Showing papers in "BMJ in 2017"

AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both

Abstract: The number of published systematic reviews of studies of healthcare interventions has increased rapidly and these are used extensively for clinical and policy decisions. Systematic reviews are subject to a range of biases and increasingly include non-randomised studies of interventions. It is important that users can distinguish high quality reviews. Many instruments have been designed to evaluate different aspects of reviews, but there are few comprehensive critical appraisal instruments. AMSTAR was developed to evaluate systematic reviews of randomised trials. In this paper, we report on the updating of AMSTAR and its adaptation to enable more detailed assessment of systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. With moves to base more decisions on real world observational evidence we believe that AMSTAR 2 will assist decision makers in the identification of high quality systematic reviews, including those based on non-randomised studies of healthcare interventions.

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Abstract: Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D 3 or vitamin D 2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. Systematic review registration PROSPERO CRD42014013953.

Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies

Abstract: Objective To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and to characterise trends in risk of mortality after initiation and cessation of treatment. Design Systematic review and meta-analysis. Data sources Medline, Embase, PsycINFO, and LILACS to September 2016. Study selection Prospective or retrospective cohort studies in people with opioid dependence that reported deaths from all causes or overdose during follow-up periods in and out of opioid substitution treatment with methadone or buprenorphine. Data extraction and synthesis Two independent reviewers performed data extraction and assessed study quality. Mortality rates in and out of treatment were jointly combined across methadone or buprenorphine cohorts by using multivariate random effects meta-analysis. Results There were 19 eligible cohorts, following 122 885 people treated with methadone over 1.3-13.9 years and 15 831 people treated with buprenorphine over 1.1-4.5 years. Pooled all cause mortality rates were 11.3 and 36.1 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 3.20, 95% confidence interval 2.65 to 3.86) and reduced to 4.3 and 9.5 in and out of buprenorphine treatment (2.20, 1.34 to 3.61). In pooled trend analysis, all cause mortality dropped sharply over the first four weeks of methadone treatment and decreased gradually two weeks after leaving treatment. All cause mortality remained stable during induction and remaining time on buprenorphine treatment. Overdose mortality evolved similarly, with pooled overdose mortality rates of 2.6 and 12.7 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 4.80, 2.90 to 7.96) and 1.4 and 4.6 in and out of buprenorphine treatment. Conclusions Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.

Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study

Abstract: Objectives: To develop and validate updated QRISK3 prediction algorithms to estimate the 10 year risk of cardiovascular disease in women and men accounting for potential new risk factors. Design: Prospective open cohort study. Setting: General practices in England providing data for the QResearch database. Participants: 1309 QResearch general practices in England: 981 practices were used to develop the scores and a separate set of 328 practices were used to validate the scores. 7.89 million patients aged 25-84 years were in the derivation cohort and 2.67 million patients in the validation cohort. Patients were free of cardiovascular disease and not prescribed statins at baseline. Methods: Cox proportional hazards models in the derivation cohort to derive separate risk equations in men and women for evaluation at 10 years. Risk factors considered included those already in QRISK2 (age, ethnicity, deprivation, systolic blood pressure, body mass index, total cholesterol: high density lipoprotein cholesterol ratio, smoking, family history of coronary heart disease in a first degree relative aged less than 60 years, type 1 diabetes, type 2 diabetes, treated hypertension, rheumatoid arthritis, atrial fibrillation, chronic kidney disease (stage 4 or 5)) and new risk factors (chronic kidney disease (stage 3, 4, or 5), a measure of systolic blood pressure variability (standard deviation of repeated measures), migraine, corticosteroids, systemic lupus erythematosus (SLE), atypical antipsychotics, severe mental illness, and HIV/AIDs). We also considered erectile dysfunction diagnosis or treatment in men. Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for individual subgroups by age group, ethnicity, and baseline disease status. Main outcome measures: Incident cardiovascular disease recorded on any of the following three linked data sources: general practice, mortality, or hospital admission records. Results: 363 565 incident cases of cardiovascular disease were identified in the derivation cohort during follow-up arising from 50.8 million person years of observation. All new risk factors considered met the model inclusion criteria except for HIV/AIDS, which was not statistically significant. The models had good calibration and high levels of explained variation and discrimination. In women, the algorithm explained 59.6% of the variation in time to diagnosis of cardiovascular disease (R2, with higher values indicating more variation), and the D statistic was 2.48 and Harrell’s C statistic was 0.88 (both measures of discrimination, with higher values indicating better discrimination). The corresponding values for men were 54.8%, 2.26, and 0.86. Overall performance of the updated QRISK3 algorithms was similar to the QRISK2 algorithms. Conclusion: Updated QRISK3 risk prediction models were developed and validated. The inclusion of additional clinical variables in QRISK3 (chronic kidney disease, a measure of systolic blood pressure variability (standard deviation of repeated measures), migraine, corticosteroids, SLE, atypical antipsychotics, severe mental illness, and erectile dysfunction) can help enable doctors to identify those at most risk of heart disease and stroke.

GRIPP2 reporting checklists: tools to improve reporting of patient and public involvement in research

Abstract: While the patient and public involvement (PPI) evidence base has expanded over the past decade, the quality of reporting within papers is often inconsistent, limiting our understanding of how it works, in what context, for whom, and why. To develop international consensus on the key items to report to enhance the quality, transparency, and consistency of the PPI evidence base. To collaboratively involve patients as research partners at all stages in the development of GRIPP2. The EQUATOR method for developing reporting guidelines was used. The original GRIPP (Guidance for Reporting Involvement of Patients and the Public) checklist was revised, based on updated systematic review evidence. A three round Delphi survey was used to develop consensus on items to be included in the guideline. A subsequent face-to-face meeting produced agreement on items not reaching consensus during the Delphi process. One hundred forty-three participants agreed to participate in round one, with an 86% (123/143) response for round two and a 78% (112/143) response for round three. The Delphi survey identified the need for long form (LF) and short form (SF) versions. GRIPP2-LF includes 34 items on aims, definitions, concepts and theory, methods, stages and nature of involvement, context, capture or measurement of impact, outcomes, economic assessment, and reflections and is suitable for studies where the main focus is PPI. GRIPP2-SF includes five items on aims, methods, results, outcomes, and critical perspective and is suitable for studies where PPI is a secondary focus. GRIPP2-LF and GRIPP2-SF represent the first international evidence based, consensus informed guidance for reporting patient and public involvement in research. Both versions of GRIPP2 aim to improve the quality, transparency, and consistency of the international PPI evidence base, to ensure PPI practice is based on the best evidence. In order to encourage its wide dissemination this article is freely accessible on The BMJ and Research Involvement and Engagement journal websites.

Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child

Abstract: Obesity is the most common medical condition in women of reproductive age. Obesity during pregnancy has short term and long term adverse consequences for both mother and child. Obesity causes problems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anomalies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of cesarean delivery and wound complications is increased. Postpartum, obese women have an increased risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of overweight or obese women gain more than recommended by Institute of Medicine gestational weight guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesity in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which increases the risk of childhood obesity. Although there is no unifying mechanism responsible for the adverse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and oxidative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysiology underlying these data and try to shed light on the specific underlying mechanisms.

Standards for Reporting Implementation Studies (StaRI) Statement

Abstract: Implementation studies are often poorly reported and indexed, reducing their potential to inform initiatives to improve healthcare services. The Standards for Reporting Implementation Studies (StaRI) initiative aimed to develop guidelines for transparent and accurate reporting of implementation studies. Informed by the findings of a systematic review and a consensus-building e-Delphi exercise, an international working group of implementation science experts discussed and agreed the StaRI Checklist comprising 27 items. It prompts researchers to describe both the implementation strategy (techniques used to promote implementation of an underused evidence-based intervention) and the effectiveness of the intervention that was being implemented. An accompanying Explanation and Elaboration document (published in BMJ Open, doi:10.1136/bmjopen-2016-013318) details each of the items, explains the rationale, and provides examples of good reporting practice. Adoption of StaRI will improve the reporting of implementation studies, potentially facilitating translation of research into practice and improving the health of individuals and populations.

Adiposity and cancer at major anatomical sites: umbrella review of the literature.

Abstract: Objective To evaluate the strength and validity of the evidence for the association between adiposity and risk of developing or dying from cancer. Design Umbrella review of systematic reviews and meta-analyses. Data sources PubMed, Embase, Cochrane Database of Systematic Reviews, and manual screening of retrieved references. Eligibility criteria Systematic reviews or meta-analyses of observational studies that evaluated the association between indices of adiposity and risk of developing or dying from cancer. Data synthesis Primary analysis focused on cohort studies exploring associations for continuous measures of adiposity. The evidence was graded into strong, highly suggestive, suggestive, or weak after applying criteria that included the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, the number of cancer cases, heterogeneity between studies, 95% prediction intervals, small study effects, excess significance bias, and sensitivity analysis with credibility ceilings. Results 204 meta-analyses investigated associations between seven indices of adiposity and developing or dying from 36 primary cancers and their subtypes. Of the 95 meta-analyses that included cohort studies and used a continuous scale to measure adiposity, only 12 (13%) associations for nine cancers were supported by strong evidence. An increase in body mass index was associated with a higher risk of developing oesophageal adenocarcinoma; colon and rectal cancer in men; biliary tract system and pancreatic cancer; endometrial cancer in premenopausal women; kidney cancer; and multiple myeloma. Weight gain and waist to hip circumference ratio were associated with higher risks of postmenopausal breast cancer in women who have never used hormone replacement therapy and endometrial cancer, respectively. The increase in the risk of developing cancer for every 5 kg/m 2 increase in body mass index ranged from 9% (relative risk 1.09, 95% confidence interval 1.06 to 1.13) for rectal cancer among men to 56% (1.56, 1.34 to 1.81) for biliary tract system cancer. The risk of postmenopausal breast cancer among women who have never used HRT increased by 11% for each 5 kg of weight gain in adulthood (1.11, 1.09 to 1.13), and the risk of endometrial cancer increased by 21% for each 0.1 increase in waist to hip ratio (1.21, 1.13 to 1.29). Five additional associations were supported by strong evidence when categorical measures of adiposity were included: weight gain with colorectal cancer; body mass index with gallbladder, gastric cardia, and ovarian cancer; and multiple myeloma mortality. Conclusions Although the association of adiposity with cancer risk has been extensively studied, associations for only 11 cancers (oesophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney) were supported by strong evidence. Other associations could be genuine, but substantial uncertainty remains. Obesity is becoming one of the biggest problems in public health; evidence on the strength of the associated risks may allow finer selection of those at higher risk of cancer, who could be targeted for personalised prevention strategies.

A three-talk model for shared decision making: multistage consultation process

Abstract: OBJECTIVES To revise an existing three-talk model for learning how to achieve shared decision making, and to consult with relevant stakeholders to update and obtain wider engagement. DESIGN Multistage consultation process. SETTING Key informant group, communities of interest, and survey of clinical specialties. PARTICIPANTS 19 key informants, 153 member responses from multiple communities of interest, and 316 responses to an online survey from medically qualified clinicians from six specialties. RESULTS After extended consultation over three iterations, we revised the three-talk model by making changes to one talk category, adding the need to elicit patient goals, providing a clear set of tasks for each talk category, and adding suggested scripts to illustrate each step. A new three-talk model of shared decision making is proposed, based on “team talk,” “option talk,” and “decision talk,” to depict a process of collaboration and deliberation. Team talk places emphasis on the need to provide support to patients when they are made aware of choices, and to elicit their goals as a means of guiding decision making processes. Option talk refers to the task of comparing alternatives, using risk communication principles. Decision talk refers to the task of arriving at decisions that reflect the informed preferences of patients, guided by the experience and expertise of health professionals. CONCLUSIONS The revised three-talk model of shared decision making depicts conversational steps, initiated by providing support when introducing options, followed by strategies to compare and discuss trade-offs, before deliberation based on informed preferences.

Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes

Abstract: Objectives To evaluate the existing evidence for associations between coffee consumption and multiple health outcomes. Design Umbrella review of the evidence across meta-analyses of observational and interventional studies of coffee consumption and any health outcome. Data sources PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, and screening of references. Eligibility criteria for selecting studies Meta-analyses of both observational and interventional studies that examined the associations between coffee consumption and any health outcome in any adult population in all countries and all settings. Studies of genetic polymorphisms for coffee metabolism were excluded. Results The umbrella review identified 201 meta-analyses of observational research with 67 unique health outcomes and 17 meta-analyses of interventional research with nine unique outcomes. Coffee consumption was more often associated with benefit than harm for a range of health outcomes across exposures including high versus low, any versus none, and one extra cup a day. There was evidence of a non-linear association between consumption and some outcomes, with summary estimates indicating largest relative risk reduction at intakes of three to four cups a day versus none, including all cause mortality (relative risk 0.83, 95% confidence interval 0.83 to 0.88), cardiovascular mortality (0.81, 0.72 to 0.90), and cardiovascular disease (0.85, 0.80 to 0.90). High versus low consumption was associated with an 18% lower risk of incident cancer (0.82, 0.74 to 0.89). Consumption was also associated with a lower risk of several specific cancers and neurological, metabolic, and liver conditions. Harmful associations were largely nullified by adequate adjustment for smoking, except in pregnancy, where high versus low/no consumption was associated with low birth weight (odds ratio 1.31, 95% confidence interval 1.03 to 1.67), preterm birth in the first (1.22, 1.00 to 1.49) and second (1.12, 1.02 to 1.22) trimester, and pregnancy loss (1.46, 1.06 to 1.99). There was also an association between coffee drinking and risk of fracture in women but not in men. Conclusion Coffee consumption seems generally safe within usual levels of intake, with summary estimates indicating largest risk reduction for various health outcomes at three to four cups a day, and more likely to benefit health than harm. Robust randomised controlled trials are needed to understand whether the observed associations are causal. Importantly, outside of pregnancy, existing evidence suggests that coffee could be tested as an intervention without significant risk of causing harm. Women at increased risk of fracture should possibly be excluded.

Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study

Abstract: Objective To determine the frequency of prescriptions for short term use of oral corticosteroids, and adverse events (sepsis, venous thromboembolism, fractures) associated with their use. Design Retrospective cohort study and self controlled case series. Setting Nationwide dataset of private insurance claims. Participants Adults aged 18 to 64 years who were continuously enrolled from 2012 to 2014. Main outcome measures Rates of short term use of oral corticosteroids defined as less than 30 days duration. Incidence rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and 31-90 day risk periods after drug initiation. Results Of 1 548 945 adults, 327 452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P Conclusion One in five American adults in a commercially insured plan were given prescriptions for short term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events.

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Abstract: Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis.

Abstract: Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation. Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library. Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation. Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin. Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis. Systematic review registration PROSPERO CRD 42013005324.

Comparison of postoperative outcomes among patients treated by male and female surgeons: a population based matched cohort study.

Abstract: Objective To examine the effect of surgeon sex on postoperative outcomes of patients undergoing common surgical procedures. Design Population based, retrospective, matched cohort study from 2007 to 2015. Setting Population based cohort of all patients treated in Ontario, Canada. Participants Patients undergoing one of 25 surgical procedures performed by a female surgeon were matched by patient age, patient sex, comorbidity, surgeon volume, surgeon age, and hospital to patients undergoing the same operation by a male surgeon. Interventions Sex of treating surgeon. Main outcome measure The primary outcome was a composite of death, readmission, and complications. We compared outcomes between groups using generalised estimating equations. Results 104 630 patients were treated by 3314 surgeons, 774 female and 2540 male. Before matching, patients treated by female doctors were more likely to be female and younger but had similar comorbidity, income, rurality, and year of surgery. After matching, the groups were comparable. Fewer patients treated by female surgeons died, were readmitted to hospital, or had complications within 30 days (5810 of 52 315, 11.1%, 95% confidence interval 10.9% to 11.4%) than those treated by male surgeons (6046 of 52 315, 11.6%, 11.3% to 11.8%; adjusted odds ratio 0.96, 0.92 to 0.99, P=0.02). Patients treated by female surgeons were less likely to die within 30 days (adjusted odds ratio 0.88; 0.79 to 0.99, P=0.04), but there was no significant difference in readmissions or complications. Stratified analyses by patient, physician, and hospital characteristics did not significant modify the effect of surgeon sex on outcome. A retrospective analysis showed no difference in outcomes by surgeon sex in patients who had emergency surgery, where patients do not usually choose their surgeon. Conclusions After accounting for patient, surgeon, and hospital characteristics, patients treated by female surgeons had a small but statistically significant decrease in 30 day mortality and similar surgical outcomes (length of stay, complications, and readmission), compared with those treated by male surgeons. These findings support the need for further examination of the surgical outcomes and mechanisms related to physicians and the underlying processes and patterns of care to improve mortality, complications, and readmissions for all patients.

Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis

Abstract: Objectives To identify trends in concurrent use of a benzodiazepine and an opioid and to identify the impact of these trends on admissions to hospital and emergency room visits for opioid overdose. Design Retrospective analysis of claims data, 2001-13. Setting Administrative health claims database. Participants 315 428 privately insured people aged 18-64 who were continuously enrolled in a health plan with medical and pharmacy benefits during the study period and who also filled at least one prescription for an opioid. Interventions Concurrent benzodiazepine/opioid use, defined as an overlap of at least one day in the time periods covered by prescriptions for each drug. Main outcome measures Annual percentage of opioid users with concurrent benzodiazepine use; annual incidence of visits to emergency room and inpatient admissions for opioid overdose. Results 9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users. Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; P<0.001) among all opioid users. The adjusted odds ratio for an emergency room visit or inpatient admission for opioid overdose was 1.42 (1.33 to 1.51; P<0.001) for intermittent opioid users and 1.81 (1.67 to 1.96; P<0.001) chronic opioid users. If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16). Conclusions From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose.

The role of the microbiome in human health and disease: an introduction for clinicians

Abstract: Research into the microbiome—the indigenous microbial communities (microbiota) and the host environment that they inhabit—has changed clinicians’ ideas about microbes in human health and disease. Perhaps the most radical change is the realization that most of the microbes that inhabit our body supply crucial ecosystem services that benefit the entire host-microbe system. These services include the production of important resources, bioconversion of nutrients, and protection against pathogenic microbes. Thus disease can result from a loss of beneficial functions or the introduction of maladaptive functions by invading microbes. This review will show how an understanding of the dynamics and function of the indigenous microbiota has altered our view of microbes in maintaining homeostasis and causing disease. It will discuss how disruption of the beneficial functions of the microbiota can lead to disease. Methods for studying the microbiota will be introduced as part of a conceptual framework for using these methods to delineate novel roles for microbes in health. Key associations between specific changes in the microbiome and disease will be discussed. This will lead to an explanation of how the intentional manipulation of the microbiota, either by restoring missing functions or eliminating harmful functions, may lead to novel methods to prevent or treat a variety of diseases. With the explosion of studies relating the microbiome to health and disease, this review aims to provide a foundation for clinicians to follow this developing area of biomedical research.

Association between active commuting and incident cardiovascular disease, cancer, and mortality: prospective cohort study.

Abstract: Objective To investigate the association between active commuting and incident cardiovascular disease (CVD), cancer, and all cause mortality. Design Prospective population based study. Setting UK Biobank. Participants 263 450 participants (106 674 (52%) women; mean age 52.6), recruited from 22 sites across the UK. The exposure variable was the mode of transport used (walking, cycling, mixed mode v non-active (car or public transport)) to commute to and from work on a typical day. Main outcome measures Incident (fatal and non-fatal) CVD and cancer, and deaths from CVD, cancer, or any causes. Results 2430 participants died (496 were related to CVD and 1126 to cancer) over a median of 5.0 years (interquartile range 4.3-5.5) follow-up. There were 3748 cancer and 1110 CVD events. In maximally adjusted models, commuting by cycle and by mixed mode including cycling were associated with lower risk of all cause mortality (cycling hazard ratio 0.59, 95% confidence interval 0.42 to 0.83, P=0.002; mixed mode cycling 0.76, 0.58 to 1.00, P Conclusions Cycle commuting was associated with a lower risk of CVD, cancer, and all cause mortality. Walking commuting was associated with a lower risk of CVD independent of major measured confounding factors. Initiatives to encourage and support active commuting could reduce risk of death and the burden of important chronic conditions.

Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data

Abstract: Objective To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs). Design Systematic review followed by a one stage bayesian individual patient data meta-analysis. Data sources Studies from Canadian and European healthcare databases. Review methods Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. Exposure and outcomes Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction. Results A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations. Conclusions All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.

Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials

Abstract: National Institute for Health Research (NIHR) Health Technology Assessment) programme (No 12/01/50)

Antiphospholipid syndrome

Abstract: 这是一系列来自患者的零星文章中的最后一篇，他们的经历为医生提供了生动教程。关于"你的患者在想什么"系列的更多信息，请联系患者编辑Rosamund Snow (rsnow@bmj.com)。

A guide to systematic review and meta-analysis of prediction model performance

Abstract: Validation of prediction models is highly recommended and increasingly common in the literature. A systematic review of validation studies is therefore helpful, with meta-analysis needed to summarise the predictive performance of the model being validated across different settings and populations. This article provides guidance for researchers systematically reviewing and meta-analysing the existing evidence on a specific prediction model, discusses good practice when quantitatively summarising the predictive performance of the model across studies, and provides recommendations for interpreting meta-analysis estimates of model performance. We present key steps of the meta-analysis and illustrate each step in an example review, by summarising the discrimination and calibration performance of the EuroSCORE for predicting operative mortality in patients undergoing coronary artery bypass grafting.

Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis.

Abstract: Objective To assess whether weight loss interventions for adults with obesity affect all cause, cardiovascular, and cancer mortality, cardiovascular disease, cancer, and body weight.Design Systematic review and meta-analysis of randomised controlled trials (RCTs) using random effects, estimating risk ratios, and mean differences. Heterogeneity investigated using Cochran's Q and I2 statistics. Quality of evidence assessed by GRADE criteria.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, and full texts in our trials' registry for data not evident in databases. Authors were contacted for unpublished data.Eligibility criteria for selecting studies RCTs of dietary interventions targeting weight loss, with or without exercise advice or programmes, for adults with obesity and follow-up ≥1 year.Results 54 RCTs with 30 206 participants were identified. All but one trial evaluated low fat, weight reducing diets. For the primary outcome, high quality evidence showed that weight loss interventions decrease all cause mortality (34 trials, 685 events; risk ratio 0.82, 95% confidence interval 0.71 to 0.95), with six fewer deaths per 1000 participants (95% confidence interval two to 10). For other primary outcomes moderate quality evidence showed an effect on cardiovascular mortality (eight trials, 134 events; risk ratio 0.93, 95% confidence interval 0.67 to 1.31), and very low quality evidence showed an effect on cancer mortality (eight trials, 34 events; risk ratio 0.58, 95% confidence interval 0.30 to 1.11). Twenty four trials (15 176 participants) reported high quality evidence on participants developing new cardiovascular events (1043 events; risk ratio 0.93, 95% confidence interval 0.83 to 1.04). Nineteen trials (6330 participants) provided very low quality evidence on participants developing new cancers (103 events; risk ratio 0.92, 95% confidence interval 0.63 to 1.36).Conclusions Weight reducing diets, usually low in fat and saturated fat, with or without exercise advice or programmes, may reduce premature all cause mortality in adults with obesity.Systematic review registration PROSPERO CRD42016033217.

Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks' gestation in France in 2011: EPIPAGE-2 cohort study.

Abstract: Objectives To describe neurodevelopmental outcomes at 2 years corrected age for children born alive at 22-26, 27-31, and 32-34 weeks' gestation in 2011, and to evaluate changes since 1997.Design Population based cohort studies, EPIPAGE and EPIPAGE-2.Setting France.Participants 5567 neonates born alive in 2011 at 22-34 completed weeks' gestation, with 4199 survivors at 2 years corrected age included in follow-up. Comparison of outcomes reported for 3334 (1997) and 2418 (2011) neonates born alive in the nine regions participating in both studies.Main outcome measures Survival; cerebral palsy (2000 European consensus definition); scores below threshold on the neurodevelopmental Ages and Stages Questionnaire (ASQ; at least one of five domains below threshold) if completed between 22 and 26 months corrected age, in children without cerebral palsy, blindness, or deafness; and survival without severe or moderate neuromotor or sensory disabilities (cerebral palsy with Gross Motor Function Classification System levels 2-5, unilateral or bilateral blindness or deafness). Results are given as percentage of outcome measures with 95% confidence intervals.Results Among 5170 liveborn neonates with parental consent, survival at 2 years corrected age was 51.7% (95% confidence interval 48.6% to 54.7%) at 22-26 weeks' gestation, 93.1% (92.1% to 94.0%) at 27-31 weeks' gestation, and 98.6% (97.8% to 99.2%) at 32-34 weeks' gestation. Only one infant born at 22-23 weeks survived. Data on cerebral palsy were available for 3599 infants (81.0% of the eligible population). The overall rate of cerebral palsy at 24-26, 27-31, and 32-34 weeks' gestation was 6.9% (4.7% to 9.6%), 4.3% (3.5% to 5.2%), and 1.0% (0.5% to 1.9%), respectively. Responses to the ASQ were analysed for 2506 children (56.4% of the eligible population). The proportion of children with an ASQ result below threshold at 24-26, 27-31, and 32-34 weeks' gestation were 50.2% (44.5% to 55.8%), 40.7% (38.3% to 43.2%), and 36.2% (32.4% to 40.1%), respectively. Survival without severe or moderate neuromotor or sensory disabilities among live births increased between 1997 and 2011, from 45.5% (39.2% to 51.8%) to 62.3% (57.1% to 67.5%) at 25-26 weeks' gestation, but no change was observed at 22-24 weeks' gestation. At 32-34 weeks' gestation, there was a non-statistically significant increase in survival without severe or moderate neuromotor or sensory disabilities (P=0.61), but the proportion of survivors with cerebral palsy declined (P=0.01).Conclusions In this large cohort of preterm infants, rates of survival and survival without severe or moderate neuromotor or sensory disabilities have increased during the past two decades, but these children remain at high risk of developmental delay.

Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study

Abstract: Objectives To investigate whether moderate alcohol consumption has a favourable or adverse association or no association with brain structure and function. Design Observational cohort study with weekly alcohol intake and cognitive performance measured repeatedly over 30 years (1985-2015). Multimodal magnetic resonance imaging (MRI) was performed at study endpoint (2012-15). Setting Community dwelling adults enrolled in the Whitehall II cohort based in the UK (the Whitehall II imaging substudy). Participants 550 men and women with mean age 43.0 (SD 5.4) at study baseline, none were “alcohol dependent” according to the CAGE screening questionnaire, and all safe to undergo MRI of the brain at follow-up. Twenty three were excluded because of incomplete or poor quality imaging data or gross structural abnormality (such as a brain cyst) or incomplete alcohol use, sociodemographic, health, or cognitive data. Main outcome measures Structural brain measures included hippocampal atrophy, grey matter density, and white matter microstructure. Functional measures included cognitive decline over the study and cross sectional cognitive performance at the time of scanning. Results Higher alcohol consumption over the 30 year follow-up was associated with increased odds of hippocampal atrophy in a dose dependent fashion. While those consuming over 30 units a week were at the highest risk compared with abstainers (odds ratio 5.8, 95% confidence interval 1.8 to 18.6; P≤0.001), even those drinking moderately (14-21 units/week) had three times the odds of right sided hippocampal atrophy (3.4, 1.4 to 8.1; P=0.007). There was no protective effect of light drinking (1- Conclusions Alcohol consumption, even at moderate levels, is associated with adverse brain outcomes including hippocampal atrophy. These results support the recent reduction in alcohol guidance in the UK and question the current limits recommended in the US.

Implementing shared decision making in the NHS: lessons from the MAGIC programme

Abstract: Shared decision making requires a shift in attitudes at all levels but can become part of routine practice with the right support, say Natalie Joseph-Williams and colleagues

E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys

Abstract: Objective To examine whether the increase in use of electronic cigarettes in the USA, which became noticeable around 2010 and increased dramatically by 2014, was associated with a change in overall smoking cessation rate at the population level.Design Population surveys with nationally representative samples.Setting Five of the US Current Population Survey-Tobacco Use Supplement (CPS-TUS) in 2001-02, 2003, 2006-07, 2010-11, and 2014-15.Participants Data on e-cigarette use were obtained from the total sample of the 2014-15 CPS-TUS (n=161 054). Smoking cessation rates were obtained from those who reported smoking cigarettes 12 months before the survey (n=23 270). Rates from 2014-15 CPS-TUS were then compared with those from 2010-11 CPS-TUS (n=27 280) and those from three other previous surveys.Main outcome measures Rate of attempt to quit cigarette smoking and the rate of successfully quitting smoking, defined as having quit smoking for at least three months.Results Of 161 054 respondents to the 2014-15 survey, 22 548 were current smokers and 2136 recent quitters. Among them, 38.2% of current smokers and 49.3% of recent quitters had tried e-cigarettes, and 11.5% and 19.0% used them currently (every day or some days). E-cigarette users were more likely than non-users to attempt to quit smoking, 65.1% v 40.1% (change=25.0%, 95% confidence interval 23.2% to 26.9%), and more likely to succeed in quitting, 8.2% v 4.8% (3.5%, 2.5% to 4.5%). The overall population cessation rate for 2014-15 was significantly higher than that for 2010-11, 5.6% v 4.5% (1.1%, 0.6% to 1.5%), and higher than those for all other survey years (range 4.3-4.5%).Conclusion The substantial increase in e-cigarette use among US adult smokers was associated with a statistically significant increase in the smoking cessation rate at the population level. These findings need to be weighed carefully in regulatory policy making regarding e-cigarettes and in planning tobacco control interventions.

Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study

Abstract: Objective To quantify the accuracy and reproducibility of pathologists’ diagnoses of melanocytic skin lesions. Design Observer accuracy and reproducibility study. Setting 10 US states. Participants Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart. Main outcome measures Pathologists’ interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, ≥pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses. Results In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted. Conclusion Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists’ visual assessments.

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

Abstract: Objective To examine clinical effectiveness and safety of apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg compared with warfarin among patients with atrial fibrillation who had not previously taken an oral anticoagulant. Design Propensity weighted (inverse probability of treatment weighted) nationwide cohort study. Setting Individual linked data from three nationwide registries in Denmark. Participants Patients with non-valvular atrial fibrillation filling a first prescription for an oral anticoagulant from August 2011 to February 2016. Patients who filled a prescription for a standard dose non-vitamin K antagonist oral anticoagulant (novel oral anticoagulants, NOACs) were excluded. To control for baseline differences in the population, a propensity score for receipt of either of the four treatment alternatives was calculated to apply an inverse probability treatment weight. Intervention Initiated anticoagulant treatment (dabigatran 110 mg, rivaroxaban 15 mg, apixaban 2.5 mg, and warfarin). Main outcome measures Patients were followed in the registries from onset of treatment for the primary effectiveness outcome of ischaemic stroke/systemic embolism and for the principal safety outcome of any bleeding events. Results Among 55 644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n=4400; dabigatran n=8875; rivaroxaban n=3476; warfarin n=38 893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow-up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non-vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban. Conclusion In this propensity weighted nationwide study of reduced dose non-vitamin K antagonist oral anticoagulant regimens, apixaban 2.5 mg twice a day was associated with a trend towards higher rates of ischaemic stroke/systemic embolism compared with warfarin, while rivaroxaban 15 mg once a day and dabigatran 110 mg twice a day showed a trend towards lower thromboembolic rates. The results were not significantly different. Rates of bleeding (the principal safety outcome) were significantly lower for dabigatran, but not significantly different for apixaban and rivaroxaban compared with warfarin.

Association between continuity of care in general practice and hospital admissions for ambulatory care sensitive conditions: cross sectional study of routinely collected, person level data

Abstract: Objective To assess whether continuity of care with a general practitioner is associated with hospital admissions for ambulatory care sensitive conditions for older patients. Design Cross sectional study. Setting Linked primary and secondary care records from 200 general practices participating in the Clinical Practice Research Datalink in England. Participants 230 472 patients aged between 62 and 82 years and who experienced at least two contacts with a general practitioner between April 2011 and March 2013. Main outcome measure Number of hospital admissions for ambulatory care sensitive conditions (those considered manageable in primary care) per patient between April 2011 and March 2013. Results We assessed continuity of care using the usual provider of care index, which we defined as the proportion of contacts occurring between April 2011 and March 2013 that were with the most frequently seen general practitioner. On average, the usual provider of care index score was 0.61. Continuity of care was lower among practices with more doctors (average score 0.59 in large practices versus 0.70 in small practices). Higher continuity of care was associated with fewer admissions for ambulatory care sensitive conditions. When modelled, controlling for demographic and clinical patient characteristics, an increase in the usual provider of care index of 0.2 for all patients would reduce these admissions by 6.22% (95% confidence interval 4.87% to 7.55%). There was greater evidence for an association among patients who were heavy users of primary care. Heavy users also experienced more admissions for ambulatory care sensitive conditions than other patients (0.36 admissions per patient for those with ≥18 contacts with a general practitioner, compared with 0.04 admissions per patient for those with 2-4 contacts). Conclusions Strategies that improve the continuity of care in general practice may reduce secondary care costs, particularly for the heaviest users of healthcare. Promoting continuity might also improve the experience of patients and those working in general practice.

Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study

Abstract: Objective To test the hypotheses that physical activity in midlife is not associated with a reduced risk of dementia and that the preclinical phase of dementia is characterised by a decline in physical activity. Design Prospective cohort study with a mean follow-up of 27 years. Setting Civil service departments in London (Whitehall II study). Participants 10 308 participants aged 35-55 years at study inception (1985-88). Exposures included time spent in mild, moderate to vigorous, and total physical activity assessed seven times between 1985 and 2013 and categorised as “recommended” if duration of moderate to vigorous physical activity was 2.5 hours/week or more. Main outcome measures A battery of cognitive tests was administered up to four times from 1997 to 2013, and incident dementia cases (n=329) were identified through linkage to hospital, mental health services, and mortality registers until 2015. Results Mixed effects models showed no association between physical activity and subsequent 15 year cognitive decline. Similarly, Cox regression showed no association between physical activity and risk of dementia over an average 27 year follow-up (hazard ratio in the “recommended” physical activity category 1.00, 95% confidence interval 0.80 to 1.24). For trajectories of hours/week of total, mild, and moderate to vigorous physical activity in people with dementia compared with those without dementia (all others), no differences were observed between 28 and 10 years before diagnosis of dementia. However, physical activity in people with dementia began to decline up to nine years before diagnosis (difference in moderate to vigorous physical activity −0.39 hours/week; P=0.05), and the difference became more pronounced (−1.03 hours/week; P=0.005) at diagnosis. Conclusion This study found no evidence of a neuroprotective effect of physical activity. Previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation—that is, due to a decline in physical activity levels in the preclinical phase of dementia.