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Summary: Background: Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors. Methods: We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis. Findings: We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4–65·1) million cases globally in 2019 to 152·8 (130·8–175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [–7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64–1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52–1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41–67]) and western Europe (74% [58–90]), and the largest in north Africa and the Middle East (367% [329–403]) and eastern sub-Saharan Africa (357% [323–395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation: Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. Funding: Bill & Melinda Gates Foundation and Gates Ventures.

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

Background: While considered less severe than major depressive disorder (MDD), chronic depression has a devastating effect on people's lives. Metabolic alterations related to chronicity are still widely unknown. We investigated metabolic alterations in patients with depression and compared the episodic and chronic forms. Methods: The study participants comprised 76 adolescent outpatients (33 MDD, 43 chronic depression). Patients’ serum samples were analyzed with targeted metabolite analysis, yielding results for 102 metabolites associated, for example, with amino acid, energy, lipid, and one-carbon metabolism. Results: After controlling for background factors, the chronic depression group had higher levels of choline (Cohen's d = 0.52 and unadjusted 95% confidence interval [0.05, 0.98]), glutamine (d = 0.42 [-0.04, 0.88]), glycine (d = 0.41 [-0.04, 0.87]), glycine betaine (d = 0.48 [0.02, 0.94]), guanidinoacetic acid (d = 0.23 [-0.23, 0.68]), octanoylcarnitine (d = 0.60 [0.13, 1.06]), phosphoethanolamine (d = 0.34 [-0.12, 0.79]) and succinate (d = 0.61 [0.14, 1.07]), and lower levels of glutamate (d = -0.66 [-1.12, -0.18]) when compared to the MDD group, although these differences did not remain after correction for multiple testing. Limitations: The sample size was small for targeted metabolomic analysis, and the study did not include a healthy control group. Conclusions: These preliminary results indicate putative differences in one-carbon metabolism and energy metabolism between chronic depression and MDD, possibly due to long-term chronic stress. Metabolic profiles appear to have the potential firstly to identify and distinguish different types of depression, and secondly to help in personalizing treatments in the future.

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

Objectives To investigate the association between changes in lifestyle risk factors and changes is sleep difficulties.Design Longitudinal repeated measures cohort study.Setting University and national institute of occupational health.Participants Participants of the Finnish Public Sector study with information on sleep and lifestyle-related risk factors collected in five repeat surveys with 4‐year intervals from 2000 to 2017. The participants were those, who had responded at least twice and had a change in sleep difficulties (having sleep difficulties vs not) (142 969 observations from 38 400 respondents (mean age 45.5 (SD 9.2) years, 83% women).Primary and secondary outcome measures Changes in sleep quality over time. Longitudinal fixed effects analysis, a method that accounts for time-invariant confounders by design, was used.Results At first available response, sleep difficulties were experienced by 13 998 (36%) of the respondents. Respectively, the mean age was 44.3 (10.0) years, 7526 (20%) were obese, 13 487 (35%) reported low physical activity, 3338 (9%) extensively drinking and 6547 (17%) were smoking. Except for smoking, the changes in the studied modifiable risks were associated with changes in sleep difficulties. The ORs for having sleep difficulties were 1.41 (95% CI 1.35 to 1.48) for obesity, 1.10 (95% CI 1.06 to 1.13) for low physical activity and 1.43 (95% CI 1.35 to 1.51) for heavy drinking. For smoking, the association was negative with OR 0.81 (95% CI 0.76 to 0.86). Including all four modifiable risks into model changed the estimates only little.Conclusions The results of this longitudinal study suggest that changes in sleep quality are interconnected with changes in lifestyle.

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise study sample differences contributing to differences in WMH variations across studies. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data.

ABSTRACT The plasma membrane (PM) must be overcome by viruses during entry and release. Furthermore, the PM represents the cellular communication compartment and the immune system interface. Hence, viruses have evolved sophisticated strategies to remodel the PM, for instance to avoid immune sensing and clearance of infected cells. We performed a comprehensive analysis of cell surface dysregulation by two human-pathogenic viruses, human cytomegalovirus (HCMV) and human immunodeficiency virus type 1 (HIV-1), in primary macrophages, which are classical antigen-presenting cells and orchestrators of the immune system. Scanning ion conductance microscopy revealed a loss of roughness and an overall smooth phenotype of HCMV-infected macrophages, in contrast to HIV-1 infection. This phenotype was also evident on the molecular level. When we screened for cell surface receptors modulated by HCMV, 42 of 332 receptors tested were up- or downregulated, whereas HIV-1 affected only 7 receptors. In particular CD164, CD84, and CD180 were targeted by HCMV. Mechanistically, HCMV induced transcriptional silencing of these receptors in an interferon (IFN)-independent manner, and expression was reduced not only by lab-adapted HCMV but also by clinical HCMV isolates. Altogether, our plasma membrane profiling of human macrophages provides clues to understand how viruses evade the immune system and identified novel cell surface receptors targeted by HCMV. IMPORTANCE The PM is a key component that viruses have to cope with. It is a barrier for infection and egress and is critically involved in antiviral immune signaling. We hence asked the question how two immunomodulatory viruses, HIV-1 and HCMV, dysregulate this compartment in infected macrophages, relevant in vivo targets of both viruses. We employed a contact-free microscopic technique to image the PM of infected cells and performed a phenotypic flow cytometry-based screen to identify receptor modulations on a molecular level. Our results show that HIV-1 and HCMV differentially manipulate the PM of macrophages. While HIV-1-mediated changes are relatively subtle, HCMV induces major alterations of the PM. We identify novel immune receptors manipulated by HCMV and define mechanisms of how HCMV interferes with receptor expression. Altogether, our study reveals differential strategies of how two human-pathogenic viruses manipulate infected cells and identifies potential novel pathways of HCMV immune evasion.

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

Summary: 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.

OBJECTIVE: This study examined the associations between shift work and use of antihypertensive, lipid-lowering, and antidiabetic medications. METHODS: Survey data from two cohorts of Finnish men (N=11 998) and women (N=49 944) working in multiple occupations where shift work was used were linked to national Drug Prescription Register data, with up to 11 years of follow-up. In each cohort, age-stratified Cox proportional hazard regression models were computed to examine any incident use of prescription medication for each of the three medical conditions, separately comparing each of two groups of rotating shift workers (those whose schedules included night shifts, and those whose schedules did not include night shifts) with day workers who worked in a similar range of occupations. RESULTS: In the larger cohort, among participants aged 40–49 at baseline, shift work without night shifts was associated with increased use of type-2 diabetes medication after adjustments for sex, occupational status, marital status, alcohol consumption, smoking, and physical activity [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01–1.62], while shift work with night shifts was associated with increased use of dyslipidemia medication after adjustments (HR 1.33, 95% CI 1.12–1.57). There were no such associations among younger and older shift workers. Also in the larger cohort, among those aged

OBJECTIVES: We examined the extent to which an increase in physical activity would reduce the excess risk of work disability among overweight and obese people (body mass index ≥ 25kg/m^2). METHODS: We used counterfactual modelling approaches to analyze longitudinal data from two Finnish prospective cohort studies (total N=38 744). Weight, height and physical activity were obtained from surveys and assessed twice and linked to electronic records of two indicators of long-term work disability (≥90-day sickness absence and disability pension) for a 7-year follow-up after the latter survey. The models were adjusted for age, sex, socioeconomic status, smoking, and alcohol consumption. RESULTS: The confounder-adjusted hazard ratio (HR) of long-term sickness absence for overweight compared to normal-weight participants was 1.43 [95% confidence interval (CI) 1.35–1.53]. An increase in physical activity among overweight compared to normal-weight individuals was estimated to reduce this HR to 1.40 (95% CI 1.31–1.48). In pseudo-trial analysis including only the persistently overweight, initially physically inactive participants, the HR for long-term sickness absence was 0.82 (95% CI 0.70–0.94) for individuals with increased physical activity compared to those who remained physically inactive. The results for disability pension as an outcome were similar. CONCLUSIONS: These findings suggest that the excess risk of work disability among overweight individuals would drop by 3–4% if they increased their average physical activity to the average level of normal-weight people. However, overweight individuals who are physically inactive would reduce their risk of work disability by about 20% by becoming physically active.

Abstract The association between physical activity and lung function is thought to depend on smoking history but most previous research uses self-reported measures of physical activity. This cross-sectional study investigates whether the association between accelerometer-derived physical activity and lung function in older adults differs by smoking history. The sample comprised 3063 participants (age = 60–83 years) who wore an accelerometer during 9 days and undertook respiratory function tests. Forced vital capacity (FVC) was associated with moderate-to-vigorous physical activity (MVPA; acceleration ≥0.1 g (gravity)) in smokers but not in never smokers: FVC differences for 10 min increase in MVPA were 58.6 (95% Confidence interval: 21.1, 96.1), 27.8 (4.9, 50.7), 16.6 (7.9, 25.4), 2.8 (−5.2, 10.7) ml in current, recent ex-, long-term ex-, and never-smokers, respectively. A similar trend was observed for forced expiratory volume in 1 second. Functional data analysis, a threshold-free approach using the entire accelerometry distribution, showed an association between physical activity and lung function in all smoking groups, with stronger association in current and recent ex-smokers than in long-term ex- and never-smokers; the associations were evident in never smokers only at activity levels above the conventional 0.1 g MVPA threshold. These findings suggest that the association between lung function and physical activity in older adults is more pronounced in smokers than non-smokers.

Abstract Background Currently, in vivo model for personalised cancer drug testing is challenging. A zebrafish larvae xenograft model has been applied in recent years to cancer research, particularly for drug testing purposes, showing promising results in drug testing against patient-derived tumour xenografts. Currently, these xenograft models apply imaging techniques to measure drug efficacy. However, this method carries several limitations, including timely imaging, thereby reducing the available number of tested fish and drugs. Here, we propose a PCR-based fast assay to evaluate drug efficacy in a zebrafish larvae xenograft model. Methods We tested two primary and corresponding metastatic head and neck squamous cell carcinoma (HNSCC) cell lines and patient-derived tongue cancer sample applying zebrafish larvae xenograft model. Cisplatin efficacy was tested using imaging technique and compared the results with PCR-based methods. Drug screening of eight compounds was applied on both cell lines and patient sample using PCR. Results In a head-to-head comparison, all the three techniques (imaging, quantitative PCR, and droplet digital PCR) showed similar reduction of the cancer cells growth after cisplatin treatment. Using the quantitative PCR assay, we demonstrated a dose-dependent response of HNSCC cells to cisplatin. Drug screening results of four HNSCC cell lines and patient sample revealed different drug efficacy between tested cancer cells. Conclusion We introduce a novel, easy, fast and cost-effective PCR-based in vivo zebrafish larvae assay to test the response of cell lines and clinical tumour samples to anti-cancer drugs. This method goes hand-by-hand with the commonly used imaging assay.

Background and purpose — While the number of working-age patients undergoing total hip arthroplasty (THA) is increasing, the effect of the surgery on patients’ return to work (RTW) is not thoroughly studied. We aimed to identify risk factors of RTW after THA among factors related to demographic variables, general health, health risk behaviors, and socioeconomic status. Patients and methods — We studied 408 employees from the Finnish Public Sector (FPS) cohort (mean age 54 years, 73% women) who underwent THA. Information on demographic and socioeconomic variables, preceding health, and health-risk behaviors was derived from linkage to national health registers and FPS surveys before the operation. The likelihood of return to work was examined using Cox proportional hazard modeling. Results — 94% of the patients returned to work after THA on average after 3 months (10 days to 1 year) of sickness absence. The observed risk factors of successful return to work were: having < 30 sick leave days during the last year (HR 1.8; 95% CI 1.4–2.3); higher occupational position (HR 2.2; CI 1.6–2.9); and BMI < 30 (HR 1.4; CI 1.1–1.7). Age, sex, preceding health status, and health-risk behaviors were not correlated with RTW after the surgery. Interpretation — Most employees return to work after total hip arthroplasty. Obese manual workers with prolonged sick leave before the total hip replacement were at increased risk of not returning to work after the surgery.

Here, the authors explore the relationship between socioeconomic position (SEP) across the life course and inflammation in a multi-cohort study and show that educational attainment is most strongly related to inflammation, suggesting that socioeconomic disadvantage in young adulthood is independently associated with later life inflammation.

BackgroundIt is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart–brain association remain unclear. Recent evidence suggests that impairments in vascular phenotypes and cerebrovascular reactivity (CVR) may play an important role in cognitive decline. The Heart and Brain Study combines state-of-the-art vascular ultrasound, cerebrovascular magnetic resonance imaging (MRI) and cognitive testing in participants of the long-running Whitehall II Imaging cohort to examine these processes together. This paper describes the study protocol, data pre-processing and overarching objectives.Methods and DesignThe 775 participants of the Whitehall II Imaging cohort, aged 65 years or older in 2019, have received clinical and vascular risk assessments at 5-year-intervals since 1985, as well as a 3T brain MRI scan and neuropsychological tests between 2012 and 2016 (Whitehall II Wave MRI-1). Approximately 25% of this cohort are selected for the Heart and Brain Study, which involves a single testing session at the University of Oxford (Wave MRI-2). Between 2019 and 2023, participants will undergo ultrasound scans of the ascending aorta and common carotid arteries, measures of central and peripheral blood pressure, and 3T MRI scans to measure CVR in response to 5% carbon dioxide in air, vessel-selective cerebral blood flow (CBF), and cerebrovascular lesions. The structural and diffusion MRI scans and neuropsychological battery conducted at Wave MRI-1 will also be repeated. Using this extensive life-course data, the Heart and Brain Study will examine how 30-year trajectories of vascular risk throughout midlife (40–70 years) affect vascular phenotypes, cerebrovascular health, longitudinal brain atrophy and cognitive decline at older ages.DiscussionThe study will generate one of the most comprehensive datasets to examine the longitudinal determinants of the heart–brain association. It will evaluate novel physiological processes in order to describe the optimal window for managing vascular risk in order to delay cognitive decline. Ultimately, the Heart and Brain Study will inform strategies to identify at-risk individuals for targeted interventions to prevent or delay dementia.

Objectives To assess the internal consistency and construct validity of the Finnish translation of the Jenkins Sleep Scale (JSS) in a large healthy working-age population with diverse work characteristics.Design Survey-based cross-sectional cohort study.Setting Survey conducted by an institute of occupational health.Participants Employees of 10 towns and 6 hospital districts.Primary and secondary outcome measures The internal consistency defined by a Cronbach’s alpha. Exploratory and confirmatory factor analyses to evaluate the construct structure of the JSS.Results Of 81 136 respondents, 14 890 (18%) were men and 66 246 (82%) were women. Their average age was 52.1 (13.2) years. Of the respondents, 41 823 (52%) were sleeping 7 or less hours per night. The mean JSS total score was 6.4 (4.8) points. The JSS demonstrated high internal consistency with an alpha of 0.80 (lower 95% confidence limit 0.80). Exploratory factor analysis supported a one-factor solution with eigenvalue of 1.94. Confirmatory factor analysis showed that all four items were positively correlated with a single common factor explaining 44%–61% of common factor’s variance.Conclusions The Finnish translation of JSS was found to be a unidimensional scale with good internal consistency. As such, the scale may be recommended as a practicable questionnaire when studying sleep difficulties in a healthy working-age population.

White matter hyperintensities (WMHs) on T2-weighted images are radiological signs of cerebral small vessel disease. As their total volume is variably associated with cognition, a new approach that integrates multiple radiological criteria is warranted. Location may matter, as periventricular WMHs have been shown to be associated with cognitive impairments. WMHs that appear as hypointense in T1-weighted images (T1w) may also indicate the most severe component of WMHs. We developed an automatic method that sub-classifies WMHs into four categories (periventricular/deep and T1w-hypointense/nonT1w-hypointense) using MRI data from 684 community-dwelling older adults from the Whitehall II study. To test if location and intensity information can impact cognition, we derived two general linear models using either overall or subdivided volumes. Results showed that periventricular T1w-hypointense WMHs were significantly associated with poorer performance in the trail making A (p = 0.011), digit symbol (p = 0.028) and digit coding (p = 0.009) tests. We found no association between total WMH volume and cognition. These findings suggest that sub-classifying WMHs according to both location and intensity in T1w reveals specific associations with cognitive performance.

Workplace discrimination may affect the health of the exposed employees, but it is not known whether workplace discrimination is also associated with an increased risk of long-term sickness absence. The aim of this study was to examine the longitudinal associations of changes in and onset of workplace discrimination with the risk of long-term sickness absence. Data on workplace discrimination were obtained from 29,597 employees participating in survey waves 2004, 2006, 2008 and/or 2010 of the Finnish Public Sector Study. Four-year changes in long-term sickness absence (≥10 days of medically certified absence with a mental or non-mental diagnosis) were assessed. This covered successive study waves in analyses of onset of workplace discrimination as well as fixed effect analyses of change in workplace discrimination (concurrent i.e. during the exposure year and 1-year lagged i.e. within one year following exposure), by using each employee as his/her own control. The risk of long-term sickness absence due to mental disorders was greater for employees with vs. without onset of workplace discrimination throughout the 4-year period, reaching a peak at the year when the onset of discrimination was reported (adjusted risk ratio 2.13; 95% confidence interval (CI) 1.80–2.52). The fixed effects analyses showed that workplace discrimination was associated with higher odds of concurrent, but not 1-year lagged, long-term sickness absence due to mental disorders (adjusted odds ratio 1.61; 95% CI 1.33–1.96 and adjusted odds ratio 1.02; 95% CI 0.83–1.25, respectively). Long-term sickness absence due to non-mental conditions was not associated with workplace discrimination. In conclusion, these findings suggest that workplace discrimination is associated with an elevated risk of long-term sickness absence due to mental disorders. Supporting an acute effect, the excess risk was confined to the year when workplace discrimination occurred.

The objective was to investigate the persistence of sleep difficulties for over 16 years amongst a population of working age. In this prospective cohort study, a group-based trajectory analysis of repeated surveys amongst 66,948 employees in public sector (mean age 44.7 [SD 9.4] years, 80% women) was employed. The main outcome measure was sleep difficulties based on Jenkins Sleep Scale (JSS). Up to 70% of the respondents did not experience sleep difficulties whereas up to 4% reported high frequency of notable sleep difficulties through the entire 16-year follow-up. Heavy drinking predicted sleep difficulties (OR 2.3 95% CI 1.6 to 3.3) except for the respondents younger than 40 years. Smoking was associated with sleep difficulties amongst women younger than 40 years (OR 1.2, 95% CI 1.0 to 1.5). Obesity was associated with sleep difficulties amongst men (OR 1.9, 95% CI 1.4 to 2.7) and women (OR 1.2, 95% CI 1.1 to 1.3) of middle age and amongst women older than 50 (OR 1.5, 95% CI 1.2 to 1.8) years. Physical inactivity predicted sleep difficulties amongst older men (OR 1.3, 95% CI 1.1 to 1.6). In this working-age population, sleep difficulties showed a great persistence over time. In most of the groups, the level of sleep difficulties during the follow-up was almost solely dependent on the level of initial severity. Depending on sex and age, increasing sleep problems were sometimes associated with high alcohol consumption, smoking, obesity and physical inactivity, but the strength of these associations varied.

BackgroundAortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.Methods and findingsThe Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007-2009 (Phase 9) and at a 4-year follow-up in 2012-2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = -5.65, 95% CI -9.75, -1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = -1.12, 95% CI -1.95, -0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = -10.85, 95% CI -17.91, -3.79, p < 0.0125) and parietal lobes (B = -12.75, 95% CI -21.58, -3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = -0.47, 95% CI -0.76 to -0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = -0.36, 95% CI -0.60 to -0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort.ConclusionsOur findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age.Trial registrationClinicalTrials.gov NCT03335696.

Brain age is becoming a widely applied imaging-based biomarker of neural aging and potential proxy for brain integrity and health. We estimated multimodal and modality-specific brain age in the Whitehall II (WHII) MRI cohort using machine learning and imaging-derived measures of gray matter (GM) morphology, white matter microstructure (WM), and resting state functional connectivity (FC). The results showed that the prediction accuracy improved when multiple imaging modalities were included in the model (R2 = 0.30, 95% CI [0.24, 0.36]). The modality-specific GM and WM models showed similar performance (R2 = 0.22 [0.16, 0.27] and R2 = 0.24 [0.18, 0.30], respectively), while the FC model showed the lowest prediction accuracy (R2 = 0.002 [-0.005, 0.008]), indicating that the FC features were less related to chronological age compared to structural measures. Follow-up analyses showed that FC predictions were similarly low in a matched sub-sample from UK Biobank, and although FC predictions were consistently lower than GM predictions, the accuracy improved with increasing sample size and age range. Cardiovascular risk factors, including high blood pressure, alcohol intake, and stroke risk score, were each associated with brain aging in the WHII cohort. Blood pressure showed a stronger association with white matter compared to gray matter, while no differences in the associations of alcohol intake and stroke risk with these modalities were observed. In conclusion, machine-learning based brain age prediction can reduce the dimensionality of neuroimaging data to provide meaningful biomarkers of individual brain aging. However, model performance depends on study-specific characteristics including sample size and age range, which may cause discrepancies in findings across studies.

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

BackgroundFrailty is associated with increased risk of various health conditions, disability, and death. Health behaviors are thought to be a potential target for frailty prevention, but the evidence from previous studies is based on older populations with short follow-ups, making results susceptible to reverse causation bias. We examined the associations of healthy behaviors at age 50, singly and in combination, as well as 10-year change in the number of healthy behaviors over midlife with future risk of frailty.Methods and findingsIn this prospective cohort study of 6,357 (29.2% women; 91.7% white) participants from the British Whitehall II cohort, healthy behaviors-nonsmoking, moderate alcohol consumption, ≥2.5 hours per week of moderate to vigorous physical activity, and consumption of fruits or vegetables at least twice a day-were measured at age 50, and change in behaviors was measured between 1985 (mean age = 44.4) and 1997 (mean age = 54.8). Fried's frailty phenotype was assessed in clinical examinations in 2002, 2007, 2012, and 2015. Participants were classified as frail if they had ≥3 of the following criteria: slow walking speed, low grip strength, weight loss, exhaustion, and low physical activity. An illness-death model accounting for both competing risk of death and interval censoring was used to examine the association between healthy behaviors and risk of frailty. Over an average follow-up of 20.4 years (standard deviation, 5.9), 445 participants developed frailty. Each healthy behavior at age 50 was associated with lower risk of incident frailty: hazard ratio (HR) after adjustment for other health behaviors and baseline characteristics 0.56 (95% confidence interval [CI] 0.44-0.71; p < 0.001) in nonsmokers, 0.73 (95% CI 0.61-0.88; p < 0.001) for moderate alcohol consumption, 0.66 (95% CI 0.54-0.81; p < 0.001) for ≥2.5 hours of physical activity per week, and 0.76 (95% CI 0.59-0.98; p = 0.03) for consumption of fruits or vegetables at least twice a day. A greater number of healthy behaviors was associated with reduced risk of frailty, with the HR for each additional healthy behavior being 0.69 (95% CI 0.62-0.76; p < 0.001) and the HR for having all versus no healthy behaviors at age 50 being 0.28 (95% CI 0.15-0.52; p < 0.001). Among participants with no or 1 healthy behavior in 1985, those who increased the number of healthy behaviors by 1997 were at a lower risk of frailty (mean follow-up = 16 years) compared with those with no such increase: the HR was 0.64 (95% CI 0.44-0.94; p = 0.02) for change to 2 healthy behaviors and 0.57 (95% CI 0.38-0.87; p < 0.001) for change to 3-4 healthy behaviors in 1997. The primary limitation of this study is potential selection bias during the follow-up due to missing data on frailty components.ConclusionsOur findings suggest that healthy behaviors at age 50, as well as improvements in behaviors over midlife, are associated with a lower risk of frailty later in life. Their benefit accumulates so that risk of frailty decreases with greater number of healthy behaviors. These results suggest that healthy behaviors in midlife are a good target for frailty prevention.

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

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

Background Lifestyle modification is a key component of cardiovascular disease prevention before and concurrently with pharmacologic interventions. We evaluated whether lifestyle factors change in relation to the initiation of antihypertensive or lipid‐lowering medication (statins). Methods and Results The study population comprised 41 225 participants of the FPS (Finnish Public Sector) study aged ≥40 years who were free of cardiovascular disease at baseline and responded to ≥2 consecutive surveys administered in 4‐year intervals in 2000–2013. Medication use was ascertained through pharmacy‐claims data. Using a series of pre–post data sets, we compared changes in body mass index, physical activity, alcohol consumption, and smoking between 8837 initiators and 46 021 noninitiators of antihypertensive medications or statins. In participants who initiated medication use, body mass index increased more (difference in change 0.19; 95% CI, 0.16–0.22) and physical activity declined (−0.09 metabolic equivalent of task hour/day; 95% CI, −0.16 to −0.02) compared with noninitiators. The likelihood of becoming obese (odds ratio: 1.82; 95% CI, 1.63–2.03) and physically inactive (odds ratio: 1.08; 95% CI, 1.01–1.17) was higher in initiators. However, medication initiation was associated with greater decline in average alcohol consumption (−1.85 g/week; 95% CI, −3.67 to −0.14) and higher odds of quitting smoking (odds ratio for current smoking in the second survey: 0.74; 95% CI, 0.64–0.85). Conclusions These findings suggest that initiation of antihypertensive and statin medication is associated with lifestyle changes, some favorable and others unfavorable. Weight management and physical activity should be encouraged in individuals prescribed these medications.

Several problems related to violence, grievances and states’ lack of legitimacy and capacity to manage economic, social and political issues are clustered together as a lump of misery in the Middle East and Northern Africa (MENA) [...]