Showing papers in "BMJ in 2019"

RoB 2: a revised tool for assessing risk of bias in randomised trials.

Abstract: 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.

The NHS long term plan

Abstract: Rightly ambitious, but can the NHS deliver?

Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis

Abstract: 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, and study specific associations with all cause mortality were analysed using Cox proportional hazards regression analyses. Study specific results were summarised using random effects meta-analysis. Main outcome measure All cause mortality. Results 39 studies were retrieved for full text review; 10 were eligible for inclusion, three were excluded owing to harmonisation challenges (eg, wrist placement of the accelerometer), and one study did not participate. Two additional studies with unpublished mortality data were also included. Thus, individual level data from eight studies (n=36 383; mean age 62.6 years; 72.8% women), with median follow-up of 5.8 years (range 3.0-14.5 years) and 2149 (5.9%) deaths were analysed. Any physical activity, regardless of intensity, was associated with lower risk of mortality, with a non-linear dose-response. Hazards ratios for mortality were 1.00 (referent) in the first quarter (least active), 0.48 (95% confidence interval 0.43 to 0.54) in the second quarter, 0.34 (0.26 to 0.45) in the third quarter, and 0.27 (0.23 to 0.32) in the fourth quarter (most active). Corresponding hazards ratios for light physical activity were 1.00, 0.60 (0.54 to 0.68), 0.44 (0.38 to 0.51), and 0.38 (0.28 to 0.51), and for moderate-to-vigorous physical activity were 1.00, 0.64 (0.55 to 0.74), 0.55 (0.40 to 0.74), and 0.52 (0.43 to 0.61). For sedentary time, hazards ratios were 1.00 (referent; least sedentary), 1.28 (1.09 to 1.51), 1.71 (1.36 to 2.15), and 2.63 (1.94 to 3.56). Conclusion Higher levels of total physical activity, at any intensity, and less time spent sedentary, are associated with substantially reduced risk for premature mortality, with evidence of a non-linear dose-response pattern in middle aged and older adults. Systematic review registration PROSPERO CRD42018091808.

Accuracy of Patient Health Questionnaire-9 (PHQ-9) for screening to detect major depression: individual participant data meta-analysis

Abstract: 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 variables in a single model. Results Data were obtained for 58 of 72 eligible studies (total n=17 357; major depression cases n=2312). Combined sensitivity and specificity was maximized at a cut-off score of 10 or above among studies using a semistructured interview (29 studies, 6725 participants; sensitivity 0.88, 95% confidence interval 0.83 to 0.92; specificity 0.85, 0.82 to 0.88). Across cut-off scores 5-15, sensitivity with semistructured interviews was 5-22% higher than for fully structured interviews (MINI excluded; 14 studies, 7680 participants) and 2-15% higher than for the MINI (15 studies, 2952 participants). Specificity was similar across diagnostic interviews. The PHQ-9 seems to be similarly sensitive but may be less specific for younger patients than for older patients; a cut-off score of 10 or above can be used regardless of age.. Conclusions PHQ-9 sensitivity compared with semistructured diagnostic interviews was greater than in previous conventional meta-analyses that combined reference standards. A cut-off score of 10 or above maximized combined sensitivity and specificity overall and for subgroups. Registration PROSPERO CRD42014010673.

Pre-eclampsia: pathophysiology and clinical implications

Abstract: 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.

Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Santé)

Abstract: Objective To assess the prospective associations between consumption of ultra-processed foods and risk of cardiovascular diseases. Design Population based cohort study. Setting NutriNet-Sante 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 1.20); P Conclusions In this large observational prospective study, higher consumption of ultra-processed foods was associated with higher risks of cardiovascular, coronary heart, and cerebrovascular diseases. These results need to be confirmed in other populations and settings, and causality remains to be established. Various factors in processing, such as nutritional composition of the final product, additives, contact materials, and neoformed contaminants might play a role in these associations, and further studies are needed to understand better the relative contributions. Meanwhile, public health authorities in several countries have recently started to promote unprocessed or minimally processed foods and to recommend limiting the consumption of ultra-processed foods. Study registration ClinicalTrials.gov NCT03335644.

Global, regional, and national burden of suicide mortality 1990 to 2016: systematic analysis for the Global Burden of Disease Study 2016

Abstract: 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 among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%). Conclusions Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates.

A guide to systematic review and meta-analysis of prognostic factor studies.

Abstract: 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.

Sepsis associated acute kidney injury

Abstract: 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.

Association between consumption of ultra-processed foods and all cause mortality: SUN prospective cohort study.

Abstract: 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 hazard ratio 1.62, 95% confidence interval 1.13 to 2.33) with a significant dose-response relation (P for linear trend=0.005). For each additional serving of ultra-processed foods, all cause mortality relatively increased by 18% (adjusted hazard ratio 1.18, 95% confidence interval 1.05 to 1.33). Conclusions A higher consumption of ultra-processed foods (>4 servings daily) was independently associated with a 62% relatively increased hazard for all cause mortality. For each additional serving of ultra-processed food, all cause mortality increased by 18%. Study registration ClinicalTrials.gov NCT02669602.

What are the respiratory effects of e-cigarettes?

Abstract: 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 chronic obstructive pulmonary disease, so the population effects of e-cigarette use may not be apparent until the middle of this century. We conclude that current knowledge of these effects is insufficient to determine whether the respiratory health effects of e-cigarette are less than those of combustible tobacco products.

Prevalence, severity, and nature of preventable patient harm across medical care settings: systematic review and meta-analysis

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 I2 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 preventable patient harm was 6% (95% confidence interval 5% to 7%). A pooled proportion of 12% (9% to 15%) of preventable patient harm was severe or led to death. Incidents related to drugs (25%, 95% confidence interval 16% to 34%) and other treatments (24%, 21% to 30%) accounted for the largest proportion of preventable patient harm. Compared with general hospitals (where most evidence originated), preventable patient harm was more prevalent in advanced specialties (intensive care or surgery; regression coefficient b=0.07, 95% confidence interval 0.04 to 0.10). Conclusions Around one in 20 patients are exposed to preventable harm in medical care. Although a focus on preventable patient harm has been encouraged by the international patient safety policy agenda, there are limited quality improvement practices specifically targeting incidents of preventable patient harm rather than overall patient harm (preventable and non-preventable). Developing and implementing evidence-based mitigation strategies specifically targeting preventable patient harm could lead to major service quality improvements in medical care which could also be more cost effective.

Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study

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 overwith 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 30 906 deaths in the heart failure group over the study period. Heart failure was listed on the death certificate in 13 093 (42.4%) of these patients, and in 2237 (7.2%) it was the primary cause of death. Improvement in survival was greater for patients not requiring admission to hospital around the time of diagnosis (median difference 2.4 years; 5.3 v 2.9 years, P Conclusions Survival after a diagnosis of heart failure has shown only modest improvement in the 21st century and lags behind other serious conditions, such as cancer. New strategies to achieve timely diagnosis and treatment initiation in primary care for all socioeconomic groups should be a priority for future research and policy.

Alternative approaches for confounding adjustment in observational studies using weighting based on the propensity score: a primer for practitioners.

Abstract: 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.

Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study

Abstract: 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 1.29), stillbirth (1.30, 1.11 to 1.53), caesarean section (1.16, 1.12 to 1.21), or if the woman had gestational diabetes in the previous pregnancy (1.19, 1.05 to 1.36). The risk of miscarriage was slightly higher in women who themselves had been small for gestational age (1.08, 1.04 to 1.13). Conclusions The risk of miscarriage varies greatly with maternal age, shows a strong pattern of recurrence, and is also increased after some adverse pregnancy outcomes. Miscarriage and other pregnancy complications might share underlying causes, which could be biological conditions or unmeasured common risk factors.

Role of diet in type 2 diabetes incidence: umbrella review of meta-analyses of prospective observational studies

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 an inverse association for type 2 diabetes incidence with increased intake of whole grains (for an increment of 30 g/day, adjusted summary hazard ratio 0.87 (95% confidence interval 0.82 to 0.93)) and cereal fibre (for an increment of 10 g/day, 0.75 (0.65 to 0.86)), as well as for moderate intake of total alcohol (for an intake of 12-24 g/day v no consumption, 0.75 (0.67 to 0.83)). Quality of evidence was also high for the association for increased incidence of type 2 diabetes with higher intake of red meat (for an increment of 100 g/day, 1.17 (1.08 to 1.26)), processed meat (for an increment of 50 g/day, 1.37 (1.22 to 1.54)), bacon (per two slices/day, 2.07 (1.40 to 3.05)), and sugar sweetened beverages (for an increase of one serving/day, 1.26 (1.11 to 1.43)). Conclusions Overall, the association between dietary factors and type 2 diabetes has been extensively studied, but few of the associations were graded as high quality of evidence. Further factors are likely to be important in type 2 diabetes prevention; thus, more well conducted research, with more detailed assessment of diet, is needed. Systematic review registration PROSPERO CRD42018088106.

CONSORT 2010 statement: extension to randomised crossover trials.

Abstract: 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 designs, and introduces a modified flowchart and baseline table to enhance transparency. Examples of good reporting and evidence based rationale for CONSORT crossover checklist items are provided.

Clinical applications of machine learning algorithms: beyond the black box.

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

Immediate impact of minimum unit pricing on alcohol purchases in Scotland: controlled interrupted time series analysis for 2015-18.

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

Prevalence of vaping and smoking among adolescents in Canada, England, and the United States: repeat national cross sectional surveys.

Abstract: 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 Conclusions Between 2017 and 2018, among 16 to 19 year olds the prevalence of vaping increased in Canada and the US, as did smoking in Canada, with little change in England. The rapidly evolving vaping market and emergence of nicotine salt based products warrant close monitoring.

Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases

Abstract: 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 significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Estradiolhad a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01). Conclusions In the present study, transdermal treatment was the safest type of hormone replacement therapy when risk of venous thromboembolism was assessed. Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.

Patient relevant outcomes of unicompartmental versus total knee replacement: systematic review and meta-analysis

Abstract: 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 varied depending on the level of data, and findings were not always significant. Analysis of the three groups of studies showed significantly shorter hospital stays after UKA than after TKA (−1.20 days (95% confidence interval −1.67 to −0.73), −1.43 (−1.53 to −1.33), and −1.73 (−2.30 to −1.16), respectively). There was no significant difference in pain, based on patient reported outcome measures (PROMs), but significantly better functional PROM scores for UKA than for TKA in both non-trial groups (standard mean difference −0.58 (−0.88 to −0.27) and −0.29 (−0.46 to −0.11), respectively). Regarding major complications, trials and cohort studies had non-significant results, but mortality after TKA was significantly higher in registry and large database studies (risk ratio 0.27 (0.16 to 0.45)), as were venous thromboembolic events (0.39 (0.27 to 0.57)) and major cardiac events (0.22 (0.06 to 0.86)). Early reoperation for any reason was higher after TKA than after UKA, but revision rates at five years remained higher for UKA in all three study groups (risk ratio 5.95 (1.29 to 27.59), 2.50 (1.77 to 3.54), and 3.13 (1.89 to 5.17), respectively). Conclusions TKA and UKA are both viable options for the treatment of isolated unicompartmental osteoarthritis. By directly comparing the two treatments, this study demonstrates better results for UKA in several outcome domains. However, the risk of revision surgery was lower for TKA. This information should be available to patients as part of the shared decision making process in choosing treatment options. Systematic review registration PROSPERO number CRD42018089972.

Association between vitamin D supplementation and mortality: systematic review and meta-analysis.

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, I2=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 D supplementation statistically significantly reduced the risk of cancer death (0.85, 0.74 to 0.97, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation (P for interaction=0.04); neither vitamin D3 nor vitamin D2 was associated with a statistically significant reduction in all cause mortality. Conclusions Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 15%. Additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all cause mortality. Study registration PROSPERO registration number CRD42018117823.

Physical activity trajectories and mortality: population based cohort study

Abstract: 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 years of follow-up, 3148 deaths occurred. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 (95% confidence interval 0.71 to 0.82) for all cause mortality, 0.71 (0.62 to 0.82) for cardiovascular disease mortality, and 0.89 (0.79 to 0.99) for cancer mortality, adjusted for baseline PAEE, and established risk factors. Similar results were observed when analyses were stratified by medical history of cardiovascular disease and cancer. Joint analyses with baseline and trajectories of physical activity show that, compared with consistently inactive individuals, those with increasing physical activity trajectories over time experienced lower risks of mortality from all causes, with hazard ratios of 0.76 (0.65 to 0.88), 0.62 (0.53 to 0.72), and 0.58 (0.43 to 0.78) at low, medium, and high baseline physical activity, respectively. At the population level, meeting and maintaining at least the minimum physical activity recommendations would potentially prevent 46% of deaths associated with physical inactivity. Conclusions Middle aged and older adults, including those with cardiovascular disease and cancer, can gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors. Considerable population health impacts can be attained with consistent engagement in physical activity during mid to late life.

Operative treatment versus nonoperative treatment of Achilles tendon ruptures : systematic review and meta-analysis

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% confidence interval. Results 29 studies were included—10 randomised controlled trials and 19 observational studies. The 10 trials included 944 (6%) patients, and the 19 observational studies included 14 918 (94%) patients. A significant reduction in re-ruptures was seen after operative treatment (2.3%) compared with nonoperative treatment (3.9%) (risk difference 1.6%; risk ratio 0.43, 95% confidence interval 0.31 to 0.60; P Conclusions This meta-analysis shows that operative treatment of Achilles tendon ruptures reduces the risk of re-rupture compared with nonoperative treatment. However, re-rupture rates are low and differences between treatment groups are small (risk difference 1.6%). Operative treatment results in a higher risk of other complications (risk difference 3.3%). The final decision on the management of acute Achilles tendon ruptures should be based on patient specific factors and shared decision making. This review emphasises the potential benefits of adding high quality observational studies in meta-analyses for the evaluation of objective outcome measures after surgical treatment.

Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

Abstract: 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. RESULTS 113 trials (262 treatment arms) that randomised 6750 patients (mean age 47.9 years; 59% women) with major depressive disorder or bipolar depression met the inclusion criteria. The most studied treatment comparisons were high frequency left rTMS and tDCS versus sham therapy, whereas recent treatments remain understudied. The quality of the evidence was typically of low or unclear risk of bias (94 out of 113 trials, 83%) and the precision of summary estimates for treatment effect varied considerably. In network meta-analysis, 10 out of 18 treatment strategies were associated with higher response compared with sham therapy: bitemporal ECT (summary odds ratio 8.91, 95% confidence interval 2.57 to 30.91), high dose right unilateral ECT (7.27, 1.90 to 27.78), priming transcranial magnetic stimulation (6.02, 2.21 to 16.38), magnetic seizure therapy (5.55, 1.06 to 28.99), bilateral rTMS (4.92, 2.93 to 8.25), bilateral theta burst stimulation (4.44, 1.47 to 13.41), low frequency right rTMS (3.65, 2.13 to 6.24), intermittent theta burst stimulation (3.20, 1.45 to 7.08), high frequency left rTMS (3.17, 2.29 to 4.37), and tDCS (2.65, 1.55 to 4.55). Network meta-analytic estimates of active interventions contrasted with another active treatment indicated that bitemporal ECT and high dose right unilateral ECT were associated with increased response. All treatment strategies were at least as acceptable as sham therapy. CONCLUSIONS These findings provide evidence for the consideration of non-surgical brain stimulation techniques as alternative or add-on treatments for adults with major depressive episodes. These findings also highlight important research priorities in the specialty of brain stimulation, such as the need for further well designed randomised controlled trials comparing novel treatments, and sham controlled trials investigating magnetic seizure therapy.

Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands

Abstract: 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 ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5). Conclusions This study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.

Arthroscopic hip surgery compared with physiotherapy and activity modification for the treatment of symptomatic femoroacetabular impingement: multicentre randomised controlled trial.

Abstract: 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 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 eight physiotherapy sessions were delivered over five months. Participants in the arthroscopic surgery group received surgery to excise the bone that impinged during hip movements, followed by routine postoperative care. Main outcome measures The primary outcome measure was the hip outcome score activities of daily living subscale (HOS ADL) at eight months post-randomisation, with a minimum clinically important difference between groups of 9 points. Secondary outcome measures included additional patient reported outcome measures and clinical assessment. Results At eight months post-randomisation, data were available for 100 patients in the arthroscopic hip surgery group (89%) and 88 patients in the physiotherapy programme group (80%). Mean HOS ADL was 78.4 (95% confidence interval 74.4 to 82.3) for patients randomised to arthroscopic hip surgery and 69.2 (65.2 to 73.3) for patients randomised to the physiotherapy programme. After adjusting for baseline HOS ADL, age, sex, and study site, the mean HOS ADL was 10.0 points higher (6.4 to 13.6) in the arthroscopic hip surgery group compared with the physiotherapy programme group (P Conclusions Patients with symptomatic FAI referred to secondary or tertiary care achieve superior outcomes with arthroscopic hip surgery than with physiotherapy and activity modification. Trial registration ClinicalTrials.gov NCT01893034.

What can we learn from China's health system reform?

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

Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials.

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 evidence with GRADE. Results 83 randomised controlled trials (mainly assessing effects of supplementary long chain omega-3) were included; 10 were at low summary risk of bias. Long chain omega-3 had little or no effect on likelihood of diagnosis of diabetes (relative risk 1.00, 95% confidence interval 0.85 to 1.17; 58 643 participants, 3.7% developed diabetes) or measures of glucose metabolism (HbA1c mean difference −0.02%, 95% confidence interval −0.07% to 0.04%; plasma glucose 0.04, 0.02 to 0.07, mmol/L; fasting insulin 1.02, −4.34 to 6.37, pmol/L; HOMA-IR 0.06, −0.21 to 0.33). A suggestion of negative outcomes was observed when dose of supplemental long chain omega-3 was above 4.4 g/d. Effects of α-linolenic acid, omega-6, and total PUFA on diagnosis of diabetes were unclear (as the evidence was of very low quality), but little or no effect on measures of glucose metabolism was seen, except that increasing α-linolenic acid may increase fasting insulin (by about 7%). No evidence was found that the omega-3/omega-6 ratio is important for diabetes or glucose metabolism. Conclusions This is the most extensive systematic review of trials to date to assess effects of polyunsaturated fats on newly diagnosed diabetes and glucose metabolism, including previously unpublished data following contact with authors. Evidence suggests that increasing omega-3, omega-6, or total PUFA has little or no effect on prevention and treatment of type 2 diabetes mellitus. Systematic review registration PROSPERO CRD42017064110.