Climate Change, Summer Temperature, and Heat-Related Mortality in Finland: Multicohort Study with Projections for a Sustainable vs. Fossil-Fueled Future to 2050.

BACKGROUND: Climate change scenarios illustrate various pathways in terms of global warming ranging from "sustainable development" (Shared Socioeconomic Pathway SSP1-1.9), the best-case scenario, to 'fossil-fueled development' (SSP5-8.5), the worst-case scenario. OBJECTIVES: We examined the extent to which increase in daily average urban summer temperature is associated with future cause-specific mortality and projected heat-related mortality burden for the current warming trend and these two scenarios. METHODS: We did an observational cohort study of 363,754 participants living in six cities in Finland. Using residential addresses, participants were linked to daily temperature records and electronic death records from national registries during summers (1 May to 30 September) 2000 to 2018. For each day of observation, heat index (average daily air temperature weighted by humidity) for the preceding 7 d was calculated for participants' residential area using a geographic grid at a spatial resolution of 1km×1km. We examined associations of the summer heat index with risk of death by cause for all participants adjusting for a wide range of individual-level covariates and in subsidiary analyses using case-crossover design, computed the related period population attributable fraction (PAF), and projected change in PAF from summers 2000-2018 compared with those in 2030-2050. RESULTS: During a cohort total exposure period of 582,111,979 summer days (3,880,746 person-summers), we recorded 4,094 deaths, including 949 from cardiovascular disease. The multivariable-adjusted rate ratio (RR) for high (≥21°C) vs. reference (14-15°C) heat index was 1.70 (95% CI: 1.28, 2.27) for cardiovascular mortality, but it did not reach statistical significance for noncardiovascular deaths, RR=1.14 (95% CI: 0.96, 1.36), a finding replicated in case-crossover analysis. According to projections for 2030-2050, PAF of summertime cardiovascular mortality attributable to high heat will be 4.4% (1.8%-7.3%) under the sustainable development scenario, but 7.6% (3.2%-12.3%) under the fossil-fueled development scenario. In the six cities, the estimated annual number of summertime heat-related cardiovascular deaths under the two scenarios will be 174 and 298 for a total population of 1,759,468 people. DISCUSSION: The increase in average urban summer temperature will raise heat-related cardiovascular mortality burden. The estimated magnitude of this burden is >1.5 times greater if future climate change is driven by fossil fuels rather than sustainable development. https://doi.org/10.1289/EHP12080.

Predicting long-term sickness absence with employee questionnaires and administrative records: a prospective cohort study of hospital employees.

OBJECTIVE: This study aimed to compare the utility of risk estimation derived from questionnaires and administrative records in predicting long-term sickness absence among shift workers. METHODS: This prospective cohort study comprised 3197 shift-working hospital employees (mean age 44.5 years, 88.0% women) who responded to a brief 8-item questionnaire on work disability risk factors and were linked to 28 variables on their working hour and workplace characteristics obtained from administrative registries at study baseline. The primary outcome was the first sickness absence lasting ≥90 days during a 4-year follow-up. RESULTS: The C-index of 0.73 [95% confidence interval (CI) 0.70-0.77] for a questionnaire-only based prediction model, 0.71 (95% CI 0.67-0.75) for an administrative records-only model, and 0.79 (95% CI 0.76-0.82) for a model combining variables from both data sources indicated good discriminatory ability. For a 5%-estimated risk as a threshold for positive test results, the detection rates were 76%, 74%, and 75% and the false positive rates were 40%, 45% and 34% for the three models. For a 20%-risk threshold, the corresponding detection rates were 14%, 8%, and 27% and the false positive rates were 2%, 2%, and 4%. To detect one true positive case with these models, the number of false positive cases accompanied varied between 7 and 10 using the 5%-estimated risk, and between 2 and 3 using the 20%-estimated risk cut-off. The pattern of results was similar using 30-day sickness absence as the outcome. CONCLUSIONS: The best predictive performance was reached with a model including both questionnaire responses and administrative records. Prediction was almost as accurate with models using only variables from one of these data sources. Further research is needed to examine the generalizability of these findings.

Estimating Dementia Risk Using Multifactorial Prediction Models.

Importance: The clinical value of current multifactorial algorithms for individualized assessment of dementia risk remains unclear. Objective: To evaluate the clinical value associated with 4 widely used dementia risk scores in estimating 10-year dementia risk. Design, Setting, and Participants: This prospective population-based UK Biobank cohort study assessed 4 dementia risk scores at baseline (2006-2010) and ascertained incident dementia during the following 10 years. Replication with a 20-year follow-up was based on the British Whitehall II study. For both analyses, participants who had no dementia at baseline, had complete data on at least 1 dementia risk score, and were linked to electronic health records from hospitalizations or mortality were included. Data analysis was conducted from July 5, 2022, to April 20, 2023. Exposures: Four existing dementia risk scores: the Cardiovascular Risk Factors, Aging and Dementia (CAIDE)-Clinical score, the CAIDE-APOE-supplemented score, the Brief Dementia Screening Indicator (BDSI), and the Australian National University Alzheimer Disease Risk Index (ANU-ADRI). Main Outcomes and Measures: Dementia was ascertained from linked electronic health records. To evaluate how well each score predicted the 10-year risk of dementia, concordance (C) statistics, detection rate, false-positive rate, and the ratio of true to false positives were calculated for each risk score and for a model including age alone. Results: Of 465 929 UK Biobank participants without dementia at baseline (mean [SD] age, 56.5 [8.1] years; range, 38-73 years; 252 778 [54.3%] female participants), 3421 were diagnosed with dementia at follow-up (7.5 per 10 000 person-years). If the threshold for a positive test result was calibrated to achieve a 5% false-positive rate, all 4 risk scores detected 9% to 16% of incident dementia and therefore missed 84% to 91% (failure rate). The corresponding failure rate was 84% for a model that included age only. For a positive test result calibrated to detect at least half of future incident dementia, the ratio of true to false positives ranged between 1 to 66 (for CAIDE-APOE-supplemented) and 1 to 116 (for ANU-ADRI). For age alone, the ratio was 1 to 43. The C statistic was 0.66 (95% CI, 0.65-0.67) for the CAIDE clinical version, 0.73 (95% CI, 0.72-0.73) for the CAIDE-APOE-supplemented, 0.68 (95% CI, 0.67-0.69) for BDSI, 0.59 (95% CI, 0.58-0.60) for ANU-ADRI, and 0.79 (95% CI, 0.79-0.80) for age alone. Similar C statistics were seen for 20-year dementia risk in the Whitehall II study cohort, which included 4865 participants (mean [SD] age, 54.9 [5.9] years; 1342 [27.6%] female participants). In a subgroup analysis of same-aged participants aged 65 (±1) years, discriminatory capacity of risk scores was low (C statistics between 0.52 and 0.60). Conclusions and Relevance: In these cohort studies, individualized assessments of dementia risk using existing risk prediction scores had high error rates. These findings suggest that the scores were of limited value in targeting people for dementia prevention. Further research is needed to develop more accurate algorithms for estimation of dementia risk.

Predicting work disability among people with chronic conditions: a prospective cohort study.

Few risk prediction scores are available to identify people at increased risk of work disability, particularly for those with an existing morbidity. We examined the predictive performance of disability risk scores for employees with chronic disease. We used prospective data from 88,521 employed participants (mean age 43.1) in the Finnish Public Sector Study including people with chronic disorders: musculoskeletal disorder, depression, migraine, respiratory disease, hypertension, cancer, coronary heart disease, diabetes, comorbid depression and cardiometabolic disease. A total of 105 predictors were assessed at baseline. During a mean follow-up of 8.6 years, 6836 (7.7%) participants were granted a disability pension. C-statistics for the 8-item Finnish Institute of Occupational Health (FIOH) risk score, comprising age, self-rated health, number of sickness absences, socioeconomic position, number of chronic illnesses, sleep problems, BMI, and smoking at baseline, exceeded 0.72 for all disease groups and was 0.80 (95% CI 0.80-0.81) for participants with musculoskeletal disorders, 0.83 (0.82-0.84) for those with migraine, and 0.82 (0.81-0.83) for individuals with respiratory disease. Predictive performance was not significantly improved in models with re-estimated coefficients or a new set of predictors. These findings suggest that the 8-item FIOH work disability risk score may serve as a scalable screening tool in identifying individuals with increased risk for work disability.

Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study.

BACKGROUND: The excess risk of cardiovascular disease associated with a wide array of infectious diseases is unknown. We quantified the short- and long-term risk of major cardiovascular events in people with severe infection and estimated the population-attributable fraction. METHODS: We analyzed data from 331 683 UK Biobank participants without cardiovascular disease at baseline (2006-2010) and replicated our main findings in an independent population from 3 prospective cohort studies comprising 271 329 community-dwelling participants from Finland (baseline 1986-2005). Cardiovascular risk factors were measured at baseline. We diagnosed infectious diseases (the exposure) and incident major cardiovascular events after infections, defined as myocardial infarction, cardiac death, or fatal or nonfatal stroke (the outcome) from linkage of participants to hospital and death registers. We computed adjusted hazard ratios (HRs) and 95% CIs for infectious diseases as short- and long-term risk factors for incident major cardiovascular events. We also calculated population-attributable fractions for long-term risk. RESULTS: In the UK Biobank (mean follow-up, 11.6 years), 54 434 participants were hospitalized for an infection, and 11 649 had an incident major cardiovascular event at follow-up. Relative to participants with no record of infectious disease, those who were hospitalized experienced increased risk of major cardiovascular events, largely irrespective of the type of infection. This association was strongest during the first month after infection (HR, 7.87 [95% CI, 6.36-9.73]), but remained elevated during the entire follow-up (HR, 1.47 [95% CI, 1.40-1.54]). The findings were similar in the replication cohort (HR, 7.64 [95% CI, 5.82-10.03] during the first month; HR, 1.41 [95% CI, 1.34-1.48] during mean follow-up of 19.2 years). After controlling for traditional cardiovascular risk factors, the population-attributable fraction for severe infections and major cardiovascular events was 4.4% in the UK Biobank and 6.1% in the replication cohort. CONCLUSIONS: Infections severe enough to require hospital treatment were associated with increased risks for major cardiovascular disease events immediately after hospitalization. A small excess risk was also observed in the long-term, but residual confounding cannot be excluded.

Association of social isolation and loneliness with risk of incident hospital-treated infections: an analysis of data from the UK Biobank and Finnish Health and Social Support studies.

BACKGROUND: Although loneliness and social isolation have been linked to an increased risk of non-communicable diseases such as cardiovascular disease and dementia, their association with the risk of severe infection is uncertain. We aimed to examine the associations between loneliness and social isolation and the risk of hospital-treated infections using data from two independent cohort studies. METHODS: We assessed the association between loneliness and social isolation and incident hospital-treated infections using data for participants from the UK Biobank study aged 38-73 years at baseline and participants from the nationwide population-based Finnish Health and Social Support (HeSSup) study aged 20-54 years at baseline. For inclusion in the study, participants had to be linked to national health registries, have no history of hospital-treated infections at or before baseline, and have complete data on loneliness or social isolation. Participants with missing data on hospital-treated infections, loneliness, and social isolation were excluded from both cohorts. The outcome was defined as a hospital admission with a primary diagnosis of infection, ascertained via linkage to electronic health records. FINDINGS: After exclusion of 8·6 million participants for not responding or not providing appropriate consent, the UK Biobank cohort consisted of 456 905 participants (249 586 women and 207 319 men). 26 860 (6·2%) of 436 001 participants with available data were reported as being lonely and 40 428 (9·0%) of 448 114 participants with available data were socially isolated. During a median 8·9 years (IQR 8·0-9·6) of follow-up, 51 361 participants were admitted to hospital due to an infectious disease. After adjustment for age, sex, demographic and lifestyle factors, and morbidities, loneliness was associated with an increased risk of a hospital-treated infection (hazard ratio [HR] 1·12 [95% CI 1·07-1·16]), whereas social isolation was not (HR 1·01 [95% CI 0·97-1·04]). Of 64 797 individuals in the HeSSup cohort, 18 468 (11 367 women and 7101 men) were eligible for inclusion. 4466 (24·4%) of 18 296 were lonely and 1776 (9·7%) of 18 376 socially isolated. During a median follow-up of 10·0 years (IQR 10·0-10·1), 814 (4·4%) participants were admitted to hospital for an infectious disease. The HRs for the HeSSup study replicated those in the UK Biobank (multivariable-adjusted HR for loneliness 1·32 [95% CI 1·06-1·64]; 1·08 [0·87-1·35] for social isolation). INTERPRETATION: Loneliness might increase susceptibility to severe infections, although the magnitude of this effect appears modest and residual confounding cannot be excluded. Interventional studies are required before policy recommendations can advance. FUNDING: Academy of Finland, the UK Medical Research Council, and Wellcome Trust UK.

Association of alcohol use with years lived without major chronic diseases: A multicohort study from the IPD-Work consortium and UK Biobank.

Background: Heavy alcohol consumption increases the risk of several chronic diseases. In this multicohort study, we estimated the number of life-years without major chronic diseases according to different characteristics of alcohol use. Methods: In primary analysis, we pooled individual-level data from up to 129,942 adults across 12 cohort studies with baseline data collection on alcohol consumption, drinking patterns, and history between 1986 and 2005 (the IPD-Work Consortium). Self-reported alcohol consumption was categorised according to UK guidelines - non-drinking (never or former drinkers); moderate consumption (1-14 units); heavy consumption (>14 units per week). We further subdivided moderate and heavy drinkers by binge drinking pattern (alcohol-induced loss of consciousness). In addition, we assessed problem drinking using linked data on hospitalisations due to alcohol abuse or poisoning. Follow-up for chronic diseases for all participants included incident type 2 diabetes, coronary heart disease, stroke, cancer, and respiratory disease (asthma and chronic obstructive pulmonary disease) as ascertained via linkage to national morbidity and mortality registries, repeated medical examinations, and/or self-report. We estimated years lived without any of these diseases between 40 and 75 years of age according to sex and characteristics of alcohol use. We repeated the main analyses using data from 427,621 participants in the UK Biobank cohort study. Findings: During 1·73 million person-years at risk, 22,676 participants in IPD-Work cohorts developed at least one chronic condition. From age 40 to 75 years, never-drinkers [men: 29·3 (95%CI 27·9-30·8) years, women 29·8 (29·2-30·4) years)] and moderate drinkers with no binge drinking habit [men 28·7 (28·4-29·0) years, women 29·6 (29·4-29·7) years] had the longest disease-free life span. A much shorter disease-free life span was apparent in participants who experienced alcohol poisoning [men 23·4 (20·9-26·0) years, women 24·0 (21·4-26·5) years] and those with self-reported heavy overall consumption and binge drinking [men: 26·0 (25·3-26·8), women 27·5 (26·4-28·5) years]. The pattern of results for alcohol poisoning and self-reported alcohol consumption was similar in UK Biobank. In IPD-Work and UK Biobank, differences in disease-free years between self-reported moderate drinkers and heavy drinkers were 1·5 years or less. Interpretation: Individuals with alcohol poisonings or heavy self-reported overall consumption combined with a binge drinking habit have a marked 3- to 6-year loss in healthy longevity. Differences in disease-free life between categories of self-reported weekly alcohol consumption were smaller. Funding: Medical Research Council, National Institute on Aging, NordForsk, Academy of Finland, Finnish Work Environment Fund.

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.

Work stress and loss of years lived without chronic disease: an 18-year follow-up of 1.5 million employees in Denmark.

We aimed to examine the association between exposure to work stress and chronic disease incidence and loss of chronic disease-free life years in the Danish workforce. The study population included 1,592,491 employees, aged 30-59 in 2000 and without prevalent chronic diseases. We assessed work stress as the combination of job strain and effort-reward imbalance using job exposure matrices. We used Cox regressions to estimate risk of incident hospital-diagnoses or death of chronic diseases (i.e., type 2 diabetes, coronary heart disease, stroke, cancer, asthma, chronic obstructive pulmonary disease, heart failure, and dementia) during 18 years of follow-up and calculated corresponding chronic disease-free life expectancy from age 30 to age 75. Individuals working in occupations with high prevalence of work stress had a higher risk of incident chronic disease compared to those in occupations with low prevalence of work stress (women: HR 1.04 (95% CI 1.02-1.05), men: HR 1.12 (95% CI 1.11-1.14)). The corresponding loss in chronic disease-free life expectancy was 0.25 (95% CI - 0.10 to 0.60) and 0.84 (95% CI 0.56-1.11) years in women and men, respectively. Additional adjustment for health behaviours attenuated these associations among men. We conclude that men working in high-stress occupations have a small loss of years lived without chronic disease compared to men working in low-stress occupations. This finding appeared to be partially attributable to harmful health behaviours. In women, high work stress indicated a very small and statistically non-significant loss of years lived without chronic disease.

Long working hours and risk of 50 health conditions and mortality outcomes: a multicohort study in four European countries.

BACKGROUND: Studies on the association between long working hours and health have captured only a narrow range of outcomes (mainly cardiometabolic diseases and depression) and no outcome-wide studies on this topic are available. To achieve wider scope of potential harm, we examined long working hours as a risk factor for a wide range of disease and mortality endpoints. METHODS: The data of this multicohort study were from two population cohorts from Finland (primary analysis, n=59 599) and nine cohorts (replication analysis, n=44 262) from Sweden, Denmark, and the UK, all part of the Individual-participant Meta-analysis in Working Populations (IPD-Work) consortium. Baseline-assessed long working hours (≥55 hours per week) were compared to standard working hours (35-40 h). Outcome measures with follow-up until age 65 years were 46 diseases that required hospital treatment or continuous pharmacotherapy, all-cause, and three cause-specific mortality endpoints, ascertained via linkage to national health and mortality registers. FINDINGS: 2747 (4·6%) participants in the primary cohorts and 3027 (6·8%) in the replication cohorts worked long hours. After adjustment for age, sex, and socioeconomic status, working long hours was associated with increased risk of cardiovascular death (hazard ratio 1·68; 95% confidence interval 1·08-2·61 in primary analysis and 1·52; 0·90-2·58 in replication analysis), infections (1·37; 1·13-1·67 and 1·45; 1·13-1·87), diabetes (1·18; 1·01-1·38 and 1·41; 0·98-2·02), injuries (1·22; 1·00-1·50 and 1·18; 0·98-1·18) and musculoskeletal disorders (1·15; 1·06-1·26 and 1·13; 1·00-1·27). Working long hours was not associated with all-cause mortality. INTERPRETATION: Follow-up of 50 health outcomes in four European countries suggests that working long hours is associated with an elevated risk of early cardiovascular death and hospital-treated infections before age 65. Associations, albeit weak, were also observed with diabetes, musculoskeletal disorders and injuries. In these data working long hours was not related to elevated overall mortality. FUNDING: NordForsk, the Medical Research Council, the National Institute on Aging, the Wellcome Trust, Academy of Finland, and Finnish Work Environment Fund.

Emotional demands at work and risk of long-term sickness absence in 1·5 million employees in Denmark: a prospective cohort study on effect modifiers.

BACKGROUND: High emotional demands at work can affect employees' health and there is a need to understand whether such an association might be modified by other working conditions. We aimed to examine emotional demands at work as a risk factor for long-term sickness absence and analyse whether influence, possibilities for development, role conflicts, and physical demands at work might modify this risk. METHODS: We did a nationwide, population-based, prospective cohort study in Denmark and included employed individuals who were residing in Denmark in 2000, aged 30-59 years, who had complete data on age, sex, and migration background, with information on emotional demands and possible effect modifiers from job exposure matrices, and covariates and outcome (sickness absence) from population registers. Individuals with long-term sickness absence (≥6 weeks of consecutive sickness absence) between Jan 1, 1998, and Dec 31, 2000, and self-employed individuals were excluded. We assessed long-term sickness absence during a 10-year period from Jan 1, 2001, to Dec 31, 2010. Using Cox regression, we estimated hazard ratios (HRs) and 95% CIs and tested interaction as departure from additivity, estimating relative excess risk due to interaction (RERI). Multivariable adjusted models included sex, age, cohabitation, migration background, and income. FINDINGS: 1 521 352 employed individuals were included and contributed data between Jan 1, 2000, and Dec 31, 2010. During 11 919 021 person-years (mean follow-up 7·8 years), we identified 480 685 new cases of long-term sickness absence. High emotional demands were associated with increased risk of long-term sickness absence compared with low emotional demands, after adjusting for age, sex, cohabitation, migration background, income, and the four possible effect modifiers (adjusted HR 1·55 [95% CI 1·53-1·56]). The association between high emotional demands and risk of long-term sickness absence was stronger in a synergistic way when individuals were also exposed to low possibilities for development (RERI 0·35 [95% CI 0·22-0·47]; 28·9 additional cases per 1000 person-years) and high role conflicts (0·13 [0·11-0·15]; 22·0 additional cases per 1000 person-years). No synergy was observed for influence and physical demands at work. INTERPRETATION: People in occupations with high emotional demands were at increased risk of long-term sickness absence. Our findings on synergistic interactions suggest that, in emotionally demanding occupations, increasing possibilities for development and reducing work-related role conflicts might reduce long-term sickness absence. Further interventional studies are needed to confirm or refute this hypothesis. FUNDING: Danish Work Environment Research Fund, NordForsk.

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 between change in cardiovascular risk scores and future cardiovascular disease: analyses of data from the Whitehall II longitudinal, prospective cohort study.

BACKGROUND: Evaluation of cardiovascular disease risk in primary care, which is recommended every 5 years in middle-aged and older adults (typical age range 40-75 years), is based on risk scores, such as the European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) and American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease (ASCVD) algorithms. This evaluation currently uses only the most recent risk factor assessment. We aimed to examine whether 5-year changes in SCORE and ASCVD risk scores are associated with future cardiovascular disease risk. METHODS: We analysed data from the Whitehall II longitudinal, prospective cohort study for individuals with no history of stroke, myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, definite angina, heart failure, or peripheral artery disease. Participants underwent clinical examinations in 5-year intervals between Aug 7, 1991, and Dec 6, 2016, and were followed up for incident cardiovascular disease until Oct 2, 2019. Levels of, and 5-year changes in, cardiovascular disease risk were assessed using the SCORE and ASCVD risk scores and were analysed as predictors of cardiovascular disease. Harrell's C index, continuous net reclassification improvement, the Akaike information criterion, and calibration analysis were used to assess whether incorporating change in risk scores into a model including only a single risk score assessment improved the predictive performance. We assessed the levels of, and 5-year changes in, SCORE and ASCVD risk scores as predictors of cardiovascular disease and disease-free life-years using Cox proportional hazards and flexible parametric survival models. FINDINGS: 7574 participants (5233 [69·1%] men, 2341 [30·9%] women) aged 40-75 years were included in analyses of risk score change between April 24, 1997, and Oct 2, 2019. During a mean follow-up of 18·7 years (SD 5·5), 1441 (19·0%; 1042 [72·3%] men and 399 [27·7%] women) participants developed cardiovascular disease. Adding 5-year change in risk score to a model that included only a single risk score assessment improved model performance according to Harrell's C index (from 0·685 to 0·690, change 0·004 [95% CI 0·000 to 0·008] for SCORE; from 0·699 to 0·700, change 0·001 [0·000 to 0·003] for ASCVD), the Akaike information criterion (from 17 255 to 17 200, change -57 [95% CI -97 to -13] for SCORE; from 14 739 to 14 729, change -10 [-28 to 7] for ASCVD), and the continuous net reclassification index (0·353 [95% CI 0·234 to 0·447] for SCORE; 0·232 [0·030 to 0·344] for ASCVD). Both favourable and unfavourable changes in SCORE and ASCVD were associated with cardiovascular disease risk and disease-free life-years. The associations were seen in both sexes and all age groups up to the age of 75 years. At the age of 45 years, each 2-unit improvement in risk scores was associated with an additional 1·3 life-years (95% CI 0·4 to 2·2) free of cardiovascular disease for SCORE and an additional 0·9 life-years (95% CI 0·5 to 1·3) for ASCVD. At age 65 years, this same improvement was associated with an additional 0·4 life-years (95% CI 0·0 to 0·7) free of cardiovascular disease for SCORE and 0·3 life-years (95% CI 0·1 to 0·5) for ASCVD. These models were developed into an interactive calculator, which enables estimation of the number of cardiovascular disease-free life-years for an individual as a function of two risk score measurements. INTERPRETATION: Changes in the SCORE and ASCVD risk scores over time inform cardiovascular disease risk prediction beyond a single risk score assessment. Repeat data might allow more accurate cardiovascular risk stratification and strengthen the evidence base for decisions on preventive interventions. FUNDING: UK Medical Research Council, British Heart Foundation, Wellcome Trust, and US National Institute on Aging.

Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort.

BACKGROUND: Infections have been hypothesised to increase the risk of dementia. Existing studies have included a narrow range of infectious diseases, relied on short follow-up periods, and provided little evidence for whether the increased risk is limited to specific dementia subtypes or attributable to specific microbes rather than infection burden. We aimed to compare the risk of Alzheimer's disease and other dementias across a wide range of hospital-treated bacterial and viral infections in two large cohorts with long follow-up periods. METHODS: In this large, multicohort, observational study, the analysis was based on a primary cohort consisting of pooled individual-level data from three prospective cohort studies in Finland (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study) and an independent replication cohort from the UK Biobank. Community-dwelling adults (≥18 years) with no dementia at study entry were included. Follow-up was until Dec 31, 2012, in the Health and Social Support study, Dec 31, 2016, in the public sector study and the Still Working study, and Feb 7, 2018, in the replication cohort. Through record linkage to national hospital inpatient registers, we ascertained exposure to 925 infectious diseases (using the International Classification of Diseases 10th Revision codes) before dementia onset, and identified incident dementia from hospital records, medication reimbursement entitlements, and death certificates. Hazard ratios (HRs) for the associations of each infectious disease or disease group (index infection) with incident dementia were assessed by use of Cox proportional hazards models. We then repeated the analysis after excluding incident dementia cases that occurred during the first 10 years after initial hospitalisation due to the index infection. FINDINGS: From March 1, 1986, to Jan 1, 2005, 260 490 people were included in the primary cohort, and from Dec 19, 2006, to Oct 1, 2010, 485 708 people were included in the replication cohort. In the primary cohort analysis based on 3 947 046 person-years at risk (median follow-up 15·4 years [IQR 9·8-21·0]), 77 108 participants had at least one hospital-treated infection before dementia onset and 2768 developed dementia. Hospitalisation for any infectious disease was associated with increased dementia risk in the primary cohort (adjusted HR [aHR] 1·48 [95% CI 1·37-1·60]) and replication cohort (2·60 [2·38-2·83]). The association remained when analyses were restricted to new dementia cases that occurred more than 10 years after infection (aHR 1·22 [95% CI 1·09-1·36] in the primary cohort, the replication cohort had insufficient follow-up data for this analysis), and when comorbidities and other dementia risk factors were considered. There was evidence of a dose-response association between the number of episodes of hospital-treated infections and dementia risk in both cohorts (ptrend=0·0007). Although the greatest dementia risk was seen for central nervous system (CNS) infections versus no infection (aHR 3·01 [95% CI 2·07-4·37]), excess risk was also evident for extra-CNS infections (1·47 [1·36-1·59]). Although we found little difference in the infection-dementia association by type of infection, associations were stronger for vascular dementia than for Alzheimer's disease (aHR 2·09 [95% CI 1·59-2·75] versus aHR 1·20 [1·08-1·33] in the primary cohort and aHR 3·28 [2·65-4·04] versus aHR 1·80 [1·53-2·13] in the replication cohort). INTERPRETATION: Severe infections requiring hospital treatment are associated with long-term increased risk of dementia, including vascular dementia and Alzheimer's disease. This association is not limited to CNS infections, suggesting that systemic effects are sufficient to affect the brain. The absence of infection specificity combined with evidence of dose-response relationships between infectious disease burden and dementia risk support the hypothesis that increased dementia risk is driven by general inflammation rather than specific microbes. FUNDING: UK Medical Research Council, US National Institute on Aging, Wellcome Trust, NordForsk, Academy of Finland, and Helsinki Institute of Life Science.

Modifications to residential neighbourhood characteristics and risk of 79 common health conditions: a prospective cohort study.

BACKGROUND: Observational studies have identified a link between unfavourable neighbourhood characteristics and increased risk of morbidity, but it is unclear whether changes in neighbourhoods affect future disease risk. We used a data-driven approach to assess the impact of neighbourhood modification on 79 health outcomes. METHODS: In this prospective cohort study, we used pooled, individual-level data from two Finnish cohort studies: the Health and Social Support study and the Finnish Public Sector study. Neighbourhood characteristics (mean educational level, median income, and employment rate of residents, and neighbourhood green space) and individual lifestyle factors of community-dwelling individuals were assessed at baseline (at different waves starting between 1998 and 2013). We repeated assessment of neighbourhood characteristics and lifestyle factors approximately 5 years from each baseline assessment, after which follow-up began for health conditions diagnosed according to the WHO International Classification of Diseases for 79 common health conditions using linkage to electronic health records. We used Cox proportional hazard regression models to compute adjusted hazard ratios (HRs) of incident disease associated with neighbourhood characteristics and changes in neighbourhood characteristics over time and logistic regression analysis to compute adjusted odds of association between changes in neighbourhood characteristics and individual lifestyle factors. FINDINGS: 114 786 individuals (87 012 [75·8%] women; mean age 44·4 years [SD 11·1]) had complete data and were included in this cohort study. During 1·17 million person-years at risk, we recorded 164 368 new-onset health conditions and 3438 deaths. Favourable changes in neighbourhood characteristics were associated with reduced risk of all-cause mortality and incidence of 19 specific health conditions. Unfavourable changes were correspondingly associated with increased risk of mortality and 27 specific health conditions. Among participants who did not move residence during the observation period, relative to individuals who continually lived in disadvantaged neighbourhoods, those who experienced favourable modifications in neighbourhood characteristics had a lower risk of future diabetes (HR 0·84, 95% CI 0·75-0·93), stroke (0·49, 0·29-0·83), skin disease (0·72, 0·53-0·97), and osteoarthritis (0·87, 0·77-0·99). Living in a neighbourhood with improving characteristics was also associated with improvements in individual-level health-related lifestyle factors. Among participants who lived in advantaged residential environments at baseline, unfavourable changes in neighbourhood characteristics were associated with an increased risk of diabetes, stroke, skin disease, and osteoarthritis compared with individuals who lived in advantaged neighbourhoods throughout the study period. INTERPRETATION: Favourable modifications to residential neighbourhoods showed robust, longitudinal associations with a range of improvements in health outcomes, including improved health behaviours and reduced risk of cardiometabolic, infectious, and orthopaedic conditions. FUNDING: UK Medical Research Council, US National Institute on Aging, NordForsk, and Academy of Finland.

The WHO/ILO report on long working hours and ischaemic heart disease - Conclusions are not supported by the evidence.

Working hours is a ubiquitous exposure given that most adults are employed, and one that is modifiable via legislative change if not always through individual-level choice. According to a recent report from the World Health Organization (WHO) and International Labour Organization (ILO), there is currently sufficient evidence to conclude that long working hours (i.e., ≥55 h per week) elevate the risk of fatal and non-fatal ischaemic heart disease to a clinically meaningful extent. After assessing the data used by the ILO/WHO, we feel that the expert group has not correctly applied their own framework for assessing the strength of the evidence. In the meta-analysis of observational studies in the report, the association between long working hours and incident heart disease appeared stronger in lower quality cohort studies with a high risk of bias (minimally-adjusted hazard ratio 1.20, 95% CI 1.01-1.41, compared to standard 35-40 weekly hours) than in the superior-quality studies with a lower risk of bias for which the estimate was not significantly different from the null (1.08, 95% CI 0.93-1.25). There was also marked effect modification, such that there was no increase in ischaemic heart disease for those working long hours in high socioeconomic status occupations, a finding also reported in analyses of a recent census-based cohort study which was not included in the report. Our meta-analysis of all these studies confirm that the findings are not consistent but differ between subgroups and that the summary age- and sex-adjusted hazard ratio for long working hours in high socioeconomic status occupations does not support excess risk: 0.85, 95% CI 0.63-1.13 (Pinteraction = 0.005, total N = 451,982). For these and other reasons detailed in this commentary, we advance a more cautious interpretation of the existing evidence. The conclusions should be restricted to low socioeconomic status occupations only and more research is still needed to confirm or refute harmfulness and determine clinical relevance.

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.

Long-term risk of dementia following hospitalization due to physical diseases: A multicohort study.

INTRODUCTION: Conventional risk factors targeted by prevention (e.g., low education, smoking, and obesity) are associated with a 1.2- to 2-fold increased risk of dementia. It is unclear whether having a physical disease is an equally important risk factor for dementia. METHODS: In this exploratory multicohort study of 283,414 community-dwelling participants, we examined 22 common hospital-treated physical diseases as risk factors for dementia. RESULTS: During a median follow-up of 19 years, a total of 3416 participants developed dementia. Those who had erysipelas (hazard ratio = 1.82; 95% confidence interval = 1.53 to 2.17), hypothyroidism (1.94; 1.59 to 2.38), myocardial infarction (1.41; 1.20 to 1.64), ischemic heart disease (1.32; 1.18 to 1.49), cerebral infarction (2.44; 2.14 to 2.77), duodenal ulcers (1.88; 1.42 to 2.49), gastritis and duodenitis (1.82; 1.46 to 2.27), or osteoporosis (2.38; 1.75 to 3.23) were at a significantly increased risk of dementia. These associations were not explained by conventional risk factors or reverse causation. DISCUSSION: In addition to conventional risk factors, several physical diseases may increase the long-term risk of dementia.