The 50 most-cited articles in BMJ, 2018

Mendelian randomisation uses genetic variation as a natural experiment to investigate the causal relations between potentially modifiable risk factors and health outcomes in observational data. As with all epidemiological approaches, findings from Mendelian randomisation studies depend on specific assumptions. We provide explanations of the information typically reported in Mendelian randomisation studies that can be used to assess the plausibility of these assumptions and guidance on how to interpret findings from Mendelian randomisation studies in the context of other sources of evidence

Ana M Valdes and colleagues discuss strategies for modulating the gut microbiota through diet and probiotics

OBJECTIVE: To assess the prospective associations between consumption of ultra-processed food and risk of cancer. DESIGN: Population based cohort study. SETTING AND PARTICIPANTS: 104 980 participants aged at least 18 years (median age 42.8 years) from the French NutriNet-Santé cohort (2009-17). Dietary intakes were collected using repeated 24 hour dietary records, designed to register participants' usual consumption for 3300 different food items. These were categorised according to their degree of processing by the NOVA classification. MAIN OUTCOME MEASURES: Associations between ultra-processed food intake and risk of overall, breast, prostate, and colorectal cancer assessed by multivariable Cox proportional hazard models adjusted for known risk factors. RESULTS: Ultra-processed food intake was associated with higher overall cancer risk (n=2228 cases; hazard ratio for a 10% increment in the proportion of ultra-processed food in the diet 1.12 (95% confidence interval 1.06 to 1.18); P for trend<0.001) and breast cancer risk (n=739 cases; hazard ratio 1.11 (1.02 to 1.22); P for…

ABSTRACT Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease…

### What you need to know Advances in cancer treatments mean that half of people now diagnosed with cancer can expect to survive for at least 10 years,1 defining many cancers as long term conditions. Psychiatric illnesses such as depression and anxiety are common, but often neglected, complications of cancer, influencing quality of life, adherence to treatment, cancer survival, and treatment costs.23 Depression and anxiety affect up to 20% and 10% of patients with cancer respectively, regardless of the point in the cancer trajectory, and whether in curative or palliative treatment.4 Geographical variations in the diagnosis and treatment of depression or anxiety in cancer settings implies under-recognition of these problems.5 Depression is associated with poor adherence to cancer treatment and poor cancer survival,6 and the increased risk of suicide in all patients with cancer7 is a concern. This clinical update outlines the prevalence, aetiology, and management of depression and anxiety in patients with cancer to raise awareness among doctors of the need to address the psychiatric…

Abstract Objective To evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women. Design Updated meta-analysis. Data sources Medline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review). Review methods Accuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women. Results 56 accuracy studies and 25 participation…

OBJECTIVE: To describe liver disease related mortality in the United States during 1999-2016 by age group, sex, race, cause of liver disease, and geographic region. DESIGN: Observational cohort study. SETTING: Death certificate data from the Vital Statistics Cooperative, and population data from the US Census Bureau compiled by the Center for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (1999-2016). PARTICIPANTS: US residents. MAIN OUTCOME MEASURE: Deaths from cirrhosis and hepatocellular carcinoma, with trends evaluated using joinpoint regression. RESULTS: From 1999 to 2016 in the US annual deaths from cirrhosis increased by 65%, to 34 174, while annual deaths from hepatocellular carcinoma doubled to 11 073. Only one subgroup-Asians and Pacific Islanders-experienced an improvement in mortality from hepatocellular carcinoma: the death rate decreased by 2.7% (95% confidence interval 2.2% to 3.3%, P<0.001) per year. Annual increases in cirrhosis related mortality were most pronounced for Native Americans (designated as "American Indians" in the…

OBJECTIVE: To investigate the association of grip strength with disease specific incidence and mortality and whether grip strength enhances the prediction ability of an established office based risk score. DESIGN: Prospective population based study. SETTING: UK Biobank. PARTICIPANTS: 502 293 participants (54% women) aged 40-69 years. MAIN OUTCOME MEASURES: All cause mortality as well as incidence of and mortality from cardiovascular disease, respiratory disease, chronic obstructive pulmonary disease, and cancer (all cancer, colorectal, lung, breast, and prostate). RESULTS: Of the participants included in analyses, 13 322 (2.7%) died over a mean of 7.1 (range 5.3-9.9) years' follow-up. In women and men, respectively, hazard ratios per 5 kg lower grip strength were higher (all at P<0.05) for all cause mortality (1.20, 95% confidence interval 1.17 to 1.23, and 1.16, 1.15 to 1.17) and cause specific mortality from cardiovascular disease (1.19, 1.13 to 1.25, and 1.22, 1.18 to 1.26), all respiratory disease (1.31, 1.22 to 1.40, and 1.24, 1.20 to 1.28), chronic obstructive pulmonary…

OBJECTIVE: To investigate the efficacy and safety of prostate-specific antigen (PSA) testing to screen for prostate cancer. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic search of Cochrane Central Register of Controlled Trials, Web of Science, Embase, Scopus, OpenGrey, LILACS, and Medline, and search of scientific meeting abstracts and trial registers to April 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing PSA screening with usual care in men without a diagnosis of prostate cancer. DATA EXTRACTION: Rapid Recommendation) provided input on the design and interpretation of the systematic review, including selection of outcomes important to patients. We used a random effects model to obtain pooled incidence rate ratios (IRR) and, when feasible, conducted subgroup analyses (defined a priori) based on age, frequency of screening, family history, ethnicity, and socioeconomic level, as well as a sensitivity analysis based on the risk of bias. The quality of the evidence was assessed with the GRADE approach. RESULTS: Five…

OBJECTIVE: To use the relation between cigarette consumption and cardiovascular disease to quantify the risk of coronary heart disease and stroke for light smoking (one to five cigarettes/day). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline 1946 to May 2015, with manual searches of references. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective cohort studies with at least 50 events, reporting hazard ratios or relative risks (both hereafter referred to as relative risk) compared with never smokers or age specific incidence in relation to risk of coronary heart disease or stroke. DATA EXTRACTION/SYNTHESIS: -1), expected to be about 5% assuming a linear relation between risk and consumption (as seen with lung cancer). The relative risks for one, five, and 20 cigarettes per day were also pooled across all studies in a random effects meta-analysis. Separate analyses were done for each combination of sex and disorder. RESULTS: The meta-analysis included 55 publications containing 141 cohort studies. Among men, the pooled relative risk for coronary heart disease…

OBJECTIVE: To conduct a systematic review and meta-analysis of epidemiological studies investigating the association of arsenic, lead, cadmium, mercury, and copper with cardiovascular disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, and Web of Science searched up to December 2017. REVIEW METHODS: Studies reporting risk estimates for total cardiovascular disease, coronary heart disease, and stroke for levels of arsenic, lead, cadmium, mercury, or copper were included. Two investigators independently extracted information on study characteristics and outcomes in accordance with PRISMA and MOOSE guidelines. Relative risks were standardised to a common scale and pooled across studies for each marker using random effects meta-analyses. RESULTS: The review identified 37 unique studies comprising 348 259 non-overlapping participants, with 13 033 coronary heart disease, 4205 stroke, and 15 274 cardiovascular disease outcomes in aggregate. Comparing top versus bottom thirds of baseline levels, pooled relative risks for arsenic and lead were 1.30 (95%…

In pharmacoepidemiology, routinely collected data from electronic health records (including primary care databases, registries, and administrative healthcare claims) are a resource for research evaluating the real world effectiveness and safety of medicines. Currently available guidelines for the reporting of research using non-randomised, routinely collected data—specifically the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) and the Strengthening the Reporting of OBservational studies in Epidemiology (STROBE) statements—do not capture the complexity of pharmacoepidemiological research. We have therefore extended the RECORD statement to include reporting guidelines specific to pharmacoepidemiological research (RECORD-PE). This article includes the RECORD-PE checklist (also available on www.record-statement.org) and explains each checklist item with examples of good reporting. We anticipate that increasing use of the RECORD-PE guidelines by researchers and endorsement and adherence by journal editors will improve the standards of…

OBJECTIVES: To examine the association between temperature and cause specific mortality, and to quantify the corresponding disease burden attributable to non-optimum ambient temperatures. DESIGN: Time series analysis. SETTING: 272 main cities in China. POPULATION: Non-accidental deaths in 272 cities covered by the Disease Surveillance Point System of China, from January 2013 to December 2015. MAIN OUTCOMES AND MEASURES: Daily numbers of deaths from all non-accidental causes and main cardiorespiratory diseases. Potential effect modifiers included demographic, climatic, geographical, and socioeconomic characteristics. The analysis used distributed lag non-linear models to estimate city specific associations, and multivariate meta-regression analysis to obtain the effect estimates at national and regional levels. RESULTS: 1 826 186 non-accidental deaths from total causes were recorded in the study period. Temperature and mortality consistently showed inversely J shaped associations. At the national average level, relative to the minimum mortality temperature (22.8°C, 79.1st centile),…

Jose Ordovas and colleagues consider that nutrition interventions tailored to individual characteristics and behaviours have promise but more work is needed before they can deliver Dietary factors are well recognised contributors to common diseases, including heart disease, stroke, type 2 diabetes and cancer.123 Despite the known link between dietary patterns and disease, interventions to alter dietary habits and to improve public health and wellbeing have had limited impact. Personalisation of interventions may be more effective in changing behaviour4 that will affect health outcomes.5 In this article we consider the evidence for personalised nutrition. There is no agreed definition of personalised nutrition. For the purposes of this review, we define it as an approach that uses information on individual characteristics to develop targeted nutritional advice, products, or services. Gibney et al6 describe it as an approach that “assists individuals in achieving a lasting dietary behaviour change that is beneficial for health.” Personalised nutrition partially overlaps with related…

Abstract Objective To investigate the impact of patient and public involvement (PPI) on rates of enrolment and retention in clinical trials and explore how this varies with the context and nature of PPI. Design Systematic review and meta-analysis. Data sources Ten electronic databases, including Medline, INVOLVE Evidence Library, and clinical trial registries. Eligibility criteria Experimental and observational studies quantitatively evaluating the impact of a PPI intervention, compared with no intervention or non-PPI intervention(s), on participant enrolment and/or retention rates in a clinical trial or trials. PPI interventions could include additional non-PPI components inseparable from the PPI (for example, other stakeholder involvement). Data extraction and analysis Two independent reviewers extracted data on enrolment and retention rates, as well as on the context and characteristics of PPI intervention, and assessed risk of bias. Random effects meta-analyses were used to determine the average effect of PPI interventions on enrolment and retention in clinical trials: main…

Rheumatoid arthritis is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. Mechanisms linking rheumatoid arthritis and cardiovascular disease include shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, alterations in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction. Despite a growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown. A multifaceted approach to reduce the burden posed by cardiovascular disease requires optimal management of traditional risk factors in addition to those intrinsic to rheumatoid arthritis such as increased disease activity. Treatments for rheumatoid arthritis seem to exert differential effects on cardiovascular risk as well as the mechanisms linking these conditions. More research is needed to establish…

Matthias B Schulze and colleagues discuss current knowledge on the associations between dietary patterns and cancer, coronary heart disease, stroke, and type 2 diabetes, focusing on areas of uncertainty and future research directions

OBJECTIVE: To quantify the effects of varying opioid prescribing patterns after surgery on dependence, overdose, or abuse in an opioid naive population. DESIGN: Retrospective cohort study. SETTING: Surgical claims from a linked medical and pharmacy administrative database of 37 651 619 commercially insured patients between 2008 and 2016. PARTICIPANTS: 1 015 116 opioid naive patients undergoing surgery. MAIN OUTCOME MEASURES: Use of oral opioids after discharge as defined by refills and total dosage and duration of use. The primary outcome was a composite of misuse identified by a diagnostic code for opioid dependence, abuse, or overdose. RESULTS: 568 612 (56.0%) patients received postoperative opioids, and a code for abuse was identified for 5906 patients (0.6%, 183 per 100 000 person years). Total duration of opioid use was the strongest predictor of misuse, with each refill and additional week of opioid use associated with an adjusted increase in the rate of misuse of 44.0% (95% confidence interval 40.8% to 47.2%, P<0.001), and 19.9% increase in hazard (18.5% to 21.4%, P<0.001),…

OBJECTIVE: To evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from ClinicalTrials.gov. STUDY SELECTION: Eligible studies included primary clinical trial data on patients with cancer with recurrent or metastatic disease. DATA EXTRACTION: Three independent investigators extracted data on adverse events from ClinicalTrials.gov and the published studies. Risk of bias was assessed using the Cochrane tool by three independent investigators. RESULTS: 13 relevant studies were included; adverse event data were available on ClinicalTrials.gov for eight. Studies compared nivolumab (n=6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ…

The role of the gut microbiome in models of inflammatory and autoimmune disease is now well characterized. Renewed interest in the human microbiome and its metabolites, as well as notable advances in host mucosal immunology, has opened multiple avenues of research to potentially modulate inflammatory responses. The complexity and interdependence of these diet-microbe-metabolite-host interactions are rapidly being unraveled. Importantly, most of the progress in the field comes from new knowledge about the functional properties of these microorganisms in physiology and their effect in mucosal immunity and distal inflammation. This review summarizes the preclinical and clinical evidence on how dietary, probiotic, prebiotic, and microbiome based therapeutics affect our understanding of wellness and disease, particularly in autoimmunity.

OBJECTIVE: To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018. REVIEW METHODS: Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group. RESULTS: 36 head-to-head phase II and III randomised…

OBJECTIVE: To evaluate the relative efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors versus conventional drugs in patients with cancer that were PD-L1 positive and PD-L1 negative. DESIGN: Meta-analysis of randomised controlled trials. DATA SOURCES: PubMed, Embase, Cochrane database, and conference abstracts presented at the American Society of Clinical Oncology and European Society of Medical Oncology up to March 2018. REVIEW METHODS: Studies of PD-1 or PD-L1 inhibitors (avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab) that had available hazard ratios for death based on PD-L1 positivity or negativity were included. The threshold for PD-L1 positivity or negativity was that PD-L1 stained cell accounted for 1% of tumour cells, or tumour and immune cells, assayed by immunohistochemistry staining methods. RESULTS: 4174 patients with advanced or metastatic cancers from eight randomised controlled trials were included in this study. Compared with conventional agents, PD-1 or PD-L1 inhibitors were associated with significantly…

OBJECTIVE: To estimate the prevalence of diagnosed total diabetes, type 1 diabetes, and type 2 diabetes in the US general population and the proportions of each among US adults with a diagnosis of diabetes. DESIGN: Nationwide, population based, cross sectional survey. SETTING: National Health Interview Survey, 2016 and 2017. PARTICIPANTS: Adults aged 20 years or older (n=58 186), as a nationally representative sample of the civilian, non-institutionalized US population. MAIN OUTCOME MEASURES: Prevalence of diagnosed diabetes, type 1 diabetes, and type 2 diabetes in the US general population, and the proportions of each subtype in participants with a diagnosis of diabetes. RESULTS: Among the 58 186 included adults, 6317 had received a diagnosis of diabetes. The weighted prevalence of diagnosed diabetes, type 1 diabetes, and type 2 diabetes among US adults was 9.7% (95% confidence interval 9.4% to 10.0%), 0.5% (0.5% to 0.6%), and 8.5% (8.2% to 8.8%), respectively. Type 1 diabetes was more prevalent among adults with lower education level, and type 2 diabetes was more prevalent among…

Complexity science offers ways to change our collective mindset about healthcare systems, enabling us to improve performance that is otherwise stagnant, argues Jeffrey Braithwaite

Dariush Mozaffarian and colleagues review strategies governments can use to improve nutrition and health

OBJECTIVES: To estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia. DESIGN: Case-control study. SETTING: General practices in the UK contributing to the Clinical Practice Research Datalink. PARTICIPANTS: 40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia. INTERVENTIONS: Daily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia. MAIN OUTCOME MEASURES: Odds ratios for incident dementia, adjusted for a range of demographic and health related covariates. RESULTS: 14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was…

The use of evidence from clinical trials to support decisions for individual patients is a form of "reference class forecasting": implicit predictions for an individual are made on the basis of outcomes in a reference class of "similar" patients treated with alternative therapies. Evidence based medicine has generally emphasized the broad reference class of patients qualifying for a trial. Yet patients in a trial (and in clinical practice) differ from one another in many ways that can affect the outcome of interest and the potential for benefit. The central goal of personalized medicine, in its various forms, is to narrow the reference class to yield more patient specific effect estimates to support more individualized clinical decision making. This article will review fundamental conceptual problems with the prediction of outcome risk and heterogeneity of treatment effect (HTE), as well as the limitations of conventional (one-variable-at-a-time) subgroup analysis. It will also discuss several regression based approaches to "predictive" heterogeneity of treatment effect analysis,…

OBJECTIVE: To investigate the association of predicted lean body mass, fat mass, and body mass index (BMI) with all cause and cause specific mortality in men. DESIGN: Prospective cohort study. SETTING: Health professionals in the United States PARTICIPANTS: 38 006 men (aged 40-75 years) from the Health Professionals Follow-up Study, followed up for death (1987-2012). MAIN OUTCOME MEASURES: All cause and cause specific mortality. RESULTS: Using validated anthropometric prediction equations previously developed from the National Health and Nutrition Examination Survey, lean body mass and fat mass were estimated for all participants. During a mean of 21.4 years of follow-up, 12 356 deaths were identified. A J shaped association was consistently observed between BMI and all cause mortality. Multivariable adjusted Cox models including predicted fat mass and lean body mass showed a strong positive monotonic association between predicted fat mass and all cause mortality. Compared with those in the lowest fifth of predicted fat mass, men in the highest fifth had a hazard ratio of 1.35 (95%…

Dariush Mozaffarian and colleagues describe how the history of modern nutrition science has shaped current thinking

Much statistical analysis seeks to identify associations between exposures and outcomes. The population attributable fraction (PAF) is an epidemiologic measure widely used to assess the public health impact of exposures in populations. PAF is defined as the fraction of all cases of a particular disease or other adverse condition in a population that is attributable to a specific exposure; PAF equals (O − E)/O, where O and E refer to the observed number of cases and the expected number of cases under no exposure, respectively. The term “attributable” has a causal interpretation: PAF is the estimated fraction of all cases that would not have occurred if there had been no exposure.1 As an example, in early 1950,2 Doll derived O = 11189 and E = 1875 using the Doll and Hill case-control study of smoking and lung cancer deaths throughout England and Wales,3 so the smoking PAF for lung cancer deaths was (11189 − 1875)/11189 = 83%. Using a cohort study, following Miettinen, we can estimate the PAF from …

This report presents the Consolidated Standards of Reporting Trials (CONSORT) extension for the stepped wedge cluster randomised trial (SW-CRT). The SW-CRT involves randomisation of clusters to different sequences that dictate the order (or timing) at which each cluster will switch to the intervention condition. The statement was developed to allow for the unique characteristics of this increasingly used study design. The guideline was developed using a Delphi survey and consensus meeting; and is informed by the CONSORT statements for individual and cluster randomised trials. Reporting items along with explanations and examples are provided. We include a glossary of terms, and explore the key properties of the SW-CRT which require special consideration in their reporting.

Common ground on dietary approaches for the prevention, management, and potential remission of type 2 diabetes can be found, argue Nita G Forouhi and colleagues

In partnership with NHS England, Genomics England’s ambitious plans to embed genomic medicine into routine patient care are well underway. Clare Turnbull and colleagues discuss its progress

OBJECTIVES: To assess whether declines in life expectancy occurred across high income countries during 2014-16, to identify the causes of death contributing to these declines, and to examine the extent to which these declines were driven by shared or differing factors across countries. DESIGN: Demographic analysis using aggregated data. SETTING: Vital statistics systems of 18 member countries of the Organisation for Economic Co-operation and Development. PARTICIPANTS: 18 countries with high quality all cause and cause specific mortality data available in 2014-16. MAIN OUTCOME MEASURES: Life expectancy at birth, 0-65 years, and 65 or more years and cause of death contributions to changes in life expectancy at birth. RESULTS: The majority of high income countries in the study experienced declines in life expectancy during 2014-15; of the 18 countries, 12 experienced declines in life expectancy among women and 11 experienced declines in life expectancy among men. The average decline was 0.21 years for women and 0.18 years for men. In most countries experiencing declines in life…

OBJECTIVE: To evaluate the efficacy and safety of artificial pancreas treatment in non-pregnant outpatients with type 1 diabetes. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, Cochrane Library, and grey literature up to 2 February 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials in non-pregnant outpatients with type 1 diabetes that compared the use of any artificial pancreas system with any type of insulin based treatment. Primary outcome was proportion (%) of time that sensor glucose level was within the near normoglycaemic range (3.9-10 mmol/L). Secondary outcomes included proportion (%) of time that sensor glucose level was above 10 mmol/L or below 3.9 mmol/L, low blood glucose index overnight, mean sensor glucose level, total daily insulin needs, and glycated haemoglobin. The Cochrane Collaboration risk of bias tool was used to assess study quality. RESULTS: 40 studies (1027 participants with data for 44 comparisons) were included in the meta-analysis. 35 comparisons assessed a single…

OBJECTIVE: To estimate the effect of a moderate to high intensity aerobic and strength exercise training programme on cognitive impairment and other outcomes in people with mild to moderate dementia. DESIGN: Multicentre, pragmatic, investigator masked, randomised controlled trial. SETTING: National Health Service primary care, community and memory services, dementia research registers, and voluntary sector providers in 15 English regions. PARTICIPANTS: 494 people with dementia: 329 were assigned to an aerobic and strength exercise programme and 165 were assigned to usual care. Random allocation was 2:1 in favour of the exercise arm. INTERVENTIONS: Usual care plus four months of supervised exercise and support for ongoing physical activity, or usual care only. Interventions were delivered in community gym facilities and NHS premises. MAIN OUTCOME MEASURES: The primary outcome was score on the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) at 12 months. Secondary outcomes included activities of daily living, neuropsychiatric symptoms, health related quality of…

Tuberculosis has a much shorter incubation period than is widely thought, say Marcel A Behr and colleagues, and this has implications for prioritising research and public health strategies

Abstract Objective To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols. Design Systematic review and meta-analysis. Data sources Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016. Eligibility criteria Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months. Data synthesis Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I2 statistics. Main outcome measures Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months). Results 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at…

OBJECTIVE: To evaluate on a large scale, across 272 common types of laboratory tests, the impact of healthcare processes on the predictive value of electronic health record (EHR) data. DESIGN: Retrospective observational study. SETTING: Two large hospitals in Boston, Massachusetts, with inpatient, emergency, and ambulatory care. PARTICIPANTS: All 669 452 patients treated at the two hospitals over one year between 2005 and 2006. MAIN OUTCOME MEASURES: The relative predictive accuracy of each laboratory test for three year survival, using the time of the day, day of the week, and ordering frequency of the test, compared to the value of the test result. RESULTS: The presence of a laboratory test order, regardless of any other information about the test result, has a significant association (P<0.001) with the odds of survival in 233 of 272 (86%) tests. Data about the timing of when laboratory tests were ordered were more accurate than the test results in predicting survival in 118 of 174 tests (68%). CONCLUSIONS: Healthcare processes must be addressed and accounted for in analysis of…

Russell Mannion and Huw Davies explore how notions of culture relate to service performance, quality, safety, and improvement ### Key messages If we believe the headlines, health services are suffering epidemics of cultural shortcomings. Extensive enquiries into failures and scandals in the NHS over several decades have indicated aspects of hospital culture as leading to those failings.(box 1).12 The recent report into over 450 premature deaths at Gosport War Memorial Hospital mentions culture 21 times.3 After such reports, widespread and fundamental cultural change is typically prescribed as the remedy (box 1).45 Box 1 ### Centrality of culture to healthcare scandals: from Kennedy to Francis From Ian Kennedy’s review of the failings in paediatric cardiac surgery in Bristol during the 1980s and 90s2 to Robert Francis’s inquiry into the systemic failings at Mid Staffordshire Hospital Trust over a decade later,1 culture has been implicated. #### Culture as culprit “There was an insular ‘club’ culture [at Bristol], in which it was difficult for anyone to stand out, to press for change,…

OBJECTIVE: To examine the association between risk factor burdens-categorized as optimal, borderline, or elevated-and the lifetime risk of atrial fibrillation. DESIGN: Community based cohort study. SETTING: Longitudinal data from the Framingham Heart Study. PARTICIPANTS: Individuals free of atrial fibrillation at index ages 55, 65, and 75 years were assessed. Smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction were assessed as being optimal (that is, all risk factors were optimal), borderline (presence of borderline risk factors and absence of any elevated risk factor), or elevated (presence of at least one elevated risk factor) at index age. MAIN OUTCOME MEASURE: Lifetime risk of atrial fibrillation at index age up to 95 years, accounting for the competing risk of death. RESULTS: At index age 55 years, the study sample comprised 5338 participants (2531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1415 (26.5%) had a borderline risk profile, and 3676 (68.9%) an elevated risk profile.…

Abstract Objective To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern. Design Register based cohort study. Setting Sweden and Denmark from July 2013 to December 2016. Participants A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists. Main outcome measures The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. Results Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to…

OBJECTIVES: To investigate sex differences in risk factors for incident myocardial infarction (MI) and whether they vary with age. DESIGN: Prospective population based study. SETTING: UK Biobank. PARTICIPANTS: 471 998 participants (56% women; mean age 56.2) with no history of cardiovascular disease. MAIN OUTCOME MEASURE: Incident (fatal and non-fatal) MI. RESULTS: 5081 participants (1463 (28.8%) of whom were women) had MI over seven years' mean follow-up, resulting in an incidence per 10 000 person years of 7.76 (95% confidence interval 7.37 to 8.16) for women and 24.35 (23.57 to 25.16) for men. Higher blood pressure indices, smoking intensity, body mass index, and the presence of diabetes were associated with an increased risk of MI in men and women, but associations were attenuated with age. In women, systolic blood pressure and hypertension, smoking status and intensity, and diabetes were associated with higher hazard ratios for MI compared with men: ratio of hazard ratios 1.09 (95% confidence interval 1.02 to 1.16) for systolic blood pressure, 1.55 (1.32 to 1.83) for current…

Abstract Objective To evaluate the relation between penicillin allergy and development of meticillin resistant Staphylococcus aureus (MRSA) and C difficile. Design Population based matched cohort study. Setting United Kingdom general practice (1995-2015). Participants 301 399 adults without previous MRSA or C difficile enrolled in the Health Improvement Network database: 64 141 had a penicillin allergy and 237 258 comparators matched on age, sex, and study entry time. Main outcome measures The primary outcome was risk of incident MRSA and C difficile. Secondary outcomes were use of β lactam antibiotics and β lactam alternative antibiotics. Results Among 64 141 adults with penicillin allergy and 237 258 matched comparators, 1365 developed MRSA (442 participants with penicillin allergy and 923 comparators) and 1688 developed C difficile (442 participants with penicillin allergy and 1246 comparators) during a mean 6.0 years of follow-up. Among patients with penicillin allergy the adjusted hazard ratio for MRSA was 1.69 (95% confidence interval 1.51 to 1.90) and for C difficile was 1.26…

### What you need to know A 54 year old man presents with neck stiffness for about a year. He complains of numbness in his fingers and difficulty buttoning up his shirt, which has not improved following surgery for carpal tunnel syndrome. Of late, he has experienced unsteadiness and has started to use a walking stick after sustaining falls. He sees a neurologist who identifies hyperreflexia in his arms and legs. An MRI scan shows multilevel cervical spondylosis and disc herniation causing cord compression. He is diagnosed with degenerative cervical myelopathy and referred to spinal surgery for operative decompression. Degenerative cervical myelopathy (DCM), earlier referred to as cervical spondylotic myelopathy, involves spinal cord dysfunction from compression in the neck.1 Patients report neurological symptoms such as pain and numbness in limbs, poor coordination, imbalance, and bladder problems. Owing to its mobility, the vertebral column of the neck is particularly prone to degenerative changes such as disc herniation, ligament hypertrophy or ossification, and osteophyte…

Abstract Objective To provide an overview of the evidence on prevalence and outcomes of incidental imaging findings. Design Umbrella review of systematic reviews. Data sources Searches of MEDLINE, EMBASE up to August 2017; screening of references in included papers. Eligibility criteria Criteria included systematic reviews and meta-analyses of observational studies that gave a prevalence of incidental abnormalities (“incidentalomas”). An incidental imaging finding was defined as an imaging abnormality in a healthy, asymptomatic patient or an imaging abnormality in a symptomatic patient, where the abnormality was not apparently related to the patient’s symptoms. Primary studies that measured the prevalence of incidentalomas in patients with a history of malignancy were also considered in sensitivity analyses. Results 20 systematic reviews (240 primary studies) were identified from 7098 references from the database search. Fifteen systematic reviews provided data to quantify the prevalence of incidentalomas, whereas 18 provided data to quantify the outcomes of incidentalomas (13…

David S Ludwig and colleagues examine the links between different types of carbohydrates and health

Abstract Objective To evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke. Design Prospective population based cohort study. Setting UK Biobank Study, UK. Participants 306 473 men and women, aged 40-73 years, recruited between 2006 and 2010. Main outcome measure Hazard ratios for a first stroke, estimated using Cox regression. A polygenic risk score of 90 single nucleotide polymorphisms previously associated with stroke was constructed at P<1×10 −5 to test for an association with incident stroke. Adherence to a healthy lifestyle was determined on the basis of four factors: non-smoker, healthy diet, body mass index <30 kg/m 2 , and regular physical exercise. Results During a median follow-up of 7.1 years (2 138 443 person years), 2077 incident strokes (1541 ischaemic stroke, 287 intracerebral haemorrhage, and 249 subarachnoid haemorrhage) were ascertained. The risk of incident stroke was 35% higher among those at high genetic risk (top third of polygenic score) compared with those at low genetic risk (bottom third): hazard ratio 1.35 (95%…

OBJECTIVE: To assess the efficacy of a single preoperative physiotherapy session to reduce postoperative pulmonary complications (PPCs) after upper abdominal surgery. DESIGN: Prospective, pragmatic, multicentre, patient and assessor blinded, parallel group, randomised placebo controlled superiority trial. SETTING: Multidisciplinary preadmission clinics at three tertiary public hospitals in Australia and New Zealand. PARTICIPANTS: 441 adults aged 18 years or older who were within six weeks of elective major open upper abdominal surgery were randomly assigned through concealed allocation to receive either an information booklet (n=219; control) or preoperative physiotherapy (n=222; intervention) and followed for 12 months. 432 completed the trial. INTERVENTIONS: Preoperatively, participants received an information booklet (control) or an additional 30 minute physiotherapy education and breathing exercise training session (intervention). Education focused on PPCs and their prevention through early ambulation and self directed breathing exercises to be initiated immediately on regaining…

OBJECTIVE: To estimate the incidence of type 1 diabetes in all age groups in China during 2010-13. DESIGN: Population based, registry study using data from multiple independent sources. SETTING: National registration system in all 505 hospitals providing diabetes care, and communities of patients with diabetes in 13 areas across China, covering more than 133 million person years at risk, approximately 10% of the whole population. PARTICIPANTS: 5018 people of all ages with newly diagnosed type 1 diabetes and resident in the study areas from 1 January 2010 to 31 December 2013. MAIN OUTCOME MEASURES: Incidence of type 1 diabetes per 100 000 person years by age, sex, and study area. Type 1 diabetes was doctor diagnosed and further validated by onsite follow-up. Completeness of case ascertainment was assessed using the capture mark recapture method. RESULTS: 5018 cases of newly diagnosed type 1 diabetes were ascertained: 1239 participants were aged <15 years, 1799 were aged 15-29 years, and 1980 were aged ≥30 years. The proportion of new onset cases in participants aged ≥20 years was…