emergency department increased across all three conditions during and beyond the 30 day post-discharge period. Overall 30 day post-acute care utilization did not change significantly. Conclusions The only condition with increasing mortality through the study period was heart failure; the increase preceded the policy and was not present among patients who received emergency department or observation unit care without admission to hospital. During this period, the overall acute care utilization in the 30 days after discharge significantly decreased for heart failure and pneumonia, but not for acute myocardial infarction.

Objective To examine how a healthy lifestyle is related to life expectancy that is free from major chronic diseases. Design Prospective cohort study. Setting and participants The Nurses’ Health Study (1980-2014; n=73 196) and the Health Professionals Follow-Up Study (1986-2014; n=38 366). Main exposures Five low risk lifestyle factors: never smoking, body mass index 18.5-24.9, moderate to vigorous physical activity (≥30 minutes/day), moderate alcohol intake (women: 5-15 g/day; men 5-30 g/day), and a higher diet quality score (upper 40%). Main outcome Life expectancy free of diabetes, cardiovascular diseases, and cancer. Results The life expectancy free of diabetes, cardiovascular diseases, and cancer at age 50 was 23.7 years (95% confidence interval 22.6 to 24.7) for women who adopted no low risk lifestyle factors, in contrast to 34.4 years (33.1 to 35.5) for women who adopted four or five low risk factors. At age 50, the life expectancy free of any of these chronic diseases was 23.5 (22.3 to 24.7) years among men who adopted no low risk lifestyle factors and 31.1 (29.5 to 32.5) years in men who adopted four or five low risk lifestyle factors. For current male smokers who smoked heavily (≥15 cigarettes/day) or obese men and women (body mass index ≥30), their disease-free life expectancies accounted for the lowest proportion (≤75%) of total life expectancy at age 50. Conclusion Adherence to a healthy lifestyle at mid-life is associated with a longer life expectancy free of major chronic diseases.

Objective To determine, in critically ill patients, the relative impact of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), sucralfate, or no gastrointestinal bleeding prophylaxis (or stress ulcer prophylaxis) on outcomes important to patients. Design Systematic review and network meta-analysis. Data sources Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, trial registers, and grey literature up to March 2019. Eligibility criteria for selecting studies and methods We included randomised controlled trials that compared gastrointestinal bleeding prophylaxis with PPIs, H2RAs, or sucralfate versus one another or placebo or no prophylaxis in adult critically ill patients. Two reviewers independently screened studies for eligibility, extracted data, and assessed risk of bias. A parallel guideline committee (BMJ Rapid Recommendation) provided critical oversight of the systematic review, including identifying outcomes important to patients. We performed random-effects pairwise and network meta-analyses and used GRADE to assess certainty of evidence for each outcome. When results differed between low risk and high risk of bias studies, we used the former as best estimates. Results Seventy two trials including 12 660 patients proved eligible. For patients at highest risk (>8%) or high risk (4-8%) of bleeding, both PPIs and H2RAs probably reduce clinically important gastrointestinal bleeding compared with placebo or no prophylaxis (odds ratio for PPIs 0.61 (95% confidence interval 0.42 to 0.89), 3.3% fewer for highest risk and 2.3% fewer for high risk patients, moderate certainty; odds ratio for H2RAs 0.46 (0.27 to 0.79), 4.6% fewer for highest risk and 3.1% fewer for high risk patients, moderate certainty). Both may increase the risk of pneumonia compared with no prophylaxis (odds ratio for PPIs 1.39 (0.98 to 2.10), 5.0% more, low certainty; odds ratio for H2RAs 1.26 (0.89 to 1.85), 3.4% more, low certainty). It is likely that neither affect mortality (PPIs 1.06 (0.90 to 1.28), 1.3% more, moderate certainty; H2RAs 0.96 (0.79 to 1.19), 0.9% fewer, moderate certainty). Otherwise, results provided no support for any affect on mortality, Clostridium difficile infection, length of intensive care stay, length of hospital stay, or duration of mechanical ventilation (varying certainty of evidence). Conclusions For higher risk critically ill patients, PPIs and H2RAs likely result in important reductions in gastrointestinal bleeding compared with no prophylaxis; for patients at low risk, the reduction in bleeding may be unimportant. Both PPIs and H2RAs may result in important increases in pneumonia. Variable quality evidence suggested no important effects of interventions on mortality or other in-hospital morbidity outcomes. Systematic review registration PROSPERO CRD42019126656.

Objective To study the effect of long term exposure to ambient fine particulate matter of diameter ≤2.5 μm (PM2.5) on the incidence of total, ischemic, and hemorrhagic stroke among Chinese adults. Design Population based prospective cohort study. Setting Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project carried out in 15 provinces across China. Participants 117 575 Chinese men and women without stroke at baseline in the China-PAR project. Main outcome measures Incidence of total, ischemic, and hemorrhagic stroke. Results The long term average PM2.5 level from 2000 to 2015 at participants’ residential addresses was 64.9 μg/m3, ranging from 31.2 μg/m3 to 97.0 μg/m3. During 900 214 person years of follow-up, 3540 cases of incident stroke were identified, of which 63.0% (n=2230) were ischemic and 27.5% (n=973) were hemorrhagic. Compared with the first quarter of exposure to PM2.5 (<54.5 μg/m3), participants in the highest quarter (>78.2 μg/m3) had an increased risk of incident stroke (hazard ratio 1.53, 95% confidence interval 1.34 to 1.74), ischemic stroke (1.82, 1.55 to 2.14), and hemorrhagic stroke (1.50, 1.16 to 1.93). For each increase of 10 μg/m3 in PM2.5 concentration, the increased risks of incident stroke, ischemic stroke, and hemorrhagic stroke were 13% (1.13, 1.09 to 1.17), 20% (1.20, 1.15 to 1.25), and 12% (1.12, 1.05 to 1.20), respectively. Almost linear exposure-response relations between long term exposure to PM2.5 and incident stroke, overall and by its subtypes, were observed. Conclusions This study provides evidence from China that long term exposure to ambient PM2.5 at relatively high concentrations is positively associated with incident stroke and its major subtypes. These findings are meaningful for both environmental and health policy development related to air pollution and stroke prevention, not only in China, but also in other low and middle income countries.

Objective To estimate the risks of daily hospital admissions for cause specific major cardiovascular diseases associated with short term exposure to ambient fine particulate matter (aerodynamic diameter ≤2.5 μm; PM2.5) pollution in China. Design National time series study. Setting 184 major cities in China. Population 8 834 533 hospital admissions for cardiovascular causes in 184 Chinese cities recorded by the national database of Urban Employee Basic Medical Insurance from 1 January 2014 to 31 December 2017. Main outcome measures Daily counts of city specific hospital admissions for primary diagnoses of ischaemic heart disease, heart failure, heart rhythm disturbances, ischaemic stroke, and haemorrhagic stroke among different demographic groups were used to estimate the associations between PM2.5 and morbidity. An overdispersed generalised additive model was used to estimate city specific associations between PM2.5 and cardiovascular admissions, and random effects meta-analysis used to combine the city specific estimates. Results Over the study period, a mean of 47 hospital admissions per day (standard deviation 74) occurred for cardiovascular disease, 26 (53) for ischaemic heart disease, one (five) for heart failure, two (four) for heart rhythm disturbances, 14 (28) for ischaemic stroke, and two (four) for haemorrhagic stroke. At the national average level, an increase of 10 μg/m3 in PM2.5 was associated with a 0.26% (95% confidence interval 0.17% to 0.35%) increase in hospital admissions on the same day for cardiovascular disease, 0.31% (0.22% to 0.40%) for ischaemic heart disease, 0.27% (0.04% to 0.51%) for heart failure, 0.29% (0.12% to 0.46%) for heart rhythm disturbances, and 0.29% (0.18% to 0.40%) for ischaemic stroke, but not with haemorrhagic stroke (−0.02% (−0.23% to 0.19%)). The national average association of PM2.5 with cardiovascular disease was slightly non-linear, with a sharp slope at PM2.5 levels below 50 μg/m3, a moderate slope at 50-250 μg/m3, and a plateau at concentrations higher than 250 μg/m3. Compared with days with PM2.5 up to 15 μg/m3, days with PM2.5 of 15-25, 25-35, 35-75, and 75 μg/m3 or more were significantly associated with increases in cardiovascular admissions of 1.1% (0 to 2.2%), 1.9% (0.6% to 3.2%), 2.6% (1.3% to 3.9%), and 3.8% (2.1% to 5.5%), respectively.According to projections, achieving the Chinese grade 2 (35 μg/m3), Chinese grade 1 (15 μg/m3), and World Health Organization (10 μg/m3) regulatory limits for annual mean PM2.5 concentrations would reduce the annual number of admissions for cardiovascular disease in China. Assuming causality, which should be done with caution, this reduction would translate into an estimated 36 448 (95% confidence interval 24 441 to 48 471), 85 270 (57 129 to 113 494), and 97 516 (65 320 to 129 820), respectively. Conclusions These data suggest that in China, short term exposure to PM2.5 is associated with increased hospital admissions for all major cardiovascular diseases except for haemorrhagic stroke, even for exposure levels not exceeding the current regulatory limits.

Objective To determine whether researchers are submitting manuscripts and peer reviews to BMJ journals out of hours and whether this has changed over time. Design Observational study of research manuscripts and peer reviews submitted between 2012 and 2019 for which an author’s address could be geocoded. Setting Online BMJ submission systems for two large general medical journals. Main outcome measures Manuscript and peer review submissions on weekends, on national holidays, and by hour of day (to determine early mornings and late nights). Logistic regression was used to estimate the probability of manuscript and peer review submissions on weekends or holidays. Results The analyses included more than 49 000 manuscript submissions and 76 000 peer reviews. Little change over time was seen in the average probability of manuscript or peer review submissions occurring on weekends or holidays. The levels of out of hours work were high, with average probabilities of 0.14 to 0.18 for work on the weekends and 0.08 to 0.13 for work on holidays compared with days in the same week. Clear and consistent differences were seen between countries. Chinese researchers most often worked at weekends and at midnight, whereas researchers in Scandinavian countries were among the most likely to submit during the week and the middle of the day. Conclusion The differences between countries that are persistent over time show that a “culture of overwork” is a literal thing, not just a figure of speech.

Objective To determine whether fast driving, luxury car ownership, and leniency by police officers differ across medical specialties. Design Observational study. Setting Florida, USA. Participants 5372 physicians and a sample of 19 639 non-physicians issued a ticket for speeding during 2004-17. Main outcome measures Observed rates of extreme speeding (defined as driving >20 mph above the speed limit), luxury car ownership, and leniency of the speeding ticket by police officers, by physician specialty, after adjustment for age and sex. Results The sample included 5372 physicians who received 14 560 speeding tickets. The proportion of drivers who were reported driving at speeds greater than 20 mph was similar between physicians and a sample of 19 639 non-physicians who received a ticket for speeding (26.4% v 26.8% of tickets, respectively). Among physicians who received a ticket, psychiatrists were most likely to be fined for extreme speeding (adjusted odds ratio of psychiatry compared with baseline specialty of anesthesia 1.51, 95% confidence interval 1.07 to 2.14). Among drivers who received a ticket, luxury car ownership was most common among cardiologists (adjusted proportion of ticketed cardiologists who owned a luxury car 40.9%, 95% confidence interval 35.9% to 45.9%) and least common among physicians in emergency medicine, family practice, pediatrics, general surgery, and psychiatry (eg, adjusted proportion of luxury car ownership among family practice physicians 20.6%, 95% confidence interval 18.2% to 23.0%). Speed discounting, a marker of leniency by police officers in which ticketed speed is recorded at just below the threshold at which a larger fine would otherwise be imposed, was common, but rates did not differ by specialty and did not differ between physicians and a sample of non-physicians. Conclusions Rates of extreme speeding were highest among psychiatrists who received a ticket, whereas cardiologists were the most likely to be driving a luxury car when ticketed. Leniency by police officers was similar across specialties and between physicians and non-physicians.

Objectives To compare the proportional representation of healthcare workers in receipt of New Year honours (NYHs) with workers in other industries and to determine whether the NYH system has gender or geographical biases. Design Observational study of the UK honours system with a comparative analysis of proportional representation of the UK workforce and subgroup analyses of gender and geographical representations. Participants Recipients of NYHs from 2009 to 2018. Main outcome measures Absolute risk of receiving an NYH based on industry, gender, or region of the UK. Relative risk of receiving an NYH for services to healthcare compared with other industries. Results 10 989 NYHs were bestowed from 2009 to 2018, 47% of which were awarded to women. 832 awards (7.6%) were for services to healthcare. People working in sport and in the arts and media were more likely to receive NYHs than those working in healthcare (relative risks of 22.01 (95% confidence interval 19.91 to 24.34) and 5.84 (5.31 to 6.44), respectively). There was no significant difference between the rate of receiving honours for healthcare and for science and technology (P=0.22). 34% (3741) of awards were issued to people living in London and in the southeast of England, and only 496 of 1447 (34%) higher order awards (knighthoods, damehoods, companions of honour, and commanders of the order of the British empire) were received by women. Conclusions In relation to the size of its workforce, a career in healthcare is not as “honourable” as careers in certain other industries. Geographical and gender biases might exist in the honours system.

Objective To explore associations between different frequencies of arts engagement and mortality over a 14 year follow-up period. Design Prospective cohort study. Participants English Longitudinal Study of Ageing cohort of 6710 community dwelling adults aged 50 years and older (53.6% women, average age 65.9 years, standard deviation 9.4) who provided baseline data in 2004-05. Intervention Self reported receptive arts engagement (going to museums, art galleries, exhibitions, the theatre, concerts, or the opera). Measurement Mortality measured through data linkage to the National Health Service central register. Results People who engaged with receptive arts activities on an infrequent basis (once or twice a year) had a 14% lower risk of dying at any point during the follow-up (809/3042 deaths, hazard ratio 0.86, 95% confidence interval 0.77 to 0.96) compared with those who never engaged (837/1762 deaths). People who engaged with receptive arts activities on a frequent basis (every few months or more) had a 31% lower risk of dying (355/1906 deaths, 0.69, 0.59 to 0.80), independent of demographic, socioeconomic, health related, behavioural, and social factors. Results were robust to a range of sensitivity analyses with no evidence of moderation by sex, socioeconomic status, or social factors. This study was observational and so causality cannot be assumed. Conclusions Receptive arts engagement could have a protective association with longevity in older adults. This association might be partly explained by differences in cognition, mental health, and physical activity among those who do and do not engage in the arts, but remains even when the model is adjusted for these factors.

Objectives To evaluate the associations between birth month, birth season, and overall and cardiovascular disease mortality, and to examine the role of familial and socioeconomic factors in these associations. Design Prospective cohort study. Setting Nurses’ Health Study, established in 1976, an ongoing prospective cohort study in the United States. Participants Female registered nurses who reported information on date of birth at study enrolment (n=116 911, 1976-2014, followed for 38 years). Exposure Birth month and astronomical birth season (based on solstices and equinoxes as boundaries of the season categories). Main outcome measures Age and various multivariable adjusted hazard ratios and 95% confidence intervals for the association between birth months (using November as the reference), astronomical birth season (using autumn as the reference), and overall and cardiovascular disease specific mortality were assessed using Cox proportional hazards models. Results Among study participants, 43 248 overall deaths were documented during 4 136 364 person years of follow-up since enrolment, including 8360 cardiovascular disease related deaths. In fully adjusted multivariable analyses, no significant association was observed between birth month, birth season, and overall mortality. Compared with women born in November, increased cardiovascular disease mortality was observed among those born from March to July (hazard ratio for March, 1.09, 95% confidence interval 0.98 to 1.21; April, 1.12, 1.00 to 1.24; May, 1.08, 0.98 to 1.20; June, 1.07, 0.96 to 1.19; and July 1.08, 0.98 to 1.20). Those born in April had the highest cardiovascular disease mortality, and those born in December had the lowest (December, 0.95, 0.85 to 1.06). The relative difference between the lowest and highest risk month was 17.89%. Women born in spring (1.10, 1.04 to 1.17) and summer (1.09, 1.03 to 1.16) had a higher cardiovascular disease mortality than women born in the autumn. Adjustment for familial and socioeconomic factors did not change these results. The relative difference between the lowest and highest risk season was 10.00%. Conclusion Participants born in the spring and summer (especially those born in March-July) had a slight but significant increase in cardiovascular disease specific mortality. However, no seasonal birth month effect was observed among women for overall mortality. Familial and socioeconomic factors did not appear to alter these associations. Further studies are required to confirm these findings and reveal mechanisms of these seasonal birth month effects in cardiovascular disease mortality.

Objective To determine the validity of the superstition that utterance of the word “quiet” in a clinical setting increases workload. Design Prospective randomised controlled non-inferiority study. Setting Microbiology department of a large teaching hospital in Lancashire, UK. Participants Two members of the medical microbiology team carried out the duty work on any given week day and an on-call team member on any weekend day. 29 days were assigned in which staff were to say “Today will be a quiet day” and 32 days were assigned in which staff were to refrain from saying the word “quiet” in any context. Interventions Each day was randomly allocated to either saying “Today will be a quiet day” (intervention group) or refraining from saying the word “quiet” (control group) in any context. Main outcome measures The primary outcome was mean overall workload: a composite of number of clinically related telephone calls, clinically significant results, or validated results processed by the duty medical microbiology team during a 24 hour period referred to collectively as “clinical episodes.” A difference of 30 clinical episodes was considered as the margin of non-inferiority. Secondary outcomes included the individual components of the primary outcome. Results Workload was measured each day over a 61 day period (1 May to 30 June 2019). A mean 139.0 clinical episodes occurred on control days compared with 144.9 on days when the experimental intervention was uttered, a difference of 5.9 (95% confidence interval−12.9 to 24.7). The upper bound was less than the specified margin of 30, providing evidence for non-inferiority. No evidence of a difference in workload was found between interventions with any of the four components, whether considering unadjusted or adjusted analyses, or looking at the subgroups of week days or weekends. Conclusions The study findings refute the long held superstition that utterance of the word “quiet” impacts on clinical workload, and therefore it should not be avoided. In the era of considerable staff shortages and increased work related stress, doctors should look to other methods to increase resilience and protect their wellbeing and mental health. Trial registration Lancashire Teaching Hospitals NHS Foundation Trust’s research department SE-259.

Objectives To identify and calculate the prevalence of spin in studies of spin. Design Meta-research analysis (research on research). Setting 35 studies of spin in the scientific literature. Main outcome measures Spin, categorised as: reporting practices that distort the presentation and interpretation of results, creating misleading conclusions; discordance between results and their interpretation, with presentation of favourable conclusions that are not supported by the data or results; attribution of causality when study design does not support it; and over-interpretation or inappropriate extrapolation of results. Results Five (14%) of 35 spin studies contained spin categorised as reporting practices that distort the presentation and interpretation of results (n=2) or categorised as over-interpretation or inappropriate extrapolation of results (n=3). Conclusion Spin occurs in research on spin. Although researchers on this topic should be sensitive to spinning their findings, our study does not undermine the need for rigorous interventions to reduce spin across various research fields. Conclusion with spin Our hypothesis that spin will be less prevalent in spin studies than in studies on other topics has been proven. Spin scholars are less likely to spin their conclusions than other researchers, and they should receive substantial resources to launch and test interventions to reduce spin and research waste in reporting.

Objective To determine the implications of car ownership for physical activity and weight in a global city. Design Quasi-experimental cross sectional study. Setting Beijing, China, 2011-15. Participants People aged 18 and older from a random sample of households who had entered a permit lottery to purchase a vehicle between January 2011 and November 2015. Interventions Permit allowing purchase of a vehicle within six months of permit issuance. Main outcome measures Transit use (number of subway and bus rides each week), physical activity (minutes of walking or bicycling each day), and weight, measured once in early 2016. Results Of 937 people analysed in total, 180 had won a permit to purchase a new vehicle. Winning the permit lottery resulted in the purchase of an additional vehicle 91% of the time (95% confidence interval 89% to 94%; P<0.001). About five years after winning, winners took significantly fewer weekly transit rides (−2.9 rides (−5.1 to −0.7); P=0.01) and walked and cycled significantly less (−24.2 minutes (−40.3 to −8.1); P=0.003) than those who did not win the lottery. Average weight did not change significantly between lottery winners and losers. Among those aged 50 and older, however, winners’ weight had increased relative to that of losers (10.3 kg (0.5 to 20.2); P=0.04) 5.1 years after winning. Conclusions These data indicate that vehicle ownership in a rapidly growing global city led to long term reductions in physical activity and increase in weight. Continuing increases in car use and ownership in developing and middle income countries could adversely affect physical health and obesity rates.

Objectives Women remain underrepresented on faculties of medicine and the life sciences more broadly. Whether gender differences in self presentation of clinical research exist and may contribute to this gender gap has been challenging to explore empirically. The objective of this study was to analyze whether men and women differ in how positively they frame their research findings and to analyze whether the positive framing of research is associated with higher downstream citations. Design Retrospective observational study. Data sources Titles and abstracts from 101 720 clinical research articles and approximately 6.2 million general life science articles indexed in PubMed and published between 2002 and 2017. Main outcome measures Analysis of article titles and abstracts to determine whether men and women differ in how positively they present their research through use of terms such as “novel” or “excellent.” For a set of 25 positive terms, we estimated the relative probability of positive framing as a function of the gender composition of the first and last authors, adjusting for scientific journal, year of publication, journal impact, and scientific field. Results Articles in which both the first and last author were women used at least one of the 25 positive terms in 10.9% of titles or abstracts versus 12.2% for articles involving a male first or last author, corresponding to a 12.3% relative difference (95% CI 5.7% to 18.9%). Gender differences in positive presentation were greatest in high impact clinical journals (impact factor >10), in which women were 21.4% less likely to present research positively. Across all clinical journals, positive presentation was associated with 9.4% (6.6% to 12.2%) higher subsequent citations, and in high impact clinical journals 13.0% (9.5% to 16.5%) higher citations. Results were similar when broadened to general life science articles published in journals indexed by PubMed, suggesting that gender differences in positive word use generalize to broader samples. Conclusions Clinical articles involving a male first or last author were more likely to present research findings positively in titles and abstracts compared with articles in which both the first and last author were women, particularly in the highest impact journals. Positive presentation of research findings was associated with higher downstream citations.

Objective To understand and report on the nature of patient group interactions with the pharmaceutical industry from the perspective of patient group representatives by exploring the range of attitudes towards pharmaceutical industry sponsorship and how, why, and when interactions occur. Design Empirical qualitative interview study informed by ethics theory. Setting Australian patient groups. Participants 27 participants from 23 Australian patient groups that represented diverse levels of financial engagement with the pharmaceutical industry. Groups were focused on general health consumer issues or disease specific topics, and had regional or national jurisdictions. Analysis Analytic techniques were informed by grounded theory. Interview transcripts were coded into data driven categories. Findings were organised into new conceptual categories to describe and explain the data, and were supported by quotes. Results A range of attitudes towards pharmaceutical industry sponsorship were identified that are presented as four different types of relationship between patient groups and the pharmaceutical industry. The dominant relationship type was of a successful business partnership, and participants described close working relationships with industry personnel. These participants acknowledged a potential for adverse industry influence, but expressed confidence in existing strategies for avoiding industry influence. Other participants described unsatisfactory or undeveloped relationships, and some participants (all from general health consumer groups) presented their groups’ missions as incompatible with the pharmaceutical industry because of fundamentally opposing interests. Participants reported that interactions between their patient group and pharmaceutical companies were more common when companies had new drugs of potential interest to group members. Patient groups that accepted industry funding engaged in exchanges of “assets” with companies. Groups received money, information, and advice in exchange for providing companies with marketing, relationship building opportunities with key opinion leaders, coordinated lobbying with companies about drug access and subsidy, assisting companies with clinical trial recruitment, and enhancing company credibility. Conclusions An understanding of the range of views patient groups have about pharmaceutical company sponsorship will be useful for groups that seek to identify and manage any ethical concerns about these relationships. Patient groups that receive pharmaceutical industry money should anticipate they might be asked for specific assets in return. Selective industry funding of groups where active product marketing opportunities exist might skew the patient group sector’s activity towards pharmaceutical industry interests and allow industry to exert proxy influence over advocacy and subsequent health policy.

Objectives To identify the frequency with which antibiotics are prescribed in the absence of a documented indication in the ambulatory care setting, to quantify the potential effect on assessments of appropriateness of antibiotics, and to understand patient, provider, and visit level characteristics associated with antibiotic prescribing without a documented indication. Design Cross sectional study. Setting 2015 National Ambulatory Medical Care Survey. Participants 28 332 sample visits representing 990.9 million ambulatory care visits nationwide. Main outcome measures Overall antibiotic prescribing and whether each antibiotic prescription was accompanied by appropriate, inappropriate, or no documented indication as identified through ICD-9-CM (international classification of diseases, 9th revision, clinical modification) codes. Survey weighted multivariable logistic regression was used to evaluate potential risk factors for receipt of an antibiotic prescription without a documented indication. Results Antibiotics were prescribed during 13.2% (95% confidence interval 11.6% to 13.7%) of the estimated 990.8 million ambulatory care visits in 2015. According to the criteria, 57% (52% to 62%) of the 130.5 million prescriptions were for appropriate indications, 25% (21% to 29%) were inappropriate, and 18% (15% to 22%) had no documented indication. This corresponds to an estimated 24 million prescriptions without a documented indication. Being an adult male, spending more time with the provider, and seeing a non-primary care specialist were significantly positively associated with antibiotic prescribing without an indication. Sulfonamides and urinary anti-infective agents were the antibiotic classes most likely to be prescribed without documentation. Conclusions This nationally representative study of ambulatory visits identified a large number of prescriptions for antibiotics without a documented indication. Antibiotic prescribing in the absence of a documented indication may severely bias national estimates of appropriate antibiotic use in this setting. This study identified a wide range of factors associated with antibiotic prescribing without a documented indication, which may be useful in directing initiatives aimed at supporting better documentation.

Objective To evaluate the impact of the US government’s Feed the Future initiative on nutrition outcomes in children younger than 5 years in sub-Saharan Africa. Design Difference-in-differences quasi-experimental approach. Setting Households in 33 low and lower middle income countries in sub-Saharan Africa. Population 883 309 children aged less than 5 years with weight, height, and age recorded in 118 surveys conducted in 33 countries between 2000 and 2017: 388 052 children were from Feed the Future countries and 495 257 were from non-Feed the Future countries. Main outcome measures A difference-in-differences approach was used to compare outcomes among children in intervention countries after implementation of the initiative with children before its introduction and children in non-intervention countries, controlling for relevant covariates, time invariant national differences, and time trends. The primary outcome was stunting (height for age >2 standard deviations below a reference median), a key indicator of undernutrition in children. Secondary outcomes were wasting (low weight for height) and underweight (low weight for age). Results Across all years and countries, 38.3% of children in the study sample were stunted, 8.9% showed wasting, and 21.3% were underweight. In the first six years of Feed the Future’s implementation, children in 12 countries with the initiative exhibited a 3.9 percentage point (95% confidence interval 2.4 to 5.5) greater decline in stunting, a 1.1 percentage point (0.1 to 2.1) greater decline in wasting, and a 2.8 percentage point (1.6 to 4.0) greater decline in underweight levels compared with children in 21 countries without the initiative and compared with trends in undernutrition before Feed the Future was launched. These decreases translate to around two million fewer stunted and underweight children aged less than 5 years and around a half million fewer children with wasting. For context, about 22 million children were stunted, 11 million children were underweight, and four million children were wasted in the Feed the Future countries at baseline. Conclusions Feed the Future’s activities were closely linked to notable improvements in stunting and underweight levels and moderate improvements in wasting in children younger than 5 years. These findings highlight the effectiveness of this large, country tailored initiative focused on agriculture and food security and have important implications for the future of this and other nutrition interventions worldwide.

Objective To determine the effectiveness of management strategies for uninvestigated dyspepsia. Design Systematic review and network meta-analysis. Data sources Medline, Embase, Embase Classic, the Cochrane Central Register of Controlled Trials, and clinicaltrials.gov from inception to September 2019, with no language restrictions. Conference proceedings between 2001 and 2019. Eligibility criteria for selecting studies Randomised controlled trials that assessed the effectiveness of management strategies for uninvestigated dyspepsia in adult participants (age ≥18 years). Strategies of interest were prompt endoscopy; test for Helicobacter pylori and perform endoscopy in participants who test positive; test for H pylori and eradication treatment in those who test positive (“test and treat”); empirical acid suppression; or symptom based management. Trials reported dichotomous assessment of symptom status at final follow-up (≥12 months). Results The review identified 15 eligible randomised controlled trials that comprised 6162 adult participants. Data were pooled using a random effects model. Strategies were ranked according to P score, which is the mean extent of certainty that one management strategy is better than another, averaged over all competing strategies. “Test and treat” ranked first (relative risk of remaining symptomatic 0.89, 95% confidence interval 0.78 to 1.02, P score 0.79) and prompt endoscopy ranked second, but performed similarly (0.90, 0.80 to 1.02, P score 0.71). However, no strategy was significantly less effective than “test and treat.” Participants assigned to “test and treat” were significantly less likely to receive endoscopy (relative risk v prompt endoscopy 0.23, 95% confidence interval 0.17 to 0.31, P score 0.98) than all other strategies, except symptom based management (relative risk v symptom based management 0.60, 0.30 to 1.18). Dissatisfaction with management was significantly lower with prompt endoscopy (P score 0.95) than with “test and treat” (relative risk v “test and treat” 0.67, 0.46 to 0.98), and empirical acid suppression (relative risk v empirical acid suppression 0.58, 0.37 to 0.91). Upper gastrointestinal cancer rates were low in all trials. Results remained stable in sensitivity analyses, with minimal inconsistencies between direct and indirect results. Risk of bias of individual trials was high; blinding was not possible because of the pragmatic trial design. Conclusions “Test and treat” was ranked first, although it performed similarly to prompt endoscopy and was not superior to any of the other strategies. “Test and treat” led to fewer endoscopies than all other approaches, except symptom based management. However, participants showed a preference for prompt endoscopy as a management strategy for their symptoms. Systematic review registration PROSPERO registration number CRD42019132528.

Objective To evaluate the associations between maternal diabetes diagnosed before or during pregnancy and early onset cardiovascular disease (CVD) in offspring during their first four decades of life. Design Population based cohort study. Setting Danish national health registries. Participants All 2 432 000 liveborn children without congenital heart disease in Denmark during 1977-2016. Follow-up began at birth and continued until first time diagnosis of CVD, death, emigration, or 31 December 2016, whichever came first. Exposures for observational studies Pregestational diabetes, including type 1 diabetes (n=22 055) and type 2 diabetes (n=6537), and gestational diabetes (n=26 272). Main outcome measures The primary outcome was early onset CVD (excluding congenital heart diseases) defined by hospital diagnosis. Associations between maternal diabetes and risks of early onset CVD in offspring were studied. Cox regression was used to assess whether a maternal history of CVD or maternal diabetic complications affected these associations. Adjustments were made for calendar year, sex, singleton status, maternal factors (parity, age, smoking, education, cohabitation, residence at childbirth, history of CVD before childbirth), and paternal history of CVD before childbirth. The cumulative incidence was averaged across all individuals, and factors were adjusted while treating deaths from causes other than CVD as competing events. Results During up to 40 years of follow-up, 1153 offspring of mothers with diabetes and 91 311 offspring of mothers who did not have diabetes were diagnosed with CVD. Offspring of mothers with diabetes had a 29% increased overall rate of early onset CVD (hazard ratio 1.29 (95% confidence interval 1.21 to 1.37); cumulative incidence among offspring unexposed to maternal diabetes at 40 years of age 13.07% (12.92% to 13.21%), difference in cumulative incidence between exposed and unexposed offspring 4.72% (2.37% to 7.06%)). The sibship design yielded results similar to those of the unpaired design based on the whole cohort. Both pregestational diabetes (1.34 (1.25 to 1.43)) and gestational diabetes (1.19 (1.07 to 1.32)) were associated with increased rates of CVD in offspring. We also observed varied increased rates of specific early onset CVDs, particularly heart failure (1.45 (0.89 to 2.35)), hypertensive disease (1.78 (1.50 to 2.11)), deep vein thrombosis (1.82 (1.38 to 2.41)), and pulmonary embolism (1.91 (1.31 to 2.80)). Increased rates of CVD were seen in different age groups from childhood to early adulthood until age 40 years. The increased rates were more pronounced among offspring of mothers with diabetic complications (1.60 (1.25 to 2.05)). A higher incidence of early onset CVD in offspring of mothers with diabetes and comorbid CVD (1.73 (1.36 to 2.20)) was associated with the added influence of comorbid CVD but not due to the interaction between diabetes and CVD on the multiplicative scale (P value for interaction 0.94). Conclusions Children of mothers with diabetes, especially those mothers with a history of CVD or diabetic complications, have increased rates of early onset CVD from childhood to early adulthood. If maternal diabetes does have a causal association with increased CVD rate in offspring, the prevention, screening, and treatment of diabetes in women of childbearing age could help to reduce the risk of CVD in the next generation.

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Objective To determine associations between important pre-arrest and intra-arrest prognostic factors and survival after in-hospital cardiac arrest. Design Systematic review and meta-analysis. Data sources Medline, PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systematic Reviews from inception to 4 February 2019. Primary, unpublished data from the United Kingdom National Cardiac Arrest Audit database. Study selection criteria English language studies that investigated pre-arrest and intra-arrest prognostic factors and survival after in-hospital cardiac arrest. Data extraction PROGRESS (prognosis research strategy group) recommendations and the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist were followed. Risk of bias was assessed by using the QUIPS tool (quality in prognosis studies). The primary analysis pooled associations only if they were adjusted for relevant confounders. The GRADE approach (grading of recommendations assessment, development, and evaluation) was used to rate certainty in the evidence. Results The primary analysis included 23 cohort studies. Of the pre-arrest factors, male sex (odds ratio 0.84, 95% confidence interval 0.73 to 0.95, moderate certainty), age 60 or older (0.50, 0.40 to 0.62, low certainty), active malignancy (0.57, 0.45 to 0.71, high certainty), and history of chronic kidney disease (0.56, 0.40 to 0.78, high certainty) were associated with reduced odds of survival after in-hospital cardiac arrest. Of the intra-arrest factors, witnessed arrest (2.71, 2.17 to 3.38, high certainty), monitored arrest (2.23, 1.41 to 3.52, high certainty), arrest during daytime hours (1.41, 1.20 to 1.66, high certainty), and initial shockable rhythm (5.28, 3.78 to 7.39, high certainty) were associated with increased odds of survival. Intubation during arrest (0.54, 0.42 to 0.70, moderate certainty) and duration of resuscitation of at least 15 minutes (0.12, 0.07 to 0.19, high certainty) were associated with reduced odds of survival. Conclusion Moderate to high certainty evidence was found for associations of pre-arrest and intra-arrest prognostic factors with survival after in-hospital cardiac arrest. Systematic review registration PROSPERO CRD42018104795

Objective To investigate whether remote ischaemic preconditioning (RIPC) prevents myocardial injury in patients undergoing hip fracture surgery. Design Phase II, multicentre, randomised, observer blinded, clinical trial. Setting Three Danish university hospitals, 2015-17. Participants 648 patients with cardiovascular risk factors undergoing hip fracture surgery. 286 patients were assigned to RIPC and 287 were assigned to standard practice (control group). Intervention The RIPC procedure was initiated before surgery with a tourniquet applied to the upper arm and consisted of four cycles of forearm ischaemia for five minutes followed by reperfusion for five minutes. Main outcome measures The original primary outcome was myocardial injury within four days of surgery, defined as a peak plasma cardiac troponin I concentration of 45 ng/L or more caused by ischaemia. The revised primary outcome was myocardial injury within four days of surgery, defined as a peak plasma cardiac troponin I concentration of 45 ng/L or more or high sensitive troponin I greater than 24 ng/L (the primary outcome was changed owing to availability of testing). Secondary outcomes were peak plasma troponin I and total troponin I release during the first four days after surgery (cardiac and high sensitive troponin I), perioperative myocardial infarction, major adverse cardiovascular events, and all cause mortality within 30 days of surgery, length of postoperative stay, and length of stay in the intensive care unit. Several planned secondary outcomes will be reported elsewhere. Results 573 of the 648 randomised patients were included in the intention-to-treat analysis (mean age 79 (SD 10) years; 399 (70%) women). The primary outcome occurred in 25 of 168 (15%) patients in the RIPC group and 45 of 158 (28%) in the control group (odds ratio 0.44, 95% confidence interval 0.25 to 0.76; P=0.003). The revised primary outcome occurred in 57 of 286 patients (20%) in the RIPC group and 90 of 287 (31%) in the control group (0.55, 0.37 to 0.80; P=0.002). Myocardial infarction occurred in 10 patients (3%) in the RIPC group and 21 patients (7%) in the control group (0.46, 0.21 to 0.99; P=0.04). Statistical power was insufficient to draw firm conclusions on differences between groups for the other clinical secondary outcomes (major adverse cardiovascular events, 30 day all cause mortality, length of postoperative stay, and length of stay in the intensive care unit). Conclusions RIPC reduced the risk of myocardial injury and infarction after emergency hip fracture surgery. It cannot be concluded that RIPC overall prevents major adverse cardiovascular events after surgery. The findings support larger scale clinical trials to assess longer term clinical outcomes and mortality. Trial registration ClinicalTrials.gov NCT02344797.

Objective To determine how the UK National Health Service (NHS) is performing relative to health systems of other high income countries, given that it is facing sustained financial pressure, increasing levels of demand, and cuts to social care. Design Observational study using secondary data from key international organisations such as Eurostat and the Organization for Economic Cooperation and Development. Setting Healthcare systems of the UK and nine high income comparator countries: Australia, Canada, Denmark, France, Germany, the Netherlands, Sweden, Switzerland, and the US. Main outcome measures 79 indicators across seven domains: population and healthcare coverage, healthcare and social spending, structural capacity, utilisation, access to care, quality of care, and population health. Results The UK spent the least per capita on healthcare in 2017 compared with all other countries studied (UK $3825 (£2972; €3392); mean $5700), and spending was growing at slightly lower levels (0.02% of gross domestic product in the previous four years, compared with a mean of 0.07%). The UK had the lowest rates of unmet need and among the lowest numbers of doctors and nurses per capita, despite having average levels of utilisation (number of hospital admissions). The UK had slightly below average life expectancy (81.3 years compared with a mean of 81.7) and cancer survival, including breast, cervical, colon, and rectal cancer. Although several health service outcomes were poor, such as postoperative sepsis after abdominal surgery (UK 2454 per 100 000 discharges; mean 2058 per 100 000 discharges), 30 day mortality for acute myocardial infarction (UK 7.1%; mean 5.5%), and ischaemic stroke (UK 9.6%; mean 6.6%), the UK achieved lower than average rates of postoperative deep venous thrombosis after joint surgery and fewer healthcare associated infections. Conclusions The NHS showed pockets of good performance, including in health service outcomes, but spending, patient safety, and population health were all below average to average at best. Taken together, these results suggest that if the NHS wants to achieve comparable health outcomes at a time of growing demographic pressure, it may need to spend more to increase the supply of labour and long term care and reduce the declining trend in social spending to match levels of comparator countries.

Objective To assess risks and costs of hospital admission associated with short term exposure to fine particulate matter with diameter less than 2.5 µm (PM2.5) for 214 mutually exclusive disease groups. Design Time stratified, case crossover analyses with conditional logistic regressions adjusted for non-linear confounding effects of meteorological variables. Setting Medicare inpatient hospital claims in the United States, 2000-12 (n=95 277 169). Participants All Medicare fee-for-service beneficiaries aged 65 or older admitted to hospital. Main outcome measures Risk of hospital admission, number of admissions, days in hospital, inpatient and post-acute care costs, and value of statistical life (that is, the economic value used to measure the cost of avoiding a death) due to the lives lost at discharge for 214 disease groups. Results Positive associations between short term exposure to PM2.5 and risk of hospital admission were found for several prevalent but rarely studied diseases, such as septicemia, fluid and electrolyte disorders, and acute and unspecified renal failure. Positive associations were also found between risk of hospital admission and cardiovascular and respiratory diseases, Parkinson’s disease, diabetes, phlebitis, thrombophlebitis, and thromboembolism, confirming previously published results. These associations remained consistent when restricted to days with a daily PM2.5 concentration below the WHO air quality guideline for the 24 hour average exposure to PM2.5. For the rarely studied diseases, each 1 µg/m3 increase in short term PM2.5 was associated with an annual increase of 2050 hospital admissions (95% confidence interval 1914 to 2187 admissions), 12 216 days in hospital (11 358 to 13 075), US$31m (£24m, €28m; $29m to $34m) in inpatient and post-acute care costs, and $2.5bn ($2.0bn to $2.9bn) in value of statistical life. For diseases with a previously known association, each 1 µg/m3 increase in short term exposure to PM2.5 was associated with an annual increase of 3642 hospital admissions (3434 to 3851), 20 098 days in hospital (18 950 to 21 247), $69m ($65m to $73m) in inpatient and post-acute care costs, and $4.1bn ($3.5bn to $4.7bn) in value of statistical life. Conclusions New causes and previously identified causes of hospital admission associated with short term exposure to PM2.5 were found. These associations remained even at a daily PM2.5 concentration below the WHO 24 hour guideline. Substantial economic costs were linked to a small increase in short term PM2.5.

Objective To examine the association of consumption of dairy foods with risk of total and cause specific mortality in women and men. Design Three prospective cohort studies with repeated measures of diet and lifestyle factors. Setting Nurses’ Health Study, Nurses’ Health Study II, and the Health Professionals Follow-up Study, in the United States. Participants 168 153 women and 49 602 men without cardiovascular disease or cancer at baseline. Main outcome measure Death confirmed by state vital records, the national death index, or reported by families and the postal system. During up to 32 years of follow-up, 51 438 deaths were documented, including 12 143 cardiovascular deaths and 15 120 cancer deaths. Multivariable analysis further adjusted for family history of cardiovascular disease and cancer, physical activity, overall dietary pattern (alternate healthy eating index 2010), total energy intake, smoking status, alcohol consumption, menopausal status (women only), and postmenopausal hormone use (women only). Results Compared to the lowest category of total dairy consumption (average 0.8 servings/day), the multivariate pooled hazard ratio for total mortality was 0.98 (95% confidence interval 0.96 to 1.01) for the second category of dairy consumption (average 1.5 servings/day), 1.00 (0.97 to 1.03) for the third (average 2.0 servings/day), 1.02 (0.99 to 1.05) for the fourth (average 2.8 servings/day), and 1.07 (1.04 to 1.10) for highest category (average 4.2 servings/day; P for trend <0.001). For the highest compared to the lowest category of total dairy consumption, the hazard ratio was 1.02 (0.95 to 1.08) for cardiovascular mortality and 1.05 (0.99 to 1.11) for cancer mortality. For subtypes of dairy products, whole milk intake was significantly associated with higher risks of total mortality (hazard ratio per 0.5 additional serving/day 1.11, 1.09 to 1.14), cardiovascular mortality (1.09, 1.03 to 1.15), and cancer mortality (1.11, 1.06 to 1.17). In food substitution analyses, consumption of nuts, legumes, or whole grains instead of dairy foods was associated with a lower mortality, whereas consumption of red and processed meat instead of dairy foods was associated with higher mortality. Conclusion These data from large cohorts do not support an inverse association between high amount of total dairy consumption and risk of mortality. The health effects of dairy could depend on the comparison foods used to replace dairy. Slightly higher cancer mortality was non-significantly associated with dairy consumption, but warrants further investigation.

Objective To determine the relation between age and troponin level and its prognostic implication. Design Retrospective cohort study. Setting Five cardiovascular centres in the UK National Institute for Health Research Health Informatics Collaborative (UK-NIHR HIC). Participants 257 948 consecutive patients undergoing troponin testing for any clinical reason between 2010 and 2017. Main outcome measure All cause mortality. Results 257 948 patients had troponin measured during the study period. Analyses on troponin were performed using the peak troponin level, which was the highest troponin level measured during the patient’s hospital stay. Troponin levels were standardised as a multiple of each laboratory’s 99th centile of the upper limit of normal (ULN). During a median follow-up of 1198 days (interquartile range 514-1866 days), 55 850 (21.7%) deaths occurred. A positive troponin result (that is, higher than the upper limit of normal) signified a 3.2 higher mortality hazard (95% confidence interval 3.1 to 3.2) over three years. Mortality varied noticeably with age, with a hazard ratio of 10.6 (8.5 to 13.3) in 18-29 year olds and 1.5 (1.4 to 1.6) in those older than 90. A positive troponin result was associated with an approximately 15 percentage points higher absolute three year mortality across all age groups. The excess mortality with a positive troponin result was heavily concentrated in the first few weeks. Results were analysed using multivariable adjusted restricted cubic spline Cox regression. A direct relation was seen between troponin level and mortality in patients without acute coronary syndrome (ACS, n=120 049), whereas an inverted U shaped relation was found in patients with ACS (n=14 468), with a paradoxical decline in mortality at peak troponin levels >70×ULN. In the group with ACS, the inverted U shaped relation persisted after multivariable adjustment in those who were managed invasively; however, a direct positive relation was found between troponin level and mortality in patients managed non-invasively. Conclusions A positive troponin result was associated with a clinically important increased mortality, regardless of age, even if the level was only slightly above normal. The excess mortality with a raised troponin was heavily concentrated in the first few weeks. Study registration ClinicalTrials.gov NCT03507309.

Objective To evaluate if induction of labour at 41 weeks improves perinatal and maternal outcomes in women with a low risk pregnancy compared with expectant management and induction of labour at 42 weeks. Design Multicentre, open label, randomised controlled superiority trial. Setting 14 hospitals in Sweden, 2016-18. Participants 2760 women with a low risk uncomplicated singleton pregnancy randomised (1:1) by the Swedish Pregnancy Register. 1381 women were assigned to the induction group and 1379 were assigned to the expectant management group. Interventions Induction of labour at 41 weeks and expectant management and induction of labour at 42 weeks. Main outcome measures The primary outcome was a composite perinatal outcome including one or more of stillbirth, neonatal mortality, Apgar score less than 7 at five minutes, pH less than 7.00 or metabolic acidosis (pH <7.05 and base deficit >12 mmol/L) in the umbilical artery, hypoxic ischaemic encephalopathy, intracranial haemorrhage, convulsions, meconium aspiration syndrome, mechanical ventilation within 72 hours, or obstetric brachial plexus injury. Primary analysis was by intention to treat. Results The study was stopped early owing to a significantly higher rate of perinatal mortality in the expectant management group. The composite primary perinatal outcome did not differ between the groups: 2.4% (33/1381) in the induction group and 2.2% (31/1379) in the expectant management group (relative risk 1.06, 95% confidence interval 0.65 to 1.73; P=0.90). No perinatal deaths occurred in the induction group but six (five stillbirths and one early neonatal death) occurred in the expectant management group (P=0.03). The proportion of caesarean delivery, instrumental vaginal delivery, or any major maternal morbidity did not differ between the groups. Conclusions This study comparing induction of labour at 41 weeks with expectant management and induction at 42 weeks does not show any significant difference in the primary composite adverse perinatal outcome. However, a reduction of the secondary outcome perinatal mortality is observed without increasing adverse maternal outcomes. Although these results should be interpreted cautiously, induction of labour ought to be offered to women no later than at 41 weeks and could be one (of few) interventions that reduces the rate of stillbirths. Trial registration Current Controlled Trials ISRCTN26113652.

Objective To determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture. Design Randomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial. Setting Secondary care trauma units across 19 hospitals in the United Kingdom’s health service. Participants Recruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions. Interventions Participants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy). Main outcomes and measures Primary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat. Results Participants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) v 38.5% (22.8%); adjusted mean difference −3.9% (95% confidence interval −10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings. Conclusions There is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit. Trial registration ISRCTN54992179.

Objective To assess the efficacy and safety of different endoscopic surgical treatments for benign prostatic hyperplasia. Design Systematic review and network meta-analysis of randomised controlled trials. Data sources A comprehensive search of PubMed, Embase, and Cochrane databases from inception to 31 March 2019. Study selection Randomised controlled trials comparing vapourisation, resection, and enucleation of the prostate using monopolar, bipolar, or various laser systems (holmium, thulium, potassium titanyl phosphate, or diode) as surgical treatments for benign prostatic hyperplasia. The primary outcomes were the maximal flow rate (Qmax) and international prostate symptoms score (IPSS) at 12 months after surgical treatment. Secondary outcomes were Qmax and IPSS values at 6, 24, and 36 months after surgical treatment; perioperative parameters; and surgical complications. Data extraction and synthesis Two independent reviewers extracted the study data and performed quality assessments using the Cochrane Risk of Bias Tool. The effect sizes were summarised using weighted mean differences for continuous outcomes and odds ratios for binary outcomes. Frequentist approach to the network meta-analysis was used to estimate comparative effects and safety. Ranking probabilities of each treatment were also calculated. Results 109 trials with a total of 13 676 participants were identified. Nine surgical treatments were evaluated. Enucleation achieved better Qmax and IPSS values than resection and vapourisation methods at six and 12 months after surgical treatment, and the difference maintained up to 24 and 36 months after surgical treatment. For Qmax at 12 months after surgical treatment, the best three methods compared with monopolar transurethral resection of the prostate (TURP) were bipolar enucleation (mean difference 2.42 mL/s (95% confidence interval 1.11 to 3.73)), diode laser enucleation (1.86 (−0.17 to 3.88)), and holmium laser enucleation (1.07 (0.07 to 2.08)). The worst performing method was diode laser vapourisation (−1.90 (−5.07 to 1.27)). The results of IPSS at 12 months after treatment were similar to Qmax at 12 months after treatment. The best three methods, versus monopolar TURP, were diode laser enucleation (mean difference −1.00 (−2.41 to 0.40)), bipolar enucleation (0.87 (−1.80 to 0.07)), and holmium laser enucleation (−0.84 (−1.51 to 0.58)). The worst performing method was diode laser vapourisation (1.30 (−1.16 to 3.76)). Eight new methods were better at controlling bleeding than monopolar TURP, resulting in a shorter catheterisation duration, reduced postoperative haemoglobin declination, fewer clot retention events, and lower blood transfusion rate. However, short term transient urinary incontinence might still be a concern for enucleation methods, compared with resection methods (odds ratio 1.92, 1.39 to 2.65). No substantial inconsistency between direct and indirect evidence was detected in primary or secondary outcomes. Conclusion Eight new endoscopic surgical methods for benign prostatic hyperplasia appeared to be superior in safety compared with monopolar TURP. Among these new treatments, enucleation methods showed better Qmax and IPSS values than vapourisation and resection methods. Study registration CRD42018099583.

Objective To review and summarise the evidence on the prevalence of colorectal adenomas and cancers at a follow-up screening colonoscopy after negative index colonoscopy, stratified by interval between examinations and by sex. Design Systematic review and meta-analysis of all available studies. Data sources PubMed, Web of Science, and Embase. Two investigators independently extracted characteristics and results of identified studies and performed standardised quality ratings. Eligibility criteria Studies assessing the outcome of a follow-up colonoscopy among participants at average risk for colorectal cancer with a negative previous colonoscopy (no adenomas). Results 28 studies were identified, including 22 cohort studies, five cross sectional studies, and one case-control study. Findings for an interval between colonoscopies of one to five, five to 10, and more than 10 years were reported by 17, 16, and three studies, respectively. Summary estimates of prevalences of any neoplasm were 20.7% (95% confidence interval 15.8% to 25.5%), 23.0% (18.0% to 28.0%), and 21.9% (14.9% to 29.0%) for one to five, five to 10, and more than 10 years between colonoscopies. Corresponding summary estimates of prevalences of any advanced neoplasm were 2.8% (2.0% to 3.7%), 3.2% (2.2% to 4.1%), and 7.0% (5.3% to 8.7%). Seven studies also reported findings stratified by sex. Summary estimates stratified by interval and sex were consistently higher for men than for women. Conclusions Although detection of any neoplasms was observed in more than 20% of participants within five years of a negative screening colonoscopy, detection of advanced neoplasms within 10 years was rare. Our findings suggest that 10 year intervals for colonoscopy screening after a negative colonoscopy, as currently recommended, may be adequate, but more studies are needed to strengthen the empirical basis for pertinent recommendations and to investigate even longer intervals. Study registration Prospero CRD42019127842.

Objectives To quantify post-colonoscopy colorectal cancer (PCCRC) rates in England by using recent World Endoscopy Organisation guidelines, compare incidence among colonoscopy providers, and explore associated factors that could benefit from quality improvement initiatives. Design Population based cohort study. Setting National Health Service in England between 2005 and 2013. Population All people undergoing colonoscopy and subsequently diagnosed as having colorectal cancer up to three years after their investigation (PCCRC-3yr). Main outcome measures National trends in incidence of PCCRC (within 6-36 months of colonoscopy), univariable and multivariable analyses to explore factors associated with occurrence, and funnel plots to measure variation among providers. Results The overall unadjusted PCCRC-3yr rate was 7.4% (9317/126 152), which decreased from 9.0% in 2005 to 6.5% in 2013 (P<0.01). Rates were lower for colonoscopies performed under the NHS bowel cancer screening programme (593/16 640, 3.6%), while they were higher for those conducted by non-NHS providers (187/2009, 9.3%). Rates were higher in women, in older age groups, and in people with inflammatory bowel disease or diverticular disease, in those with higher comorbidity scores, and in people with previous cancers. Substantial variation in rates among colonoscopy providers remained after adjustment for case mix. Conclusions Wide variation exists in PCCRC-3yr rates across NHS colonoscopy providers in England. The lowest incidence was seen in colonoscopies performed under the NHS bowel cancer screening programme. Quality improvement initiatives are needed to address this variation in rates and prevent colorectal cancer by enabling earlier diagnosis, removing premalignant polyps, and therefore improving outcomes.

Objective To assess the effect of disclosing authors’ conflict of interest declarations to peer reviewers at a medical journal. Design Randomized controlled trial. Setting Manuscript review process at the Annals of Emergency Medicine. Participants Reviewers (n=838) who reviewed manuscripts submitted between 2 June 2014 and 23 January 2018 inclusive (n=1480 manuscripts). Intervention Reviewers were randomized to either receive (treatment) or not receive (control) authors’ full International Committee of Medical Journal Editors format conflict of interest disclosures before reviewing manuscripts. Reviewers rated the manuscripts as usual on eight quality ratings and were then surveyed to obtain “counterfactual scores”—that is, the scores they believed they would have given had they been assigned to the opposite arm—as well as attitudes toward conflicts of interest. Main outcome measure Overall quality score that reviewers assigned to the manuscript on submitting their review (1 to 5 scale). Secondary outcomes were scores the reviewers submitted for the seven more specific quality ratings and counterfactual scores elicited in the follow-up survey. Results Providing authors’ conflict of interest disclosures did not affect reviewers’ mean ratings of manuscript quality (Mcontrol=2.70 (SD 1.11) out of 5; Mtreatment=2.74 (1.13) out of 5; mean difference 0.04, 95% confidence interval –0.05 to 0.14), even for manuscripts with disclosed conflicts (Mcontrol= 2.85 (1.12) out of 5; Mtreatment=2.96 (1.16) out of 5; mean difference 0.11, –0.05 to 0.26). Similarly, no effect of the treatment was seen on any of the other seven quality ratings that the reviewers assigned. Reviewers acknowledged conflicts of interest as an important matter and believed that they could correct for them when they were disclosed. However, their counterfactual scores did not differ from actual scores (Mactual=2.69; Mcounterfactual=2.67; difference in means 0.02, 0.01 to 0.02). When conflicts were reported, a comparison of different source types (for example, government, for-profit corporation) found no difference in effect. Conclusions Current ethical standards require disclosure of conflicts of interest for all scientific reports. As currently implemented, this practice had no effect on any quality ratings of real manuscripts being evaluated for publication by real peer reviewers.

Objective To evaluate the association between gifts from pharmaceutical companies to French general practitioners (GPs) and their drug prescribing patterns. Design Retrospective study using data from two French databases (National Health Data System, managed by the French National Health Insurance system, and Transparency in Healthcare). Setting Primary care, France. Participants 41 257 GPs who in 2016 worked exclusively in the private sector and had at least five registered patients. The GPs were divided into six groups according to the monetary value of the received gifts reported by pharmaceutical, medical device, and other health related companies in the Transparency in Healthcare database. Main outcome measures The main outcome measures were the amount reimbursed by the French National Health Insurance for drug prescriptions per visit (to the practice or at home) and 11 drug prescription efficiency indicators used by the National Health Insurance to calculate the performance related financial incentives of the doctors. Doctor and patient characteristics were used as adjustment variables. The significance threshold was 0.001 for statistical analyses. Results The amount reimbursed by the National Health Insurance for drug prescriptions per visit was lower in the GP group with no gifts reported in the Transparency in Healthcare database in 2016 and since its launch in 2013 (no gift group) compared with the GP groups with at least one gift in 2016 (−€5.33 (99.9% confidence interval −€6.99 to −€3.66) compared with the GP group with gifts valued at €1000 or more reported in 2016) (P<0.001). The no gift group also more frequently prescribed generic antibiotics (2.17%, 1.47% to 2.88% compared with the ≥€1000 group), antihypertensives (4.24%, 3.72% to 4.77% compared with the ≥€1000 group), and statins (12.14%, 11.03% to 13.26% compared with the ≥€1000 group) than GPs with at least one gift between 2013 and 2016 (P<0.001). The no gift group also prescribed fewer benzodiazepines for more than 12 weeks (−0.68%, −1.13% to −0.23% compared with the €240-€999 group) and vasodilators (−0.15%, −0.28% to −0.03% compared with the ≥€1000 group) than GPs with gifts valued at €240 or more reported in 2016, and more angiotensin converting enzyme (ACE) inhibitors compared with all ACE and sartan prescriptions (1.67%, 0.62% to 2.71%) compared with GPs with gifts valued at €1000 or more reported in 2016 (P<0.001). Differences were not significant for the prescription of aspirin and generic antidepressants and generic proton pump inhibitors. Conclusion The findings suggest that French GPs who do not receive gifts from pharmaceutical companies have better drug prescription efficiency indicators and less costly drug prescriptions than GPs who receive gifts. This observational study is susceptible to residual confounding and therefore no causal relation can be concluded. Trial registration OSF register OSF.IO/8M3QR.

Objective To investigate the clinical effectiveness and safety of stand alone and blended internet based vestibular rehabilitation (VR) in the management of chronic vestibular syndromes in general practice. Design Pragmatic, three armed, parallel group, individually randomised controlled trial. Setting 59 general practices in the Netherlands. Participants 322 adults aged 50 and older with a chronic vestibular syndrome. Interventions Stand alone VR comprising a six week, internet based intervention with weekly online sessions and daily exercises (10-20 minutes a day). In the blended VR group, the same internet based intervention was supplemented by face-to-face physiotherapy support (home visits in weeks 1 and 3). Participants in the usual care group received standard care from a general practitioner, without any restrictions. Main outcome measures The primary outcome was vestibular symptoms after six months as measured by the vertigo symptom scale-short form (VSS-SF range 0-60, clinically relevant difference ≥3 points). Secondary outcomes were dizziness related impairment, anxiety, depressive symptoms, subjective improvement of vestibular symptoms after three and six months, and adverse events. Results In the intention-to-treat analysis, participants in the stand alone and blended VR groups had lower VSS-SF scores at six months than participants in the usual care group (adjusted mean difference −4.1 points, 95% confidence interval −5.8 to −2.5; and −3.5 points, −5.1 to −1.9, respectively). Similar differences in VSS-SF scores were seen at three months follow-up. Participants in the stand alone and blended VR groups also experienced less dizziness related impairment, less anxiety, and more subjective improvement of vestibular symptoms at three and six months. No serious adverse events related to online VR occurred during the trial. Conclusion Stand alone and blended internet based VR are clinically effective and safe interventions to treat adults aged 50 and older with a chronic vestibular syndrome. Online VR is an easily accessible form of treatment, with the potential to improve care for an undertreated group of patients in general practice. Trial registration Netherlands Trial Register NTR5712.

Objective To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. Design International cross sectional survey. Setting International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. Participants Key stakeholders identified by ISN’s national and regional leaders. Main outcome measures Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. Results Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world’s population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management—namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney disease was available in 91 (42%) of 218 countries worldwide. Estimates varied more than 800-fold from 4 to 3392 per million population. Rwanda was the only low income country to report data on the prevalence of treated disease; 5 (<10%) of 53 African countries reported these data. Of 159 countries, 102 (64%) provided public funding for kidney replacement therapy. Sixty eight (43%) of 159 countries charged no fees at the point of care delivery and 34 (21%) made some charge. Haemodialysis was reported as available in 156 (100%) of 156 countries, peritoneal dialysis in 119 (76%) of 156 countries, and kidney transplantation in 114 (74%) of 155 countries. Dialysis and kidney transplantation were available to more than 50% of patients in only 108 (70%) and 45 (29%) of 154 countries that offered these services, respectively. Conservative kidney management was available in 124 (81%) of 154 countries. Worldwide, the median number of nephrologists was 9.96 per million population, which varied with income level. Conclusions These comprehensive data show the capacity of countries (including low income countries) to provide optimal care for patients with end stage kidney disease. They demonstrate substantial variability in the burden of such disease and capacity for kidney replacement therapy and conservative kidney management, which have implications for policy.

Objective To evaluate whether calorie labeling of menus in large restaurant chains was associated with a change in mean calories purchased per transaction. Design Quasi-experimental longitudinal study. Setting Large franchise of a national fast food company with three different restaurant chains located in the southern United States (Louisiana, Texas, and Mississippi) from April 2015 until April 2018. Participants 104 restaurants with calorie information added to in-store and drive-thru menus in April 2017 and with weekly aggregated sales data during the pre-labeling (April 2015 to April 2017) and post-labeling (April 2017 to April 2018) implementation period. Main outcome measures Primary outcome was the overall level and trend changes in mean purchased calories per transaction after implementation of calorie labeling compared with the counterfactual (ie, assumption that the pre-intervention trend would have persisted had the intervention not occurred) using interrupted time series analyses with linear mixed models. Secondary outcomes were by item category (entrees, sides, and sugar sweetened beverages). Subgroup analyses estimated the effect of calorie labeling in stratums defined by the sociodemographic characteristics of restaurant census tracts (defined region for taking census). Results The analytic sample comprised 14 352 restaurant weeks. Over three years and among 104 restaurants, 49 062 440 transactions took place and 242 726 953 items were purchased. After labeling implementation, a level decrease was observed of 60 calories/transaction (95% confidence interval 48 to 72; about 4%), followed by an increasing trend of 0.71 calories/transaction/week (95% confidence interval 0.51 to 0.92) independent of the baseline trend over the year after implementation. These results were generally robust to different analytic assumptions in sensitivity analyses. The level decrease and post-implementation trend change were stronger for sides than for entrees or sugar sweetened beverages. The level decrease was similar between census tracts with higher and lower median income, but the post-implementation trend in calories per transaction was higher in low income (change in calories/transaction/week 0.94, 95% confidence interval 0.67 to 1.21) than in high income census tracts (0.50, 0.19 to 0.81). Conclusions A small decrease in mean calories purchased per transaction was observed after implementation of calorie labeling in a large franchise of fast food restaurants. This reduction diminished over one year of follow-up.

Objective To measure the association between phenotypic drug resistance and the risk of tuberculosis infection and disease among household contacts of patients with pulmonary tuberculosis. Setting 106 district health centers in Lima, Peru between September 2009 and September 2012. Design Prospective cohort study. Participants 10 160 household contacts of 3339 index patients with tuberculosis were classified on the basis of the drug resistance profile of the patient: 6189 were exposed to drug susceptible strains of Mycobacterium tuberculosis, 1659 to strains resistant to isoniazid or rifampicin, and 1541 to strains that were multidrug resistant (resistant to isoniazid and rifampicin). Main outcome measures Tuberculosis infection (positive tuberculin skin test) and the incidence of active disease (diagnosed by positive sputum smear or chest radiograph) after 12 months of follow-up. Results Household contacts exposed to patients with multidrug resistant tuberculosis had an 8% (95% confidence interval 4% to 13%) higher risk of infection by the end of follow-up compared with household contacts of patients with drug sensitive tuberculosis. The relative hazard of incident tuberculosis disease did not differ among household contacts exposed to multidrug resistant tuberculosis and those exposed to drug sensitive tuberculosis (adjusted hazard ratio 1.28, 95% confidence interval 0.9 to 1.83). Conclusion Household contacts of patients with multidrug resistant tuberculosis were at higher risk of tuberculosis infection than contacts exposed to drug sensitive tuberculosis. The risk of developing tuberculosis disease did not differ among contacts in both groups. The evidence invites guideline producers to take action by targeting drug resistant and drug sensitive tuberculosis, such as early detection and effective treatment of infection and disease. Trial registration ClinicalTrials.gov NCT00676754.

Objective To assess whether severe psychiatric reactions to trauma and other adversities are associated with subsequent risk of life threatening infections. Design Population and sibling matched cohort study. Setting Swedish population. Participants 144 919 individuals with stress related disorders (post-traumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, and other stress reactions) identified from 1987 to 2013 compared with 184 612 full siblings of individuals with a diagnosed stress related disorder and 1 449 190 matched individuals without such a diagnosis from the general population. Main outcome measures A first inpatient or outpatient visit with a primary diagnosis of severe infections with high mortality rates (ie, sepsis, endocarditis, and meningitis or other central nervous system infections) from the Swedish National Patient Register, and deaths from these infections or infections of any origin from the Cause of Death Register. After controlling for multiple confounders, Cox models were used to estimate hazard ratios of these life threatening infections. Results The average age at diagnosis of a stress related disorder was 37 years (55 541, 38.3% men). During a mean follow-up of eight years, the incidence of life threatening infections per 1000 person years was 2.9 in individuals with a stress related disorder, 1.7 in siblings without a diagnosis, and 1.3 in matched individuals without a diagnosis. Compared with full siblings without a diagnosis of a stress related disorder, individuals with such a diagnosis were at increased risk of life threatening infections (hazard ratio for any stress related disorder was 1.47 (95% confidence intervals1.37 to 1.58) and for PTSD was 1.92 (1.46 to 2.52)). Corresponding estimates in the population based analysis were similar (1.58 (1.51 to 1.65) for any stress related disorder, P=0.09 for difference between sibling and population based comparison, and 1.95 (1.66 to 2.28) for PTSD, P=0.92 for difference). Stress related disorders were associated with all studied life threatening infections, with the highest relative risk observed for meningitis (sibling based analysis 1.63 (1.23 to 2.16)) and endocarditis (1.57 (1.08 to 2.30)). Younger age at diagnosis of a stress related disorder and the presence of psychiatric comorbidity, especially substance use disorders, were associated with higher hazard ratios, whereas use of selective serotonin reuptake inhibitors in the first year after diagnosis of a stress related disorder was associated with attenuated hazard ratios. Conclusion In the Swedish population, stress related disorders were associated with a subsequent risk of life threatening infections, after controlling for familial background and physical or psychiatric comorbidities.

Objective To determine the extent to which late stage development of new drugs relies on support from public funding. Design Cohort study. Setting All new drugs containing one or more new molecular entities approved by the US Food and Drug Administration (FDA) between January 2008 and December 2017 via the new drug application pathway. Main outcome measures Patents or drug development histories documenting late stage research contributions by a public sector research institution or a spin-off company, as well as each drug’s regulatory approval pathway and first-in-class designation. Results Over the 10 year study period, the FDA approved 248 drugs containing one or more new molecular entities. Of these drugs, 48 (19%) had origins in publicly supported research and development and 14 (6%) originated in companies spun off from a publicly supported research program. Drugs in these groups were more likely to receive expedited FDA approval (68% v 47%, P=0.005) or be designated first in class (45% v 26%, P=0.007), indicating therapeutic importance. Conclusions A review of the patents associated with new drugs approved over the past decade indicates that publicly supported research had a major role in the late stage development of at least one in four new drugs, either through direct funding of late stage research or through spin-off companies created from public sector research institutions. These findings could have implications for policy makers in determining fair prices and revenue flows for these products.

Objective To assess the efficacy of three months of antibiotic treatment compared with placebo in patients with chronic low back pain, previous disc herniation, and vertebral endplate changes (Modic changes). Design Double blind, parallel group, placebo controlled, multicentre trial. Setting Hospital outpatient clinics at six hospitals in Norway. Participants 180 patients with chronic low back pain, previous disc herniation, and type 1 (n=118) or type 2 (n=62) Modic changes enrolled from June 2015 to September 2017. Interventions Patients were randomised to three months of oral treatment with either 750 mg amoxicillin or placebo three times daily. The allocation sequence was concealed by using a computer generated number on the prescription. Main outcome measures The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (range 0-24) at one year follow-up in the intention to treat population. The minimal clinically important between group difference in mean RMDQ score was predefined as 4. Results In the primary analysis of the total cohort at one year, the difference in the mean RMDQ score between the amoxicillin group and the placebo group was −1.6 (95% confidence interval −3.1 to 0.0, P=0.04). In the secondary analysis, the difference in the mean RMDQ score between the groups was −2.3 (−4.2 to−0.4, P=0.02) for patients with type 1 Modic changes and −0.1 (−2.7 to 2.6, P=0.95) for patients with type 2 Modic changes. Fifty patients (56%) in the amoxicillin group experienced at least one drug related adverse event compared with 31 (34%) in the placebo group. Conclusions In this study on patients with chronic low back pain and Modic changes at the level of a previous disc herniation, three months of treatment with amoxicillin did not provide a clinically important benefit compared with placebo. Secondary analyses and sensitivity analyses supported this finding. Therefore, our results do not support the use of antibiotic treatment for chronic low back pain and Modic changes. Trial registration ClinicalTrials.gov NCT02323412.

Objective To determine if postnatal transfer or birth in a non-tertiary hospital is associated with adverse outcomes. Design Observational cohort study with propensity score matching. Setting National health service neonatal care in England; population data held in the National Neonatal Research Database. Participants Extremely preterm infants born at less than 28 gestational weeks between 2008 and 2015 (n=17 577) grouped based on birth hospital and transfer within 48 hours of birth: upward transfer (non-tertiary to tertiary hospital, n=2158), non-tertiary care (born in non-tertiary hospital; not transferred, n=2668), and controls (born in tertiary hospital; not transferred, n=10 866). Infants were matched on propensity scores and predefined background variables to form subgroups with near identical distributions of confounders. Infants transferred between tertiary hospitals (horizontal transfer) were separately matched to controls in a 1:5 ratio. Main outcome measures Death, severe brain injury, and survival without severe brain injury. Results 2181 infants, 727 from each group (upward transfer, non-tertiary care, and control) were well matched. Compared with controls, infants in the upward transfer group had no significant difference in the odds of death before discharge (odds ratio 1.22, 95% confidence interval 0.92 to 1.61) but significantly higher odds of severe brain injury (2.32, 1.78 to 3.06; number needed to treat (NNT) 8) and significantly lower odds of survival without severe brain injury (0.60, 0.47 to 0.76; NNT 9). Compared with controls, infants in the non-tertiary care group had significantly higher odds of death (1.34, 1.02 to 1.77; NNT 20) but no significant difference in the odds of severe brain injury (0.95, 0.70 to 1.30) or survival without severe brain injury (0.82, 0.64 to 1.05). Compared with infants in the upward transfer group, infants in the non-tertiary care group had no significant difference in death before discharge (1.10, 0.84 to 1.44) but significantly lower odds of severe brain injury (0.41, 0.31 to 0.53; NNT 8) and significantly higher odds of survival without severe brain injury (1.37, 1.09 to 1.73; NNT 14). No significant differences were found in outcomes between the horizontal transfer group (n=305) and controls (n=1525). Conclusions In extremely preterm infants, birth in a non-tertiary hospital and transfer within 48 hours are associated with poor outcomes when compared with birth in a tertiary setting. We recommend perinatal services promote pathways that facilitate delivery of extremely preterm infants in tertiary hospitals in preference to postnatal transfer.

Objective To investigate the association between weight changes across adulthood and mortality. Design Prospective cohort study. Setting US National Health and Nutrition Examination Survey (NHANES) 1988-94 and 1999-2014. Participants 36 051 people aged 40 years or over with measured body weight and height at baseline and recalled weight at young adulthood (25 years old) and middle adulthood (10 years before baseline). Main outcome measures All cause and cause specific mortality from baseline until 31 December 2015. Results During a mean follow-up of 12.3 years, 10 500 deaths occurred. Compared with participants who remained at normal weight, those moving from the non-obese to obese category between young and middle adulthood had a 22% (hazard ratio 1.22, 95% confidence interval 1.11 to 1.33) and 49% (1.49, 1.21 to 1.83) higher risk of all cause mortality and heart disease mortality, respectively. Changing from obese to non-obese body mass index over this period was not significantly associated with mortality risk. An obese to non-obese weight change pattern from middle to late adulthood was associated with increased risk of all cause mortality (1.30, 1.16 to 1.45) and heart disease mortality (1.48, 1.14 to 1.92), whereas moving from the non-obese to obese category over this period was not significantly associated with mortality risk. Maintaining obesity across adulthood was consistently associated with increased risk of all cause mortality; the hazard ratio was 1.72 (1.52 to 1.95) from young to middle adulthood, 1.61 (1.41 to 1.84) from young to late adulthood, and 1.20 (1.09 to 1.32) from middle to late adulthood. Maximum overweight had a very modest or null association with mortality across adulthood. No significant associations were found between various weight change patterns and cancer mortality. Conclusions Stable obesity across adulthood, weight gain from young to middle adulthood, and weight loss from middle to late adulthood were associated with increased risks of mortality. The findings imply that maintaining normal weight across adulthood, especially preventing weight gain in early adulthood, is important for preventing premature deaths in later life.

Objectives To investigate the effectiveness of routine ultrasonography in the third trimester in reducing adverse perinatal outcomes in low risk pregnancies compared with usual care and the effect of this policy on maternal outcomes and obstetric interventions. Design Pragmatic, multicentre, stepped wedge cluster randomised trial. Setting 60 midwifery practices in the Netherlands. Participants 13 046 women aged 16 years or older with a low risk singleton pregnancy. Interventions 60 midwifery practices offered usual care (serial fundal height measurements with clinically indicated ultrasonography). After 3, 7, and 10 months, a third of the practices were randomised to the intervention strategy. As well as receiving usual care, women in the intervention strategy were offered two routine biometry scans at 28-30 and 34-36 weeks’ gestation. The same multidisciplinary protocol for detecting and managing fetal growth restriction was used in both strategies. Main outcome measures The primary outcome measure was a composite of severe adverse perinatal outcomes: perinatal death, Apgar score <4, impaired consciousness, asphyxia, seizures, assisted ventilation, septicaemia, meningitis, bronchopulmonary dysplasia, intraventricular haemorrhage, periventricular leucomalacia, or necrotising enterocolitis. Secondary outcomes were two composite measures of severe maternal morbidity, and spontaneous labour and birth. Results Between 1 February 2015 and 29 February 2016, 60 midwifery practices enrolled 13 520 women in mid-pregnancy (mean 22.8 (SD 2.4) weeks’ gestation). 13 046 women (intervention n=7067, usual care n=5979) with data based on the national Dutch perinatal registry or hospital records were included in the analyses. Small for gestational age at birth was significantly more often detected in the intervention group than in the usual care group (179 of 556 (32%) v 78 of 407 (19%), P<0.001). The incidence of severe adverse perinatal outcomes was 1.7% (n=118) for the intervention strategy and 1.8% (n=106) for usual care. After adjustment for confounders, the difference between the groups was not significant (odds ratio 0.88, 95% confidence interval 0.70 to 1.20). The intervention strategy showed a higher incidence of induction of labour (1.16, 1.04 to 1.30) and a lower incidence of augmentation of labour (0.78, 0.71 to 0.85). Maternal outcomes and other obstetric interventions did not differ between the strategies. Conclusion In low risk pregnancies, routine ultrasonography in the third trimester along with clinically indicated ultrasonography was associated with higher antenatal detection of small for gestational age fetuses but not with a reduced incidence of severe adverse perinatal outcomes compared with usual care alone. The findings do not support routine ultrasonography in the third trimester for low risk pregnancies. Trial registration Netherlands Trial Register NTR4367.

Objective To assess the effects of different oral antithrombotic drugs that prevent saphenous vein graft failure in patients undergoing coronary artery bypass graft surgery. Design Systematic review and network meta-analysis. Data sources Medline, Embase, Web of Science, CINAHL, and the Cochrane Library from inception to 25 January 2019. Eligibility criteriafor selecting studies Randomised controlled trials of participants (aged ≥18) who received oral antithrombotic drugs (antiplatelets or anticoagulants) to prevent saphenous vein graft failure after coronary artery bypass graft surgery. Main outcome measures The primary efficacy endpoint was saphenous vein graft failure and the primary safety endpoint was major bleeding. Secondary endpoints were myocardial infarction and death. Results This review identified 3266 citations, and 21 articles that related to 20 randomised controlled trials were included in the network meta-analysis. These 20 trials comprised 4803 participants and investigated nine different interventions (eight active and one placebo). Moderate certainty evidence supports the use of dual antiplatelet therapy with either aspirin plus ticagrelor (odds ratio 0.50, 95% confidence interval 0.31 to 0.79, number needed to treat 10) or aspirin plus clopidogrel (0.60, 0.42 to 0.86, 19) to reduce saphenous vein graft failure when compared with aspirin monotherapy. The study found no strong evidence of differences in major bleeding, myocardial infarction, and death among different antithrombotic therapies. The possibility of intransitivity could not be ruled out; however, between-trial heterogeneity and incoherence were low in all included analyses. Sensitivity analysis using per graft data did not change the effect estimates. Conclusions The results of this network meta-analysis suggest an important absolute benefit of adding ticagrelor or clopidogrel to aspirin to prevent saphenous vein graft failure after coronary artery bypass graft surgery. Dual antiplatelet therapy after surgery should be tailored to the patient by balancing the safety and efficacy profile of the drug intervention against important patient outcomes. Study registration PROSPERO registration number CRD42017065678.

In a prospective meta-analysis (PMA), study selection criteria, hypotheses, and analyses are specified before the results of the studies related to the PMA research question are known, reducing many of the problems associated with a traditional (retrospective) meta-analysis. PMAs have many advantages: they can help reduce research waste and bias, and they are adaptive, efficient, and collaborative. Despite an increase in the number of health research articles labelled as PMAs, the methodology remains rare, novel, and often misunderstood. This paper provides detailed guidance on how to address the key elements for conducting a high quality PMA with a case study to illustrate each step. ### Summary points

Objective To estimate the risk of acute myocardial infarction (AMI) or stroke in adults with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). Design Matched cohort study. Setting Population based, electronic primary healthcare databases before 31 December 2015 from four European countries: Italy (n=1 542 672), Netherlands (n=2 225 925), Spain (n=5 488 397), and UK (n=12 695 046). Participants 120 795 adults with a recorded diagnosis of NAFLD or NASH and no other liver diseases, matched at time of NAFLD diagnosis (index date) by age, sex, practice site, and visit, recorded at six months before or after the date of diagnosis, with up to 100 patients without NAFLD or NASH in the same database. Main outcome measures Primary outcome was incident fatal or non-fatal AMI and ischaemic or unspecified stroke. Hazard ratios were estimated using Cox models and pooled across databases by random effect meta-analyses. Results 120 795 patients with recorded NAFLD or NASH diagnoses were identified with mean follow-up 2.1-5.5 years. After adjustment for age and smoking the pooled hazard ratio for AMI was 1.17 (95% confidence interval 1.05 to 1.30; 1035 events in participants with NAFLD or NASH, 67 823 in matched controls). In a group with more complete data on risk factors (86 098 NAFLD and 4 664 988 matched controls), the hazard ratio for AMI after adjustment for systolic blood pressure, type 2 diabetes, total cholesterol level, statin use, and hypertension was 1.01 (0.91 to 1.12; 747 events in participants with NAFLD or NASH, 37 462 in matched controls). After adjustment for age and smoking status the pooled hazard ratio for stroke was 1.18 (1.11 to 1.24; 2187 events in participants with NAFLD or NASH, 134 001 in matched controls). In the group with more complete data on risk factors, the hazard ratio for stroke was 1.04 (0.99 to 1.09; 1666 events in participants with NAFLD, 83 882 in matched controls) after further adjustment for type 2 diabetes, systolic blood pressure, total cholesterol level, statin use, and hypertension. Conclusions The diagnosis of NAFLD in current routine care of 17.7 million patient appears not to be associated with AMI or stroke risk after adjustment for established cardiovascular risk factors. Cardiovascular risk assessment in adults with a diagnosis of NAFLD is important but should be done in the same way as for the general population.

Objective To compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). Design Systematic review and network meta-analysis. Data sources PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019. Eligibility criteria for selecting studies Published and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher. Results 18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation. Conclusions These results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively. Systematic review registration PROSPERO CRD42018111954.

Objective To map and assess prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease (COPD). Design Systematic review. Data sources PubMed until November 2018 and hand searched references from eligible articles. Eligibility criteria for study selection Studies developing, validating, or updating a prediction model in COPD patients and focusing on any potential clinical outcome. Results The systematic search yielded 228 eligible articles, describing the development of 408 prognostic models, the external validation of 38 models, and the validation of 20 prognostic models derived for diseases other than COPD. The 408 prognostic models were developed in three clinical settings: outpatients (n=239; 59%), patients admitted to hospital (n=155; 38%), and patients attending the emergency department (n=14; 3%). Among the 408 prognostic models, the most prevalent endpoints were mortality (n=209; 51%), risk for acute exacerbation of COPD (n=42; 10%), and risk for readmission after the index hospital admission (n=36; 9%). Overall, the most commonly used predictors were age (n=166; 41%), forced expiratory volume in one second (n=85; 21%), sex (n=74; 18%), body mass index (n=66; 16%), and smoking (n=65; 16%). Of the 408 prognostic models, 100 (25%) were internally validated and 91 (23%) examined the calibration of the developed model. For 286 (70%) models a model presentation was not available, and only 56 (14%) models were presented through the full equation. Model discrimination using the C statistic was available for 311 (76%) models. 38 models were externally validated, but in only 12 of these was the validation performed by a fully independent team. Only seven prognostic models with an overall low risk of bias according to PROBAST were identified. These models were ADO, B-AE-D, B-AE-D-C, extended ADO, updated ADO, updated BODE, and a model developed by Bertens et al. A meta-analysis of C statistics was performed for 12 prognostic models, and the summary estimates ranged from 0.611 to 0.769. Conclusions This study constitutes a detailed mapping and assessment of the prognostic models for outcome prediction in COPD patients. The findings indicate several methodological pitfalls in their development and a low rate of external validation. Future research should focus on the improvement of existing models through update and external validation, as well as the assessment of the safety, clinical effectiveness, and cost effectiveness of the application of these prognostic models in clinical practice through impact studies. Systematic review registration PROSPERO CRD42017069247

Objective To determine whether total exposure to penicillin V can be reduced while maintaining adequate clinical efficacy when treating pharyngotonsillitis caused by group A streptococci. Design Open label, randomised controlled non-inferiority study. Setting 17 primary healthcare centres in Sweden between September 2015 and February 2018. Participants Patients aged 6 years and over with pharyngotonsillitis caused by group A streptococci and three or four Centor criteria (fever ≥38.5°C, tender lymph nodes, coatings of the tonsils, and absence of cough). Interventions Penicillin V 800 mg four times daily for five days (total 16 g) compared with the current recommended dose of 1000 mg three times daily for 10 days (total 30 g). Main outcome measures Primary outcome was clinical cure five to seven days after the end of antibiotic treatment. The non-inferiority margin was prespecified to 10 percentage points. Secondary outcomes were bacteriological eradication, time to relief of symptoms, frequency of relapses, complications and new tonsillitis, and patterns of adverse events. Results Patients (n=433) were randomly allocated to the five day (n=215) or 10 day (n=218) regimen. Clinical cure in the per protocol population was 89.6% (n=181/202) in the five day group and 93.3% (n=182/195) in the 10 day group (95% confidence interval −9.7 to 2.2). Bacteriological eradication was 80.4% (n=156/194) in the five day group and 90.7% (n=165/182) in the 10 day group. Eight and seven patients had relapses, no patients and four patients had complications, and six and 13 patients had new tonsillitis in the five day and 10 day groups, respectively. Time to relief of symptoms was shorter in the five day group. Adverse events were mainly diarrhoea, nausea, and vulvovaginal disorders; the 10 day group had higher incidence and longer duration of adverse events. Conclusions Penicillin V four times daily for five days was non-inferior in clinical outcome to penicillin V three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci. The number of relapses and complications did not differ between the two intervention groups. Five day treatment with penicillin V four times daily might be an alternative to the currently recommended 10 day regimen. Trial registration EudraCT 2015-001752-30; ClinicalTrials.gov NCT02712307.

Objectives To determine how clinicians vary in their response to new guidance on existing or new interventions, by measuring the timing and magnitude of change at healthcare institutions. Design Automated change detection in longitudinal prescribing data. Setting Prescribing data in English primary care. Participants English general practices. Main outcome measures In each practice the following were measured: the timing of the largest changes, steepness of the change slope (change in proportion per month), and magnitude of the change for two example time series (expiry of the Cerazette patent in 2012, leading to cheaper generic desogestrel alternatives becoming available; and a change in antibiotic prescribing guidelines after 2014, favouring nitrofurantoin over trimethoprim for uncomplicated urinary tract infection (UTI)). Results Substantial heterogeneity was found between institutions in both timing and steepness of change. The range of time delay before a change was implemented was large (interquartile range 2-14 months (median 8) for Cerazette, and 5-29 months (18) for UTI). Substantial heterogeneity was also seen in slope following a detected change (interquartile range 2-28% absolute reduction per month (median 9%) for Cerazette, and 1-8% (2%) for UTI). When changes were implemented, the magnitude of change showed substantially less heterogeneity (interquartile range 44-85% (median 66%) for Cerazette and 28-47% (38%) for UTI). Conclusions Substantial variation was observed in the speed with which individual NHS general practices responded to warranted changes in clinical practice. Changes in prescribing behaviour were detected automatically and robustly. Detection of structural breaks using indicator saturation methods opens up new opportunities to improve patient care through audit and feedback by moving away from cross sectional analyses, and automatically identifying institutions that respond rapidly, or slowly, to warranted changes in clinical practice.

Objective To estimate benefits and harms of different colorectal cancer screening strategies, stratified by (baseline) 15-year colorectal cancer risk. Design Microsimulation modelling study using MIcrosimulation SCreening ANalysis-Colon (MISCAN-Colon). Setting A parallel guideline committee (BMJ Rapid Recommendations) defined the time frame and screening interventions, including selection of outcome measures. Population Norwegian men and women aged 50-79 years with varying 15-year colorectal cancer risk (1-7%). Comparisons Four screening strategies were compared with no screening: biennial or annual faecal immunochemical test (FIT) or single sigmoidoscopy or colonoscopy at 100% adherence. Main outcome measures Colorectal cancer mortality and incidence, burdens, and harms over 15 years of follow-up. The certainty of the evidence was assessed using the GRADE approach. Results Over 15 years of follow-up, screening individuals aged 50-79 at 3% risk of colorectal cancer with annual FIT or single colonoscopy reduced colorectal cancer mortality by 6 per 1000 individuals. Single sigmoidoscopy and biennial FIT reduced it by 5 per 1000 individuals. Colonoscopy, sigmoidoscopy, and annual FIT reduced colorectal cancer incidence by 10, 8, and 4 per 1000 individuals, respectively. The estimated incidence reduction for biennial FIT was 1 per 1000 individuals. Serious harms were estimated to be between 3 per 1000 (biennial FIT) and 5 per 1000 individuals (colonoscopy); harms increased with older age. The absolute benefits of screening increased with increasing colorectal cancer risk, while harms were less affected by baseline risk. Results were sensitive to the setting defined by the guideline panel. Because of uncertainty associated with modelling assumptions, we applied a GRADE rating of low certainty evidence to all estimates. Conclusions Over a 15 year period, all screening strategies may reduce colorectal cancer mortality to a similar extent. Colonoscopy and sigmoidoscopy may also reduce colorectal cancer incidence, while FIT shows a smaller incidence reduction. Harms are rare and of similar magnitude for all screening strategies.

Objective To investigate whether fenofibrate as add-on to statin treatment reduce persistent cardiovascular risk in adults with metabolic syndrome in a real world setting. Design Propensity matched cohort study. Setting Population based cohort in Korea. Participants 29 771 adults with metabolic syndrome (≥40 years) receiving statin treatment. 2156 participants receiving combined treatment (statin plus fenofibrate) were weighted based on propensity score in a 1:5 ratio with 8549 participants using statin only treatment. Main outcome measure Primary outcome was composite cardiovascular events including incident coronary heart disease, ischaemic stroke, and death from cardiovascular causes. Results The incidence rate per 1000 person years of composite cardiovascular events was 17.7 (95% confidence interval 14.4 to 21.8) in the combined treatment group and 22.0 (20.1 to 24.1) in the statin group. The risk of composite cardiovascular events was significantly reduced in the combined treatment group compared with statin group (adjusted hazard ratio 0.74, 95% confidence interval 0.58 to 0.93; P=0.01). The significance was maintained in the on-treatment analysis (hazard ratio 0.63, 95% confidence interval 0.44 to 0.92; P=0.02). The risk of incident coronary heart disease, ischaemic stroke, and cardiovascular death was lower in the combined treatment group than statin group but was not significant. Participant characteristics did not appear to be associated with the low risk of composite cardiovascular events with combined treatment. Conclusion In this propensity weighted cohort study of adults with metabolic syndrome, the risk of major cardiovascular events was significantly lower with fenofibrate as add-on to statin treatment than with statin treatment alone.

Objective To assess the immediate impact of the introduction of minimum unit pricing in Scotland on household alcohol purchases. Design Controlled interrupted time series analysis. Setting Purchase data from Kantar Worldpanel’s household shopping panel for 2015-18. Participants 5325 Scottish households, 54 807 English households as controls, and 10 040 households in northern England to control for potential cross border effects. Interventions Introduction of a minimum price of 50p (€0.55; $0.61) per UK unit (6.25p per gram) for the sale of alcohol in Scotland on 1 May 2018. Main outcome measures Price per gram of alcohol, number of grams of alcohol purchased from off-trade by households, and weekly household expenditure on alcohol. Results The introduction of minimum unit pricing in Scotland was associated with an increase in purchase price of 0.64p per gram of alcohol (95% confidence interval 0.54 to 0.75), a reduction in weekly purchases of 9.5 g of alcohol per adult per household (5.1 to 13.9), and a non-significant increase in weekly expenditure on alcohol per household of 61p (−5 to 127). The increase in purchase price was higher in lower income households and in households that purchased the largest amount of alcohol. The reduction in purchased grams of alcohol was greater in lower income households and only occurred in the top fifth of households by income that purchased the greatest amount of alcohol, where the reduction was 15 g of alcohol per week (6 to 24). Changes in weekly expenditure were not systematically related to household income but increased with increasing household purchases. Conclusions In terms of immediate impact, the introduction of minimum unit pricing appears to have been successful in reducing the amount of alcohol purchased by households in Scotland. The action was targeted, in that reductions of purchased alcohol only occurred in the households that bought the most alcohol.

Objective To compare the risk and severity of prostate cancer between men achieving fatherhood by assisted reproduction and men conceiving naturally. Design National register based cohort study. Setting Sweden from January 1994 to December 2014. Participants 1 181 490 children born alive in Sweden during 1994-2014 to the same number of fathers. Fathers were grouped according to fertility status by mode of conception: 20 618 by in vitro fertilisation (IVF), 14 882 by intra-cytoplasmic sperm injection (ICSI), and 1 145 990 by natural conception. Main outcome measures Prostate cancer diagnosis, age of onset, and androgen deprivation therapy (serving as proxy for advanced or metastatic malignancy). Results Among men achieving fatherhood by IVF, by ICSI, and by non-assisted means, 77 (0.37%), 63 (0.42%), and 3244 (0.28%), respectively, were diagnosed as having prostate cancer. Mean age at onset was 55.9, 55.1, and 57.1 years, respectively. Men who became fathers through assisted reproduction had a statistically significantly increased risk of prostate cancer compared with men who conceived naturally (hazard ratio 1.64, 95% confidence interval 1.25 to 2.15, for ICSI; 1.33, 1.06 to 1.66, for IVF). They also had an increased risk of early onset disease (that is, diagnosis before age 55 years) (hazard ratio 1.86, 1.25 to 2.77, for ICSI; 1.51, 1.09 to 2.08, for IVF). Fathers who conceived through ICSI and developed prostate cancer received androgen deprivation therapy to at least the same extent as the reference group (odds ratio 1.91; P=0.07). Conclusions Men who achieved fatherhood through assisted reproduction techniques, particularly through ICSI, are at increased risk for early onset prostate cancer and thus constitute a risk group in which testing and careful long term follow-up for prostate cancer may be beneficial.

Objective To examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA). Design Cross sectional analysis. Setting European regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices. Eligibility criteria Pivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016. Main outcome measures Study design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Cochrane tool (bias arising from the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result); and reporting adequacy (completeness and consistency of information in trial protocols, publications, supplementary appendices, clinical trial registry records, and regulatory documents). Results Between 2014 and 2016, the EMA approved 32 new cancer drugs on the basis of 54 pivotal studies. Of these, 41 (76%) were randomised controlled trials and 13 (24%) were either non-randomised studies or single arm studies. 39/41 randomised controlled trials had available publications and were included in our study. Only 10 randomised controlled trials (26%) measured overall survival as either a primary or coprimary endpoint, with the remaining trials evaluating surrogate measures such as progression free survival and response rates. Overall, 19 randomised controlled trials (49%) were judged to be at high risk of bias for their primary outcome. Concerns about missing outcome data (n=10) and measurement of the outcome (n=7) were the most common domains leading to high risk of bias judgments. Fewer randomised controlled trials that evaluated overall survival as the primary endpoint were at high risk of bias than those that evaluated surrogate efficacy endpoints (2/10 (20%) v 16/29 (55%), respectively). When information available in regulatory documents and the scientific literature was considered separately, overall risk of bias judgments differed for eight randomised controlled trials (21%), which reflects reporting inadequacies in both sources of information. Regulators identified additional deficits beyond the domains captured in risk of bias assessments for 10 drugs (31%). These deficits included magnitude of clinical benefit, inappropriate comparators, and non-preferred study endpoints, which were not disclosed as limitations in scientific publications. Conclusions Most pivotal studies forming the basis of EMA approval of new cancer drugs between 2014 and 2016 were randomised controlled trials. However, almost half of these were judged to be at high risk of bias based on their design, conduct, or analysis, some of which might be unavoidable because of the complexity of cancer trials. Regulatory documents and the scientific literature had gaps in their reporting. Journal publications did not acknowledge the key limitations of the available evidence identified in regulatory documents.