Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study.

BACKGROUND: The accumulation of disparate diseases in complex multimorbidity makes prevention difficult if each disease is targeted separately. We aimed to examine obesity as a shared risk factor for common diseases, determine associations between obesity-related diseases, and examine the role of obesity in the development of complex multimorbidity (four or more comorbid diseases). METHODS: We did an observational study and used pooled prospective data from two Finnish cohort studies (the Health and Social Support Study and the Finnish Public Sector Study) comprising 114 657 adults aged 16-78 years at study entry (1998-2013). A cohort of 499 357 adults (aged 38-73 years at study entry; 2006-10) from the UK Biobank provided replication in an independent population. BMI and clinical characteristics were assessed at baseline. BMIs were categorised as obesity (≥30·0 kg/m2), overweight (25·0-29·9 kg/m2), healthy weight (18·5-24·9 kg/m2), and underweight (<18·5 kg/m2). Via linkage to national health records, participants were followed-up for death and diseases diagnosed according to the International Classification of Diseases 10th Revision (ICD-10). Hazard ratios (HRs) with 95% CIs and population attributable fractions (PAFs) for associations between BMI and multimorbidity were calculated. FINDINGS: Mean follow-up duration was 12·1 years (SD 3·8) in the Finnish cohorts and 11·8 years (1·7) in the UK Biobank cohort. Obesity was associated with 21 non-overlapping cardiometabolic, digestive, respiratory, neurological, musculoskeletal, and infectious diseases after Bonferroni multiple testing adjustment and ignoring HRs of less than 1·50. Compared with healthy weight, the confounder-adjusted HR for obesity was 2·83 (95% CI 2·74-2·93; PAF 19·9% [95% CI 19·3-20·5]) for developing at least one obesity-related disease, 5·17 (4·84-5·53; 34·4% [33·2-35·5]) for two diseases, and 12·39 (9·26-16·58; 55·2% [50·9-57·5]) for complex multimorbidity. The proportion of participants of healthy weight with complex multimorbidity by age 75 years was observed by age 55 years in participants with obesity, and degree of obesity was associated with complex multimorbidity in a dose-response relationship. Compared with obesity, the association between overweight and complex multimorbidity was more modest (HR 2·67, 95% CI 1·94-3·68; PAF 13·3% [95% CI 9·6-16·3]). The same pattern of results was observed in the UK Biobank cohort. INTERPRETATION: Obesity is associated with diverse, increasing disease burdens, and might represent an important target for multimorbidity prevention that avoids the complexities of multitarget preventive regimens. FUNDING: Wellcome Trust, Medical Research Council, National Institute on Aging.

Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies.

INTRODUCTION: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. METHODS: In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions. DISCUSSION: This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia.

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies.

OBJECTIVES: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN: Multicohort study with three sets of analyses. SETTING: United Kingdom, Europe, and the United States. PARTICIPANTS: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted ß -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted ß -0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted ß -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.

Association of Alcohol-Induced Loss of Consciousness and Overall Alcohol Consumption With Risk for Dementia.

Importance: Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective: To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants: Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures: Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures: Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results: Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (<65 y: HR, 2.21; 95% CI, 1.46-3.34) and late-onset (≥65 y: HR, 2.25; 95% CI, 1.38-3.66) dementia, Alzheimer disease (HR, 1.98; 95% CI, 1.28-3.07), and dementia with features of atherosclerotic cardiovascular disease (HR, 4.18; 95% CI, 1.86-9.37). The association with dementia was not explained by 14 other alcohol-related conditions. With moderate drinkers (1-14 U/wk) who had not lost consciousness as the reference group, the HR for dementia was twice as high in participants who reported having lost consciousness, whether their mean weekly consumption was moderate (HR, 2.19; 95% CI, 1.42-3.37) or heavy (HR, 2.36; 95% CI, 1.57-3.54). Conclusions and Relevance: The findings of this study suggest that alcohol-induced loss of consciousness, irrespective of overall alcohol consumption, is associated with a subsequent increase in the risk of dementia.

Job Strain as a Risk Factor for Peripheral Artery Disease: A Multi-Cohort Study.

Background Job strain is implicated in many atherosclerotic diseases, but its role in peripheral artery disease (PAD) is unclear. We investigated the association of job strain with hospital records of PAD, using individual-level data from 11 prospective cohort studies from Finland, Sweden, Denmark, and the United Kingdom. Methods and Results Job strain (high demands and low control at work) was self-reported at baseline (1985-2008). PAD records were ascertained from national hospitalization data. We used Cox regression to examine the associations of job strain with PAD in each study, and combined the study-specific estimates in random effects meta-analyses. We used τ2, I2, and subgroup analyses to examine heterogeneity. Of the 139 132 participants with no previous hospitalization with PAD, 32 489 (23.4%) reported job strain at baseline. During 1 718 132 person-years at risk (mean follow-up 12.8 years), 667 individuals had a hospital record of PAD (3.88 per 10 000 person-years). Job strain was associated with a 1.41-fold (95% CI, 1.11-1.80) increased average risk of hospitalization with PAD. The study-specific estimates were moderately heterogeneous (τ2=0.0427, I2: 26.9%). Despite variation in their magnitude, the estimates were consistent in both sexes, across the socioeconomic hierarchy and by baseline smoking status. Additional adjustment for baseline diabetes mellitus did not change the direction or magnitude of the observed associations. Conclusions Job strain was associated with small but consistent increase in the risk of hospitalization with PAD, with the relative risks on par with those for coronary heart disease and ischemic stroke.

Association between socioeconomic status and the development of mental and physical health conditions in adulthood: a multi-cohort study.

BACKGROUND: Socioeconomic disadvantage is a risk factor for many diseases. We characterised cascades of these conditions by using a data-driven approach to examine the association between socioeconomic status and temporal sequences in the development of 56 common diseases and health conditions. METHODS: In this multi-cohort study, we used data from two Finnish prospective cohort studies: the Health and Social Support study and the Finnish Public Sector study. Our pooled prospective primary analysis data comprised 109 246 Finnish adults aged 17-77 years at study entry. We captured socioeconomic status using area deprivation and education at baseline (1998-2013). Participants were followed up for health conditions diagnosed according to the WHO International Classification of Diseases until 2016 using linkage to national health records. We tested the generalisability of our findings with an independent UK cohort study-the Whitehall II study (9838 people, baseline in 1997, follow-up to 2017)-using a further socioeconomic status indicator, occupational position. FINDINGS: During 1 110 831 person-years at risk, we recorded 245 573 hospitalisations in the Finnish cohorts; the corresponding numbers in the UK study were 60 946 hospitalisations in 186 572 person-years. Across the three socioeconomic position indicators and after adjustment for lifestyle factors, compared with more advantaged groups, low socioeconomic status was associated with increased risk for 18 (32·1%) of the 56 conditions. 16 diseases formed a cascade of inter-related health conditions with a hazard ratio greater than 5. This sequence began with psychiatric disorders, substance abuse, and self-harm, which were associated with later liver and renal diseases, ischaemic heart disease, cerebral infarction, chronic obstructive bronchitis, lung cancer, and dementia. INTERPRETATION: Our findings highlight the importance of mental health and behavioural problems in setting in motion the development of a range of socioeconomically patterned physical illnesses. Policy and health-care practice addressing psychological health issues in social context and early in the life course could be effective strategies for reducing health inequalities. FUNDING: UK Medical Research Council, US National Institute on Aging, NordForsk, British Heart Foundation, Academy of Finland, and Helsinki Institute of Life Science.

Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis.

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 initially free of dementia, had a measurement of physical inactivity at study entry, and were linked to electronic health records. In 6.0 million person-years at risk, we recorded 2044 incident cases of all-cause dementia. In studies with data on dementia subtype, the number of incident cases of Alzheimer's disease was 1602 in 5.2 million person-years. When measured <10 years before dementia diagnosis (that is, the preclinical stage of dementia), physical inactivity was associated with increased incidence of all-cause dementia (hazard ratio 1.40, 95% confidence interval 1.23 to 1.71) and Alzheimer's disease (1.36, 1.12 to 1.65). When reverse causation was minimised by assessing physical activity ≥10 years before dementia onset, no difference in dementia risk between physically active and inactive participants was observed (hazard ratios 1.01 (0.89 to 1.14) and 0.96 (0.85 to 1.08) for the two outcomes). Physical inactivity was consistently associated with increased risk of incident diabetes (hazard ratio 1.42, 1.25 to 1.61), coronary heart disease (1.24, 1.13 to 1.36), and stroke (1.16, 1.05 to 1.27). Among people in whom cardiometabolic disease preceded dementia, physical inactivity was non-significantly associated with dementia (hazard ratio for physical activity assessed >10 before dementia onset 1.30, 0.79 to 2.14). CONCLUSIONS: In analyses that addressed bias due to reverse causation, physical inactivity was not associated with all-cause dementia or Alzheimer's disease, although an indication of excess dementia risk was observed in a subgroup of physically inactive individuals who developed cardiometabolic disease.

Obesity and loss of disease-free years owing to major non-communicable diseases: a multicohort study.

BACKGROUND: Obesity increases the risk of several chronic diseases, but the extent to which the obesity-related loss of disease-free years varies by lifestyle category and across socioeconomic groups is unclear. We estimated the number of years free from major non-communicable diseases in adults who are overweight and obese, compared with those who are normal weight. METHODS: We pooled individual-level data on body-mass index (BMI) and non-communicable diseases from men and women with no initial evidence of these diseases in European cohort studies from the Individual-Participant-Data Meta-Analysis in Working Populations consortium. BMI was assessed at baseline (1991-2008) and non-communicable diseases (incident type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease) were ascertained via linkage to records from national health registries, repeated medical examinations, or self-report. Disease-free years from age 40 years to 75 years associated with underweight (BMI <18·5 kg/m2), overweight (≥25 kg/m2 to <30 kg/m2), and obesity (class I [mild] ≥30 kg/m2 to <35 kg/m2; class II-III [severe] ≥35 kg/m2) compared with normal weight (≥18·5 kg/m2 to <25 kg/m2) were estimated. FINDINGS: Of 137 503 participants from ten studies, we excluded 6973 owing to missing data and 10 349 with prevalent disease at baseline, resulting in an analytic sample of 120 181 participants. Of 47 127 men, 211 (0·4%) were underweight, 21 468 (45·6%) normal weight, 20 738 (44·0%) overweight, 3982 (8·4%) class I obese, and 728 (1·5%) class II-III obese. The corresponding numbers among the 73 054 women were 1493 (2·0%), 44 760 (61·3%), 19 553 (26·8%), 5670 (7·8%), and 1578 (2·2%), respectively. During 1 328 873 person-years at risk (mean follow-up 11·5 years [range 6·3-18·6]), 8159 men and 8100 women developed at least one non-communicable disease. Between 40 years and 75 years, the estimated number of disease-free years was 29·3 (95% CI 28·8-29·8) in normal-weight men and 29·4 (28·7-30·0) in normal-weight women. Compared with normal weight, the loss of disease-free years in men was 1·8 (95% CI -1·3 to 4·9) for underweight, 1·1 (0·7 to 1·5) for overweight, 3·9 (2·9 to 4·9) for class I obese, and 8·5 (7·1 to 9·8) for class II-III obese. The corresponding estimates for women were 0·0 (-1·4 to 1·4) for underweight, 1·1 (0·6 to 1·5) for overweight, 2·7 (1·5 to 3·9) for class I obese, and 7·3 (6·1 to 8·6) for class II-III obese. The loss of disease-free years associated with class II-III obesity varied between 7·1 and 10·0 years in subgroups of participants of different socioeconomic level, physical activity level, and smoking habit. INTERPRETATION: Mild obesity was associated with the loss of one in ten, and severe obesity the loss of one in four potential disease-free years during middle and later adulthood. This increasing loss of disease-free years as obesity becomes more severe occurred in both sexes, among smokers and non-smokers, the physically active and inactive, and across the socioeconomic hierarchy. FUNDING: NordForsk, UK Medical Research Council, US National Institute on Aging, Academy of Finland, Helsinki Institute of Life Science, and Cancer Research UK.

Unfavorable and favorable changes in modifiable risk factors and incidence of coronary heart disease: The Whitehall II cohort study.

BACKGROUND: Few studies have examined long-term associations of unfavorable and favorable changes in vascular risk factors with incident coronary heart disease (CHD). We examined this issue in a middle-aged disease-free population. METHODS: We used repeat data from the Whitehall II cohort study. Five biomedical, behavioral and psychosocial examinations of 8335 participants without CHD produced up to 20,357 person-observations to mimic a non-randomized pseudo-trial. After measurement of potential change in 6 risk factors twice (total cholesterol, blood pressure, smoking, overweight, psychological distress, problems in social relationships), a 5-year follow-up of CHD was undertaken. RESULTS: Incidence of CHD was 7.4/1000 person-years. Increases from normal to high cholesterol (hazard ratio, HR = 1.59, 95% CI 1.26-2.00) and from normal to high blood pressure (HR = 1.64, 95% CI 1.33-2.03), as compared to remaining at the normal level, were associated with increased risk of CHD. In contrast, decreases from high to low levels of cholesterol (HR = 0.73, 95% CI 0.58-0.91), psychological distress (HR = 0.68, 95% CI 0.51-0.90), and problems in social relationships (HR = 0.65, 95% CI 0.50-0.85), and quitting smoking (HR = 0.49, 95% CI 0.29-0.82) were associated with a reduced CHD risk compared to remaining at high risk factor levels. The highest absolute risk was associated with persistent exposure to both high cholesterol and hypertension (incidence 18.1/1000 person-years) and smoking and overweight (incidence 17.7/1000 person-years). CONCLUSIONS: While persistent exposures and changes in biological and behavioral risk factors relate to the greatest increases and reductions in 5-year risk of CHD, also favorable changes in psychosocial risk factors appear to reduce CHD risk.

Neighbourhood socioeconomic disadvantage, risk factors, and diabetes from childhood to middle age in the Young Finns Study: a cohort study.

BACKGROUND: Neighbourhood socioeconomic disadvantage has been linked to increased diabetes risk, but little is known about differences in risk factors in childhood and adulthood in those with high and low neighbourhood socioeconomic disadvantage, or about the association between long-term neighbourhood socioeconomic disadvantage and incidence of diabetes in adulthood. We used data from the prospective, population-based Young Finns Study to address these questions. METHODS: We did a nationwide population-based cohort study in Finland using data from The Young Finns Study, which included 3467 participants aged 6-18 years followed up for over 30 years via eight repeated biomedical examinations and linkage to electronic health records. Participants were also linked to national grid data on neighbourhood disadvantage via their residential address from age 6-48 years. We used these data to examine differences in ten risk factors (dietary habits, physical activity, daily smoking, body-mass index, systolic blood pressure, fasting HDL cholesterol, fasting triglycerides, fasting plasma glucose, fasting serum insulin, and homoeostasis model assessment insulin sensitivity) from childhood (6-21 years) to adulthood (22-48 years) among individuals with high (>0·5 SD above the national mean) and low (≥0·5 SD below the national mean) neighbourhood socioeconomic disadvantage, and the association of cumulative neighbourhood socioeconomic disadvantage with six cardiometabolic risk factors (obesity, high waist circumference, fatty liver, hypertension, carotid plaque, and left ventricle mass index) and diabetes by middle age (22-48 years). We used logistic and linear regression analyses to assess the effects of neighbourhood disadvantage on cardiometabolic and diabetes risk, controlling for potential confounders (age, sex, and individual socioeconomic disadvantage). FINDINGS: We included data for 3002 individuals with risk factor assessment in childhood and adulthood. Of whom, 2048 underwent a clinical examination during the last follow-up at age 33-48 years. Differences in risk factors by neighbourhood socioeconomic disadvantage at the beginning of follow-up were small, but large differences emerged over the follow-up. High neighbourhood socioeconomic disadvantage was characterised by decreased fruit and vegetable intake as early as age 6 years, decreased physical activity, and increased prevalence of daily smoking from adolescence (12 years) onwards, and decreased homoeostasis model assessment insulin sensitivity and increased fasting glucose and insulin concentration from early adulthood (27 years; all p<0·03). Individuals consistently exposed to high neighbourhood socioeconomic disadvantage were more likely to be obese (odds ratio [OR] 1·44, 95% CI 1·01-2·06), hypertensive (1·83, 1·14-2·93), have a fatty liver (1·73, 1·11-2·71), and diabetes (3·71, 1·77-7·75), compared with those who were consistently exposed to low neighbourhood socioeconomic disadvantage. INTERPRETATION: Living in socioeconomically disadvantaged areas can shape health in childhood and adulthood. Neighbourhood socioeconomic disadvantage is associated with differences in health risks across the life course, including detrimental lifestyle factors from childhood and adolescence onwards and worse glucose metabolism from early adulthood. By middle age, cumulative neighbourhood socioeconomic disadvantage is associated with increased cardiometabolic risk factors and increased incidence of diabetes. FUNDING: Academy of Finland, NordForsk, UK Medical Research Council, European Commission, and European Research Council.

Work stress and risk of death in men and women with and without cardiometabolic disease: a multicohort study.

BACKGROUND: Although some cardiovascular disease prevention guidelines suggest a need to manage work stress in patients with established cardiometabolic disease, the evidence base for this recommendation is weak. We sought to clarify the status of stress as a risk factor in cardiometabolic disease by investigating the associations between work stress and mortality in men and women with and without pre-existing cardiometabolic disease. METHODS: In this multicohort study, we used data from seven cohort studies in the IPD-Work consortium, initiated between 1985 and 2002 in Finland, France, Sweden, and the UK, to examine the association between work stress and mortality. Work stress was denoted as job strain or effort-reward imbalance at work. We extracted individual-level data on prevalent cardiometabolic diseases (coronary heart disease, stroke, or diabetes [without differentiation by diabetes type]) at baseline. Work stressors, socioeconomic status, and conventional and lifestyle risk factors (systolic and diastolic blood pressure, total cholesterol, smoking status, BMI, physical activity, and alcohol consumption) were also assessed at baseline. Mortality data, including date and cause of death, were obtained from national death registries. We used Cox proportional hazards regression to study the associations of work stressors with mortality in men and women with and without cardiometabolic disease. RESULTS: We identified 102 633 individuals with 1 423 753 person-years at risk (mean follow-up 13·9 years [SD 3·9]), of whom 3441 had prevalent cardiometabolic disease at baseline and 3841 died during follow-up. In men with cardiometabolic disease, age-standardised mortality rates were substantially higher in people with job strain (149·8 per 10 000 person-years) than in those without (97·7 per 10 000 person-years; mortality difference 52·1 per 10 000 person-years; multivariable-adjusted hazard ratio [HR] 1·68, 95% CI 1·19-2·35). This mortality difference for job strain was almost as great as that for current smoking versus former smoking (78·1 per 10 000 person-years) and greater than those due to hypertension, high total cholesterol concentration, obesity, physical inactivity, and high alcohol consumption relative to the corresponding lower risk groups (mortality difference 5·9-44·0 per 10 000 person-years). Excess mortality associated with job strain was also noted in men with cardiometabolic disease who had achieved treatment targets, including groups with a healthy lifestyle (HR 2·01, 95% CI 1·18-3·43) and those with normal blood pressure and no dyslipidaemia (6·17, 1·74-21·9). In all women and in men without cardiometabolic disease, relative risk estimates for the work stress-mortality association were not significant, apart from effort-reward imbalance in men without cardiometabolic disease (mortality difference 6·6 per 10 000 person-years; multivariable-adjusted HR 1·22, 1·06-1·41). INTERPRETATION: In men with cardiometabolic disease, the contribution of job strain to risk of death was clinically significant and independent of conventional risk factors and their treatment, and measured lifestyle factors. Standard care targeting conventional risk factors is therefore unlikely to mitigate the mortality risk associated with job strain in this population. FUNDING: NordForsk, UK Medical Research Council, and Academy of Finland.

Long working hours and depressive symptoms: systematic review and meta-analysis of published studies and unpublished individual participant data.

Objectives This systematic review and meta-analysis combined published study-level data and unpublished individual-participant data with the aim of quantifying the relation between long working hours and the onset of depressive symptoms. Methods We searched PubMed and Embase for published prospective cohort studies and included available cohorts with unpublished individual-participant data. We used a random-effects meta-analysis to calculate summary estimates across studies. Results We identified ten published cohort studies and included unpublished individual-participant data from 18 studies. In the majority of cohorts, long working hours was defined as working ≥55 hours per week. In multivariable-adjusted meta-analyses of 189 729 participants from 35 countries [96 275 men, 93 454 women, follow-up ranging from 1-5 years, 21 747 new-onset cases), there was an overall association of 1.14 (95% confidence interval (CI) 1.03-1.25] between long working hours and the onset of depressive symptoms, with significant evidence of heterogeneity (I 2=45.1%, P=0.004). A moderate association between working hours and depressive symptoms was found in Asian countries (1.50, 95% CI 1.13-2.01), a weaker association in Europe (1.11, 95% CI 1.00-1.22), and no association in North America (0.97, 95% CI 0.70-1.34) or Australia (0.95, 95% CI 0.70-1.29). Differences by other characteristics were small. Conclusions This observational evidence suggests a moderate association between long working hours and onset of depressive symptoms in Asia and a small association in Europe.

Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals.

INTRODUCTION: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects. METHODS: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis. RESULTS: Hazard ratios per 5-kg/m2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis. CONCLUSIONS: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short.

Long working hours as a risk factor for atrial fibrillation: a multi-cohort study.

AIMS: Studies suggest that people who work long hours are at increased risk of stroke, but the association of long working hours with atrial fibrillation, the most common cardiac arrhythmia and a risk factor for stroke, is unknown. We examined the risk of atrial fibrillation in individuals working long hours (≥55 per week) and those working standard 35-40 h/week. METHODS AND RESULTS: In this prospective multi-cohort study from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium, the study population was 85 494 working men and women (mean age 43.4 years) with no recorded atrial fibrillation. Working hours were assessed at study baseline (1991-2004). Mean follow-up for incident atrial fibrillation was 10 years and cases were defined using data on electrocardiograms, hospital records, drug reimbursement registers, and death certificates. We identified 1061 new cases of atrial fibrillation (10-year cumulative incidence 12.4 per 1000). After adjustment for age, sex and socioeconomic status, individuals working long hours had a 1.4-fold increased risk of atrial fibrillation compared with those working standard hours (hazard ratio = 1.42, 95% CI = 1.13-1.80, P = 0.003). There was no significant heterogeneity between the cohort-specific effect estimates (I2 = 0%, P = 0.66) and the finding remained after excluding participants with coronary heart disease or stroke at baseline or during the follow-up (N = 2006, hazard ratio = 1.36, 95% CI = 1.05-1.76, P = 0.0180). Adjustment for potential confounding factors, such as obesity, risky alcohol use and high blood pressure, had little impact on this association. CONCLUSION: Individuals who worked long hours were more likely to develop atrial fibrillation than those working standard hours.

Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe.

BACKGROUND: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight. METHODS: We pooled individual-participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow-up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20·0-24·9 kg/m2), overweight (25·0-29·9 kg/m2), class I (mild) obesity (30·0-34·9 kg/m2), and class II and III (severe) obesity (≥35·0 kg/m2). We used an inclusive definition of underweight (<20 kg/m2) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis. FINDINGS: Participants were 120  813 adults (mean age 51·4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10·7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2·0, 95% CI 1·7-2·4; p<0·0001), almost five times higher for individuals with class I obesity (4·5, 3·5-5·8; p<0·0001), and almost 15 times higher for individuals with classes II and III obesity combined (14·5, 10·1-21·0; p<0·0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2·2 (95% CI 1·9-2·6) for vascular disease only (coronary heart disease or stroke), 12·0 (8·1-17·9) for vascular disease followed by diabetes, 18·6 (16·6-20·9) for diabetes only, and 29·8 (21·7-40·8) for diabetes followed by vascular disease. INTERPRETATION: The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes. FUNDING: NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland.

Sleep Apnea, Disability Pensions, and Cause-Specific Mortality: A Swedish Nationwide Register Linkage Study.

Sleep apnea is a common problem affecting daily functioning and health. We evaluated associations between sleep apnea and receipt of a disability pension and mortality in a prospective study of 74,543 cases of sleep apnea (60,125 outpatient, 14,418 inpatient) from the Swedish Patient Register (2000-2009 inclusive). Cases were matched to 5 noncases (n = 371,592) and followed from diagnosis/inclusion to December 31, 2010, via nationwide registers. During a mean follow-up period of 5.1 (standard deviation, 2.7) years, 13% of men and 21% of women with inpatient sleep apnea received a disability pension. Inpatient sleep apnea was associated with higher total mortality (for men, hazard ratio (HR) = 1.71, 95% confidence interval (CI): 1.59, 1.84; for women, HR = 2.33, 95% CI: 2.04, 2.67), with associations being strongest for deaths due to ischemic heart disease (for men, HR = 2.27, 95% CI: 1.94, 2.65; for women, HR = 5.27, 95% CI: 3.78, 7.34), respiratory disorders (for men, HR = 3.29, 95% CI: 2.45, 4.42; for women, HR= 5.24, 95% CI: 3.52, 7.81), and suicide (for men, HR = 1.76, 95% CI: 1.19, 2.60; for women, HR = 4.33, 95% CI: 1.96, 9.56). There were no associations of inpatient sleep apnea with cancer mortality. Outpatient sleep apnea was associated with a higher risk of receiving a disability pension but not higher total mortality. In conclusion, inpatient sleep apnea is related to a higher risk of disability pension receipt and mortality a decade after diagnosis.

Metabolic Syndrome and Symptom Resolution in Depression: A 5-Year Follow-Up of Older Adults.

OBJECTIVE: Although metabolic syndrome is associated with the incidence of depression, little is known about its contribution to the course of depression. We examined whether metabolic syndrome and its components are associated with long-term symptom resolution in older adults with depressive symptoms. METHODS: Data from 965 participants in the Whitehall II cohort study (mean age = 62 years at baseline) were used to generate 1,172 person-observations of metabolic syndrome and its components (abdominal obesity, low level of high-density lipoprotein [HDL] cholesterol, high level of triglycerides, hypertension, and elevated fasting glucose or diabetes). All participants were depression cases at the beginning of 2 consecutive follow-up cycles: from 2002-2004 to 2007-2009 and from 2007-2009 to 2012-2013 (mean follow-up = 4.6 years). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale caseness at the beginning and the end of the 2 cycles. RESULTS: In multivariable adjusted analyses, metabolic syndrome per se was not associated with symptom resolution. Of its components, low HDL cholesterol (risk ratio [RR] = 0.82; 95% CI, 0.68-1.00; P = .045) and high triglyceride levels (RR = 0.81; 95% CI, 0.70-0.95; P = .007) were associated with a lower likelihood of symptom resolution. These findings were replicated in a subpopulation without coronary heart disease and stroke (RR = 0.77 [95% CI, 0.63-0.95; P = .015] for low HDL cholesterol; RR = 0.79 [95% CI, 0.67-0.94; P = .006] for high triglycerides). CONCLUSIONS: Low HDL cholesterol and high triglyceride levels are associated with lower likelihood of long-term symptom resolution in depression. These data suggest that an adverse lipid profile, but not other components of metabolic syndrome, may delay recovery from depression.

Job insecurity and risk of diabetes: a meta-analysis of individual participant data.

BACKGROUND: Job insecurity has been associated with certain health outcomes. We examined the role of job insecurity as a risk factor for incident diabetes. METHODS: We used individual participant data from 8 cohort studies identified in 2 open-access data archives and 11 cohort studies participating in the Individual-Participant-Data Meta-analysis in Working Populations Consortium. We calculated study-specific estimates of the association between job insecurity reported at baseline and incident diabetes over the follow-up period. We pooled the estimates in a meta-analysis to produce a summary risk estimate. RESULTS: The 19 studies involved 140 825 participants from Australia, Europe and the United States, with a mean follow-up of 9.4 years and 3954 incident cases of diabetes. In the preliminary analysis adjusted for age and sex, high job insecurity was associated with an increased risk of incident diabetes compared with low job insecurity (adjusted odds ratio [OR] 1.19, 95% confidence interval [CI] 1.09-1.30). In the multivariable-adjusted analysis restricted to 15 studies with baseline data for all covariates (age, sex, socioeconomic status, obesity, physical activity, alcohol and smoking), the association was slightly attenuated (adjusted OR 1.12, 95% CI 1.01-1.24). Heterogeneity between the studies was low to moderate (age- and sex-adjusted model: I2 = 24%, p = 0.2; multivariable-adjusted model: I2 = 27%, p = 0.2). In the multivariable-adjusted analysis restricted to high-quality studies, in which the diabetes diagnosis was ascertained from electronic medical records or clinical examination, the association was similar to that in the main analysis (adjusted OR 1.19, 95% CI 1.04-1.35). INTERPRETATION: Our findings suggest that self-reported job insecurity is associated with a modest increased risk of incident diabetes. Health care personnel should be aware of this association among workers reporting job insecurity.