Impact of hypertension prevalence trend on mortality and burdens of dementia and disability in England and Wales to 2060: a simulation modelling study.

BACKGROUND: Previous estimates of the impact of public health interventions targeting hypertension usually focus on one health outcome. This study aims to consider the effects of change in future hypertension prevalence on mortality, dementia, and disability simultaneously. METHODS: We modelled three plausible scenarios based on observed trends of hypertension prevalence from 2003 to 2017 in England: observed trends continue (baseline scenario); 2017 prevalence remains unchanged; and 2017 prevalence decreases by 50% by 2060. We used a probabilistic Markov model to integrate calendar trends in incidence of cardiovascular disease, dementia, disability, and mortality to forecast their future occurrence in the population of England and Wales. Assuming the hypertension prevalence trend modifies health transition probabilities, we compared mortality outcomes and the burden of dementia and disability to 2060 for the scenarios. FINDINGS: If the decline in hypertension prevalence stops, there would be a slight increase in the number of additional deaths to 2060 (22·9 [95% uncertainty interval 19·0-26·6] more deaths per 100 000 population), although the burdens of disability and dementia in absolute terms would change little. Alternatively, if the downward hypertension prevalence trend accelerates (with prevalence falling by 50% between 2017 and 2060), there would be a modest additional reduction in deaths (57·0 [50·4-63·5] fewer deaths per 100 000 population), a small increase in dementia burden (9·0 [5·1-13·2] more cases per 100 000 population), no significant effect on disability burden, and an 8% gain in healthy life expectancy at age 65 years from 2020 to 2060 (5·3 years vs 4·9 years) compared with the baseline scenario. INTERPRETATION: The major future impact of alternative hypertension prevention strategies appears to be on future life expectancy. The salutary effect of lower population blood pressure distribution on incidence of dementia and disability might not offset expansion of the susceptible population due to reduced mortality. FUNDING: British Heart Foundation and UK Economic and Social Research Council.

Trends in health and health inequality during the Japanese economic stagnation: Implications for a healthy planet.

Introduction: Human health and wellbeing may depend on economic growth, the implication being that policymakers need to choose between population health and the health of ecosystems. Over two decades of low economic growth, Japan's life expectancy grew. Here we assess the temporal changes of subjective health and health inequality during the long-term low economic growth period. Methods: Eight triennial cross-sectional nationally representative surveys in Japan over the period of economic stagnation from 1992 to 2013 were used (n = 625,262). Health is defined positively as wellbeing, and negatively as poor health, based on self-rated health. We used Slope and Relative Indices of Inequality to model inequalities in self-rated health based on household income. Temporal changes in health and health inequalities over time were examined separately for children/adolescents, working-age adults, young-old and old-old. Results: At the end of the period of economic stagnation (2013), compared to the beginning (1992), the overall prevalence of wellbeing declined slightly in all age groups. However, poor health was stable or declined in the young-old and old-old, respectively, and increased only in working-age adults (Prevalence ratio: 1.14, 95% CI 1.08, 1.20, <0.001). Over time, inequality in wellbeing and poor self-rated health were observed in adults but less consistently for children, but the inequalities did not widen in any age group between the start and end of the stagnation period. Conclusions: Although this study was a case study of one country, Japan, and inference to other countries cannot be made with certainty, the findings provide evidence that low economic growth over two decades did not inevitably translate to unfavourable population health. Japanese health inequalities according to income were stable during the study period. Therefore, this study highlighted the possibility that for high-income countries, low economic growth may be compatible with good population health.

Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study.

BACKGROUND: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease. METHODS: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min-1·1.73 m-2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants. RESULTS: Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population. CONCLUSIONS: More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.

Cross-Sectional Blood Metabolite Markers of Hypertension: A Multicohort Analysis of 44,306 Individuals from the COnsortium of METabolomics Studies.

Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine intercontinental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra-platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension.

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.

What will the cardiovascular disease slowdown cost? Modelling the impact of CVD trends on dementia, disability, and economic costs in England and Wales from 2020-2029.

BACKGROUND: There is uncertainty around the health impact and economic costs of the recent slowing of the historical decline in cardiovascular disease (CVD) incidence and the future impact on dementia and disability. METHODS: Previously validated IMPACT Better Ageing Markov model for England and Wales, integrating English Longitudinal Study of Ageing (ELSA) data for 17,906 ELSA participants followed from 1998 to 2012, linked to NHS Hospital Episode Statistics. Counterfactual design comparing two scenarios: Scenario 1. CVD Plateau-age-specific CVD incidence remains at 2011 levels, thus continuing recent trends. Scenario 2. CVD Fall-age-specific CVD incidence goes on declining, following longer-term trends. The main outcome measures were age-related healthcare costs, social care costs, opportunity costs of informal care, and quality adjusted life years (valued at £60,000 per QALY). FINDINGS: The total 10 year cumulative incremental net monetary cost associated with a persistent plateauing of CVD would be approximately £54 billion (95% uncertainty interval £14.3-£96.2 billion), made up of some £13 billion (£8.8-£16.7 billion) healthcare costs, £1.5 billion (-£0.9-£4.0 billion) social care costs, £8 billion (£3.4-£12.8 billion) informal care and £32 billion (£0.3-£67.6 billion) value of lost QALYs. INTERPRETATION: After previous, dramatic falls, CVD incidence has recently plateaued. That slowdown could substantially increase health and social care costs over the next ten years. Healthcare costs are likely to increase more than social care costs in absolute terms, but social care costs will increase more in relative terms. Given the links between COVID-19 and cardiovascular health, effective cardiovascular prevention policies need to be revitalised urgently.

Aortic Pulse Wave Velocity as Adjunct Risk Marker for Assessing Cardiovascular Disease Risk: Prospective Study.

BACKGROUND: Aortic pulse wave velocity is a noninvasive measure of aortic stiffness and arterial aging. Its current value in cardiovascular risk estimation practice is unknown. We aimed to establish whether aortic pulse wave velocity identified individuals with higher risk of incident major adverse cardiovascular events and improved performance of the American Heart Association/American College of Cardiology atherosclerotic cardiovascular disease risk score. METHODS: This prospective analysis included 3837 Whitehall II cohort participants screened in 2008 to 2009, and followed for 11.7 years (mean=10.3, SD=1.81), without history of stroke, myocardial infarction, or coronary heart disease. RESULTS: Mean age of the sample was 65.0 years (SD=5.6), 2831 participants (73.8%) were male and mean atherosclerotic cardiovascular disease risk score was 13.8%. At the end of follow-up, 411 individuals (10.7%) had suffered a major cardiovascular event. Those in the highest aortic pulse wave velocity quartile were at high risk (hazard ratio, 2.99 [95% CI, 2.25-3.97]) and reached the threshold for statin medication (7.5% risk) after 5 years whereas others reached it after 10 years (difference P<0.001). The addition of aortic pulse wave velocity to the risk score improved the C statistic (0.68 versus 0.67, P=0.03) and net reclassification index (4.6%, P=0.04 and 11.3%, P=0.02). CONCLUSIONS: Our results show that aortic stiffness predicted major adverse cardiovascular events in a cohort of elderly individuals, improving the performance of a widely used cardiovascular disease risk estimator. Aortic pulse wave velocity measurement is scalable, radiation-free, and easy to perform. Further studies on its applicability in cardiovascular disease risk assessment in primary care settings are needed.

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

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

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

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

Serum transthyretin and risk of cognitive decline and dementia: 22-year longitudinal study.

Serum transthyretin (TTR) may be an early biomarker for Alzheimer's disease and related disorders (ADRD). We investigated associations of TTR measured at baseline with cognitive decline and incident ADRD and whether TTR trajectories differ between ADRD cases and non-cases, over 22 years before diagnosis. A total of 6024 adults aged 45-69 in 1997-1999 were followed up until 2019. TTR was assessed three times, and 297 cases of dementia were recorded. Higher TTR was associated with higher cognitive function at baseline; however, TTR was unrelated to subsequent change in cognitive function. TTR at baseline did not predict ADRD risk (hazard ratio per SD TTR (4.8 mg/dL) = 0.97; 95% confidence interval: 0.94-1.00). Among those later diagnosed with ADRD, there was a marginally steeper downward TTR trajectory than those free of ADRD over follow-up (P=0.050). Our findings suggest TTR is not neuroprotective. The relative decline in TTR level in the preclinical stage of ADRD is likely to be a consequence of disease processes.

Associations between arterial stiffening and brain structure, perfusion, and cognition in the Whitehall II Imaging Sub-study: A retrospective cohort study.

BACKGROUND: Aortic 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 FINDINGS: The 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. CONCLUSIONS: Our 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 REGISTRATION: ClinicalTrials.gov NCT03335696.

Association of circulating metabolites in plasma or serum and risk of stroke: Meta-analysis from seven prospective cohorts.

OBJECTIVE: To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings. METHODS: We investigated the association of metabolites with risk of stroke in seven prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by Nuclear Magnetic Resonance (1H-NMR) technology. The relationship between metabolites and stroke was assessed using Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately. RESULTS: The analyses revealed ten significant metabolite associations. Amino acid histidine (hazard ratio (HR) per standard deviation (SD) = 0.90, 95% confidence interval (CI): 0.85, 0.94; P = 4.45×10-5), glycolysis-related metabolite pyruvate (HR per SD = 1.09, 95% CI: 1.04, 1.14; P = 7.45×10-4), acute phase reaction marker glycoprotein acetyls (HR per SD = 1.09, 95% CI: 1.03, 1.15; P = 1.27×10-3), cholesterol in high-density lipoprotein (HDL) 2 and several other lipoprotein particles were associated with risk of stroke. When focusing on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD = 1.12, 95% CI: 1.05, 1.19; P = 4.13×10-4) and total and free cholesterol in large HDL particles. CONCLUSIONS: We found association of amino acids, glycolysis-related metabolites, acute phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.

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

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

Association of attrition with mortality: findings from 11 waves over three decades of the Whitehall II study.

BACKGROUND: Attrition, the loss of participants as a study progresses, is a considerable challenge in longitudinal studies. This study examined whether two forms of attrition, 'withdrawal' (formal discontinued participation) and 'non-response' (non-response among participants continuing in the study), have different associations with mortality and whether these associations differed across time in a multi-wave longitudinal study. METHODS: Participants were 10 012 civil servants who participated at the baseline of the Whitehall II cohort study with 11 data waves over an average follow-up of 28 years. We performed competing-risks analyses to estimate sub-distribution HRs and 95% CIs, and likelihood ratio tests to examine whether hazards differed between the two forms of attrition. We then applied linear regression to examine any trend of hazards against time. RESULTS: Attrition rate at data collections ranged between 13% and 34%. There were 495 deaths recorded from cardiovascular disease and 1367 deaths from other causes. Study participants lost due to attrition had 1.55 (95% CI 1.26 to 1.89) and 1.56 (1.39 to 1.76) times higher hazard of cardiovascular and non-cardiovascular mortality than responders, respectively. Hazards for withdrawal and non-response did not differ for either cardiovascular (p value =0.28) or non-cardiovascular mortality (p value =0.38). There was no linear trend in hazards over the 11 waves (cardiovascular mortality p value =0.11, non-cardiovascular mortality p value =0.61). CONCLUSION: Attrition can be a problem in longitudinal studies resulting in selection bias. Researchers should examine the possibility of selection bias and consider applying statistical approaches that minimise this bias.

Association of Healthy Lifestyle With Years Lived Without Major Chronic Diseases.

Importance: It is well established that selected lifestyle factors are individually associated with lower risk of chronic diseases, but how combinations of these factors are associated with disease-free life-years is unknown. Objective: To estimate the association between healthy lifestyle and the number of disease-free life-years. Design, Setting, and Participants: A prospective multicohort study, including 12 European studies as part of the Individual-Participant-Data Meta-analysis in Working Populations Consortium, was performed. Participants included 116 043 people free of major noncommunicable disease at baseline from August 7, 1991, to May 31, 2006. Data analysis was conducted from May 22, 2018, to January 21, 2020. Exposures: Four baseline lifestyle factors (smoking, body mass index, physical activity, and alcohol consumption) were each allocated a score based on risk status: optimal (2 points), intermediate (1 point), or poor (0 points) resulting in an aggregated lifestyle score ranging from 0 (worst) to 8 (best). Sixteen lifestyle profiles were constructed from combinations of these risk factors. Main Outcomes and Measures: The number of years between ages 40 and 75 years without chronic disease, including type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease. Results: Of the 116 043 people included in the analysis, the mean (SD) age was 43.7 (10.1) years and 70 911 were women (61.1%). During 1.45 million person-years at risk (mean follow-up, 12.5 years; range, 4.9-18.6 years), 17 383 participants developed at least 1 chronic disease. There was a linear association between overall healthy lifestyle score and the number of disease-free years, such that a 1-point improvement in the score was associated with an increase of 0.96 (95% CI, 0.83-1.08) disease-free years in men and 0.89 (95% CI, 0.75-1.02) years in women. Comparing the best lifestyle score with the worst lifestyle score was associated with 9.9 (95% CI 6.7-13.1) additional years without chronic diseases in men and 9.4 (95% CI 5.4-13.3) additional years in women (P < .001 for dose-response). All of the 4 lifestyle profiles that were associated with the highest number of disease-free years included a body-mass index less than 25 (calculated as weight in kilograms divided by height in meters squared) and at least 2 of the following factors: never smoking, physical activity, and moderate alcohol consumption. Participants with 1 of these lifestyle profiles reached age 70.3 (95% CI, 69.9-70.8) to 71.4 (95% CI, 70.9-72.0) years disease free depending on the profile and sex. Conclusions and Relevance: In this multicohort analysis, various healthy lifestyle profiles appeared to be associated with gains in life-years without major chronic diseases.

Association between socioeconomic status and the development of mental and physical health conditions in adulthood: a multi-cohort study.

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.

Associations of depression-anxiety and dyslipidaemia with subclinical carotid arterial disease: Findings from the Whitehall II Study.

AIMS: There is mixed evidence for an association between depression and/or anxiety and carotid intima-media thickness, and limited information on the related role of dyslipidaemia. Here we report associations between depression and/or anxiety and intima-media thickness in the Whitehall II cohort, considering the moderating effects of sex and dyslipidaemia. METHODS: A total of 2822 men and 1112 women (61 ± 6 years) were studied during phase 7 (2002-2004) of the Whitehall II study. Intima-media thickness and lipid levels were assessed, and questionnaires (general health questionnaire and the Centre for Epidemiologic Studies depression scale) were completed. Linear regression was used to explore relationships between depression and/or anxiety and intima-media thickness and the moderating effects of sex and dyslipidaemia. RESULTS: A total of 1461 participants were categorised with depression and/or anxiety. The association between depression and/or anxiety and intima-media thickness differed between men and women so analyses were undertaken separately by sex. In men, intima-media thickness was significantly associated with dyslipidaemia (P = 0.002) but not depression and/or anxiety (P = 0.29). In women, both dyslipidaemia and depression and/or anxiety were independently associated with intima-media thickness (P = 0.028 and P = 0.031). The greatest intima-media thickness was in women with both depression and/or anxiety and dyslipidaemia. These results were replicated when the general health questionnaire score was substituted for depression and/or anxiety and non-high-density lipoprotein cholesterol for dyslipidaemia. CONCLUSIONS: Depression and/or anxiety is associated with increased intima-media thickness in women but not in men. Dyslipidaemia is associated with intima-media thickness in both men and women. Women with both depression and/or anxiety and dyslipidaemia are potentially at the greatest risk of cardiovascular disease.

Association of aortic stiffness with cognitive decline: Whitehall II longitudinal cohort study.

Aortic stiffness is associated with an increased risk of cardio- and cerebrovascular disease and mortality and may increase risk of dementia. The aim of the present study is to examine the association between arterial stiffness and cognitive decline in a large prospective cohort study with three repeated cognitive assessment over 7 years of follow-up. Aortic pulse wave velocity (PWV) was measured among 4300 participants (mean ± standard deviation age 65.1 ± 5.2 years) in 2007-2009 and categorized based on the tertiles: (lowest third: < 7.41 m/s), (middle third: 7.41-8.91 m/s), and (highest third: > 8.91 m/s). A global cognitive score was calculated in 2007-2009, 2012-2013, and 2015-2016 based on responses to memory, reasoning and fluency tests. Standardized global cognitive score (mean = 0, SD = 1) in highest third versus lowest third of PWV category was lower at baseline (- 0.12, 95% CI - 0.18, - 0.06). Accelerated 7-year cognitive decline was observed among individuals with the highest PWV [difference in 7-year cognitive change for highest third versus lowest third PWV: - 0.06, 95% CI - 0.11, - 0.01, P < 0.01]. Higher aortic stiffness was associated with faster cognitive decline. Clinicians may be able to use arterial stiffness severity as an indicator to administer prompt treatments to prevent or delay the onset of cognitive decline or dementia. Future studies need to determine whether early intervention of vascular stiffness is effective in delaying these outcomes.

Potential impact of diabetes prevention on mortality and future burden of dementia and disability: a modelling study.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of dementia. We estimated the potential impact of trends in diabetes prevalence upon mortality and the future burden of dementia and disability in England and Wales. METHODS: We used a probabilistic multi-state, open cohort Markov model to integrate observed trends in diabetes, cardiovascular disease and dementia to forecast the occurrence of disability and dementia up to the year 2060. Model input data were taken from the English Longitudinal Study of Ageing, Office for National Statistics vital data and published effect estimates for health-state transition probabilities. The baseline scenario corresponded to recent trends in obesity: a 26% increase in the number of people with diabetes by 2060. This scenario was evaluated against three alternative projected trends in diabetes: increases of 49%, 20% and 7%. RESULTS: Our results suggest that changes in the trend in diabetes prevalence will lead to changes in mortality and incidence of dementia and disability, which will become visible after 10-15 years. If the relative prevalence of diabetes increases 49% by 2060, expected additional deaths would be approximately 255,000 (95% uncertainty interval [UI] 236,000-272,200), with 85,900 (71,500-101,600) cumulative additional cases of dementia and 104,900 (85,900-125,400) additional cases of disability. With a smaller relative increase in diabetes prevalence (7% increase by 2060), we estimated 222,200 (205,700-237,300) fewer deaths, and 77,000 (64,300-90,800) and 93,300 (76,700-111,400) fewer additional cases of dementia and disability, respectively, than the baseline case of a 26% increase in diabetes. CONCLUSIONS/INTERPRETATION: Reducing the burden of diabetes could result in substantial reductions in the incidence of dementia and disability over the medium to long term.

Plasma protein patterns as comprehensive indicators of health.

Proteins are effector molecules that mediate the functions of genes1,2 and modulate comorbidities3-10, behaviors and drug treatments11. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning12-16 coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.