The 100 most-cited articles in BMJ, 2019

Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.

OBJECTIVE: To examine the dose-response associations between accelerometer assessed total physical activity, different intensities of physical activity, and sedentary time and all cause mortality. DESIGN: Systematic review and harmonised meta-analysis. DATA SOURCES: PubMed, PsycINFO, Embase, Web of Science, Sport Discus from inception to 31 July 2018. ELIGIBILITY CRITERIA: Prospective cohort studies assessing physical activity and sedentary time by accelerometry and associations with all cause mortality and reported effect estimates as hazard ratios, odds ratios, or relative risks with 95% confidence intervals. DATA EXTRACTION AND ANALYSIS: Guidelines for meta-analyses and systematic reviews for observational studies and PRISMA guidelines were followed. Two authors independently screened the titles and abstracts. One author performed a full text review and another extracted the data. Two authors independently assessed the risk of bias. Individual level participant data were harmonised and analysed at study level. Data on physical activity were categorised by quarters at study level,…

OBJECTIVE: To determine the accuracy of the Patient Health Questionnaire-9 (PHQ-9) for screening to detect major depression. DESIGN: Individual participant data meta-analysis. DATA SOURCES: Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-February 2015). INCLUSION CRITERIA: Eligible studies compared PHQ-9 scores with major depression diagnoses from validated diagnostic interviews. Primary study data and study level data extracted from primary reports were synthesized. For PHQ-9 cut-off scores 5-15, bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, among studies that used semistructured diagnostic interviews, which are designed for administration by clinicians; fully structured interviews, which are designed for lay administration; and the Mini International Neuropsychiatric (MINI) diagnostic interviews, a brief fully structured interview. Sensitivity and specificity were examined among participant subgroups and, separately, using meta-regression, considering all subgroup…

Pre-eclampsia is a common disorder that particularly affects first pregnancies. The clinical presentation is highly variable but hypertension and proteinuria are usually seen. These systemic signs arise from soluble factors released from the placenta as a result of a response to stress of syncytiotrophoblast. There are two sub-types: early and late onset pre-eclampsia, with others almost certainly yet to be identified. Early onset pre-eclampsia arises owing to defective placentation, whilst late onset pre-eclampsia may center around interactions between normal senescence of the placenta and a maternal genetic predisposition to cardiovascular and metabolic disease. The causes, placental and maternal, vary among individuals. Recent research has focused on placental-uterine interactions in early pregnancy. The aim now is to translate these findings into new ways to predict, prevent, and treat pre-eclampsia.

OBJECTIVES: To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. DESIGN: Systematic analysis. MAIN OUTCOME MEASURES: Crude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education). RESULTS: The total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was…

OBJECTIVE: To assess the prospective associations between consumption of ultra-processed foods and risk of cardiovascular diseases. DESIGN: Population based cohort study. SETTING: NutriNet-Santé cohort, France 2009-18. PARTICIPANTS: 105 159 participants aged at least 18 years. Dietary intakes were collected using repeated 24 hour dietary records (5.7 for each participant on average), designed to register participants' usual consumption of 3300 food items. These foods were categorised using the NOVA classification according to degree of processing. MAIN OUTCOME MEASURES: Associations between intake of ultra-processed food and overall risk of cardiovascular, coronary heart, and cerebrovascular diseases assessed by multivariable Cox proportional hazard models adjusted for known risk factors. RESULTS: During a median follow-up of 5.2 years, intake of ultra-processed food was associated with a higher risk of overall cardiovascular disease (1409 cases; hazard ratio for an absolute increment of 10 in the percentage of ultra-processed foods in the diet 1.12 (95% confidence interval 1.05 to…

Sepsis is defined as organ dysfunction resulting from the host's deleterious response to infection. One of the most common organs affected is the kidneys, resulting in sepsis associated acute kidney injury (SA-AKI) that contributes to the morbidity and mortality of sepsis. A growing body of knowledge has illuminated the clinical risk factors, pathobiology, response to treatment, and elements of renal recovery that have advanced our ability to prevent, detect, and treat SA-AKI. Despite these advances, SA-AKI remains an important concern and clinical burden, and further study is needed to reduce the acute and chronic consequences. This review summarizes the relevant evidence, with a focus on the risk factors, early recognition and diagnosis, treatment, and long term consequences of SA-AKI. In addition to literature pertaining to SA-AKI specifically, pertinent sepsis and acute kidney injury literature relevant to SA-AKI was included.

Abstract Objective To systematically quantify the prevalence, severity, and nature of preventable patient harm across a range of medical settings globally. Design Systematic review and meta-analysis. Data sources Medline, PubMed, PsycINFO, Cinahl and Embase, WHOLIS, Google Scholar, and SIGLE from January 2000 to January 2019. The reference lists of eligible studies and other relevant systematic reviews were also searched. Review methods Observational studies reporting preventable patient harm in medical care. The core outcomes were the prevalence, severity, and types of preventable patient harm reported as percentages and their 95% confidence intervals. Data extraction and critical appraisal were undertaken by two reviewers working independently. Random effects meta-analysis was employed followed by univariable and multivariable meta regression. Heterogeneity was quantified by using the I 2 statistic, and publication bias was evaluated. Results Of the 7313 records identified, 70 studies involving 337 025 patients were included in the meta-analysis. The pooled prevalence for…

Evidence shows the quality of reporting of randomised controlled trials is not optimal. The lack of transparent reporting impedes readers from judging the reliability and validity of trial findings, prevents researchers from extracting information for systematic reviews, and results in research waste. The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of randomised controlled trials. The primary focus of the statement was on parallel group trials with two treatment groups. Crossover trials are a particular type of trial for chronic conditions in which participants are randomised to a sequence of interventions. They are a useful and efficient design because participants act as their own control. However, the reporting of crossover trials has been variable and incomplete, which hinders their use in clinical decision making and by future researchers. We present the CONSORT extension to randomised crossover trials, which aims to facilitate better reporting of crossover trials. The CONSORT 2010 checklist is revised for crossover…

Prognostic factors are associated with the risk of future health outcomes in individuals with a particular health condition or some clinical start point (eg, a particular diagnosis). Research to identify genuine prognostic factors is important because these factors can help improve risk stratification, treatment, and lifestyle decisions, and the design of randomised trials. Although thousands of prognostic factor studies are published each year, often they are of variable quality and the findings are inconsistent. Systematic reviews and meta-analyses are therefore needed that summarise the evidence about the prognostic value of particular factors. In this article, the key steps involved in this review process are described.

OBJECTIVES: To estimate the burden of miscarriage in the Norwegian population and to evaluate the associations with maternal age and pregnancy history. DESIGN: Prospective register based study. SETTING: Medical Birth Register of Norway, the Norwegian Patient Register, and the induced abortion register. PARTICIPANTS: All Norwegian women that were pregnant between 2009-13. MAIN OUTCOME MEASURE: Risk of miscarriage according to the woman's age and pregnancy history estimated by logistic regression. RESULTS: There were 421 201 pregnancies during the study period. The risk of miscarriage was lowest in women aged 25-29 (10%), and rose rapidly after age 30, reaching 53% in women aged 45 and over. There was a strong recurrence risk of miscarriage, with age adjusted odds ratios of 1.54 (95% confidence interval 1.48 to 1.60) after one miscarriage, 2.21 (2.03 to 2.41) after two, and 3.97 (3.29 to 4.78) after three consecutive miscarriages. The risk of miscarriage was modestly increased if the previous birth ended in a preterm delivery (adjusted odds ratio 1.22, 95% confidence interval 1.12 to…

This report aims to provide methodological guidance to help practitioners select the most appropriate weighting method based on propensity scores for their analysis out of many available options (eg, inverse probability treatment weights, standardised mortality ratio weights, fine stratification weights, overlap weights, and matching weights), and outlines recommendations for transparent reporting of studies using weighting based on the propensity scores.

OBJECTIVE: To evaluate the association between consumption of ultra-processed foods and all cause mortality. DESIGN: Prospective cohort study. SETTING: Seguimiento Universidad de Navarra (SUN) cohort of university graduates, Spain 1999-2018. PARTICIPANTS: 19 899 participants (12 113 women and 7786 men) aged 20-91 years followed-up every two years between December 1999 and February 2014 for food and drink consumption, classified according to the degree of processing by the NOVA classification, and evaluated through a validated 136 item food frequency questionnaire. MAIN OUTCOME MEASURE: Association between consumption of energy adjusted ultra-processed foods categorised into quarters (low, low-medium, medium-high, and high consumption) and all cause mortality, using multivariable Cox proportional hazard models. RESULTS: 335 deaths occurred during 200 432 persons years of follow-up. Participants in the highest quarter (high consumption) of ultra-processed foods consumption had a higher hazard for all cause mortality compared with those in the lowest quarter (multivariable adjusted…

Electronic cigarettes (e-cigarettes) are alternative, non-combustible tobacco products that generate an inhalable aerosol containing nicotine, flavors, propylene glycol, and vegetable glycerin. Vaping is now a multibillion dollar industry that appeals to current smokers, former smokers, and young people who have never smoked. E-cigarettes reached the market without either extensive preclinical toxicology testing or long term safety trials that would be required of conventional therapeutics or medical devices. Their effectiveness as a smoking cessation intervention, their impact at a population level, and whether they are less harmful than combustible tobacco products are highly controversial. Here, we review the evidence on the effects of e-cigarettes on respiratory health. Studies show measurable adverse biologic effects on organ and cellular health in humans, in animals, and in vitro. The effects of e-cigarettes have similarities to and important differences from those of cigarettes. Decades of chronic smoking are needed for development of lung diseases such as lung cancer or…

Abstract Objective To summarise the evidence of associations between dietary factors and incidence of type 2 diabetes and to evaluate the strength and validity of these associations. Design Umbrella review of systematic reviews with meta-analyses of prospective observational studies. Data sources PubMed, Web of Science, and Embase, searched up to August 2018. Eligibility criteria Systematic reviews with meta-analyses reporting summary risk estimates for the associations between incidence of type 2 diabetes and dietary behaviours or diet quality indices, food groups, foods, beverages, alcoholic beverages, macronutrients, and micronutrients. Results 53 publications were included, with 153 adjusted summary hazard ratios on dietary behaviours or diet quality indices (n=12), food groups and foods (n=56), beverages (n=10), alcoholic beverages (n=12), macronutrients (n=32), and micronutrients (n=31), regarding incidence of type 2 diabetes. Methodological quality was high for 75% (n=115) of meta-analyses, moderate for 23% (n=35), and low for 2% (n=3). Quality of evidence was rated high for…

Abstract Objectives To report reliable estimates of short term and long term survival rates for people with a diagnosis of heart failure and to assess trends over time by year of diagnosis, hospital admission, and socioeconomic group. Design Population based cohort study. Setting Primary care, United Kingdom. Participants Primary care data for 55 959 patients aged 45 and over with a new diagnosis of heart failure and 278 679 age and sex matched controls in the Clinical Practice Research Datalink from 1 January 2000 to 31 December 2017 and linked to inpatient Hospital Episode Statistics and Office for National Statistics mortality data. Main outcome measures Survival rates at one, five, and 10 years and cause of death for people with and without heart failure; and temporal trends in survival by year of diagnosis, hospital admission, and socioeconomic group. Results Overall, one, five, and 10 year survival rates increased by 6.6% (from 74.2% in 2000 to 80.8% in 2016), 7.2% (from 41.0% in 2000 to 48.2% in 2012), and 6.4% (from 19.8% in 2000 to 26.2% in 2007), respectively. There were…

To maximise the clinical benefits of machine learning algorithms, we need to rethink our approach to explanation, argue David Watson and colleagues

OBJECTIVE: To assess the association between risk of venous thromboembolism and use of different types of hormone replacement therapy. DESIGN: Two nested case-control studies. SETTING: UK general practices contributing to the QResearch or Clinical Practice Research Datalink (CPRD) databases, and linked to hospital, mortality, and social deprivation data. PARTICIPANTS: 80 396 women aged 40-79 with a primary diagnosis of venous thromboembolism between 1998 and 2017, matched by age, general practice, and index date to 391 494 female controls. MAIN OUTCOME MEASURES: Venous thromboembolism recorded on general practice, mortality, or hospital records. Odds ratios were adjusted for demographics, smoking status, alcohol consumption, comorbidities, recent medical events, and other prescribed drugs. RESULTS: Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date. Of these two groups, 4915 (85%)and 16 938 (78%) women used oral therapy, respectively, which was associated with a…

OBJECTIVE: To estimate the comparative clinical efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults. DESIGN: Systematic review with pairwise and network meta-analysis. DATA SOURCES: Electronic search of Embase, PubMed/Medline, and PsycINFO up to 8 May 2018, supplemented by manual searches of bibliographies of several reviews (published between 2009 and 2018) and included trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Clinical trials with random allocation to electroconvulsive therapy (ECT), transcranial magnetic stimulation (repetitive (rTMS), accelerated, priming, deep, and synchronised), theta burst stimulation, magnetic seizure therapy, transcranial direct current stimulation (tDCS), or sham therapy. MAIN OUTCOME MEASURES: Primary outcomes were response (efficacy) and all cause discontinuation (discontinuation of treatment for any reason) (acceptability), presented as odds ratios with 95% confidence intervals. Remission and continuous depression severity scores after treatment were also examined.…

OBJECTIVE: To assess the prospective associations of baseline and long term trajectories of physical activity on mortality from all causes, cardiovascular disease, and cancer. DESIGN: Population based cohort study. SETTING: Adults from the general population in the UK. PARTICIPANTS: 14 599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, assessed at baseline (1993 to 1997) up to 2004 for lifestyle and other risk factors; then followed to 2016 for mortality (median of 12.5 years of follow-up, after the last exposure assessment). MAIN EXPOSURE: Physical activity energy expenditure (PAEE) derived from questionnaires, calibrated against combined movement and heart rate monitoring. MAIN OUTCOME MEASURES: Mortality from all causes, cardiovascular disease, and cancer. Multivariable proportional hazards regression models were adjusted for age, sex, sociodemographics, and changes in medical history, overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol levels. RESULTS: During 171 277 person…

Disseminating innovation across the healthcare system is challenging but potentially achievable through different logics: mechanistic, ecological, and social, say Trisha Greenhalgh and Chrysanthi Papoutsi

OBJECTIVE: To assess the benefits and harms of spinal manipulative therapy (SMT) for the treatment of chronic low back pain. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, Physiotherapy Evidence Database (PEDro), Index to Chiropractic Literature, and trial registries up to 4 May 2018, including reference lists of eligible trials and related reviews. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials examining the effect of spinal manipulation or mobilisation in adults (≥18 years) with chronic low back pain with or without referred pain. Studies that exclusively examined sciatica were excluded, as was grey literature. No restrictions were applied to language or setting. REVIEW METHODS: Two reviewers independently selected studies, extracted data, and assessed risk of bias and quality of the evidence. The effect of SMT was compared with recommended therapies, non-recommended therapies, sham (placebo) SMT, and SMT as an adjuvant…

OBJECTIVE: To present a clear and comprehensive summary of the published data on unicompartmental knee replacement (UKA) or total knee replacement (TKA), comparing domains of outcome that have been shown to be important to patients and clinicians to allow informed decision making. DESIGN: Systematic review using data from randomised controlled trials, nationwide databases or joint registries, and large cohort studies. DATA SOURCES: Medline, Embase, Cochrane Controlled Register of Trials (CENTRAL), and Clinical Trials.gov, searched between 1 January 1997 and 31 December 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies published in the past 20 years, comparing outcomes of primary UKA with TKA in adult patients. Studies were excluded if they involved fewer than 50 participants, or if translation into English was not available. RESULTS: 60 eligible studies were separated into three methodological groups: seven publications from six randomised controlled trials, 17 national joint registries and national database studies, and 36 cohort studies. Results for each domain of outcome…

OBJECTIVE: To investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population. DESIGN: Retrospective, nationwide cohort study. SETTING: Specialised tertiary gender clinic in Amsterdam, the Netherlands. PARTICIPANTS: 2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment. MAIN OUTCOME MEASURES: Incidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people. RESULTS: The total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of…

Abstract Objective To investigate whether vitamin D supplementation is associated with lower mortality in adults. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, and the Cochrane Central Register from their inception to 26 December 2018. Eligibility criteria for selecting studies Randomised controlled trials comparing vitamin D supplementation with a placebo or no treatment for mortality were included. Independent data extraction was conducted and study quality assessed. A meta-analysis was carried out by using fixed effects and random effects models to calculate risk ratio of death in the group receiving vitamin D supplementation and the control group. Main outcome measures All cause mortality. Results 50 trials with a total of 74 655 participants were identified. Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I 2 =0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin…

Abstract Objectives To compare re-rupture rate, complication rate, and functional outcome after operative versus nonoperative treatment of Achilles tendon ruptures; to compare re-rupture rate after early and late full weight bearing; to evaluate re-rupture rate after functional rehabilitation with early range of motion; and to compare effect estimates from randomised controlled trials and observational studies. Design Systematic review and meta-analysis. Data sources PubMed/Medline, Embase, CENTRAL, and CINAHL databases were last searched on 25 April 2018 for studies comparing operative versus nonoperative treatment of Achilles tendon ruptures. Study selection criteria Randomised controlled trials and observational studies reporting on comparison of operative versus nonoperative treatment of acute Achilles tendon ruptures. Data extraction Data extraction was performed independently in pairs, by four reviewers, with the use of a predefined data extraction file. Outcomes were pooled using random effects models and presented as risk difference, risk ratio, or mean difference, with 95%…

OBJECTIVE: To develop and validate an integrative system to predict long term kidney allograft failure. DESIGN: International cohort study. SETTING: Three cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States. PARTICIPANTS: Derivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157). MAIN OUTCOME MEASURE: Allograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed. RESULTS: Among the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and…

Qingyue Meng and colleagues assess what China’s health system reform has achieved and what needs to be done over the next decade

A whole systems approach that integrates action on the social determinants of health is essential to reduce the burden of non-communicable disease, argue Michael Marmot and Ruth Bell

OBJECTIVE: To assess what proportions of studies reported increasing, stable, or declining trends in the incidence of diagnosed diabetes. DESIGN: Systematic review of studies reporting trends of diabetes incidence in adults from 1980 to 2017 according to PRISMA guidelines. DATA SOURCES: Medline, Embase, CINAHL, and reference lists of relevant publications. ELIGIBILITY CRITERIA: Studies of open population based cohorts, diabetes registries, and administrative and health insurance databases on secular trends in the incidence of total diabetes or type 2 diabetes in adults were included. Poisson regression was used to model data by age group and year. RESULTS: Among the 22 833 screened abstracts, 47 studies were included, providing data on 121 separate sex specific or ethnicity specific populations; 42 (89%) of the included studies reported on diagnosed diabetes. In 1960-89, 36% (8/22) of the populations studied had increasing trends in incidence of diabetes, 55% (12/22) had stable trends, and 9% (2/22) had decreasing trends. In 1990-2005, diabetes incidence increased in 66% (33/50) of…

Malnutrition and unhealthy diets are important risk factors for non-communicable diseases. Francesco Branca and colleagues call for changes in both what and how food is produced, marketed, and consumed

family, Orthopneumovirus genus. It is a negative sense, single stranded RNA virus that results in epidemics of respiratory infections that typically peak in the winter in temperate climates and during the rainy season in tropical climates. Generally, one of the two genotypes (A and B) predominates in a single season, alternating annually, although regional variation occurs. RSV is a cause of disease and death in children, older people, and immunocompromised patients, and its clinical effect on adults admitted to hospital is clarified with expanded use of multiplex molecular assays. Among adults, RSV produces a wide range of clinical symptoms including upper respiratory tract infections, severe lower respiratory tract infections, and exacerbations of underlying disease. Here we discuss the latest evidence on the burden of RSV related disease in adults, especially in those with immunocompromise or other comorbidities. We review current therapeutic and prevention options, as well as those in development.

OBJECTIVE: To investigate the association between weight changes across adulthood and mortality. DESIGN: Prospective cohort study. SETTING: US National Health and Nutrition Examination Survey (NHANES) 1988-94 and 1999-2014. PARTICIPANTS: 36 051 people aged 40 years or over with measured body weight and height at baseline and recalled weight at young adulthood (25 years old) and middle adulthood (10 years before baseline). MAIN OUTCOME MEASURES: All cause and cause specific mortality from baseline until 31 December 2015. RESULTS: During a mean follow-up of 12.3 years, 10 500 deaths occurred. Compared with participants who remained at normal weight, those moving from the non-obese to obese category between young and middle adulthood had a 22% (hazard ratio 1.22, 95% confidence interval 1.11 to 1.33) and 49% (1.49, 1.21 to 1.83) higher risk of all cause mortality and heart disease mortality, respectively. Changing from obese to non-obese body mass index over this period was not significantly associated with mortality risk. An obese to non-obese weight change pattern from middle to late…

Patient reported outcome measures can help drive global patient centred healthcare reform, but we need a more efficient coordinated approach to assessment if we are to fully realise benefits for patients and society, say Melanie Calvert and colleagues

Abstract Objective To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder. Design Population based case-control study. Setting California’s main agricultural region, Central Valley, using 1998-2010 birth data from the Office of Vital Statistics. Population 2961 individuals with a diagnosis of autism spectrum disorder based on the Diagnostic and Statistical Manual of Mental Disorders , fourth edition, revised (up to 31 December 2013), including 445 with intellectual disability comorbidity, were identified through records maintained at the California Department of Developmental Services and linked to their birth records. Controls derived from birth records were matched to cases 10:1 by sex and birth year. Exposure Data from California state mandated Pesticide Use Reporting were integrated into a geographic information system tool to estimate prenatal and infant exposures to pesticides (measured as pounds of pesticides applied per acre/month within 2000 m from the maternal residence). 11 high use pesticides were selected for…

It is common to measure continuous outcomes using different scales (eg, quality of life, severity of anxiety or depression), therefore these outcomes need to be standardized before pooling in a meta-analysis. Common methods of standardization include using the standardized mean difference, the odds ratio derived from continuous data, the minimally important difference, and the ratio of means. Other ways of making data more meaningful to end users include transforming standardized effects back to original scales and transforming odds ratios to absolute effects using an assumed baseline risk. For these methods to be valid, the scales or instruments being combined across studies need to have assessed the same or a similar construct

OBJECTIVES: To determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence for recurrent VTE up to 10 years. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019). STUDY SELECTION: Randomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment. DATA EXTRACTION AND SYNTHESIS: Two investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of…

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid β in the form of extracellular plaques and by intracellular neurofibrillary tangles, with eventual neurodegeneration and dementia. There is currently no disease-modifying treatment though several symptomatic medications exist with modest benefit on cognition. Acetylcholinesterase inhibitors have a consistent benefit across all stages of dementia; their benefit in mild cognitive impairment and prodromal AD is unproven. Memantine has a smaller benefit on cognition overall which is limited to the moderate to severe stages, and the combination of a cholinesterase inhibitor and memantine may have additional efficacy. Evidence for the efficacy of vitamin E supplementation and medical foods is weak but might be considered in the context of cost, availability, and safety in individual patients. Apparently promising disease-modifying interventions, mostly addressing the amyloid cascade hypothesis of AD, have recently failed to demonstrate efficacy so novel approaches must be…

Abstract Objectives To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. Design Mendelian randomisation study. Setting UK Biobank and international genome-wide association study data. Participants Predominantly participants of European ancestry. Exposure Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. Main outcomes measure The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. Results Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63,…

OBJECTIVE: To examine differences in vaping and smoking prevalence among adolescents in Canada, England, and the United States. DESIGN: Repeat cross sectional surveys. SETTING: Online surveys in Canada, England, and the US. PARTICIPANTS: National samples of 16 to 19 year olds in 2017 and 2018, recruited from commercial panels in Canada (n=7891), England (n=7897), and the US (n=8140). MAIN OUTCOME MEASURES: Prevalence of vaping and smoking was assessed for use ever, in the past 30 days, in the past week, and on 15 days or more in the past month. Use of JUUL (a nicotine salt based electronic cigarette with high nicotine concentration) and usual vaping brands were also assessed. Logistic regression models examined differences in vaping and smoking between countries and over time. RESULTS: The prevalence of vaping in the past 30 days, in the past week, and on 15 days or more in the past month increased in Canada and the US between 2017 and 2018 (P<0.001 for all), including among non-smokers and experimental smokers, with no changes in England. Smoking prevalence increased in Canada…

Abstract Objective To assess effects of increasing omega-3, omega-6, and total polyunsaturated fatty acids (PUFA) on diabetes diagnosis and glucose metabolism. Design Systematic review and meta-analyses. Data sources Medline, Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, Clinicaltrials.gov, and trials in relevant systematic reviews. Eligibility criteria Randomised controlled trials of at least 24 weeks’ duration assessing effects of increasing α-linolenic acid, long chain omega-3, omega-6, or total PUFA, which collected data on diabetes diagnoses, fasting glucose or insulin, glycated haemoglobin (HbA1c), and/or homoeostatic model assessment for insulin resistance (HOMA-IR). Data synthesis Statistical analysis included random effects meta-analyses using relative risk and mean difference, and sensitivity analyses. Funnel plots were examined and subgrouping assessed effects of intervention type, replacement, baseline risk of diabetes and use of antidiabetes drugs, trial duration, and dose. Risk of bias was assessed with the Cochrane tool and quality of…

OBJECTIVE: To examine whether physical inactivity is a risk factor for dementia, with attention to the role of cardiometabolic disease in this association and reverse causation bias that arises from changes in physical activity in the preclinical (prodromal) phase of dementia. DESIGN: Meta-analysis of 19 prospective observational cohort studies. DATA SOURCES: The Individual-Participant-Data Meta-analysis in Working Populations Consortium, the Inter-University Consortium for Political and Social Research, and the UK Data Service, including a total of 19 of a potential 9741 studies. REVIEW METHOD: The search strategy was designed to retrieve individual-participant data from prospective cohort studies. Exposure was physical inactivity; primary outcomes were incident all-cause dementia and Alzheimer's disease; and the secondary outcome was incident cardiometabolic disease (that is, diabetes, coronary heart disease, and stroke). Summary estimates were obtained using random effects meta-analysis. RESULTS: Study population included 404 840 people (mean age 45.5 years, 57.7% women) who were…

Upper gastrointestinal bleeding (UGIB) is a common medical emergency, with a reported mortality of 2-10%. Patients identified as being at very low risk of either needing an intervention or death can be managed as outpatients. For all other patients, intravenous fluids as needed for resuscitation and red cell transfusion at a hemoglobin threshold of 70-80 g/L are recommended. After resuscitation is initiated, proton pump inhibitors (PPIs) and the prokinetic agent erythromycin may be administered, with antibiotics and vasoactive drugs recommended in patients who have cirrhosis. Endoscopy should be undertaken within 24 hours, with earlier endoscopy considered after resuscitation in patients at high risk, such as those with hemodynamic instability. Endoscopic treatment is used for variceal bleeding (for example, ligation for esophageal varices and tissue glue for gastric varices) and for high risk non-variceal bleeding (for example, injection, thermal probes, or clips for lesions with active bleeding or non-bleeding visible vessel). Patients who require endoscopic therapy for ulcer…

OBJECTIVE: To evaluate the associations between maternal diabetes diagnosed before or during pregnancy and early onset cardiovascular disease (CVD) in offspring during their first four decades of life. DESIGN: Population based cohort study. SETTING: Danish national health registries. PARTICIPANTS: All 2 432 000 liveborn children without congenital heart disease in Denmark during 1977-2016. Follow-up began at birth and continued until first time diagnosis of CVD, death, emigration, or 31 December 2016, whichever came first. EXPOSURES FOR OBSERVATIONAL STUDIES: Pregestational diabetes, including type 1 diabetes (n=22 055) and type 2 diabetes (n=6537), and gestational diabetes (n=26 272). MAIN OUTCOME MEASURES: The primary outcome was early onset CVD (excluding congenital heart diseases) defined by hospital diagnosis. Associations between maternal diabetes and risks of early onset CVD in offspring were studied. Cox regression was used to assess whether a maternal history of CVD or maternal diabetic complications affected these associations. Adjustments were made for calendar year, sex,…

### What you need to know Hypertension in pregnancy is a common condition, affecting about 10% of pregnant women. This includes women with chronic hypertension—which may be diagnosed before pregnancy or in the early stages of pregnancy (<20 weeks’ gestation)—and women with hypertension related to pregnancy (gestational hypertension and pre-eclampsia) (see box 1). If not identified and treated, hypertension can lead to adverse events for both the woman and her baby, including increased risk of maternal stroke, lower birth weight, and increased risk of the baby requiring neonatal intensive care. Box 1 ### Definitions for hypertensive disorders of pregnancyRETURN TO TEXT General practitioners and specialists other than obstetricians play a vital role in the identification of hypertension during pregnancy, first …

OBJECTIVE: To assess the immediate impact of the introduction of minimum unit pricing in Scotland on household alcohol purchases. DESIGN: Controlled interrupted time series analysis. SETTING: Purchase data from Kantar Worldpanel's household shopping panel for 2015-18. PARTICIPANTS: 5325 Scottish households, 54 807 English households as controls, and 10 040 households in northern England to control for potential cross border effects. INTERVENTIONS: Introduction of a minimum price of 50p (€0.55; $0.61) per UK unit (6.25p per gram) for the sale of alcohol in Scotland on 1 May 2018. MAIN OUTCOME MEASURES: Price per gram of alcohol, number of grams of alcohol purchased from off-trade by households, and weekly household expenditure on alcohol. RESULTS: The introduction of minimum unit pricing in Scotland was associated with an increase in purchase price of 0.64p per gram of alcohol (95% confidence interval 0.54 to 0.75), a reduction in weekly purchases of 9.5 g of alcohol per adult per household (5.1 to 13.9), and a non-significant increase in weekly expenditure on alcohol per household…

Abstract Objective To assess risks and costs of hospital admission associated with short term exposure to fine particulate matter with diameter less than 2.5 µm (PM 2.5 ) for 214 mutually exclusive disease groups. Design Time stratified, case crossover analyses with conditional logistic regressions adjusted for non-linear confounding effects of meteorological variables. Setting Medicare inpatient hospital claims in the United States, 2000-12 (n=95 277 169). Participants All Medicare fee-for-service beneficiaries aged 65 or older admitted to hospital. Main outcome measures Risk of hospital admission, number of admissions, days in hospital, inpatient and post-acute care costs, and value of statistical life (that is, the economic value used to measure the cost of avoiding a death) due to the lives lost at discharge for 214 disease groups. Results Positive associations between short term exposure to PM 2.5 and risk of hospital admission were found for several prevalent but rarely studied diseases, such as septicemia, fluid and electrolyte disorders, and acute and unspecified renal…

OBJECTIVE: To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. DESIGN: International cross sectional survey. SETTING: International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. PARTICIPANTS: Key stakeholders identified by ISN's national and regional leaders. MAIN OUTCOME MEASURES: Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. RESULTS: Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world's population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management-namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney disease was available in 91 (42%) of 218 countries worldwide. Estimates varied more than 800-fold…

OBJECTIVE: To assess the association between intake of non-sugar sweeteners (NSS) and important health outcomes in generally healthy or overweight/obese adults and children. DESIGN: Systematic review following standard Cochrane review methodology. DATA SOURCES: Medline (Ovid), Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, Clinicaltrials.gov, and reference lists of relevant publications. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies including generally healthy adults or children with or without overweight or obesity were eligible. Included study designs allowed for a direct comparison of no intake or lower intake of NSS with higher NSS intake. NSSs had to be clearly named, the dose had to be within the acceptable daily intake, and the intervention duration had to be at least seven days. MAIN OUTCOME MEASURES: Body weight or body mass index, glycaemic control, oral health, eating behaviour, preference for sweet taste, cancer, cardiovascular disease, kidney disease, mood, behaviour, neurocognition, and adverse effects. RESULTS: The search resulted…

OBJECTIVE: To compare arthroscopic hip surgery with physiotherapy and activity modification for improving patient reported outcome measures in patients with symptomatic femoroacetabular impingement (FAI). DESIGN: Two group parallel, assessor blinded, pragmatic randomised controlled trial. SETTING: Secondary and tertiary care centres across seven NHS England sites. PARTICIPANTS: 222 participants aged 18 to 60 years with symptomatic FAI confirmed clinically and with imaging (radiography or magnetic resonance imaging) were randomised (1:1) to receive arthroscopic hip surgery (n=112) or a programme of physiotherapy and activity modification (n=110). Exclusion criteria included previous surgery, completion of a physiotherapy programme targeting FAI within the preceding 12 months, established osteoarthritis (Kellgren-Lawrence grade ≥2), and hip dysplasia (centre-edge angle <20 degrees). INTERVENTIONS: Participants in the physiotherapy group received a goal based programme tailored to individual patient needs, with emphasis on improving core stability and movement control. A maximum of…

OBJECTIVE: To investigate the relation between preterm birth (gestational age <37 weeks) and risk of CKD from childhood into mid-adulthood. DESIGN: National cohort study. SETTING: Sweden. PARTICIPANTS: 4 186 615 singleton live births in Sweden during 1973-2014. EXPOSURES: Gestational age at birth, identified from nationwide birth records in the Swedish birth registry. MAIN OUTCOME MEASURES: CKD, identified from nationwide inpatient and outpatient diagnoses through 2015 (maximum age 43 years). Cox regression was used to examine gestational age at birth and risk of CKD while adjusting for potential confounders, and co-sibling analyses assessed the influence of unmeasured shared familial (genetic or environmental) factors. RESULTS: 4305 (0.1%) participants had a diagnosis of CKD during 87.0 million person years of follow-up. Preterm birth and extremely preterm birth (<28 weeks) were associated with nearly twofold and threefold risks of CKD, respectively, from birth into mid-adulthood (adjusted hazard ratio 1.94, 95% confidence interval 1.74 to 2.16; P<0.001; 3.01, 1.67 to 5.45;…

Prevention of harms related to gambling requires investment in population based approaches, say Heather Wardle and colleagues ### Key messages In 2017 the gambling regulator for Great Britain, the Gambling Commission, described problem gambling as a public health concern (box 1)3 and emphasised the need to increase protection from harm.4 In 2018 the Faculty of Public Health released a position paper arguing for the introduction of harm prevention measures, underpinned by legislation, targeted at the whole population.5 The Labour Party recently shared plans for a radical overhaul of legislation to reduce the harms associated with “Britain’s hidden epidemic.”6 Box 1 ### Gambling behaviour in Great Britain12RETURN TO TEXT

M Jeeva Sankar and colleagues call for urgent action to improve quality of care at birth and implement antimicrobial stewardship in health facilities in South Asia to reduce neonatal deaths from sepsis

OBJECTIVE: To estimate the risk of acute myocardial infarction (AMI) or stroke in adults with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). DESIGN: Matched cohort study. SETTING: Population based, electronic primary healthcare databases before 31 December 2015 from four European countries: Italy (n=1 542 672), Netherlands (n=2 225 925), Spain (n=5 488 397), and UK (n=12 695 046). PARTICIPANTS: 120 795 adults with a recorded diagnosis of NAFLD or NASH and no other liver diseases, matched at time of NAFLD diagnosis (index date) by age, sex, practice site, and visit, recorded at six months before or after the date of diagnosis, with up to 100 patients without NAFLD or NASH in the same database. MAIN OUTCOME MEASURES: Primary outcome was incident fatal or non-fatal AMI and ischaemic or unspecified stroke. Hazard ratios were estimated using Cox models and pooled across databases by random effect meta-analyses. RESULTS: 120 795 patients with recorded NAFLD or NASH diagnoses were identified with mean follow-up 2.1-5.5 years. After adjustment for age and…

OBJECTIVE: To assess the appropriateness of outpatient antibiotic prescribing for privately insured children and non-elderly adults in the US using a comprehensive classification scheme of diagnosis codes in ICD-10-CM (international classification of diseases-clinical modification, 10th revision), which replaced ICD-9-CM in the US on 1 October 2015. DESIGN: Cross sectional study. SETTING: MarketScan Commercial Claims and Encounters database, 2016. PARTICIPANTS: 19.2 million enrollees aged 0-64 years. MAIN OUTCOME MEASURES: A classification scheme was developed that determined whether each of the 91 738 ICD-10-CM diagnosis codes "always," "sometimes," or "never" justified antibiotics. For each antibiotic prescription fill, this scheme was used to classify all diagnosis codes in claims during a look back period that began three days before antibiotic prescription fills and ended on the day fills occurred. The main outcome was the proportion of fills in each of four mutually exclusive categories: "appropriate" (associated with at least one "always" code during the look back period,…

Mental disorders often coexist with other non-communicable diseases and they share many risk factors. Dan Stein and colleagues examine the evidence for an integrated approach

Abstract Objective To examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA). Design Cross sectional analysis. Setting European regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices. Eligibility criteria Pivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016. Main outcome measures Study design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Cochrane tool (bias arising from the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result); and reporting adequacy (completeness and consistency of information in trial protocols, publications, supplementary appendices, clinical trial registry records, and regulatory documents). Results Between 2014 and 2016, the EMA approved 32 new cancer drugs on the basis of 54 pivotal studies. Of…

OBJECTIVE: To determine patient, institution, and machine characteristics that contribute to variation in radiation doses used for computed tomography (CT). DESIGN: Prospective cohort study. SETTING: Data were assembled and analyzed from the University of California San Francisco CT International Dose Registry. PARTICIPANTS: Standardized data from over 2.0 million CT examinations of adults who underwent CT between November 2015 and August 2017 from 151 institutions, across seven countries (Switzerland, Netherlands, Germany, United Kingdom, United States, Israel, and Japan). MAIN OUTCOME MEASURES: Mean effective doses and proportions of high dose examinations for abdomen, chest, combined chest and abdomen, and head CT were determined by patient characteristics (sex, age, and size), type of institution (trauma center, care provision 24 hours per day and seven days per week, academic, private), institutional practice volume, machine factors (manufacturer, model), country, and how scanners were used, before and after adjustment for patient characteristics, using hierarchical linear and…

Abstract Objective To assess the effects of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation in the prevention of gastric cancer. Design Blinded randomized placebo controlled trial. Setting Linqu County, Shandong province, China. Participants 3365 residents of a high risk region for gastric cancer. 2258 participants seropositive for antibodies to H pylori were randomly assigned to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2×2×2 factorial design, and 1107 H pylori seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2×2 factorial design. Interventions H pylori treatment with amoxicillin and omeprazole for two weeks; vitamin (C, E, and selenium) and garlic (extract and oil) supplementation for 7.3 years (1995-2003). Main outcome measures Primary outcomes were cumulative incidence of gastric cancer identified through scheduled gastroscopies and active clinical follow-up through 2017, and deaths due to gastric cancer ascertained from…

CLINICAL QUESTION: What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice. CURRENT PRACTICE: Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing. RECOMMENDATION: The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those ≤30 years old). HOW THIS GUIDELINE WAS CREATED: A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. THE EVIDENCE: The systematic review…

OBJECTIVE: To quantify the effect on cervical disease at age 20 years of immunisation with bivalent human papillomavirus (HPV) vaccine at age 12-13 years. DESIGN: Retrospective population study, 1988-96. SETTING: National vaccination and cervical screening programmes in Scotland. PARTICIPANTS: 138 692 women born between 1 January 1988 and 5 June 1996 and who had a smear test result recorded at age 20. MAIN OUTCOME MEASURES: Effect of vaccination on cytology results and associated histological diagnoses from first year of screening (while aged 20), calculated using logistic regression. RESULTS: 138 692 records were retrieved. Compared with unvaccinated women born in 1988, vaccinated women born in 1995 and 1996 showed an 89% reduction (95% confidence interval 81% to 94%) in prevalent cervical intraepithelial neoplasia (CIN) grade 3 or worse (from 0.59% (0.48% to 0.71%) to 0.06% (0.04% to 0.11%)), an 88% reduction (83% to 92%) in CIN grade 2 or worse (from 1.44% (1.28% to 1.63%) to 0.17% (0.12% to 0.24%)), and a 79% reduction (69% to 86%) in CIN grade 1 (from 0.69% (0.58% to 0.63%) to…

Abstract Objective To study the effect of long term exposure to ambient fine particulate matter of diameter ≤2.5 μm (PM2.5) on the incidence of total, ischemic, and hemorrhagic stroke among Chinese adults. Design Population based prospective cohort study. Setting Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project carried out in 15 provinces across China. Participants 117 575 Chinese men and women without stroke at baseline in the China-PAR project. Main outcome measures Incidence of total, ischemic, and hemorrhagic stroke. Results The long term average PM2.5 level from 2000 to 2015 at participants’ residential addresses was 64.9 μg/m3, ranging from 31.2 μg/m3 to 97.0 μg/m3. During 900 214 person years of follow-up, 3540 cases of incident stroke were identified, of which 63.0% (n=2230) were ischemic and 27.5% (n=973) were hemorrhagic. Compared with the first quarter of exposure to PM2.5 (<54.5 μg/m3), participants in the highest quarter (>78.2 μg/m3) had an increased risk of incident stroke (hazard ratio 1.53, 95% confidence interval 1.34 to…

OBJECTIVE: To evaluate the associations between adiposity measures (body mass index, waist circumference, and waist-to-height ratio) with decline in glomerular filtration rate (GFR) and with all cause mortality. DESIGN: Individual participant data meta-analysis. SETTING: Cohorts from 40 countries with data collected between 1970 and 2017. PARTICIPANTS: Adults in 39 general population cohorts (n=5 459 014), of which 21 (n=594 496) had data on waist circumference; six cohorts with high cardiovascular risk (n=84 417); and 18 cohorts with chronic kidney disease (n=91 607). MAIN OUTCOME MEASURES: ) and all cause mortality. RESULTS: Over a mean follow-up of eight years, 246 607 (5.6%) individuals in the general population cohorts had GFR decline (18 118 (0.4%) end stage kidney disease events) and 782 329 (14.7%) died. Adjusting for age, sex, race, and current smoking, the hazard ratios for GFR decline comparing body mass indices 30, 35, and 40 with body mass index 25 were 1.18 (95% confidence interval 1.09 to 1.27), 1.69 (1.51 to 1.89), and 2.02 (1.80 to 2.27), respectively. Results were…

Clinical prediction models estimate the risk of existing disease or future outcome for an individual, which is conditional on the values of multiple predictors such as age, sex, and biomarkers. In this article, Bonnett and colleagues provide a guide to presenting clinical prediction models so that they can be implemented in practice, if appropriate. They describe how to create four presentation formats and discuss the advantages and disadvantages of each format. A key message is the need for stakeholder engagement to determine the best presentation option in relation to the clinical context of use and the intended users

Burnout is an occupational phenomenon and we need to look beyond the individual to find effective solutions, argue A Montgomery and colleagues

OBJECTIVE: To estimate all cause mortality and cause specific mortality among patients taking proton pump inhibitors (PPIs). DESIGN: Longitudinal observational cohort study. SETTING: US Department of Veterans Affairs. PARTICIPANTS: New users of PPIs (n=157 625) or H2 blockers (n=56 842). MAIN OUTCOME MEASURES: All cause mortality and cause specific mortality associated with taking PPIs (values reported as number of attributable deaths per 1000 patients taking PPIs). RESULTS: There were 45.20 excess deaths (95% confidence interval 28.20 to 61.40) per 1000 patients taking PPIs. Circulatory system diseases (number of attributable deaths per 1000 patients taking PPIs 17.47, 95% confidence interval 5.47 to 28.80), neoplasms (12.94, 1.24 to 24.28), infectious and parasitic diseases (4.20, 1.57 to 7.02), and genitourinary system diseases (6.25, 3.22 to 9.24) were associated with taking PPIs. There was a graded relation between cumulative duration of PPI exposure and the risk of all cause mortality and death due to circulatory system diseases, neoplasms, and genitourinary system diseases.…

Abstract Objective To assess the association between stress related disorders and subsequent risk of cardiovascular disease. Design Population based, sibling controlled cohort study. Setting Population of Sweden. Participants 136 637 patients in the Swedish National Patient Register with stress related disorders, including post-traumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, and other stress reactions, from 1987 to 2013; 171 314 unaffected full siblings of these patients; and 1 366 370 matched unexposed people from the general population. Main outcome measures Primary diagnosis of incident cardiovascular disease—any or specific subtypes (ischaemic heart disease, cerebrovascular disease, emboli/thrombosis, hypertensive diseases, heart failure, arrhythmia/conduction disorder, and fatal cardiovascular disease)—and 16 individual diagnoses of cardiovascular disease. Hazard ratios for cardiovascular disease were derived from Cox models, after controlling for multiple confounders. Results During up to 27 years of follow-up, the crude incidence rate of any…

OBJECTIVE: To assess the associations between the consumption of sugary drinks (such as sugar sweetened beverages and 100% fruit juices), artificially sweetened beverages, and the risk of cancer. DESIGN: Population based prospective cohort study. SETTING AND PARTICIPANTS: Overall, 101 257 participants aged 18 and over (mean age 42.2, SD 14.4; median follow-up time 5.1 years) from the French NutriNet-Santé cohort (2009-2017) were included. Consumptions of sugary drinks and artificially sweetened beverages were assessed by using repeated 24 hour dietary records, which were designed to register participants' usual consumption for 3300 different food and beverage items. MAIN OUTCOME MEASURES: Prospective associations between beverage consumption and the risk of overall, breast, prostate, and colorectal cancer were assessed by multi-adjusted Fine and Gray hazard models, accounting for competing risks. Subdistribution hazard ratios were computed. RESULTS: The consumption of sugary drinks was significantly associated with the risk of overall cancer (n=2193 cases, subdistribution hazard…

OBJECTIVES: To summarise and compare the accuracy of physical examination, computed tomography (CT), sonography of the optic nerve sheath diameter (ONSD), and transcranial Doppler pulsatility index (TCD-PI) for the diagnosis of elevated intracranial pressure (ICP) in critically ill patients. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Six databases, including Medline, EMBASE, and PubMed, from inception to 1 September 2018. STUDY SELECTION CRITERIA: English language studies investigating accuracy of physical examination, imaging, or non-invasive tests among critically ill patients. The reference standard was ICP of 20 mm Hg or more using invasive ICP monitoring, or intraoperative diagnosis of raised ICP. DATA EXTRACTION: Two reviewers independently extracted data and assessed study quality using the quality assessment of diagnostic accuracy studies tool. Summary estimates were generated using a hierarchical summary receiver operating characteristic (ROC) model. RESULTS: 40 studies (n=5123) were included. Of physical examination signs, pooled sensitivity and specificity…

What you need to know• Cannabis based products for medicinal use contain cannabinoids derived from the cannabis plant, including ∆ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC and CBD.Synthetic cannabinoids for medicinal use typically mimic the effects of specific cannabinoids such as THC• THC is the constituent of cannabis that causes the "high," whereas CBD is not intoxicating at typical doses.THC and CBD have contrasting mechanisms of action and therapeutic indications; THC carries a higher risk of adverse events compared with CBD• Rescheduling on 1 November 2018 permits some unlicensed cannabis based products to be prescribed for the first time in the UK, but only by doctors on the relevant Specialist Register of the General Medical Council• Indications for treatment, supported by evidence of low to moderate certainty, include chronic pain, some treatment resistant epilepsies, and nausea and vomiting caused by chemotherapy (table 2)• Non-medicinal CBD products are legal and widely available on the internet and from health food retailers, but they…

OBJECTIVES: Women remain underrepresented on faculties of medicine and the life sciences more broadly. Whether gender differences in self presentation of clinical research exist and may contribute to this gender gap has been challenging to explore empirically. The objective of this study was to analyze whether men and women differ in how positively they frame their research findings and to analyze whether the positive framing of research is associated with higher downstream citations. DESIGN: Retrospective observational study. DATA SOURCES: Titles and abstracts from 101 720 clinical research articles and approximately 6.2 million general life science articles indexed in PubMed and published between 2002 and 2017. MAIN OUTCOME MEASURES: Analysis of article titles and abstracts to determine whether men and women differ in how positively they present their research through use of terms such as "novel" or "excellent." For a set of 25 positive terms, we estimated the relative probability of positive framing as a function of the gender composition of the first and last authors, adjusting…

OBJECTIVE: To evaluate the association of changes in red meat consumption with total and cause specific mortality in women and men. DESIGN: Two prospective cohort studies with repeated measures of diet and lifestyle factors. SETTING: Nurses' Health Study and the Health Professionals Follow-up Study, United States. PARTICIPANTS: 53 553 women and 27 916 men without cardiovascular disease or cancer at baseline. MAIN OUTCOME MEASURE: Death confirmed by state vital statistics records, the national death index, or reported by families and the postal system. RESULTS: 14 019 deaths occurred during 1.2 million person years of follow-up. Increases in red meat consumption over eight years were associated with a higher mortality risk in the subsequent eight years among women and men (both P for trend<0.05, P for heterogeneity=0.97). An increase in total red meat consumption of at least half a serving per day was associated with a 10% higher mortality risk (pooled hazard ratio 1.10, 95% confidence interval 1.04 to 1.17). For processed and unprocessed red meat consumption, an increase of at least…

Abstract Objective To evaluate the association between antibiotic treatment for urinary tract infection (UTI) and severe adverse outcomes in elderly patients in primary care. Design Retrospective population based cohort study. Setting Clinical Practice Research Datalink (2007-15) primary care records linked to hospital episode statistics and death records in England. Participants 157 264 adults aged 65 years or older presenting to a general practitioner with at least one diagnosis of suspected or confirmed lower UTI from November 2007 to May 2015. Main outcome measures Bloodstream infection, hospital admission, and all cause mortality within 60 days after the index UTI diagnosis. Results Among 312 896 UTI episodes (157 264 unique patients), 7.2% (n=22 534) did not have a record of antibiotics being prescribed and 6.2% (n=19 292) showed a delay in antibiotic prescribing. 1539 episodes of bloodstream infection (0.5%) were recorded within 60 days after the initial UTI. The rate of bloodstream infection was significantly higher among those patients not prescribed an antibiotic (2.9%;…

CLINICAL QUESTION: Recent 15-year updates of sigmoidoscopy screening trials provide new evidence on the effectiveness of colorectal cancer screening. Prompted by the new evidence, we asked: "Does colorectal cancer screening make an important difference to health outcomes in individuals initiating screening at age 50 to 79? And which screening option is best?" CURRENT PRACTICE: Numerous guidelines recommend screening, but vary on recommended test, age and screening frequency. This guideline looks at the evidence and makes recommendations on screening for four screening options: faecal immunochemical test (FIT) every year, FIT every two years, a single sigmoidoscopy, or a single colonoscopy. RECOMMENDATIONS: These recommendations apply to adults aged 50-79 years with no prior screening, no symptoms of colorectal cancer, and a life expectancy of at least 15 years. For individuals with an estimated 15-year colorectal cancer risk below 3%, we suggest no screening (weak recommendation). For individuals with an estimated 15-year risk above 3%, we suggest screening with one of the four…

Abstract Objective To estimate the risks of daily hospital admissions for cause specific major cardiovascular diseases associated with short term exposure to ambient fine particulate matter (aerodynamic diameter ≤2.5 μm; PM2.5) pollution in China. Design National time series study. Setting 184 major cities in China. Population 8 834 533 hospital admissions for cardiovascular causes in 184 Chinese cities recorded by the national database of Urban Employee Basic Medical Insurance from 1 January 2014 to 31 December 2017. Main outcome measures Daily counts of city specific hospital admissions for primary diagnoses of ischaemic heart disease, heart failure, heart rhythm disturbances, ischaemic stroke, and haemorrhagic stroke among different demographic groups were used to estimate the associations between PM2.5 and morbidity. An overdispersed generalised additive model was used to estimate city specific associations between PM2.5 and cardiovascular admissions, and random effects meta-analysis used to combine the city specific estimates. Results Over the study period, a mean of 47…

Manjulaa Narasimhan and colleagues argue that there is a pressing need for a clearer conceptualisation of self care to support health policy

The risks, measurements of severity, and management of severe acute pancreatitis and its complications have evolved rapidly over the past decade. Evidence suggests that initial goal directed therapy, nutritional support, and vigilance for pancreatic complications are best practice. Patients can develop pancreatic fluid collections including acute pancreatic fluid collections, pancreatic pseudocysts, acute necrotic collections, and walled-off necrosis. Several randomized controlled trials and cohort studies have recently highlighted the advantage of managing these conditions with a progressive approach, with initial draining for infection followed by less invasive techniques. Surgery is no longer an early intervention and may not be needed. Instead, interventional radiologic and endoscopic methods seem to be safer with at least as good survival outcomes. Newly developed evidence based quality indicators are available to assess and improve performance. Development and clinical testing of drugs to target the mechanisms of disease are necessary for further advancements.

OBJECTIVES: To examine the association between the Life Simple 7 cardiovascular health score at age 50 and incidence of dementia. DESIGN: Prospective cohort study. SETTING: Civil service departments in London (Whitehall II study; study inception 1985-88). PARTICIPANTS: 7899 participants with data on the cardiovascular health score at age 50. EXPOSURES: The cardiovascular health score included four behavioural (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics, coded on a three point scale (0, 1, 2). The cardiovascular health score was the sum of seven metrics (score range 0-14) and was categorised into poor (scores 0-6), intermediate (7-11), and optimal (12-14) cardiovascular health. MAIN OUTCOME MEASURE: Incident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017. RESULTS: 347 incident cases of dementia were recorded over a median follow-up of 24.7 years. Compared with an incidence rate of dementia of 3.2 (95% confidence interval 2.5 to 4.0)…

OBJECTIVE: To measure the association of China's universal two child policy, announced in October 2015, with changes in births and health related birth characteristics. DESIGN: National, descriptive before-and-after comparative study. SETTING: Every county in 28 of 31 provinces of mainland China. PARTICIPANTS: Births included in two national databases: 67 786 749 births from county level monthly aggregated data between January 2014 and December 2017; and 31 786 279 deliveries from individual level delivery information records between January 2015 and December 2017. MAIN OUTCOME MEASURES: Monthly mean number of births and mean proportion of multiparous mothers and mothers aged 35 and over, preterm deliveries, and caesarean deliveries. RESULTS: The study had two phases: the baseline period (up to and including June 2016, nine months after the policy announcement) and the effective period (from July 2016 to December 2017). The estimated number of additional births attributable to the new policy between July 2016 and December 2017 was 5.40 million (95% confidence interval 4.34 to 6.46).…

Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome (HHS) are life threatening complications that occur in patients with diabetes. In addition to timely identification of the precipitating cause, the first step in acute management of these disorders includes aggressive administration of intravenous fluids with appropriate replacement of electrolytes (primarily potassium). In patients with diabetic ketoacidosis, this is always followed by administration of insulin, usually via an intravenous insulin infusion that is continued until resolution of ketonemia, but potentially via the subcutaneous route in mild cases. Careful monitoring by experienced physicians is needed during treatment for diabetic ketoacidosis and HHS. Common pitfalls in management include premature termination of intravenous insulin therapy and insufficient timing or dosing of subcutaneous insulin before discontinuation of intravenous insulin. This review covers recommendations for acute management of diabetic ketoacidosis and HHS, the complications associated with these disorders, and methods for…

The 2018 WHO draft guidance on fatty acids fails to consider the importance of the food matrix, argue Arne Astrup and colleagues

Abstract Objective To compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent. Design Cohort study. Setting 22 centres across England, Scotland, and Wales in UK Biobank (2006-10). Participants 451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification. Main outcome measure Odds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women. Results Of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of…

As improvement practice and research begin to come of age, Mary Dixon-Woods considers the key areas that need attention if we are to reap their benefits

Peripartum cardiomyopathy (PPCM) is a rare, often dilated, cardiomyopathy with systolic dysfunction that presents in late pregnancy or, more commonly, the early postpartum period. Although the condition is prevalent worldwide, women with black ancestry seem to be at greatest risk, and the condition has a particularly high incidence in Nigeria and Haiti. Other risk factors include pre-eclampsia, advanced maternal age, and multiple gestation pregnancy. Although the complete pathophysiology of peripartum cardiomyopathy remains unclear, research over the past decade suggests the importance of vasculo-hormonal pathways in women with underlying susceptibility. At least some women with the condition harbor an underlying sarcomere gene mutation. More than half of affected women recover systolic function, although some are left with a chronic cardiomyopathy, and a minority requires mechanical support or cardiac transplantation (or both). Other potential complications include thromboembolism and arrhythmia. Currently, management entails standard treatments for heart failure with reduced…

OBJECTIVE: To map and assess prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Systematic review. DATA SOURCES: PubMed until November 2018 and hand searched references from eligible articles. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Studies developing, validating, or updating a prediction model in COPD patients and focusing on any potential clinical outcome. RESULTS: The systematic search yielded 228 eligible articles, describing the development of 408 prognostic models, the external validation of 38 models, and the validation of 20 prognostic models derived for diseases other than COPD. The 408 prognostic models were developed in three clinical settings: outpatients (n=239; 59%), patients admitted to hospital (n=155; 38%), and patients attending the emergency department (n=14; 3%). Among the 408 prognostic models, the most prevalent endpoints were mortality (n=209; 51%), risk for acute exacerbation of COPD (n=42; 10%), and risk for readmission after the index hospital admission (n=36; 9%). Overall, the most commonly…

Abstract Objective To examine the effect of regular breakfast consumption on weight change and energy intake in people living in high income countries. Design Systematic review and meta-analysis. Data sources PubMed, Ovid Medline, and CINAHL were searched for randomised controlled trials published between January 1990 and January 2018 investigating the effect of breakfast on weight or energy intake. ClinicalTrials.gov and the World Health Organization’s International Clinical Trials Registry Platform search portal were also searched in October 2018 to identify any registered yet unpublished or ongoing trials. Eligibility criteria for selecting studies Randomised controlled trials from high income countries in adults comparing breakfast consumption with no breakfast consumption that included a measure of body weight or energy intake. Two independent reviewers extracted the data and assessed the risk of bias of included studies. Random effects meta-analyses of the effect of breakfast consumption on weight and daily energy intake were performed. Results Of 13 included trials, seven…

Hai Fang and colleagues highlight the need for better financial protection for poor people

EDITOR'S NOTE: Please see the Editor's Note (doi: https://doi.org/10.1136/bmj.l1042) on Methodological Criticism and an Updated Analysis OBJECTIVE: To investigate the shape of the causal relation between body mass index (BMI) and mortality. DESIGN: Linear and non-linear mendelian randomisation analyses. SETTING: Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom). PARTICIPANTS: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank. MAIN OUTCOME MEASURES: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality. RESULTS: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI…

### What you need to know Sciatica is commonly used to describe radiating leg pain. It is caused by inflammation or compression of the lumbosacral nerve roots (L4-S1) forming the sciatic nerve.1 Sciatica can cause severe discomfort and functional limitation. Recently updated clinical guidelines in Denmark, the US, and the UK highlight the role of conservative treatment for sciatica.234 In this Clinical Update, we provide an overview for non-specialists on diagnosing sciatica and key principles in its management. The term “sciatica” is not clearly defined and it is often used inconsistently by clinicians and patients.5 Radicular pain and lumbosacral radicular syndrome have been suggested as alternatives.6 In this article, we use sciatica and radicular pain synonymously. Radiculopathy describes involvement of the nerve root, which causes neurological deficit including weakness or numbness. Box 1 ### Symptoms and signs suggesting sciaticaRETURN TO TEXT

OBJECTIVE: To examine the associations of vegetarianism with risks of ischaemic heart disease and stroke. DESIGN: Prospective cohort study. SETTING: The EPIC-Oxford study, a cohort in the United Kingdom with a large proportion of non-meat eaters, recruited across the country between 1993 and 2001. PARTICIPANTS: 48 188 participants with no history of ischaemic heart disease, stroke, or angina (or cardiovascular disease) were classified into three distinct diet groups: meat eaters (participants who consumed meat, regardless of whether they consumed fish, dairy, or eggs; n=24 428), fish eaters (consumed fish but no meat; n=7506), and vegetarians including vegans (n=16 254), based on dietary information collected at baseline, and subsequently around 2010 (n=28 364). MAIN OUTCOME MEASURES: Incident cases of ischaemic heart disease and stroke (including ischaemic and haemorrhagic types) identified through record linkage until 2016. RESULTS: Over 18.1 years of follow-up, 2820 cases of ischaemic heart disease and 1072 cases of total stroke (519 ischaemic stroke and 300 haemorrhagic stroke)…

General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these…

People with immunoreactivity to tuberculosis are thought to have lifelong asymptomatic infection and remain at risk for active tuberculosis. Marcel A Behr and colleagues argue that most of these people are no longer infected

The Glasgow coma scale (GCS) is a tool used to assess and calculate a patient’s level of consciousness. It was developed more than 40 years ago by two neurosurgeons in Glasgow and is widely applied today.1 The GCS uses a triple criteria scoring system: best eye opening (maximum 4 points), best verbal response (maximum 5 points), and best motor response (maximum 6 points). These scores are added together to provide a total score between 3 and 15 (fig 1). Fig 1 Glasgow coma scale. Score the best level of response seen for each component. Adapted from Teasdale G. Forty years on: updating the Glasgow Coma Scale. Nursing Times 2014;110:42;12-16 The GCS was initially used to assess level of consciousness in patients after head injury, but the scale is now used in many acutely unwell patients. In hospitals it is also used to monitor patients in intensive care units. During placements you may hear the GCS used to describe confused patients on care of the elderly wards, trauma patients in the emergency department, or patients seen by the “crash” medical emergency team. As a student, you…

Abstract Objective To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. Design Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. Data sources Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. Eligibility criteria for selecting studies Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative…

Essential tremor is one of the most common movement disorders in adults and can affect both children and adults. An updated consensus statement in 2018 redefined essential tremor as an isolated action tremor present in bilateral upper extremities for at least three years. Tremor may also be present in other locations, commonly the neck or the vocal cords. Patients with additional neurologic symptoms are now categorized as "essential tremor plus." Additional clinical features associated with the condition include but are not limited to cognitive impairment, psychiatric disorders, and hearing loss. When treatment is needed, propranolol and primidone are considered first line treatments. Patients who are severely affected are often offered deep brain stimulation. Although the ventral intermediate nucleus of the thalamus is the traditional surgical target, the caudal zona incerta is also being studied as a possible superior alternative. Magnetic resonance imaging guided high intensity focused ultrasound is a newer surgical alternative that may be ideal for patients with substantial…

OBJECTIVE: To evaluate if induction of labour at 41 weeks improves perinatal and maternal outcomes in women with a low risk pregnancy compared with expectant management and induction of labour at 42 weeks. DESIGN: Multicentre, open label, randomised controlled superiority trial. SETTING: 14 hospitals in Sweden, 2016-18. PARTICIPANTS: 2760 women with a low risk uncomplicated singleton pregnancy randomised (1:1) by the Swedish Pregnancy Register. 1381 women were assigned to the induction group and 1379 were assigned to the expectant management group. INTERVENTIONS: Induction of labour at 41 weeks and expectant management and induction of labour at 42 weeks. MAIN OUTCOME MEASURES: The primary outcome was a composite perinatal outcome including one or more of stillbirth, neonatal mortality, Apgar score less than 7 at five minutes, pH less than 7.00 or metabolic acidosis (pH <7.05 and base deficit >12 mmol/L) in the umbilical artery, hypoxic ischaemic encephalopathy, intracranial haemorrhage, convulsions, meconium aspiration syndrome, mechanical ventilation within 72 hours, or obstetric…

OBJECTIVE: ) of <6.5% is associated with lower risk for retinopathy and nephropathy than less tight control in children and adults with type 1 diabetes. DESIGN: Population based cohort study. SETTING: Swedish National Diabetes Registry, 1 January 1998 to 31 December 2017. PARTICIPANTS: 10 398 children and adults with type 1 diabetes followed from diagnosis, or close thereafter, until end of 2017. MAIN OUTCOME MEASURES: . RESULTS: <6.5% compared with 6.5-6.9% (relative risk 1.34, 95% confidence interval 1.09 to 1.64, P=0.005). CONCLUSIONS: levels >7.0%.

OBJECTIVES: To compare the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis for Alzheimer's disease. DESIGN: Nationwide case-control study. SETTING: Finnish national population and drug register, between 1999 and 2013. PARTICIPANTS: All postmenopausal women (n=84 739) in Finland who, between 1999 and 2013, received a diagnosis of Alzheimer's disease from a neurologist or geriatrician, and who were identified from a national drug register. Control women without a diagnosis (n=84 739), matched by age and hospital district, were traced from the Finnish national population register. INTERVENTIONS: Data on hormone therapy use were obtained from the Finnish national drug reimbursement register. MAIN OUTCOME MEASURES: Odds ratios and 95% confidence intervals for Alzheimer's disease, calculated with conditional logistic regression analysis. RESULTS: In 83 688 (98.8%) women, a diagnosis for Alzheimer's disease was made at the age of 60 years or older, and 47 239 (55.7%) women had been over 80 years of age at diagnosis. Use of systemic hormone therapy…