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.

Associations of broad eating disorder symptoms with later alcohol problems in Finnish adult twins: A nationwide 10-year follow-up.

OBJECTIVE: Eating disorders are associated with subsequent alcohol problems, but it is not known whether this association also extends to broader eating disorder symptoms not captured by clinical diagnoses. We assessed the longitudinal association of broad eating disorder symptoms with alcohol problems in a nationwide twin sample (FinnTwin16). METHODS: Finnish women (N = 1905) and men (N = 1449) self-reported their eating disorder symptoms using the Eating Disorder Inventory-2 Bulimia, Drive for Thinness, and Body Dissatisfaction subscales at the mean age of 24.4 years in 2000-2003. A subsample of participants also completed items on drive for muscularity, height dissatisfaction, and muscle-enhancing supplement use. Alcohol problems were assessed 10 years later at the age of 34.1 in 2010-2012 with the Rutgers Alcohol Problem Index. RESULTS: Eating disorder symptoms were associated with later alcohol problems (odds ratio per point increase 1.02-1.18). Bulimia showed stronger associations among men than women (p for interaction .012). Drive for muscularity and height dissatisfaction were also associated with later alcohol problems, but supplement use was not. When accounting for baseline alcohol problems, only Bulimia (among women and men) and Drive for Thinness (among men) were significantly associated with later alcohol problems. Bulimia was also significantly associated with later alcohol problems in within-twin-pair analyses among dizygotic twins, but not among monozygotic twins. DISCUSSION: In a longitudinal setting, eating disorder symptoms were associated with later alcohol problems. Bulimic symptoms were a stronger risk factor for men than women. These associations may be attributable to baseline alcohol problems, childhood environment and genetic liability. PUBLIC SIGNIFICANCE: This study found that both young adult women and men with broad eating disorder symptoms are at a higher risk of alcohol-related problems than those without such symptoms. Men with bulimic symptoms were at a particularly high risk. These findings emphasize the need for better prevention and treatment of disordered eating, body image concerns and alcohol problems for both young adult women and men.

Paternal and Maternal Problem Drinking and Lifetime Problem Drinking of Their Adult Children.

Parents' alcohol use is associated with alcohol use of their adolescent offspring, but does this association extend to the adulthood of the offspring? We examined associations of paternal and maternal problem drinking with lifetime problem drinking of their adult offspring prospectively assessed in a population-based Finnish twin-family cohort (FinnTwin16). Problem drinking (Malmö-modified Michigan Alcoholism Screening Test) was self-reported separately by mothers and fathers when their children were 16. The children reported on an extended lifetime version of the same measure during their mid-twenties (21-28 years) and mid-thirties (31-37 years). 1235 sons and 1461 daughters in mid-twenties and 991 sons and 1278 daughters in mid-thirties had complete data. Correlations between fathers' and their adult children's problem drinking ranged from .12 to .18. For mothers and their adult children, these correlations ranged from .09 to .14. In multivariate models, adjustment for potential confounders had little effect on the observed associations. In this study, parental problem drinking was modestly associated with lifetime problem drinking of their adult children. This association could be detected even when the children had reached the fourth decade of life.

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

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

Relationship between sensation seeking, alcohol problems and bulimic symptoms: a community-based, longitudinal study.

PURPOSE: The association of bulimic symptoms with sensation seeking is uncertain; however, both behaviors have been linked to alcohol problems. We assessed in a longitudinal, community-based setting whether sensation seeking in adolescence is associated with bulimic symptoms in early adulthood, also accounting for alcohol problems. METHODS: Finnish men (N = 2000) and women (N = 2467) born between 1974-1979 completed Zuckerman's sensation seeking scale (SSS) at age 18. Alcohol problems (Malmö-modified Michigan alcoholism screening test (Mm-MAST) and bulimic symptoms [eating disorder inventory-2, bulimia subscale (EDI-Bulimia), population and clinical scoring systems] were defined at age 22-27. We examined relationships between SSS, Mm-MAST, and EDI-Bulimia using Pearson's correlation coefficient (r) and linear regression. RESULTS: Alcohol problems were moderately correlated with sensation seeking and bulimic symptoms (population scoring) among women and men (r = 0.21-0.31). The correlation between sensation seeking and bulimic symptoms (population scoring) was weak among men (r = 0.06, p = 0.006) and even weaker and non-significant among women (r = 0.03, p = 0.214). Adjustment for alcohol problems removed the association between sensation seeking and bulimic symptoms among men. Furthermore, there were no significant correlations between sensation seeking and bulimic symptoms when assessing EDI-Bulimia clinical scoring. CONCLUSION: Sensation seeking and bulimic symptoms were not associated among women. The association between sensation seeking and bulimic symptoms among men was entirely attributable to increased alcohol problems among those with higher sensation seeking. While this association may be important on the population level, its clinical significance may be minor. LEVEL OF EVIDENCE: Level III, well-designed cohort study.

Detection, treatment, and course of eating disorders in Finland: A population-based study of adolescent and young adult females and males.

OBJECTIVE: We assessed the detection, treatment and outcomes of DSM-5 eating disorders in a nationwide community setting. METHOD: The FinnTwin12 cohort comprises twins born in 1983-1987 in Finland (n = 5,600), with follow-up starting at age 12. We outline treatment and outcomes of the 127 females and 15 males diagnosed with a lifetime DSM-5 eating disorder in interviews conducted for a subsample (n = 1,347) in their early 20s. RESULTS: Only 45 (32%) of those diagnosed with eating disorder in the interviews had their condition detected in healthcare, and even fewer received treatment (30% of females, 13% of males). Anorexia nervosa (AN), bulimia nervosa, and atypical AN were detected and treated more often than other eating disorders. Five years after disease onset, 41% of those diagnosed had recovered. There were no statistically significant differences in the course of different eating disorders (log-rank p = 0.66) but the outcome was more favourable among males (log-rank p = 0.008). The likelihood of 5-year recovery did not differ between those who had and who had not received treatment (41.1% vs. 40.5%, log-rank p = 0.66). CONCLUSION: Although eating disorders are common and symptoms are persistent for many, they remain under-diagnosed and under-treated. In real-world settings, effectiveness of provided treatments may be limited.

DSM-5 eating disorders among adolescents and young adults in Finland: A public health concern.

OBJECTIVE: We aimed to assess the lifetime prevalence, 10-year incidence, and peak periods of onset for eating disorders as defined by the Fifth Diagnostic and Statistical Manual of Mental Disorders (DSM-5) among adolescents and young adults born in the 1980s in Finland. METHOD: Virtually all Finnish twins born in 1983-1987 (n = 5,600) were followed prospectively from the age of 12 years. A subsample of participants (n = 1,347) was interviewed using a semi-structured diagnostic interview in their early twenties. RESULTS: The prevalence of lifetime DSM-5 eating disorders was 17.9% for females and 2.4% for males (pooled across genders, 10.5%). The estimated lifetime prevalences for females and males, respectively, were 6.2 and 0.3% for anorexia nervosa (AN), 2.4 and 0.16% for bulimia nervosa (BN), 0.6 and 0.3% for binge-eating disorder (BED), 4.5 and 0.16% for other specified feeding or eating disorder (OSFED), and 4.5 and 1.6% for unspecified feeding or eating disorder (UFED). Among females, the prevalence of OSFED subcategories was as follows: atypical AN 2.1%, purging disorder 1.3%, BED of low frequency/limited duration 0.7%, and BN of low frequency/limited duration 0.4%. The 10-year incidence rate of eating disorders was 1,700 per 100,000 person-years among females (peak age of onset 16-19 years) and 220 per 100,000 person-years among males. DISCUSSION: Eating disorders are a common public health concern among youth and young adults, affecting one in six females and one in 40 males. Adequate screening efforts, prevention, and interventions are urgently needed.

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.

FinnTwin16: A Longitudinal Study from Age 16 of a Population-Based Finnish Twin Cohort.

The purpose of this review is to provide a detailed and updated description of the FinnTwin16 (FT16) study and its future directions. The Finnish Twin Cohort comprises three different cohorts: the Older Twin Cohort established in the 1970s and the FinnTwin12 and FT16 initiated in the 1990s. FT16 was initiated in 1991 to identify the genetic and environmental precursors of alcoholism, but later the scope of the project expanded to studying the determinants of various health-related behaviors and diseases in different stages of life. The main areas addressed are alcohol use and its consequences, smoking, physical activity, overall physical health, eating behaviors and eating disorders, weight development, obesity, life satisfaction and personality. To date, five waves of data collection have been completed and the sixth is now planned. Data from the FT16 cohort have contributed to several hundred studies and many substudies, with more detailed phenotyping and collection of omics data completed or underway. FT16 has also contributed to many national and international collaborations.

Association of LEAF-Q and EDE-QS scores with cholesterol levels in Finnish female athletes.

Objective: Low energy availability (LEA) is common in athletes. Disturbances in sex hormone levels due to insufficient energy availability have been suggested to influence cholesterol metabolism and impact the overall risk for cardiovascular disease. We assessed the relationship between Low Energy Availability in Females Questionnaire (LEAF-Q) and Eating Disorder Examination Questionnaire Short (EDE-QS) scores with cholesterol levels in a cross-sectional study of female athletes. Method: Finnish national- to international-level female athletes self-reported physiological symptoms of LEA, including menstrual disturbances, using the LEAF-Q (n=176) and eating disorder symptoms using the EDE-QS (n=294). Serum cholesterol concentrations (mmol/L) were determined from venous blood samples. We analysed the relationship between the different variables using Pearson's r and linear regression. We also studied separately participants representing lean sports, that is, sports that emphasise leanness (LEAF-Q, n=60; EDE-QS, n=80). Results: LEA symptoms were common; 72 (41%) of 176 participants scored ≥8 points in the LEAF-Q, which is indicative of a high risk of problematic LEA. A one-point increase in LEAF-Q score was associated with a small, non-significant increase in low-density lipoprotein (LDL) cholesterol level (beta=0.024, 95% CI -0.0011 to 0.049, p=0.061). Higher EDE-QS scores were associated with higher LDL cholesterol levels (beta=0.028, 95% CI 0.0098 to 0.046, p=0.0029). These associations were somewhat stronger among athletes representing lean sports (LEAF-Q and LDL: beta=0.043, 95% CI 0.0041 to 0.08, p=0.031; EDE-QS and LDL: beta=0.036, 95% CI 0.0041 to 0.068, p=0.028). Conclusion: In this study, LEAF-Q and EDE-QS were associated with higher LDL cholesterol levels among athletes representing lean sports.

Maternal sex-hormone exposure and the risk of eating disorders in daughters.

Potential effects of prenatal sex hormones on later eating disorders in offspring have been investigated with two indirect methods (finger length ratio, opposite- versus same-sex twins). We utilized a direct, prospective method, examining the association between prenatal sex-hormones in maternal sera and the risk of bulimia nervosa (BN) and anorexia nervosa (AN) among daughters. Females with BN (55), AN (150), sister controls without eating disorders (one per case), and population controls (one per case) were derived from Finnish registers. Maternal gestational testosterone and estradiol levels were assayed from archived specimens stored in a national serum biobank. When females with BN were compared to their sister controls, those with higher gestational testosterone levels were at an increased risk of BN. No significant associations with BN were found when the comparison was made to population controls, and when estradiol levels and testosterone/estrogen ratio were assessed. We neither found associations between gestational sex-hormone levels and the risk of AN. Among females with familial liability for BN, higher gestational testosterone exposure may have a role in later development of BN, whereas lower testosterone exposure may have a protective effect. We found no evidence for the involvement of gestational sex-hormones in the etiology of AN.

Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline.

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aß42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.

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.

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.

Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases.

Immune system and blood-brain barrier dysfunction are implicated in the development of Alzheimer's and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood-brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-ß, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer's disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49-0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.

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.

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.

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.