Life-course pathways to exceptional longevity: Evidence from the Lothian Birth Cohort of 1921.

BACKGROUND: Longevity, a hallmark of successful ageing, is a multifactorial trait with influences from birth onwards. However, limited evidence exists on the pathways linking diverse life-course exposures to longevity, especially within a single cohort. METHODS: We investigated associations between life-course factors and longevity among community-dwelling adults aged 79 (N=547) from the Lothian Birth Cohort 1921 with a mortality follow-up of 24 years. Cox proportional hazards and structural equation (path) models were used to explore how factors from early-life (social class, childhood IQ, education), mid-life (social class), later-life (health, lifestyle, psychosocial well-being), as well as sex, personality and APOE e4 status, influence survival time in days. RESULTS: During follow-up (1999-2023), 538 participants (98%) died (mean age of death=89.3 years) and 9 survived (mean age=101.6 years). Factors associated with lower mortality risk in the multivariable Cox model were higher cognitive function (HR=0.72; 95% CI:0.59-0.88), better physical function (HR=0.61; 95% CI:0.44-0.85), and greater physical activity (HR=0.81; 95% CI 0.71-0.92), while history of cancer was associated with higher mortality risk (HR=1.84; 95% CI:1.22-2.77). The life-course path model identified the same direct predictors, with additional contributions from female sex and non-smoking status, to greater longevity. Early- and mid-life factors (IQ, education, social class), and emotional stability, conscientiousness, and female sex, were indirectly and positively associated with survival trajectories via multiple dimensions of adult health. CONCLUSIONS: In understanding why people live to very old ages it is necessary to consider factors from throughout the life course, and to include demographic, psychosocial, and health variables.

Impact of physical and sexual abuse on risk of hospitalisations for physical and mental illnesses: insights from two large prospective cohort studies.

Background: Physical abuse can lead to severe health consequences that extend beyond immediate harm. We explored the associations of physical abuse experienced during childhood and adulthood with a wide range of adult health conditions requiring hospital treatment. Methods: We utilised data from a sub-cohort of 157,366 UK Biobank participants (46.4% of the baseline population; age range 45-81; 89,101 women) and repeated analyses in an independent population of 85,929 adults from the Finnish Public Sector (FPS) study (age range 17-78; 68,544 women). Participants in both cohorts reported instances of physical and sexual abuse at study baseline. Follow-up included 77 common health conditions ascertained from linkage data to national hospital and mortality registries. Findings: Mean follow-up duration was 4.6 years (SD 0.14) in UK Biobank and 10.6 years (4.3) in FPS. Physical and sexual abuse was associated with 22 mental and physical health conditions. After multivariable adjustments, participants who experienced abuse during both early and later stages of life had a 2.12- (95% confidence interval 1.39-3.23) to 3.37-fold (1.52-7.45) increased risk of mental and behavioural disorders, a 1.46 (1.20-1.79) to 1.83 (1.05-3.20) times increased risk of metabolic, haematologic, and respiratory diseases, and a 1.24 (1.07-1.45) times higher risk of inflammatory diseases compared with non-exposed participants. The absolute risk difference between these groups was greatest for metabolic and haematologic conditions (rate 381 and risk difference 160 per 100,000 person-years). Frailty, comorbidities, and competing risk of death did not modify these associations, but the possibility of bias or residual confounding cannot be excluded. Interpretation: Repeated exposure to physical and sexual abuse amplifies the risk of hospitalisations from mental disorders and physical diseases spanning diverse organ systems. Addressing this issue may necessitate multifaceted strategies, including shifts in societal norms, legal measures, and increased healthcare provision for affected individuals and their families. Funding: Wellcome Trust, UK Medical Research Council, U.S. National Institute on Aging, Academy of Finland.

Cardiovascular Disease Events in Adults with a History of State Care in Childhood: Pooling of Unpublished Results from 9 Cohort Studies.

Background: Individuals who were separated from their biological family and placed into the care of the state during childhood (out-of-home care) are more prone to developing selected physical and mental health problems in adulthood, however, their risk of cardiovascular disease (CVD) is uncertain. Accordingly, we pooled published and unpublished results from cohort studies of childhood care and adult CVD. Methods: We used two approaches to identifying relevant data on childhood care and adult CVD (PROSPERO registration CRD42021254665). First, to locate published studies, we searched PubMed (Medline) until November 2023. Second, with the aim of identifying unpublished studies with the potential to address the present research question, we scrutinised retrieved reviews of the impact of childhood state care on related adult health outcomes. All included studies were required to have prospective measurement of state care in childhood and a follow-up of CVD events in adulthood as the primary outcome (incident coronary heart disease and/or stroke). Collaborating investigators provided study-specific estimates which were aggregated using random-effects meta-analysis. The Newcastle-Ottawa Scale was used to assess individual study quality. Findings: Thirteen studies (2 published, 11 unpublished) met the inclusion criteria, and investigators from nine provided viable results, including updated analyses of the published studies. Studies comprised 611,601 individuals (301,129 women) from the US, UK, Sweden, Finland, and Australia. Relative to the unexposed, individuals with a care placement during childhood had a 50% greater risk of CVD in adulthood (summary rate ratio after basic adjustment [95% confidence interval]: 1.50 [1.22, 1.84]); range of study-specific estimates: 1.28 to 2.06; I2 = 69%, p = 0.001). This association was attenuated but persisted after multivariable adjustment for socioeconomic status in childhood (8 studies; 1.41 [1.15, 1.72]) and adulthood (9 studies, 1.28 [1.10, 1.50]). There was a suggestion of a stronger state care-CVD association in women. Interpretation: Our findings show that individuals with experience of state care in childhood have a moderately raised risk of CVD in adulthood. For timely prevention, clinicians and policy makers should be aware that people with a care history may need additional attention in risk factor management.

Dementia risk factors in former contact sports participants: prospective cohort study.

Background: The elevated dementia incidence in retired contact sport participants might be explained by a higher prevalence of established risk factors for the disease relative to the general population. Methods: In this cohort study, former elite participants active between 1920 and 1965 in soccer (N=303), boxing (N=281), and wrestling (N=318) were recruited using sports yearbooks and records of sports associations. Men in a population control group were identified using records from a compulsory medical examination (N=1712). All study members were linked to hospital registers (1970-2015) and self-completion questionnaires were circulated (1985, 1995) from which we captured data on nine established risk factors for dementia: hypertension and diabetes status, alcohol intake, loneliness, depressive symptoms, cigarette smoking, body weight, educational attainment, and physical activity. Results: There was little suggestion that former participants in contact sports had a higher prevalence of dementia risk factors relative to the general population. Rather, the balance of evidence was for more favourable risk factor levels in former athletes, as was particularly evident for ever having smoked cigarettes (range in odds ratios [95% confidence interval]: 0.32 [0.21, 0.48] for wrestling to 0.52 [0.36, 0.75] for soccer) and leisure-time physical activity (range in beta coefficients [95% confidence interval]: 1.34 [0.66, 2.02] for soccer to 1.80 [1.07, 2.52] for boxing). Conclusions: The increased dementia rates in retired contact sport participants evident in epidemiological studies is unlikely to be explained by the risk factors examined here. This implicates other characteristics of contact sports, including a history of repeated head impact.

Childhood cognitive ability and self-harm and suicide in later life.

Background: Self-harm and suicide remain prevalent in later life. For younger adults, higher early-life cognitive ability appears to predict lower self-harm and suicide risk. Comparatively little is known about these associations among middle-aged and older adults. Methods: This study examined the association between childhood (age 11) cognitive ability and self-harm and suicide risk among a Scotland-wide cohort (N = 53037), using hospital admission and mortality records to follow individuals from age 34 to 85. Multistate models examined the association between childhood cognitive ability and transitions between unaffected, self-harm, and then suicide or non-suicide death. Results: After adjusting for childhood and adulthood socioeconomic conditions, higher childhood cognitive ability was significantly associated with reduced risk of self-harm among both males (451 events; HR = 0.90, 95% CI [0.82, 0.99]) and females (516 events; HR = 0.89, 95% CI [0.81, 0.98]). Childhood cognitive ability was not significantly associated with suicide risk among those with (Male: 16 events, HR = 1.05, 95% CI [0.61, 1.80]; Female: 13 events, HR = 1.08, 95% CI [0.55, 2.15]) or without self-harm events (Male: 118 events, HR = 1.17, 95% CI [0.84, 1.63]; Female: 31 events, HR = 1.30, 95% CI [0.70, 2.41]). Limitations: The study only includes self-harm events that result in a hospital admission and does not account for self-harm prior to follow-up. Conclusions: This extends work on cognitive ability and mental health, demonstrating that these associations can span the life course and into middle and older age.

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.

Neighborhood Characteristics and Elevated Blood Pressure in Older Adults.

Importance: The local environment remains an understudied contributor to elevated blood pressure among older adults. Untargeted approaches can identify neighborhood conditions interrelated with racial segregation that drive hypertension disparities. Objective: To evaluate independent associations of sociodemographic, economic, and housing neighborhood factors with elevated blood pressure. Design, Setting, and Participants: In this cohort study, the sample included Health and Retirement Study participants who had between 1 and 3 sets of biennial sphygmomanometer readings from 2006 to 2014 or 2008 to 2016. Statistical analyses were conducted from February 5 to November 30, 2021. Exposures: Fifty-one standardized American Community Survey census tract variables (2005-2009). Main Outcomes and Measures: Elevated sphygmomanometer readings over the study period (6-year period prevalence): a value of at least 140 mm Hg for systolic blood pressure and/or at least 90 mm Hg for diastolic blood pressure. Participants were divided 50:50 into training and test data sets. Generalized estimating equations were used to summarize multivariable associations between each neighborhood variable and the period prevalence of elevated blood pressure, adjusting for individual-level covariates. Any neighborhood factor associated (Simes-adjusted for multiple comparisons P ≤ .05) with elevated blood pressure in the training data set was rerun in the test data set to gauge model performance. Lastly, in the full cohort, race- and ethnicity-stratified associations were evaluated for each identified neighborhood factor on the likelihood of elevated blood pressure. Results: Of 12 946 participants, 4565 (35%) had elevated sphygmomanometer readings (median [IQR] age, 68 [63-73] years; 2283 [50%] male; 228 [5%] Hispanic or Latino, 502 [11%] non-Hispanic Black, and 3761 [82%] non-Hispanic White). Between 2006 and 2016, a lower likelihood of elevated blood pressure was observed (relative risk for highest vs lowest tertile, 0.91; 95% CI, 0.86-0.96) among participants residing in a neighborhood with recent (post-1999) in-migration of homeowners. This association was precise among participants with non-Hispanic White and other race and ethnicity (relative risk, 0.91; 95% CI, 0.85-0.97) but not non-Hispanic Black participants (relative risk, 0.97; 95% CI, 0.85-1.11; P = .48 for interaction) or Hispanic or Latino participants (relative risk, 0.84; 95% CI, 0.65-1.09; P = .78 for interaction). Conclusions and Relevance: In this cohort study of older adults, recent relocation of homeowners to a neighborhood was robustly associated with reduced likelihood of elevated blood pressure among White participants but not their racially and ethnically marginalized counterparts. Our findings indicate that gentrification may influence later-life blood pressure control.

Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: Prospective cohort study.

BACKGROUND: While systemic inflammation has been implicated in the etiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS), a condition with high case-fatality, is untested. Accordingly, we quantified the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with subsequent ALS occurrence. METHODS: We used data from UK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centers between 2006 and 2010. Venous blood was collected at baseline in the full cohort and assayed for CRP, and repeat measurement was made 3-7 years later in a representative subgroup (N = 14,514) enabling correction for regression dilution. ALS was ascertained via national hospitalization and mortality registries until 2021. We computed multivariable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles. RESULTS: In an analytical sample of 400,884 initially ALS-free individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalizations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviors, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalizations (1.20; 1.00, 1.39). There was evidence of dose-response effects across tertiles of CRP for both outcomes (p for trend ≤ 0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalizations (1.37; 1.05, 1.76). CONCLUSIONS: Higher levels of CRP, a blood-based biomarker widely captured in clinical practice, is associated with moderately increased future risk of amyotrophic lateral sclerosis.

Dementia in former amateur and professional contact sports participants: population-based cohort study, systematic review, and meta-analysis.

Background: Although there is growing evidence that former professional athletes from sports characterised by repetitive head impact subsequently experience an elevated risk of dementia, the occurrence of this disorder in retired amateurs, who represent a larger population, is uncertain. The present meta-analysis integrates new results from individual-participant analyses of a cohort study of former amateur contact sports participants into a systematic review of existing studies of retired professionals and amateurs. Methods: The cohort study comprised 2005 male retired amateur athletes who had competed internationally for Finland (1920-1965) and a general population comparison group of 1386 age-equivalent men. Dementia occurrence was ascertained from linked national mortality and hospital records. For the PROSPERO-registered (CRD42022352780) systematic review, we searched PubMed and Embase from their inception to April 2023, including cohort studies published in English that reported standard estimates of association and variance. Study-specific estimates were aggregated using random-effect meta-analysis. An adapted Cochrane Risk of Bias Tool was used to assess study quality. Findings: In the cohort study, up to 46 years of health surveillance of 3391 men gave rise to 406 dementia cases (265 Alzheimer's disease). After adjustment for covariates, former boxers experienced elevated rates of dementia (hazard ratio: 3.60 [95% CI 2.46, 5.28]) and Alzheimer's disease (4.10 [2.55, 6.61]) relative to general population controls. Associations were of lower magnitude in retired wrestlers (dementia: 1.51 [0.98, 2.34]; Alzheimer's disease: 2.11 [1.28, 3.48]) and soccer players (dementia: 1.55 [1.00, 2.41]; Alzheimer's disease: 2.07 [1.23, 3.46]), with some estimates including unity. The systematic review identified 827 potentially eligible published articles, of which 9 met our inclusion criteria. These few retrieved studies all sampled men and the majority were of moderate quality. In sport-specific analyses according to playing level, there was a marked difference in dementia rates in onetime professional American football players (2 studies; summary risk ratio: 2.96 [95% CI 1.66, 5.30]) relative to amateurs in whom there was no suggestion of an association (2 studies; 0.90 [0.52, 1.56]). For soccer players, while dementia occurrence was raised in both erstwhile professionals (2 studies; 3.61 [2.92, 4.45]) and amateurs (1 study; 1.60 [1.11, 2.30]) there was again a suggestion of a risk differential. The only studies of boxers comprised former amateurs in whom there was a tripling in the rates of dementia (2 studies; 3.14 [95% CI 1.72, 5.74]) and Alzheimer's disease (2 studies; 3.07 [1.01, 9.38]) at follow-up compared to controls. Interpretation: Based on a small number of studies exclusively sampling men, former amateur participants in soccer, boxing, and wrestling appeared to experience an elevated risk of dementia relative to the general population. Where data allowed comparison, there was a suggestion that risks were greater amongst retired professionals relative to amateurs in the sports of soccer and American football. Whether these findings are generalisable to the contact sports not featured, and to women, warrants examination. Funding: This work was unfunded.

Suicide and depression in former contact sports participants: population-based cohort study, systematic review, and meta-analysis.

Background: Former participants in sports characterised by low intensity repetitive head impact appear to have elevated rates of later dementia, but links with other psychological health outcomes such as depression and suicide are uncertain. We quantified the occurrence of these endpoints in former contact sports athletes against general population controls using new data from a cohort study and a meta-analysis. Methods: The cohort study comprised 2004 retired male athletes, who had competed internationally as amateurs for Finland across a range of sports, and 1385 general population controls. All study members were linked to mortality and hospitalisation registries. In the PROSPERO-registered systematic review (CRD42022352780), we searched PubMed and Embase to October 31 2022 for cohort studies that reported standard estimates of association and precision. Study-specific estimates were aggregated in a random-effect meta-analysis. The Newcastle-Ottawa Scale was used to appraise the quality of each study. Findings: In survival analyses of the Finnish cohort data, former boxers (depression: hazard ratio 1.43 [95% CI 0.73, 2.78]; suicide: 1.75 [0.64, 4.38]), Olympic-style wrestlers (depression: 0.94 [0.44, 2.00]; suicide: 1.60 [0.64, 3.99]), and soccer players (depression: 0.62 [0.26, 1.48]; suicide: 0.50 [0.11, 2.16]) did not have statistically higher rates of major depressive disorder or suicide at follow-up relative to controls. In the systematic review, 7 cohort studies met inclusion criteria. After aggregating results with the Finnish cohort, retired soccer players appeared to have a lower risk of depression (summary risk ratio: 0.71 [0.54, 0.93]) relative to general population controls, while the rate of suicide was statistically the same across groups (0.70 [0.40, 1.23]). Past participation in American football seemed to be associated with some protection against suicide (0.58 [0.43, 0.80]) but there were insufficient studies of depression in this sport to facilitate aggregation. The aggregation of results from the soccer and American football studies showed directionally consistent relationships and there was no indication of inter-study heterogeneity (I2 = 0%). Interpretation: Based on a small cluster of studies exclusively comprising men, retired soccer players had a lower rate of later depression and former American football players had a lower risk of suicide relative to comparator groups. Whether these findings are generalisable to women requires testing. Funding: The preparation of this manuscript was unfunded.

Association of workplace violence and bullying with later suicide risk: a multicohort study and meta-analysis of published data.

BACKGROUND: Workplace offensive behaviours, such as violence and bullying, have been linked to psychological symptoms, but their potential impact on suicide risk remains unclear. We aimed to assess the association of workplace violence and bullying with the risk of death by suicide and suicide attempt in multiple cohort studies. METHODS: In this multicohort study, we used individual-participant data from three prospective studies: the Finnish Public Sector study, the Swedish Work Environment Survey, and the Work Environment and Health in Denmark study. Workplace violence and bullying were self-reported at baseline. Participants were followed up for suicide attempt and death using linkage to national health records. We additionally searched the literature for published prospective studies and pooled our effect estimates with those from published studies. FINDINGS: During 1 803 496 person-years at risk, we recorded 1103 suicide attempts or deaths in participants with data on workplace violence (n=205 048); the corresponding numbers for participants with data on workplace bullying (n=191 783) were 1144 suicide attempts or deaths in 1 960 796 person-years, which included data from one identified published study. Workplace violence was associated with an increased risk of suicide after basic adjustment for age, sex, educational level, and family situation (hazard ratio 1·34 [95% CI 1·15-1·56]) and full adjustment (additional adjustment for job demands, job control, and baseline health problems, 1·25 [1·08-1·47]). Where data on frequency were available, a stronger association was observed among people with frequent exposure to violence (1·75 [1·27-2·42]) than occasional violence (1·27 [1·04-1·56]). Workplace bullying was also associated with an increased suicide risk (1·32 [1·09-1·59]), but the association was attenuated after adjustment for baseline mental health problems (1·16 [0·96-1·41]). INTERPRETATION: Observational data from three Nordic countries suggest that workplace violence is associated with an increased suicide risk, highlighting the importance of effective prevention of violent behaviours at workplaces. FUNDING: Swedish Research Council for Health, Working Life and Welfare, Academy of Finland, Finnish Work Environment Fund, and Danish Working Environment Research Fund.

Association Between Depression and Physical Conditions Requiring Hospitalization.

Importance: Depression is associated with an increased risk of physical illness, but the most common causes of hospitalization among people with depression are unclear. Objective: To examine the association of depression with an array of physical conditions requiring hospital treatment. Design, Setting, and Participants: In this outcomewide prospective multicohort study, primary analysis was based on data from the UK Biobank, a population-based study in the United Kingdom. Analyses were repeated in an independent data set of 2 cohorts in Finland, a population-based study and an occupational cohort. Data analysis was conducted between April and September 2022. Exposures: Self-reported depression, recurrent severe major depression, recurrent moderate major depression, and a single major depressive episode. Main Outcomes and Measures: A total of 77 common health conditions ascertained from linkage data to national hospital and mortality registries. Results: The analytical sample of UK Biobank participants consisted of 130 652 individuals (71 565 women [54.8%]; 59 087 men [45.2%]; mean [SD] age at baseline, 63.3 [7.8] years). The pooled data from the Finnish replication cohorts included 109 781 participants (82 921 women [78.6%]; 26 860 men [21.4%]; mean [SD] age, 42 [10.8] years). In the main analysis, severe/moderately severe depression was associated with the incidence of 29 nonoverlapping conditions requiring hospital treatment during a 5-year follow-up. Twenty-five of these associations remained after adjustment for confounders and multiple testing (adjusted hazard ratio [HR] range, 1.52-23.03) and were confirmed in the analysis of the Finnish cohorts. These included sleep disorders (HR, 5.97; 95% CI, 3.27-10.89), diabetes (HR, 5.15; 95% CI, 2.52-10.50), ischemic heart disease (HR, 1.76; 95% CI, 1.36-2.29), chronic obstructive bronchitis (HR, 4.11; 95% CI, 2.56-6.60), bacterial infections (HR, 2.52; 95% CI, 1.99-3.19), back pain (HR, 3.99; 95% CI, 2.96-5.38), and osteoarthritis (HR, 1.80; 95% CI, 1.46-2.20). The highest cumulative incidence was observed for endocrine and related internal organ diseases (245 per 1000 persons with depression; risk difference relative to unaffected individuals: 9.8%), musculoskeletal diseases (91 per 1000 persons; risk difference, 3.7%), and diseases of the circulatory system and blood (86 per 1000 persons; risk difference, 3.9%). The cumulative incidence was lower for hospital-treated mental, behavioral, and neurological disorders (20 in 1000 persons; risk difference, 1.7%). Depression was also associated with disease progression in people with prevalent heart disease or diabetes, and for 12 conditions, there was evidence of a bidirectional relationship. Conclusions and Relevance: In this study, the most common causes of hospitalization in people with depression were endocrine, musculoskeletal, and vascular diseases, not psychiatric disorders. These findings suggest that depression should be considered as a target for the prevention of physical and mental disease.

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.

Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: prospective cohort study.

Importance: While systemic inflammation has been implicated in the aetiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS) is untested. Objective: To quantify the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with ALS occurrence. Design Setting Participants: UK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centres between 2006 and 2010. Exposure: Venous blood was collected at baseline in the full cohort and assayed for CRP. Repeat measurement was made 3-7 years later in a representative subgroup (N=14,514) enabling correction for regression dilution. Main Outcomes and Measures: ALS as ascertained via national hospitalisation and mortality registries. We computed multi-variable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles. Results: In an analytical sample of 400,884 individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalisations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviours, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalisations (1.20; 1.00, 1.39). There was evidence of dose-response effects across tertiles of CRP for both outcomes (p for trend≤0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalisations (1.37; 1.05, 1.76) ascribed to ALS. Conclusions and Relevance: Higher levels of CRP, a blood-based biomarker widely captured in clinical practice, were associated with a higher subsequent risk of ALS. Key Points: Question: Is C-reactive protein (CRP), a marker of systemic inflammation widely used in clinical practice, associated with later risk of amyotrophic lateral sclerosis (ALS)?Findings: Following 11 years disease surveillance in 400,884 individuals (218,203 women), after adjustment for covariates and correction for regression dilution, a one standard deviation higher CRP levels were associations with both mortality (hazard ratio; 95% confidence interval: 1.62; 1.27, 2.08) and hospitalisations (1.37; 1.05, 1.76) ascribed to ALS.Meaning: In the present study, CRP has a dose-response relationship with the risk of later ALS.

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.

Low-level lithium in drinking water and subsequent risk of dementia: Cohort study.

BACKGROUND: Lithium, a mood stabilizer, is known to exhibit neuroprotective effects in animal models and may have anti-dementia effects. AIMS: We used data from Scottish Mental Survey 1932, a population-based cohort study, to investigate the association between lithium in drinking water and dementia rate in humans. METHOD: Lithium levels in drinking water from 285 sampling sites across Scotland dating from 2014 were obtained from the sole public water provider (Scottish Water). Dementia and non dementia cases were identified from cohort data by electronic health records until 2012, and linked to postcode. RESULTS: The mean lithium level at all sampling sites was 1.45 µg/L (SD 1.83, range 0.5-18.2) and was 1.26 (SD 0.63, range 0.55-9.19) for sites matched to participant data. Of 37,597 study members, 3605 developed dementia until June 2012. Lithium levels were positively associated with the risk of dementia in women (highest in second quartile, HR 1.17, 95%CI 1.04-1.32), but there was no relationship in men (highest in second quartile, HR 0.95, 95% CI 0.81-1.12). The pattern of association was explored further by decile, and in females there was an association between lithium level and increased dementia risk compared to the lowest decile (0.55-0.68 µg/L) in all deciles except the highest, corresponding with lithium levels 0.68-2.1 µg/L. CONCLUSIONS: Lithium levels in drinking water are very low across Scotland which limited detection of potential effect. Our results do not support an association between extremely low levels of lithium and later dementia risk. We found a trend to increased risk in females at lithium levels below but not above 2.1 µg/L.

Childhood cognitive ability and self-harm and suicide in later life.

Self-harm and suicide remain prevalent in later life. For younger adults, work has highlighted an association between higher early-life cognitive ability and lower self-harm and suicide risk. Comparatively little is known about its association with self-harm and suicide among older adults. Furthermore, most work has measured cognitive ability in early adulthood, raising issues of potential confounding by emerging psychiatric conditions. The present study examined the association between childhood (age 11) cognitive ability and self-harm and suicide risk among a Scotland-wide cohort of older adults (N = 53037), using health data linkage to follow individuals from age 34 to 85. Self-harm events were extracted from hospital admissions and suicide deaths were extracted from national mortality records. Multistate models were used to model transitions between unaffected, self-harm, and then suicide or non-suicide death, and to examine the association between childhood cognitive ability and each transition. After adjusting for childhood and adulthood socioeconomic conditions, higher childhood cognitive ability was significantly associated with reduced risk of self-harm among older females (N events = 516; HR = 0.90, 95% CI = [0.81, 0.99]). A similar, though non-significant, association was observed among older males (N events = 451; HR = 0.90, 95% CI = [0.82, 1.00]). Although suicide risk was higher among older adults experiencing self-harm, childhood cognitive ability was not significantly associated with suicide risk among either older adults experiencing no self-harm events (Male: N events = 118, HR = 1.17, 95% CI = [0.84, 1.63]; Female: N events = 31, HR = 1.30, 95% CI = [0.70, 2.41]) or those experiencing a self-harm event during follow-up (Male: N events = 16, HR = 1.05, 95% CI = [0.61, 1.80]; Female: N events = 13, HR = 1.08, 95% CI = [0.55, 2.14]). Higher suicide risk was significantly associated with covariates including higher adulthood deprivation and longer time in the self-harm state. These results extend work on cognitive ability and mental health, demonstrating that these associations can span across the life course and into older age.