Genomic atlas of the human plasma proteome.

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

The potential for current sodium and potassium production to support a global switch to the use of potassium-enriched salt: a desktop research study.

OBJECTIVE: Switching regular salt (sodium chloride) to salt enriched with potassium chloride (25 % potassium chloride, 75 % sodium chloride) has been shown to reduce blood pressure and the risk of cardiovascular diseases. We sought to define the potential for the current production of sodium chloride and potassium chloride to support a global switch to the use of potassium-enriched salt. DESIGN: We summarised data from geological surveys, government reports and trade organisations describing the global production and supply of sodium chloride and potash (the primary source of potassium chloride) and compared this to potential requirements for potassium-enriched salt. SETTING: Global. PARTICIPANTS: Not applicable. RESULTS: Approximately 280 million tonnes of sodium chloride were produced in 2020 with China and the USA the main producers. Global production of potash from which potassium chloride is extracted was about forty-four million tonnes with Canada, Belarus, Russia and China providing 77 % of the world's supply. There were forty-eight countries in which potassium-enriched salt is currently marketed with seventy-nine different brands identified. Allowing for loss of salt between manufacture and consumption, a full global switch from regular salt to potassium-enriched salt would require about 9·7 million tonnes of sodium chloride to be replaced with 9·7 million tonnes of potassium chloride annually. CONCLUSIONS: Significant upscaling of the production of potassium chloride and the capacity of companies able to manufacture potassium-enriched salt, as well as a robust business case for the switch to potassium chloride, would be required.

Evidence supporting the choice of a new cardiovascular risk equation for Australia.

This article reviews the risk equations recommended for use in international cardiovascular disease (CVD) primary prevention guidelines and assesses their suitability for use in Australia against a set of a priori defined selection criteria. The review and assessment were commissioned by the National Heart Foundation of Australia on behalf of the Australian Chronic Disease Prevention Alliance to inform recommendations on CVD risk estimation as part of the 2023 update of the Australian CVD risk assessment and management guidelines. Selected international risk equations were assessed against eight selection criteria: development using contemporary data; inclusion of established cardiovascular risk factors; inclusion of ethnicity and deprivation measures; prediction of a broad selection of fatal and non-fatal CVD outcomes; population representativeness; model performance; external validation in an Australian dataset; and the ability to be recalibrated or modified. Of the ten risk prediction equations reviewed, the New Zealand PREDICT equation met seven of the eight selection criteria, and met additional usability criteria aimed at assessing the ability to apply the risk equation in practice in Australia.

Observed and predicted premature mortality in Australia due to non-communicable diseases: a population-based study examining progress towards the WHO 25X25 goal.

BACKGROUND: The World Health Organization's (WHO) 25X25 goal aims for a 25% relative reduction in premature death due to four non-communicable diseases (NCD4)-cancer, cardiovascular disease, chronic respiratory diseases and diabetes-by 2025 compared to 2010. This study aimed to quantify the premature mortality in the Australian population due to NCD4, quantify the variation in mortality rates by age and sex, predict the premature mortality due to NCD4 in 2025 and evaluate the progress towards the WHO 25X25 goal. METHODS: A population-based study using cause-specific mortality data of all deaths which occurred in Australia from 2010 to 2016 and registered up to 2017, for adults aged 30-69 years, was conducted. Age-specific and age-standardised mortality rates (ASMR) and probability of death for NCD4 were calculated for each year. ASMRs in 2016 were calculated for men and women. Deaths and the probability of death in 2025 were predicted using Poisson regression based on data from 2006 to 2016. To assess the progress against the WHO 25X25 goal, the relative reduction in the probability of death from NCD4 conditions in 2025 compared to 2010 was calculated. RESULTS: ASMRs for NCD4 decreased from 2010 to 2016, except for diabetes which increased on average by 2.5% per year. Across sociodemographic factors, ASMRs were highest in males and increased with age. The projected probability of premature death in 2025 was 7.36%, equivalent to a relative reduction of 25.16% compared to 2010 levels. CONCLUSIONS: Premature mortality due to cancer, cardiovascular disease, respiratory diseases and diabetes declined in Australia from 2010 to 2016. This trend is consistent across age groups and by sex, and higher mortality rates were observed in males and at older ages. Nationally, if the current trends continue, we estimate that Australia will achieve a 25.16% relative reduction in premature deaths due to NCD4 in 2025 compared to 2010, signifying substantial progress towards the WHO 25X25 goal. Concerted efforts will need to continue to meet the 25X25 goal, especially in the context of the COVID-19 pandemic.

The relationship of socioeconomic factors to the use of preventative cardiovascular disease medications: A prospective Australian cohort study.

Cardiovascular disease (CVD) events are highly preventable through appropriate treatment and disproportionally affect socioeconomically disadvantaged individuals. This study quantified the relationship of socioeconomic factors to dispensing and persistent use of lipid- and blood pressure-lowering medication following hospital admission for a major CVD event (myocardial infarction, ischaemic stroke/transient ischaemic attack). Data from 8285 people with such events aged ≥45 years from the Australian 45 and Up Study with linked medication data were used to estimate relative risks (RRs) for combined lipid- and blood pressure-lowering dispensing at three-months following hospital discharge and for 12-month persistent use, in relation to education, income, and level of medication subsidisation. Overall, 56% were dispensed guideline-recommended medications at three months and 37% persistently used them across 12 months. After adjusting for demographic factors, type of CVD and history of CVD hospitalisation, RRs for lowest (no educational qualifications) compared to highest education level (university degree) were 1.14 (95% CI: 1.06, 1.22) for medication dispensing and 1.15 (1.02, 1.29) for persistent medication use; 1.14 (1.06, 1.22) and 1.17 (1.04, 1.32) respectively for lowest (<$20,000) versus highest (≥$70,000) household pre-tax income; and 1.25 (1.17, 1.33) and 1.28 (1.15, 1.43) respectively for those receiving highest versus lowest subsidisation. There was little to no evidence of a relationship of income and education to medication use after adjustment for medication subsidisation. While preventive medication use is sub-optimal, subsidisation is substantially associated with increased use and accounts for most of the relationship with socioeconomic position, suggesting subsidy schemes are working in the intended direction.

A Versatile Big Data Health System for Australia: Driving Improvements in Cardiovascular Health.

Cardiovascular diseases (CVD) are leading causes of death and morbidity in Australia and worldwide. Despite improvements in treatment, there remain large gaps in our understanding to prevent, treat and manage CVD events and associated morbidities. This article lays out a vision for enhancing CVD research in Australia through the development of a Big Data system, bringing together the multitude of rich administrative and health datasets available. The article describes the different types of Big Data available for CVD research in Australia and presents an overview of the potential benefits of a Big Data system for CVD research and some of the major challenges in establishing the system for Australia. The steps for progressing this vision are outlined.

Education-related variation in coronary procedure rates and the contribution of private health care in Australia: a prospective cohort study.

BACKGROUND: Contemporary Australian evidence on socioeconomic variation in secondary cardiovascular disease (CVD) care, a possible contributor to inequalities in cardiovascular disease outcomes, is lacking. This study examined the relationship between education, an individual-level indicator of socioeconomic position, and receipt of angiography and revascularisation procedures following incident hospitalisation for acute myocardial infarction (AMI) or angina, and the role of private care in this relationship. METHODS: Participants aged ≥45 from the New South Wales population-based 45 and Up Study with no history of prior ischaemic heart disease hospitalised for AMI or angina were followed for receipt of angiography or revascularisation within 30 days of hospital admission, ascertained through linked hospital records. Education attainment, measured on baseline survey, was categorised as low (no school certificate/qualifications), intermediate (school certificate/trade/apprenticeship/diploma) and high (university degree). Cox regression estimated the association (hazard ratios [HRs]) between education and coronary procedure receipt, adjusting for demographic and health-related factors, and testing for linear trend. Private health insurance was investigated as a mediating variable. RESULTS: Among 4454 patients with AMI, 68.3% received angiography within 30 days of admission (crude rate: 25.8/person-year) and 48.8% received revascularisation (rate: 11.7/person-year); corresponding figures among 4348 angina patients were 59.7% (rate: 17.4/person-year) and 30.8% (rate: 5.3/person-year). Procedure rates decreased with decreasing levels of education. Comparing low to high education, angiography rates were 29% lower among AMI patients (adjusted HR = 0.71, 95% CI: 0.56-0.90) and 40% lower among angina patients (0.60, 0.47-0.76). Patterns were similar for revascularisation among those with angina (0.78, 0.61-0.99) but not AMI (0.93, 0.69-1.25). After adjustment for private health insurance status, the HRs were attenuated and there was little evidence of an association between education and angiography among those admitted for AMI. CONCLUSIONS: There is a socioeconomic gradient in coronary procedures with the most disadvantaged patients being less likely to receive angiography following hospital admission for AMI or angina, and revascularisation procedures for angina. Unequal access to private health care contributes to these differences. The extent to which the remaining variation is clinically appropriate, or whether angiography is being underused among people with low socioeconomic position or overused among those with higher socioeconomic position, is unclear.

Cardiovascular disease risk assessment for Aboriginal and Torres Strait Islander adults aged under 35 years: a consensus statement.

Cardiovascular disease (CVD) is a leading cause of preventable morbidity and mortality in Aboriginal and Torres Strait Islander peoples. This statement from the Australian Chronic Disease Prevention Alliance, the Royal Australian College of General Practitioners, the National Aboriginal Community Controlled Health Organisation and the Editorial Committee for Remote Primary Health Care Manuals communicates the latest consensus advice of guideline developers, aligning recommendations on the age to commence Aboriginal and Torres Strait Islander CVD risk assessment across three guidelines. MAIN RECOMMENDATIONS: In Aboriginal and Torres Strait Islander peoples without existing CVD: CVD risk factor screening should commence from the age of 18 years at the latest, including for blood glucose level or glycated haemoglobin, estimated glomerular filtration rate, serum lipids, urine albumin to creatinine ratio, and other risk factors such as blood pressure, history of familial hypercholesterolaemia, and smoking status. Individuals aged 18-29 years with the following clinical conditions are automatically conferred high CVD risk: ▶type 2 diabetes and microalbuminuria; ▶moderate to severe chronic kidney disease; ▶systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg; ▶familial hypercholesterolaemia; or ▶serum total cholesterol > 7.5 mmol/L. Assessment using the National Vascular Disease Prevention Alliance absolute CVD risk algorithm should commence from the age of 30 years at the latest - consider upward adjustment of calculated CVD risk score, accounting for local guideline use, risk factor and CVD epidemiology, and clinical discretion. Assessment should occur as part of an annual health check or opportunistically. Subsequent review should be conducted according to level of risk. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: From age 18 years (at the latest), Aboriginal and Torres Strait Islander adults should undergo CVD risk factor screening, and from age 30 years (at the latest), they should undergo absolute CVD risk assessment using the NVDPA risk algorithm.

Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma.

The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

A Prospective Study of Health Conditions Related to Alcohol Consumption Cessation Among 97,852 Drinkers Aged 45 and Over in Australia.

BACKGROUND: Evidence suggests that people who develop serious health conditions are likely to cease drinking alcohol (sometimes known as "sick-quitters"). We quantified the likelihood of quitting drinking in relation to the onset of a variety of health conditions. METHODS: Odds ratios (ORs) and 95% confidence intervals (CIs) of ceasing alcohol consumption after diagnosis of 28 health conditions and 4 general indicators of health were derived from logistic regression among 97,852 drinkers aged ≥ 45 years between baseline (2006 to 2009) and median 5.3 years of follow-up in the New South Wales 45 and Up Study. Incident health conditions at follow-up were self-reported. RESULTS: At follow-up, 9.6% (n = 9,438) of drinkers had ceased drinking. Drinking cessation was significantly associated with 24 of 32 health conditions examined: 15.4% of participants with newly diagnosed diabetes quit drinking (OR for quitting vs. continuing 1.77, 95% CI: 1.60 to 1.96), 16.4% with Parkinson's disease (1.71, 1.35 to 2.17), 17.8% with poor memory (1.68, 1.43 to 1.97), 19.2% with hip fracture (1.64, 1.30 to 2.06), 14.7% with stroke (1.45, 1.27 to 1.66), 12.5% with depression (1.40, 1.26 to 1.55), 15.0% with breast cancer (1.38, 1.18 to 1.61), 12.3% with heart disease (1.34, 1.25 to 1.44), and 13.3% with osteoarthritis (1.22, 1.12 to 1.33). Strong associations with quitting were observed in those with a decline in self-rated overall health (2.93, 2.53 to 3.40) and quality of life (2.68, 2.24 to 3.21). Some health conditions not significantly associated with quitting were prostate cancer, melanoma, nonmelanoma skin cancer, hay fever, and hearing loss. Findings were generally consistent for men and women, by age group and by smoking status. CONCLUSIONS: Diagnosis with a variety of health conditions appears to prompt drinking cessation in older adults.

Mid- and Long-Term Health Risks in Living Kidney Donors: A Systematic Review and Meta-analysis.

Background: Long-term health risks for adults who donate kidneys are unclear. Purpose: To summarize evidence about mid- and long-term health risks associated with living kidney donation in adults. Data Sources: PubMed, Embase, Scopus, and PsycINFO without language restriction from April 1964 to July 2017. Study Selection: Observational studies with at least 1 year of follow-up that compared health outcomes in adult living kidney donors versus nondonor populations. Data Extraction: Two investigators independently extracted study data and assessed study quality. Data Synthesis: 52 studies, comprising 118 426 living kidney donors and 117 656 nondonors, were included. Average follow-up was 1 to 24 years. No evidence suggested higher risk for all-cause mortality, cardiovascular disease, hypertension, type 2 diabetes, or adverse psychosocial health outcomes in living kidney donors than in nondonor populations. Donors had higher diastolic blood pressure, lower estimated glomerular filtration rates, and higher risk for end-stage renal disease (ESRD) (relative risk [RR], 8.83 [95% CI, 1.02 to 20.93]) and preeclampsia in female donors (RR, 2.12 [CI, 1.06 to 4.27]). Despite the increased RR, donors had low absolute risk for ESRD (incidence rate, 0.5 event [CI, 0.1 to 4.9 events] per 1000 person-years) and preeclampsia (incidence rate, 5.9 events [CI, 2.9 to 8.9 events] per 100 pregnancies). Limitation: Generalizability was limited by selected control populations, few studies reported pregnancy-related outcomes, and few studies were from low- and middle-income countries. Conclusion: Although living kidney donation is associated with higher RRs for ESRD and preeclampsia, the absolute risk for these outcomes remains low. Compared with nondonor populations, living kidney donors have no increased risk for other major chronic diseases, such as type 2 diabetes, or for adverse psychosocial outcomes. Primary Funding Source: National Health Service Blood and Transplant and National Institute for Health Research. (PROSPERO: CRD42017072284).

Landmark Models for Optimizing the Use of Repeated Measurements of Risk Factors in Electronic Health Records to Predict Future Disease Risk.

The benefits of using electronic health records (EHRs) for disease risk screening and personalized health-care decisions are being increasingly recognized. Here we present a computationally feasible statistical approach with which to address the methodological challenges involved in utilizing historical repeat measures of multiple risk factors recorded in EHRs to systematically identify patients at high risk of future disease. The approach is principally based on a 2-stage dynamic landmark model. The first stage estimates current risk factor values from all available historical repeat risk factor measurements via landmark-age-specific multivariate linear mixed-effects models with correlated random intercepts, which account for sporadically recorded repeat measures, unobserved data, and measurement errors. The second stage predicts future disease risk from a sex-stratified Cox proportional hazards model, with estimated current risk factor values from the first stage. We exemplify these methods by developing and validating a dynamic 10-year cardiovascular disease risk prediction model using primary-care EHRs for age, diabetes status, hypertension treatment, smoking status, systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol in 41,373 persons from 10 primary-care practices in England and Wales contributing to The Health Improvement Network (1997-2016). Using cross-validation, the model was well-calibrated (Brier score = 0.041, 95% confidence interval: 0.039, 0.042) and had good discrimination (C-index = 0.768, 95% confidence interval: 0.759, 0.777).

Socioeconomic variation in absolute cardiovascular disease risk and treatment in the Australian population.

Cardiovascular disease (CVD), preventable through appropriate management of absolute CVD risk, disproportionately affects socioeconomically disadvantaged individuals. The aim of this study was to estimate absolute and relative socioeconomic inequalities in absolute CVD risk and treatment in the Australian population using cross-sectional representative data on 4751 people aged 45-74 from the 2011-12 Australian Health Survey. Poisson regression was used to calculate prevalence differences (PD) and ratios (PR) for prior CVD, high 5-year absolute risk of a primary CVD event and guideline-recommended medication use, in relation to socioeconomic position (SEP, measured by education). After adjusting for age and sex, the prevalence of high absolute risk of a primary CVD event among those of low, intermediate and high SEP was 12.6%, 10.9% and 7.7% (PD, low vs. high = 5.0 [95% CI: 2.3, 7.7], PR = 1.6 [1.2, 2.2]) and for prior CVD was 10.7%, 9.1% and 6.7% (PD = 4.0 [1.4, 6.6], PR = 1.6 [1.1, 2.2]). The proportions using preventive medication use among those with high primary risk were 21.3%, 19.5% and 29.4% for low, intermediate and high SEP and for prior CVD, were 37.8%, 35.7% and 17.7% (PD = 20.1 [9.7, 30.5], PR = 2.1 [1.3, 3.5]). Proportions at high primary risk and not using medications among those of low, intermediate and high SEP were 10.6%, 8.8% and 4.7% and with prior CVD and not using medications were 8.5%, 6.3% and 4.1%. Findings indicate substantial potential to prevent CVD and reduce inequalities through appropriate management of high absolute risk in the population.

Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis.

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.

Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents.

BACKGROUND: Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. METHODS: Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4-14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5-<25·0 kg/m(2). FINDINGS: All-cause mortality was minimal at 20·0-25·0 kg/m(2) (HR 1·00, 95% CI 0·98-1·02 for BMI 20·0-<22·5 kg/m(2); 1·00, 0·99-1·01 for BMI 22·5-<25·0 kg/m(2)), and increased significantly both just below this range (1·13, 1·09-1·17 for BMI 18·5-<20·0 kg/m(2); 1·51, 1·43-1·59 for BMI 15·0-<18·5) and throughout the overweight range (1·07, 1·07-1·08 for BMI 25·0-<27·5 kg/m(2); 1·20, 1·18-1·22 for BMI 27·5-<30·0 kg/m(2)). The HR for obesity grade 1 (BMI 30·0-<35·0 kg/m(2)) was 1·45, 95% CI 1·41-1·48; the HR for obesity grade 2 (35·0-<40·0 kg/m(2)) was 1·94, 1·87-2·01; and the HR for obesity grade 3 (40·0-<60·0 kg/m(2)) was 2·76, 2·60-2·92. For BMI over 25·0 kg/m(2), mortality increased approximately log-linearly with BMI; the HR per 5 kg/m(2) units higher BMI was 1·39 (1·34-1·43) in Europe, 1·29 (1·26-1·32) in North America, 1·39 (1·34-1·44) in east Asia, and 1·31 (1·27-1·35) in Australia and New Zealand. This HR per 5 kg/m(2) units higher BMI (for BMI over 25 kg/m(2)) was greater in younger than older people (1·52, 95% CI 1·47-1·56, for BMI measured at 35-49 years vs 1·21, 1·17-1·25, for BMI measured at 70-89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46-1·56, vs 1·30, 1·26-1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. INTERPRETATION: The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature.

AIMS: We aimed to (1) assess the association between lipoprotein(a) [Lp(a)] concentration and incident type-2 diabetes in the Bruneck study, a prospective population-based study, and (2) combine findings with evidence from published studies in a literature-based meta-analysis. METHODS: We used Cox proportional hazards models to calculate hazard ratios (HR) for incident type-2 diabetes over 20 years of follow-up in 815 participants of the Bruneck study according to their long-term average Lp(a) concentration. For the meta-analysis, we searched Medline, Embase and Web of Science for relevant prospective cohort studies published up to October 2016. RESULTS: In the Bruneck study, there was a 12% higher risk of type-2 diabetes for a one standard deviation lower concentration of log Lp(a) (HR = 1.12 [95% CI 0.95-1.32]; P = 0.171), after adjustment for age, sex, alcohol consumption, body mass index, smoking status, socioeconomic status, physical activity, systolic blood pressure, HDL cholesterol, log high-sensitivity C-reactive protein and waist-hip ratio. In a meta-analysis involving four prospective cohorts with a total of 74,575 participants and 4514 incident events, the risk of type-2 diabetes was higher in the lowest two quintiles of Lp(a) concentrations (weighted mean Lp(a) = 3.3 and 7.0 mg/dL, respectively) compared to the highest quintile (62.9 mg/dL), with the highest risk of type-2 diabetes seen in quintile 1 (HR = 1.28 [1.14-1.43]; P < 0.001). CONCLUSIONS: The current available evidence from prospective studies suggests that there is an inverse association between Lp(a) concentration and risk of type-2 diabetes, with a higher risk of type-2 diabetes at low Lp(a) concentrations (approximately <7 mg/dL).

Tobacco smoking and all-cause mortality in a large Australian cohort study: findings from a mature epidemic with current low smoking prevalence.

BACKGROUND: The smoking epidemic in Australia is characterised by historic levels of prolonged smoking, heavy smoking, very high levels of long-term cessation, and low current smoking prevalence, with 13% of adults reporting that they smoked daily in 2013. Large-scale quantitative evidence on the relationship of tobacco smoking to mortality in Australia is not available despite the potential to provide independent international evidence about the contemporary risks of smoking. METHODS: This is a prospective study of 204,953 individuals aged ≥45 years sampled from the general population of New South Wales, Australia, who joined the 45 and Up Study from 2006-2009, with linked questionnaire, hospitalisation, and mortality data to mid-2012 and with no history of cancer (other than melanoma and non-melanoma skin cancer), heart disease, stroke, or thrombosis. Hazard ratios (described here as relative risks, RRs) for all-cause mortality among current and past smokers compared to never-smokers were estimated, adjusting for age, education, income, region of residence, alcohol, and body mass index. RESULTS: Overall, 5,593 deaths accrued during follow-up (874,120 person-years; mean: 4.26 years); 7.7% of participants were current smokers and 34.1% past smokers at baseline. Compared to never-smokers, the adjusted RR (95% CI) of mortality was 2.96 (2.69-3.25) in current smokers and was similar in men (2.82 (2.49-3.19)) and women (3.08 (2.63-3.60)) and according to birth cohort. Mortality RRs increased with increasing smoking intensity, with around two- and four-fold increases in mortality in current smokers of ≤14 (mean 10/day) and ≥25 cigarettes/day, respectively, compared to never-smokers. Among past smokers, mortality diminished gradually with increasing time since cessation and did not differ significantly from never-smokers in those quitting prior to age 45. Current smokers are estimated to die an average of 10 years earlier than non-smokers. CONCLUSIONS: In Australia, up to two-thirds of deaths in current smokers can be attributed to smoking. Cessation reduces mortality compared with continuing to smoke, with cessation earlier in life resulting in greater reductions.

A record linkage study of antidepressant medication use and weight change in Australian adults.

OBJECTIVE: Antidepressant use is widespread. While weight gain is a commonly reported side-effect of antidepressant use and has the potential to affect population health, there is little large-scale population-based evidence on the issue, particularly for long-term use (⩾12 months). The aim of this study is to investigate the association between antidepressant use and weight change, including whether this relationship varies according to antidepressant class, recency of use, duration of use and dose. METHODS: Annual percentage weight change was calculated from self-reported weight at two time-points from 20,751 participants aged ⩾45 years from the 45 and Up Study - a population-based cohort study from New South Wales, Australia. Antidepressant use, ascertained from linked pharmaceutical data, from 19 months before baseline until end of follow-up (mean = 3.3 years of follow-up), was categorised as current, past-only, non-persistent or non-use. The association between antidepressant use and weight change was modelled using linear and multinomial logistic regressions and according to antidepressant class, recency, duration and dose. RESULTS: Antidepressants were dispensed to 23% of participants (n = 4748) during the study period. Current antidepressant users were significantly more likely to gain >3% of their body weight annually than non-users (adjusted relative risk ratio = 1.19; 95% confidence interval: [1.03, 1.38]); the risk increased with increasing dose among current users (p[trend] = 0.003). Risk of weight gain did not vary significantly according to antidepressant class, recency or duration of use; however, statistical power was limited. No significant associations were found between antidepressant use and weight loss. CONCLUSION: Current antidepressant use was associated with modest but statistically significant annual gains in weight, with similar effects observed across the different classes of antidepressants used.