Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study.

BACKGROUND: Ageing hallmarks, characterising features of cellular ageing, have a role in the pathophysiology of many age-related diseases. We examined whether obesity is associated with an increased risk of developing such hallmark-related diseases. METHODS: In this multicohort study, we included people aged 38-72 years with data on weight, height, and waist circumference measured during a clinical examination at baseline between March 13, 2006, and Oct 1, 2010, from the UK Biobank with follow-up until Nov 12, 2021. To test reproducibility of the findings (replication analysis), we used data from people aged 40 years or older included in the Finnish Public Sector study and the Finnish Health and Social Support study who responded to the study surveys, had data on BMI, and were successfully linked to electronic health records from national registers up to Dec 31, 2016. Obesity and clinical characteristics were assessed at baseline. Via linkage to national health records, participants were followed up for 83 diseases related to nine ageing hallmarks (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication). Outcomes were the first instance of hallmark-related disease, in addition to co-occurrence of three or more hallmark-related diseases and mortality. FINDINGS: 496 530 adults (mean age 57·0 years [SD 8·1]) from the UK Biobank were included in the primary analysis, and 83 249 (mean age 48·2 years [6·4]) adults from the Finnish cohorts were included in the replication analysis. Median follow-up was 12·7 years (IQR 12·0-13·4) in the UK Biobank and 14·0 years (8·0-15·0) in the Finnish cohorts. After adjusting for demographic characteristics, lifestyle factors, and depression, UK Biobank participants with obesity (BMI ≥30·0 kg/m2) had a 1·40 (95% CI 1·38-1·41) times higher hazard ratio for the first hallmark-related disease than those with a healthy weight (BMI 18·5-24·9 kg/m2). The corresponding hazard ratios for three co-occurring diseases were 2·92 (95% CI 2·64-3·22) for deregulated nutrient sensing, 2·73 (2·46-3·02) for telomere attrition, 2·33 (2·10-2·60) for epigenetic alterations, 2·30 (2·14-2·48) for mitochondrial dysfunction, 2·23 (2·04-2·45) for stem cell exhaustion, 2·02 (1·89-2·16) for altered intercellular communication, 2·01 (1·89-2·15) for cellular senescence, 1·83 (1·67-2·00) for loss of proteostasis, and 1·39 (1·27-1·52) for genomic instability. These findings were replicated in the Finnish cohorts. In both studies, the associations between other risk factors (low education, unhealthy dietary factors [available only in the UK Biobank], smoking, high alcohol consumption, physical inactivity, and depression) and hallmark-related diseases were weaker than those with obesity. 45-60% of the excess mortality in people with obesity was attributable to hallmark-related diseases. INTERPRETATION: Obesity might have an important role in the development of diseases associated with cellular ageing. Tackling ageing mechanisms could potentially help to reduce the disease and mortality burden resulting from the obesity epidemic. FUNDING: Wellcome Trust, UK Medical Research Council, US National Institute on Aging, Academy of Finland, and Finnish Foundation for Cardiovascular Research. TRANSLATIONS: For the German and Finnish translations of the abstract see Supplementary Materials section.

Does the effect of adolescent health behaviours on adult cardiometabolic health differ by socioeconomic background? Protocol for a population-based cohort study.

INTRODUCTION: Adolescence is a sensitive period for cardiometabolic health. Yet, it remains unknown if adolescent health behaviours, such as alcohol use, smoking, diet and physical activity, have differential effects across socioeconomic strata. Adopting a life-course perspective and a causal inference framework, we aim to assess whether the effects of adolescent health behaviours on adult cardiometabolic health differ by levels of neighbourhood deprivation, parental education and occupational class. Gaining a better understanding of these social disparities in susceptibility to health behaviours can inform policy initiatives that aim to improve population health and reduce socioeconomic inequalities in cardiometabolic health. METHODS AND ANALYSIS: We will conduct a secondary analysis of the Young Finns Study, which is a longitudinal population-based cohort study. We will use measures of health behaviours-smoking, alcohol use, fruit and vegetable consumption, and physical activity-as exposure and parental education, occupational class and neighbourhood deprivation as effect modifiers during adolescence (ages 12-18 years). Eight biomarkers of cardiometabolic health (outcomes)-waist circumference, body mass index, blood pressure, low-density lipoprotein cholesterol, apolipoprotein B, plasma glucose and insulin resistance-will be measured when participants were aged 33-40. A descriptive analysis will investigate the clustering of health behaviours. Informed by this, we will conduct a causal analysis to estimate effects of single or clustered adolescent health behaviours on cardiometabolic health conditional on socioeconomic background. This analysis will be based on a causal model implemented via a directed acyclic graph and inverse probability-weighted marginal structural models to estimate effect modification. ETHICS AND DISSEMINATION: The Young Finns study was conducted according to the guidelines of the Declaration of Helsinki, and the protocol was approved by ethics committees of University of Helsinki, Kuopio, Oulu, Tampere and Turku. We will disseminate findings at international conferences and a manuscript in an open-access peer-reviewed journal.

Cohort study on incidence of new-onset type 2 diabetes in patients after bariatric surgery and matched controls.

BACKGROUND: Metabolic bariatric surgery the reduces risk of new-onset type 2 diabetes in individuals with obesity, but it is unclear whether the benefit varies by sex, age, or socioeconomic status. The aim was to assess the risk of new-onset type 2 diabetes after metabolic bariatric surgery in these subgroups. METHODS: The Finnish Public Sector study, a follow-up study with matched controls nested in a large employee cohort, included patients without type 2 diabetes and with a diagnosis of obesity or self-reported BMI of at least 35 kg/m2. For each patient who had laparoscopic metabolic bariatric surgery (2008-2016), two propensity-score matched controls were selected. New-onset type 2 diabetes was ascertained from linked records from national health registries. RESULTS: The study included a total of 917 patients and 1811 matched controls with obesity. New-onset type 2 diabetes was diagnosed in 15 of the patients who had metabolic bariatric surgery (4.1 per 1000 person-years) and 164 controls (20.2 per 1000 person-years). The corresponding rate ratio (RR) was 0.20 (95% c.i. 0.12 to 0.35) and the rate difference (RD) was -16.1 (-19.8 to -12.3) per 1000 person-years. The risk reduction was more marked in individuals of low socioeconomic status (RR 0.10 (0.04 to 0.26) and RD -20.6 (-25.6 to -15.5) per 1000 person-years) than in those with higher socioeconomic status (RR 0.35 (0.18 to 0.66) and RD -11.5 (-16.9 to -6.0) per 1000 person-years) (Pinteraction = 0.017). No differences were observed between sexes or age groups. CONCLUSION: Metabolic bariatric surgery was associated with a reduced risk of new-onset type 2 diabetes in men and women and in all age groups. The greatest benefit was observed in individuals of low socioeconomic status.

Metabolic bariatric surgery reduces the risk of new-onset type 2 diabetes in individuals with obesity or severe obesity. The risk of new-onset type 2 diabetes after metabolic bariatric surgery varies between socioeconomic status subgroups. In this prospective study, new-onset type 2 diabetes occurred in 1.6% of 917 patients who underwent metabolic bariatric surgery and 9.1% of 1811 propensity score-matched controls. Risk reduction was more marked in individuals of low socioeconomic status. There were no differences between sex or age groups. The reduced risk of new-onset type 2 diabetes after metabolic bariatric surgery emphasizes the need to increase access to treatment in patients with severe obesity. As the preventive effect was most pronounced in individuals of low socioeconomic status associated with both greater burden of disease and worse access to healthcare, the findings need to be taken into account in health policies to reduce health inequalities.

NMR metabolomic modeling of age and lifespan: A multicohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24-86 years). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Role of cardiovascular health factors in mediating social inequalities in the incidence of dementia in the UK: two prospective, population-based cohort studies.

Background: The contribution of modifiable risk factors to social inequalities in dementia, observed in longitudinal studies, remains unclear. We aimed to quantify the role of cardiovascular health factors, assessed using Life's Essential 8 (LE8) score, in mediating social inequalities in incidence of dementia and, for comparison, in incidence of stroke, coronary heart disease, and mortality. Methods: In this prospective, population-based cohort study, we collected data from the UK Whitehall II Study and UK Biobank databases. Participants were included if data were available on SEP, outcomes and LE8 (smoking, physical activity, diet, body mass index, blood pressure, fasting blood glucose, lipid levels, sleep duration). The primary outcome was incident dementia and secondary outcomes were stroke, coronary heart disease, and mortality. Outcomes were derived from electronic healthcare records. Socioeconomic position (SEP) was measured by occupation in Whitehall II and education in UK Biobank. Counterfactual mediation analysis was used to quantify the extent to which LE8 score explained the associations of SEP with all outcomes. Analyses involved Cox regression, accelerated failure time models, and linear regression; and were adjusted for age, sex, and ethnicity. Findings: Between 10.09.1985 and 29.03.1988, a total of 9688 participants (mean age ± SD 44.9 ± 6.0; 67% men) from the Whitehall II study, and between 19.12.2006 and 01.10.2010, 278,215 participants (mean age ± SD 56.0 ± 8.1; 47% men) from the UK Biobank were included. There were 606 and 4649 incident dementia cases over a median (interquartile range) follow-up of 31.7 (31.1-32.7) and 13.5 (12.7-14.1) years respectively in Whitehall II and UK Biobank. In Whitehall II, the hazard ratio was 1.85 [95% CI 1.42, 2.32] for the total effect of SEP on dementia and 1.20 [1.12, 1.28] for the indirect effect via the LE8, the proportion mediated being 36%. In UK Biobank, the total effect of SEP on dementia was 1.65 [1.54, 1.78]; the indirect effect was 1.11 [1.09, 1.12], and the proportion mediated was 24%. The proportions mediated for stroke, coronary heart disease, and mortality were higher, ranging between 34% and 63% in Whitehall II and between 36% and 50% in UK Biobank. Interpretation: In two well-characterised cohort studies, up to one third of the social inequalities in incidence of dementia was attributable to cardiovascular health factors. Promotion of cardiovascular health in midlife may contribute to reducing social inequalities in risk of dementia, in addition to cardiovascular diseases and all-cause mortality. This study used adult measures of SEP, further research is warranted using lifecourse measures of SEP. Funding: NIH (RF1AG062553).

Life course epidemiology and public health.

Life course epidemiology aims to study the effect of exposures on health outcomes across the life course from a social, behavioural, and biological perspective. In this Review, we describe how life course epidemiology changes the way the causes of chronic diseases are understood, with the example of hypertension, breast cancer, and dementia, and how it guides prevention strategies. Life course epidemiology uses complex methods for the analysis of longitudinal, ideally population-based, observational data and takes advantage of new approaches for causal inference. It informs primordial prevention, the prevention of exposure to risk factors, from an eco-social and life course perspective in which health and disease are conceived as the results of complex interactions between biological endowment, health behaviours, social networks, family influences, and socioeconomic conditions across the life course. More broadly, life course epidemiology guides population-based and high-risk prevention strategies for chronic diseases from the prenatal period to old age, contributing to evidence-based and data-informed public health actions. In this Review, we assess the contribution of life course epidemiology to public health and reflect on current and future challenges for this field and its integration into policy making.

Sleep duration in midlife and old age and risk of mortality over a 48-year follow-up: The Helsinki businessmen study (HBS) cohort.

OBJECTIVES: Both short and long sleep duration have been associated with increased mortality, but there are few truly long-term studies. STUDY DESIGN: This is a cohort study of 2504 men born between 1919 and 1934. In 1974-1975 (mean age 48), participants underwent baseline clinical examinations and sleep duration assessments. A follow-up examination took place 35 years later, in 2010 (mean age 82). MAIN OUTCOME MEASURE: All-cause mortality data from baseline and from old age were collected through to December 31, 2022. RESULTS: At baseline, short sleep duration (≤6 h per night), normal sleep duration (>6 and ≤ 8 h), and long sleep duration (>8 h) was reported by 266, 2019 and 219 men, respectively. Men with short sleep duration had higher levels of smoking, alcohol consumption, body mass index, and poorer self-rated health than those with normal sleep duration. During the 48-year follow-up, 2287 men died. The unadjusted hazard ratio for mortality was 1.20 (95 % confidence interval [CI] 1.05-1.37) for short compared with normal sleep duration, but this association vanished after adjustments (1.01, 95 % CI 0.87-1.17). In old age, the corresponding hazard ratios were 1.41 (1.16-1.72) and 1.19 (0.94-1.51) for short sleep duration and 1.33 (1.09-1.63) and 1.31 (1.02-1.67) for long sleep duration. CONCLUSIONS: In a comprehensive lifespan follow-up, the modestly increased mortality among men with short sleep duration in midlife was attributed to unhealthy lifestyle factors. In old age both long and short sleep duration seemed to be associated with modestly increased mortality. CLINICALTRIALS: gov identifier for the HBS: NCT02526082.

NMR metabolomic modelling of age and lifespan: a multi-cohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. 98 metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈ 31,000 individuals, age range 24-86 years). We used non-linear and penalised regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with ageing risk factors and phenotypes. Within the UK Biobank (N≈ 102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, chronic obstructive pulmonary disease) and all-cause mortality. Cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47-0.65 in the training set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with chronological age were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06 / metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Preterm birth and the risk of multimorbidity in adolescence: a multiregister-based cohort study.

BACKGROUND: Multimorbidity affects people of all ages, but the risk factors of multimorbidity in adolescence are unclear. The aim of this study was to examine preterm birth (<37 weeks) as a shared risk factor for multiple health outcomes and the role of gestational age (degree of prematurity) in the development of increasingly complex multimorbidity (two, three, or four health outcomes) in adolescence (age 10-18 years). METHODS: We used population-wide data from Finland (1 187 610 adolescents born 1987-2006) and Norway (555 431 adolescents born 1998-2007). Gestational age at birth was ascertained from medical birth registers and categorised as 23-27 weeks (extremely preterm), 28-31 weeks (very preterm), 32-33 weeks (moderately preterm), 34-36 weeks (late preterm), 37-38 weeks (early term), 39-41 weeks (term, reference category) and 42-44 weeks (post-term). Children who died or emigrated before their 10th birthday, and those with missing or implausible data on gestational age, birthweight, or covariates, were excluded. Health outcomes at age 10-18 years were ascertained from specialised health care and mortality registers. We calculated hazard ratios (HRs) and population attributable fractions (PAFs) with 95% CIs for multiple health outcomes during adolescence. FINDINGS: Individuals were followed up from age 10 to 18 years (mean follow-up: 6 years, SD: 3 years). Preterm birth was associated with increased risks of 20 hospital-treated malignant, cardiovascular, endocrinological, neuropsychiatric, respiratory, genitourinary, and congenital health outcomes, after correcting for multiple testing and ignoring small effects (HR <1·2). Confounder-adjusted HRs comparing preterm with term-born adolescents were 2·29 (95% CI 2·19-2·39) for two health outcomes (PAF 9·0%; 8·3-9·6), and 4·22 (3·66-4·87) for four health outcomes (PAF 22·7%; 19·4-25·8) in the Finnish data. Results in the Norwegian data showed a similar pattern. We observed a consistent dose-response relationship between an earlier gestational age and elevated risks of increasingly complex multimorbidity in both datasets. INTERPRETATION: Preterm birth is associated with increased risks of diverse multimorbidity patterns at age 10-18 years. Adolescents with a preterm-born background could benefit from diagnostic vigilance directed at multimorbidity and a multidisciplinary approach to health care. FUNDING: European Union Horizon 2020, Academy of Finland, Foundation for Pediatric Research, Sigrid Jusélius Foundation, Signe and Ane Gyllenberg Foundation.

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.

Trajectories of physical and mental functioning over 25 years before onset of frailty: results from the Whitehall II cohort study.

BACKGROUND: Research on frailty, a major contributor to heterogeneity in health, is undertaken on older adults although the processes leading to frailty are likely to begin earlier in the life course. Using repeat data spanning 25 years, we examined changes in physical and mental functioning before the onset of frailty, defined using Fried's frailty phenotype (FFP). METHODS: Functioning was measured using the Short-Form 36 General Health Survey (SF-36) on nine occasions from 1991 (age range 40-63 years) to 2015 (age range 63-85 years). The poorest of four FFP scores from 2002, 2007, 2012 and 2015 was used to classify participants as frail, pre-frail, or robust. We used linear mixed models with a backward timescale such that time 0 was the person-specific date of frailty classification for frail and pre-frail participants and the end of follow-up for robust participants. Analyses adjusted for socio-demographic factors, health behaviours, body mass index and multi-morbidity status were used to compare SF-36 physical (PCS) and mental (MCS) component summary scores over 25 years before time 0 as a function of FFP classification, with estimates extracted at time 0, -5, -10, -15, -20 and -25 years. We also used illness-death models to examine the prospective association between SF-36 component summary scores at age 50 and incident FFP-defined frailty. RESULTS: Among 7044 participants of the Whitehall II cohort study included in the analysis [29% female, mean age 49.7 (SD = 6.0) at baseline in 1991], 2055 (29%) participants remained robust, and 4476 (64%) became pre-frail and 513 (7%) frail during follow-up. Frail compared with robust participants had lower SF-36 scores at t = -25 before onset of frailty with a difference of 3.4 [95% confidence interval (CI) 1.6, 5.1] in PCS and 1.8 (-0.2, 3.8) in MCS. At t = 0, the differences increased to 11.5 (10.5, 12.5) and 9.1 (8.0, 10.2), respectively. The differences in SF-36 between the robust and pre-frail groups, although smaller [at t = 0, 1.7 (1.2, 2.2) in PCS and 4.0 (3.4, 4.5) in MCS], were already observed 20 and 25 years, respectively, before the onset of pre-frailty. Prospective analyses showed that at age 50, scores in the bottom quartiles of PCS [hazard ratio (HR) compared with the top quartile = 2.39, 95% CI 1.85, 3.07] and MCS [HR = 1.49 (1.15, 1.93)] were associated with a higher risk of FFP-defined frailty at older ages. CONCLUSIONS: Differences in trajectories of physical and mental functioning in individuals who developed physical frailty at older ages were observable 25 years before onset of FFP-defined frailty. These findings highlight the need for a life course approach in efforts to prevent frailty.

Contribution of smoking towards the association between socioeconomic position and dementia: 32-year follow-up of the Whitehall II prospective cohort study.

Background: There is consistent evidence of social inequalities in dementia but the mechanisms underlying this association remain unclear. We examined the role of smoking in midlife in socioeconomic differences in dementia at older ages. Methods: Analyses were based on 9951 (67% men) participants, median age 44.3 [IQR=39.6, 50.3] years at baseline in 1985-1988, from the Whitehall II cohort study. Socioeconomic position (SEP) and smoking (smoking status (current, ex-, never-smoker), pack years of smoking, and smoking history score (combining status and pack-years)) were measured at baseline. Counterfactual mediation analysis was used to examine the contribution of smoking to the association between SEP and dementia. Findings: During a median follow-up of 31.6 (IQR 31.1, 32.6) years, 628 participants were diagnosed with dementia and 2110 died. Analyses adjusted for age, sex, ethnicity, education, and SEP showed smokers (hazard ratio [HR] 1.36 [95% CI 1.10-1.68]) but not ex-smokers (HR 0.95 [95% CI 0.79-1.14]) to have a higher risk of dementia compared to never-smokers; similar results for smoking were obtained for pack-years of smoking and smoking history score. Mediation analysis showed low SEP to be associated with higher risk of dementia (HRs between 1.97 and 2.02, depending on the measure of smoking in the model); estimate for the mediation effect was 16% for smoking status (Indirect Effect HR 1.09 [95% CI 1.03-1.15]), 7% for pack-years of smoking (Indirect Effect HR 1.03 [95% CI 1.01-1.06]) and 11% for smoking history score (Indirect Effect HR 1.06 [95% CI 1.02-1.10]). Interpretation: Our findings suggest that part of the social inequalities in dementia is mediated by smoking. Funding: NIH.

Concurrent trajectories of self-rated health and working hour patterns in health care shift workers: A longitudinal analysis with 8-year follow-up.

Background: The association between health and working hours is hypothesized to be reciprocal, but few longitudinal studies have examined changes in both health and working hour patterns over time. We examined combined trajectories of self-related health and two working hour patterns (working <35 h/week and working night shifts) and the extent to which these trajectories were predicted by employees' lifestyle and mental health. Methods: Participants of this cohort study with a 8-year follow-up were 5,947 health care shift workers. We linked self-reports of health from three repeated surveys with objective pay-roll based data on working hours. Using group-based multi-trajectory analysis we identified concurrent trajectories for self-rated health and working hour patterns. We examined their associations with baseline lifestyle-related factors (smoking, at-risk alcohol use, obesity, and physical inactivity) and mental health (sleep problems and psychological distress) using multinomial regression analysis. Results: Three combined trajectories of self-rated health and working <35 h/week and four combined trajectories of self-rated health and night work were identified. Unhealthy lifestyle and poor mental health were associated with trajectories of moderate and declining health. Sleep problems were linked with working <35 h/week. Younger age and good mental health were associated with a combined trajectory of good health and continued night shift work. Conclusion: Trajectories of suboptimal and declining health are associated with trajectories of reducing working hours and leaving night work, and are more common in employees with unhealthy lifestyle, sleep problems, and psychological distress.

Metabolomic profiles predict individual multidisease outcomes.

Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.

State care in childhood and adult mortality: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Removal from family of origin to state care can be a highly challenging childhood experience and is itself linked to an array of unfavourable outcomes in adult life. We aim to synthetise evidence on the risk of adult mortality in people with a history of state care in early life, and assess the association according to different contexts. METHODS: In this systematic review and meta-analysis, we focused on four health outcomes hypothesised to be associated with exposure to early state care: total mortality, cardiovascular disease, cancer, and suicide. We searched the electronic databases PubMed and Embase from inception to Jan 21, 2022, for studies fulfilling the following criteria: it was a prospective study in which the assessment of care was made up to 18 years of age; it included an unexposed comparator group; the focus of the study was temporary out-of-home care and not adoption; mortality surveillance was extended into adulthood; standard estimates of association (eg, relative risk, odds ratios, or hazard ratios) and variance (eg, CIs and SE) were provided; the study appeared in a peer-reviewed journal; and the study was published in English. An adapted Cochrane Risk of Bias Tool was used to assess study quality. We extracted estimates of association and variance from qualifying studies and augmented these findings with analyses of unpublished data from individual participants in two UK birth cohorts-ie, the 1958 and 1970 studies (total n=21 936). We computed hazard ratios with accompanying 95% CIs for care and each health outcome separately for each study, and then pooled the results using a random-effects meta-analysis. This review is registered at PROSPERO, CRD42021254665. FINDINGS: We identified 210 potentially eligible published articles, of which 14 met our inclusion criteria (two studies were unpublished). Of 3 223 580 individuals drawn from 13 studies, those who were exposed to care in childhood had twice the risk of total mortality in adulthood relative to those without a history of care in childhood (summary risk ratio 2·21 [95% CI 1·62-3·02]), with study-specific estimates varying between 1·04 and 5·77 (I2 =98%). Despite some attenuation, this association remained following adjustment for other measures of early-life adversity; extended into middle and older age; was stronger in higher-quality studies; and was of equal magnitude according to sex, geographical region, and birth year. There was some suggestion of sensitive periods of exposure to care, whereby individuals who entered state care for the first time in adolescence (2·47 [0·98-6·52]) had greater rates of mortality than those doing so early in the life course (1·75 [1·25-2·45]). In four studies including 534 890 people, children in care had more than three times the risk of completed suicide in adulthood relative to their unexposed peers (3·35 [2·41-4·68]), with study-specific estimates ranging between 2·42 and 5·85 (I2=72%). The magnitude of this association was weaker after adjustment for multiple covariates; in men than in women; and in lower-quality studies. INTERPRETATION: Our results for adult mortality suggest child protection systems, social policy, and health services following care graduation are insufficient to mitigate the adverse experiences that might have preceded placement into care and those that might accompany it. FUNDING: None.

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.

Return to work following anterior cruciate ligament reconstruction.

BACKGROUND AND PURPOSE: Amongst people of working age, the return to work (RTW) after anterior cruciate ligament (ACL) reconstruction is an important marker of success of surgery. We determined when patients are able to return to work after ACL reconstruction and identified factors that are associated with the timing of RTW. PATIENTS AND METHODS: We used logistic regression analyses to examine patient-related factors that may be associated with the length of RTW (above vs. below the median 59 days) after arthroscopic ACLR in a large cohort of patients working in the public sector in Finland (n = 803; n = 334 male, n = 469 female; mean age 41 years [SD 8.6]). RESULTS: The mean length of RTW was 65 days (SD 41). Higher odds ratios (OR) were observed for age groups 40-49 and ≥ 50 years compared with ≤ 30 years old (OR 2.0, 95% confidence interval 1.3-3.1 and 2.0, 1.2-3.4, respectively); for lower level non-manual and manual work compared with higher level non-manual work (3.0, 2.0-4.3 and 4.9, 3.4-7.0, respectively); and for those who had been on sick leave > 30 days in the preceding year (2.0, 1.4-2.9). Sex, comorbid conditions, preceding antidepressant treatment and concomitant procedures were not associated with the length of RTW. INTERPRETATION: Factors associated with prolonged sick leave beyond the median time of 59 days are higher age, lower occupational status, and preoperative sick leaves.

Plasma ceramides independently predict all-cause mortality in men aged 85.

BACKGROUND: assessing cardiovascular and mortality risk with conventional biomarkers is challenging in oldest-old due to multimorbidity and polypharmacy. Ceramides are bioactive lipids shown to predict mortality in late middle-aged cohorts. OBJECTIVE: to assess whether plasma ceramides have independent prognostic value for mortality among oldest-old (85+). DESIGN: longitudinal cohort study (Helsinki Businessmen Study, HBS) with a 3.5-year follow-up. SETTING AND SUBJECTS: survivors of HBS (125 men born in 1919-1934) visited the clinic for laboratory and clinical examination. METHODS: functional status including physical (short physical performance battery) and Montreal Cognitive Assessment (MoCA) cognitive performance was assessed and laboratory examinations included a large set of biomarkers. Plasma ceramide concentration (Cer(d18:1/16:0)) was measured using a targeted liquid chromatography-tandem mass spectrometry assay. Mortality was retrieved from national registers. RESULTS: median age was 88 years, two-thirds had multimorbidity and 59% were on statin treatment. During the follow-up, 22 (18%) men died. In a model adjusted for variables associated with mortality in the whole cohort at P < 0.20 (log glucose, SPPB, MoCA and statin use), Cer(d18:1/16:0) as a continuous trait was associated with increased mortality: hazard ratio (HR) per 1 SD 1.64 (95% confidence interval [CI] 1.23-2.18). Compared with the bottom tertile of Cer(d18:1/16:0), HR of mortality was 5.44-fold (95% CI 1.17-25.3) in the top tertile. CONCLUSIONS: these data raise the hypothesis that plasma ceramide concentrations and especially Cer(d18:1/1:60) may offer a clinically useful biomarker to evaluate prognosis in very old age. Such biomarkers are needed for geriatrics, where multimorbidity and pharmacotherapies, such as statins are prevalent hampering assessment of prognosis using conventional methods.

Association of neighbourhood disadvantage and individual socioeconomic position with all-cause mortality: a longitudinal multicohort analysis.

BACKGROUND: Few studies have examined the interactions between individual socioeconomic position and neighbourhood deprivation and the findings so far are heterogeneous. Using a large sample of diverse cohorts, we investigated the interaction effect of neighbourhood socioeconomic deprivation and individual socioeconomic position, assessed using education, on mortality. METHODS: We did a longitudinal multicohort analysis that included six cohort studies participating in the European LIFEPATH consortium: the CoLaus (Lausanne, Switzerland), E3N (France), EPIC-Turin (Turin, Italy), EPIPorto (Porto, Portugal), Melbourne Collaborative Cohort Study (Melbourne, VIC, Australia), and Whitehall II (London, UK) cohorts. All participants with data on mortality, educational attainment, and neighbourhood deprivation were included in the present study. The data sources were the databases of each cohort study. Poisson regression was used to estimate the mortality rates and associations (relative risk, 95% CIs) with neighbourhood deprivation (Q1 being least deprived to Q5 being the most deprived). Baseline educational attainment was used as an indicator of individual socioeconomic position. Estimates were combined using pooled analysis and the relative excess risk due to the interaction was computed to identify additive interactions. FINDINGS: The cohorts comprised a total population of 168 801 individuals. The recruitment dates were 2003-06 for CoLaus, 1989-91 for E3N, 1992-98 for EPIC-Turin, 1999-2003 for EPIPorto, 1990-94 for MCCS, and 1991-94 for Whitehall II. We use baseline data only and mortality data obtained using record linkage. Age-adjusted mortality rates were higher among participants residing in more deprived neighbourhoods than those in the least deprived neighbourhoods (Q1 least deprived neighbourhoods, 369·7 per 100 000 person-years [95% CI 356·4-383·2] vs Q5-most deprived neighbourhoods 445·7 per 100 000 person-years [430·2-461·7]), but the magnitude of the association varied according to educational attainment (relative excess risk due to interaction=0·18, 95% CI 0·08-0·28). The relative risk for Q5 versus Q1 was 1·31 (1·23-1·40) among individuals with primary education or less, but less pronounced among those with secondary education (1·12; 1·04-1·21) and tertiary education (1·16; 1·07-1·27). Associations remained after adjustment for individual-level factors, such as smoking, physical activity, and alcohol intake, among others. INTERPRETATION: Our study suggests that the detrimental health effect of living in disadvantaged neighbourhoods is more pronounced among individuals with low education attainment, amplifying social inequalities in health. This finding is relevant to policies aimed at reducing health inequalities, suggesting that these issues should be addressed at both the individual level and the community level. FUNDING: The European Commission, European Regional Development Fund, the Portugese Foundation for Science and Technology.

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.