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This is a pre-copyedited, author-produced version of an article accepted for publication in the European Journal of Preventive Cardiology following peer review. The version of record Hansen, K.W., Peytz, N., Blokstra, A., Bojesen, S.E., Celis-Morales, C., Chrysohoou, C, ... Prescott, E. (2021). Association of fatal myocardial infarction with past level of physical activity: a pooled analysis of cohort studies. European Journal of Preventive Cardiology, zwaa146, is available online at: https://doi.org/10.1093/eurjpc/zwaa146. Aims: To assess the association between past level of physical activity (PA) and risk for death during the acute phase of myocardial infarction (MI) in a pooled analysis of cohort studies. Methods and results: European cohorts including participants with a baseline assessment of PA, conventional cardiovascular (CV) risk factors, and available follow-up on MI and death were eligible. Patients with an incident MI were included. Leisure-time PA was grouped as sedentary (32 MET-hours) based on calculated net weekly energy expenditure. The main outcome measures were instant and 28-day case fatality of MI. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using multivariate random-effects models. Adjustments for age, sex, CV risk factors, alcohol consumption, and socioeconomic status were made. From 10 cohorts including a total of 1 495 254 participants, 28 140 patients with an incident MI comprised the study population. A total of 4976 (17.7%) died within 28 days—of these 3101 (62.3%) were classified as instant fatal MI. Compared with sedentary individuals, those with a higher level of PA had lower adjusted odds of instant fatal MI: low PA [OR, 0.79 (95% CI, 0.60–1.04)], moderate PA [0.67 (0.51–0.89)], and high PA [0.55 (0.40–0.76)]. Similar results were found for 28-day fatal MI: low PA [0.85 (0.71–1.03)], moderate PA [0.64 (0.51–0.80)], and high PA [0.72 (0.51–1.00)]. A low-to-moderate degree of heterogeneity was detected in the analysis of instant fatal MI (I2 = 47.3%), but not in that of 28-day fatal MI (I2 = 0.0%). Conclusion: A moderate-to-high level of PA was associated with a lower risk of instant and 28-day death in relation to a MI.

BACKGROUND: Diet, in particular the Mediterranean diet, has been associated with better cognitive function and less cognitive decline in older populations.OBJECTIVES: To quantify associations of a healthy diet, defined by adherence to either the Mediterranean diet, the WHO guidelines, or Dutch Health Council dietary guidelines, with cognitive function and cognitive decline from middle age into old age.METHODS: From the Doetinchem Cohort Study, a large population-based longitudinal study, 3644 participants (51% females) aged 45-75 y at baseline, were included. Global cognitive function, memory, processing speed, and cognitive flexibility were assessed at 5-y time intervals up to 20-y follow-up. Adherence to the Mediterranean diet was measured with the modified Mediterranean Diet Score (mMDS), adherence to the WHO dietary guidelines with the Healthy Diet Indicator (HDI), and adherence to the Dutch Health Council dietary guidelines 2015 with the modified Dutch Healthy Diet 2015 index (mDHD15-index). The scores on the dietary indices were classified in tertiles (low, medium, high adherence). Linear mixed models were used to model level and change in cognitive function by adherence to healthy diets.RESULTS: The highest tertiles of the mMDS, HDI, and mDHD15-index were associated with better cognitive function compared with the lowest tertiles (P values CONCLUSIONS: Healthier dietary habits, determined by higher adherence to dietary guidelines, are associated with better cognitive function and slower cognitive decline with aging from middle age onwards.

BackgroundMajor depressive disorder (MDD) is a common mood disorder, with a heritability of around 34%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression.MethodsWithin the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n ≈ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS).ResultsEstimates of current and lifetime MDD prevalence were 6.7% and 18.1%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95% CI 1.15–1.32, R2 = 1.47%).ConclusionsBy assessing MDD status in the Netherlands using the LIDAS instrument, we were able to confirm previously reported MDD prevalence and heritability estimates, which suggests that this instrument can be used in epidemiological and genetic association studies of depression.

Background and Aims: It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). Methods: We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). Results: Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m 2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I 2 = 0%) compared with normal BMI (18.5 to 2). Each 5 kg/m 2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I 2 = 0%). Similarly, with each 5 kg/m 2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I 2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I 2 = 0%). No associations were observed between measures of obesity and risk of UC. Conclusions: In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.

Background Dietary guidelines on pure fruit juice consumption vary from country to country regarding the inclusion of pure fruit juice in the recommendations as an acceptable alternative for fruit. Current epidemiological evidence on the association between pure fruit juice consumption and diabetes risk is scarce. Objective We studied the association of both pure fruit juice and fruit consumption with diabetes risk and investigated the differences between low and high fruit consumers in the association of pure fruit juice consumption with diabetes risk. Methods This prospective cohort study included 36,147 participants in the European Prospective Investigation into Cancer and Nutrition–Netherlands (EPIC-NL) Study aged 20–69 y at baseline. Fruit juice and fruit consumption were assessed using a validated food-frequency questionnaire; amounts of consumption were divided into 5 categories and quintiles, respectively. Incident type 2 diabetes cases were mainly self-reported and verified against medical records. Cox regression was used to estimate adjusted HRs and 95% CIs. Results After an average follow-up of 14.6 y, 1477 verified incident cases of type 2 diabetes were documented. Compared with no consumption, pure fruit juice consumption was not significantly associated with type 2 diabetes, with adjusted HRs ranging from 0.92 (95% CI: 0.79, 1.09) to 1.03 (95% CI: 0.83, 1.26). The associations did not differ between participants with low and high fruit consumption. None of the categories of fruit consumption were associated with type 2 diabetes (lowest quintile as reference). Adjusted HRs ranged between 0.93 (95% CI: 0.78, 1.10) and 1.00 (95% CI: 0.84, 1.19). Adjustment for the Dutch Healthy Diet Index, as an overall measure of dietary quality, strongly attenuated the observed associations of type 2 diabetes with both fruit juice and fruit consumption. Conclusions We found no evidence for associations between pure fruit juice and fruit consumption and diabetes risk after adjustment for overall dietary quality for participants in the EPIC-NL study. This trial was registered at https://www.trialregister.nl/trial/6939 as NL6939.

EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270; MR/L003120/1), British Heart Foundation (BHF) (SP/09/002; RG13/13/30194; RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_ 2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro--AIRC--Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands); Health Research Fund-Instituto de Salud Carlos III, Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_ 00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215--20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R. Z.-R. thanks the "Miguel Servet" program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund--European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart).R.C.was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. The funders of the study had no role in study design, data collection, analysis, data interpretation, or writing of the article, or in the decision to submit for publication. M.S. had full access to all the data in the study, and M.S. and N.G.F. had final responsibility for the decision to submit for publication., BACKGROUND: There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. METHODS AND RESULTS: We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). CONCLUSIONS: This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix., European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), European Commission 268834, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) G0800270 MR/L003120/1, British Heart Foundation SP/09/002 RG13/13/30194 RG/18/13/33946, National Institute for Health Research (NIHR) BRC-1215-20014, European Commission LSHM_CT_ 2006_037197, Medical Research Council UK (MRC) MC_UU_ 00006/1 MC_UU_00006/3, International Agency for Research on Cancer, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam, Rehbruecke, Federal Ministry of Education and Research (Germany), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III, Junta de Andalucia, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of Oncology (Spain), Swedish Cancer Society, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, Medical Research Council UK (MRC) 1000143 MR/M012190/1, Hellenic Health Foundation (Greece), NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, Institute of Health Carlos III (European Social Fund-European Social Fund Investing in Your Future) CP15/00100, BHF-Turing Cardiovascular Data Science Award, European Commission-Innovative Medicines Initiative (BigData@Heart), MRC-Newton project grant MR/P013880/1, United Kingdom Research and Innovation-Global Challenges Research Fund, NIHR Senior Investigator Award

Objective Obesity is becoming a global public health problem, but it is unclear how it impacts different generations over the life course. Here, a descriptive analysis of the age‐related changes in anthropometric measures and related cardiometabolic risk factors across different generations was performed. Methods The development of anthropometric measures and related cardiometabolic risk factors was studied during 26 years of follow‐up in the Doetinchem Cohort Study (N = 6,314 at baseline). All analyses were stratified by sex and generation, i.e., 10‐year age groups (20‐29, 30‐39, 40‐49, and 50‐59 years) at baseline. Generalized estimating equations were used to test for generational differences. Results Weight, BMI, waist circumference, and prevalence of overweight and obesity were higher, in general, in the younger generations during the first 10 to 15 years of follow‐up. From age 50 to 59 years onward, these measures converged in all generations of men and women. Among cardiometabolic risk factors, only type 2 diabetes showed an unfavorable shift between the two oldest generations of men. Conclusions It was observed that, compared with the older generations, the younger generations had obesity at an earlier age but did not reach higher levels at midlife and beyond. This increased exposure to obesity was not (yet) associated with increased prevalence of cardiometabolic risk factors.

Background: Elderly often show reduced immune functioning and develop chronic low-grade inflammation. Why some elderly are more prone to become frail is unknown. We investigated whether frailty is associated with differences in cytokine signaling through the JAK-STAT pathway in leukocytes of 34 individuals aged 65-77 years. In addition, we investigated how this relation is affected by chronic low-grade inflammation during the previous 20 years. Cytokine signaling was quantified by measuring intracellular STAT1, STAT3, and STAT5 phosphorylation in monocytes, B cells, CD4+ T cells and CD8+ T cells upon stimulation with IL-2, IL-6, IL-10, IFNα and IFNγ, using phospho-flow cytometry. Plasma inflammatory markers had been measured repeatedly in the same individuals over the previous 20 years. Frailty was assessed as a score on a frailty index. Results: We found that lower cytokine-induced pSTAT responsiveness in the various cell subsets was seen with higher frailty scores in both men and women, indicative of dysfunctional pSTAT responses in frailer individuals. Associations differed between men and women, with frailer women showing lower pSTAT1 responses in monocytes and frailer men showing lower pSTAT5 responses in CD4+ and CD8+ T cells. Notably, lower IL-10-induced pSTAT3 responses in men were related to both higher frailty scores and higher CRP levels over the past 20 years. This might indicate poor resolution of low-grade inflammation due to defective regulatory pSTAT signaling in older men. Conclusions: Our results emphasize the importance of preserved JAK-STAT pathway signaling in healthy aging and reveal cellular pSTAT levels as a candidate biomarker of frailty.

Learning objectives A healthy diet is the cornerstone of cardiovascular disease (CVD) prevention.1 Dietary habits influence cardiovascular risk, through an effect on, for example, blood pressure (BP), blood lipids, obesity, inflammation and endothelial function.2 Over the past decades, knowledge about the components of a healthy diet has grown. Since there are few randomised controlled trials, most evidence on diet–disease relationships comes from prospective cohort studies, with inherent methodological problems, such as measurement error in dietary intake and correlations between dietary components. Still, the basic principles of a healthy diet can certainly be outlined. Since average dietary intake in most countries is far from optimal, the potential health gain is large, not only for CVDs but for other chronic diseases as well. Diet also has a large impact on the environment.3 Food production systems are associated with approximately 25% of the worldwide greenhouse gas (GHG) emissions, 80% of the loss of biodiversity, 70% of water withdrawals for irrigation and 40% of land use. Therefore, dealing with environmental challenges is also a major food system challenge, especially when the foreseen growth of the world population and increasing demands for meat are considered. The EAT-Lancet commission recently introduced ‘The Great Food Transformation’: an urgent call for a transformation of the whole food system, from production to consumption,to decrease the total environmental impact of our current and future food system.4 In this paper, we will discuss diet in relation to both cardiovascular and planetary health. ### Diet and cardiovascular health The focus of dietary …

Objectives Psychosocial factors have been hypothesized to increase the risk of cancer. This study aims (1) to test whether psychosocial factors (depression, anxiety, recent loss events, subjective social support, relationship status, general distress, and neuroticism) are associated with the incidence of any cancer (any, breast, lung, prostate, colorectal, smoking‐related, and alcohol‐related); (2) to test the interaction between psychosocial factors and factors related to cancer risk (smoking, alcohol use, weight, physical activity, sedentary behavior, sleep, age, sex, education, hormone replacement therapy, and menopausal status) with regard to the incidence of cancer; and (3) to test the mediating role of health behaviors (smoking, alcohol use, weight, physical activity, sedentary behavior, and sleep) in the relationship between psychosocial factors and the incidence of cancer. Methods The psychosocial factors and cancer incidence (PSY‐CA) consortium was established involving experts in the field of (psycho‐)oncology, methodology, and epidemiology. Using data collected in 18 cohorts (N = 617,355), a preplanned two‐stage individual participant data (IPD) meta‐analysis is proposed. Standardized analyses will be conducted on harmonized datasets for each cohort (stage 1), and meta‐analyses will be performed on the risk estimates (stage 2). Conclusion PSY‐CA aims to elucidate the relationship between psychosocial factors and cancer risk by addressing several shortcomings of prior meta‐analyses., Psychosocial factors and cancer incidence (PSY‐CA) consortium endeavor to understand the role of several different psychosocial factors—including depression and anxiety—in the onset of cancer. The study will employ the use of individual participant data meta‐analyses, combining results from several large, international cohorts with longitudinal designs. Furthermore, PSY‐CA aims to elucidate the role of health behaviors in the relationship between psychosocial factors and cancer risk.

Aims/hypothesis Given its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is considered to be a marker of reproductive ageing. Although accelerated reproductive ageing has been associated with a higher risk of type 2 diabetes, research on the relationship between AMH and type 2 diabetes risk is scarce. Therefore, we aimed to investigate whether age-specific AMH levels and age-related AMH trajectories are associated with type 2 diabetes risk in women. Methods We measured AMH in repeated plasma samples from 3293 female participants (12,460 samples in total), aged 20–59 years at recruitment, from the Doetinchem Cohort Study, a longitudinal study with follow-up visits every 5 years. We calculated age-specific AMH tertiles at baseline to account for the strong AMH–age correlation. Cox proportional hazards models adjusted for confounders were used to assess the association between baseline age-specific AMH tertiles and incident type 2 diabetes. We applied linear mixed models to compare age-related AMH trajectories for women who developed type 2 diabetes with trajectories for women who did not develop diabetes. Results During a median follow-up of 20 years, 163 women developed type 2 diabetes. Lower baseline age-specific AMH levels were associated with a higher type 2 diabetes risk (HRT2vsT3 1.24 [95% CI 0.81, 1.92]; HRT1vsT3 1.62 [95% CI 1.06, 2.48]; ptrend = 0.02). These findings seem to be supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages in women who developed type 2 diabetes compared with women who did not. The trajectories also suggested that AMH levels declined at a slower rate in women who developed type 2 diabetes, although differences in trajectories were not statistically significant. Conclusions/interpretation We observed that lower age-specific AMH levels were associated with a higher risk of type 2 diabetes in women. Longitudinal analyses did not show clear evidence of differing AMH trajectories between women who developed type 2 diabetes compared with women who did not, possibly because these analyses were underpowered. Further research is needed to investigate whether AMH is part of the biological mechanism explaining the association between reproductive ageing and type 2 diabetes.

Importance: Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes.Objective: To investigate the association between time spent cycling and all-cause and CVD mortality among persons with diabetes, as well as to evaluate the association between change in time spent cycling and risk of all-cause and CVD mortality.Design, Setting, and Participants: This prospective cohort study included 7459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition study. Questionnaires regarding medical history, sociodemographic, and lifestyle information were administered in 10 Western European countries from 1992 through 2000 (baseline examination) and at a second examination 5 years after baseline. A total of 5423 participants with diabetes completed both examinations. The final updated primary analysis was conducted on November 13, 2020.Exposures: The primary exposure was self-reported time spent cycling per week at the baseline examination. The secondary exposure was change in cycling status from baseline to the second examination.Main Outcomes and Measures: The primary and secondary outcomes were all-cause and CVD mortality, respectively, adjusted for other physical activity modalities, diabetes duration, and sociodemographic and lifestyle factors.Results: Of the 7459 adults with diabetes included in the analysis, the mean (SD) age was 55.9 (7.7) years, and 3924 (52.6%) were female. During 110 944 person-years of follow-up, 1673 deaths from all causes were registered. Compared with the reference group of people who reported no cycling at baseline (0 min/wk), the multivariable-adjusted hazard ratios for all-cause mortality were 0.78 (95% CI, 0.61-0.99), 0.76 (95% CI, 0.65-0.88), 0.68 (95% CI, 0.57-0.82), and 0.76 (95% CI, 0.63-0.91) for cycling 1 to 59, 60 to 149, 150 to 299, and 300 or more min/wk, respectively. In an analysis of change in time spent cycling with 57 802 person-years of follow-up, a total of 975 deaths from all causes were recorded. Compared with people who reported no cycling at both examinations, the multivariable-adjusted hazard ratios for all-cause mortality were 0.90 (95% CI, 0.71-1.14) in those who cycled and then stopped, 0.65 (95% CI, 0.46-0.92) in initial noncyclists who started cycling, and 0.65 (95% CI, 0.53-0.80) for people who reported cycling at both examinations. Similar results were observed for CVD mortality.Conclusion and Relevance: In this cohort study, cycling was associated with lower all-cause and CVD mortality risk among people with diabetes independent of practicing other types of physical activity. Participants who took up cycling between the baseline and second examination had a considerably lower risk of both all-cause and CVD mortality compared with consistent noncyclists.

Background and Purpose: The few epidemiological studies that addressed the association between age at menopause and ischemic and hemorrhagic stroke risk in women had conflicting findings. We aimed to investigate whether age at (natural and surgical) menopause is a risk factor for total, ischemic, and hemorrhagic stroke in women. Methods: We analyzed data from 16 244 postmenopausal women, aged 26 to 70 years at recruitment who were enrolled in the European Prospective Investigation into Cancer and Nutrition–Netherlands cohort between 1993 and 1997. Participants were followed for the occurrence of stroke until January 1, 2011. At baseline, participants filled in questionnaires about health, reproductive history including age at menopause, diet, and lifestyle. Cox regression was used to investigate the association between age at menopause and stroke. All analyses were adjusted for age, smoking, systolic blood pressure, and body mass index. Results: Mean age of menopause was 46.4 (7.0) years. A total of 830 strokes (571 ischemic, 162 hemorrhagic, 97 unclassified) were identified. Earlier menopause was associated with an increased risk of total stroke. Compared with women who experienced menopause between 50 and 54 years old, women who underwent menopause before age 40 years had 1.48× higher risk (95% CI, 1.19–1.85) of total stroke. In continuous analyses, we observed a 2% lower total stroke risk for each year menopause was delayed (hazard ratio, 0.98 [95% CI, 0.97–0.99]). The risk between earlier menopause and stroke was confined to ischemic stroke, earlier menopause was not associated with hemorrhagic stroke. The association with age at menopause was stronger for natural menopause (hazard ratio Conclusions: The risk of total and ischemic stroke decreased with an increase in age at menopause. Whether this should have clinical consequences such as intensified risk factor control should be subject of further studies.

Objectives The aim of this study is to determine whether combinations of specific Life’s Simple 7 (LS7) components are associated with reduced risk for heart failure (HF). Background The American Heart Association recommends the concept of LS7: healthy behaviors that have been shown to reduce cardiovascular disease. Methods A total of 37,803 participants from the EPIC-NL (European Prospective Investigation Into Cancer and Nutrition–Netherlands) cohort were included (mean age: 49.4 ± 11.9 years, 74.7% women). The LS7 score ranged from 0 to 14 and was calculated by assigning 0, 1, or 2 points for smoking, physical activity, body mass index, diet, blood pressure, total cholesterol, and blood glucose. An overall ideal score (11 to 14 points) was present in 23.2% of participants, an intermediate score (9 or 10 points) in 35.3%, and an inadequate score (0 to 8 points) in 41.5%. Results Over a median follow-up period of 15.2 years (interquartile range: 14.1 to 16.5 years), 690 participants (1.8%) developed HF. In Cox proportional hazards models, ideal and intermediate LS7 scores were associated with reduced risk for HF compared with the inadequate category (hazard ratio: 0.45 [95% confidence interval (CI): 0.34 to 0.60] and hazard ratio: 0.53 [95% CI: 0.44 to 0.64], respectively). Our analyses show that combinations with specific LS7 components, notably glucose, body mass index, smoking, and blood pressure, are associated with a lower incidence of HF. Conclusions A healthy lifestyle, as reflected in an ideal LS7 score, was associated with a 55% lower risk for HF compared with an inadequate LS7 score. Preventive strategies that target combinations of specific LS7 components could have a significant impact on decreasing incident HF in the population at large.

Generational differences in health-related factors will affect forecasts of future disease patterns and health care needs. We studied whether participation in sports activity and being physically active are different between 10-year generations over a part of their life course. We used three different datasets on Dutch adults: a cohort study running for 20 years, the Doetinchem Cohort Study (DCS), multiple yearly databases (2001-2015) from the Netherlands health interview study (HIS), and a retrospective cohort study on life time sports careers, the Sports Participation Monitor (SPM). Based on a different questionnaire in each study, frequencies of weekly sport participation and being physically active according to recommended levels were determined by generation and sex. All data sets showed that self-reported sport participation has been increasing with every 10-year generation already for many decades. Especially for those generations born in the 1930s up to the 1960s, sport participation is higher compared to their predecessors. For instance at age 50, 43% of those born in the 1940s engaged in sports activities compared to 55% of those born in the 1950s (DCS data). Physical activity according to recommended levels showed no systematic differences by generation. In conclusion, favourable generation-specific trends in participation in sports activities are found: recent generations are doing better than the older generations. It is unclear whether this also reflects higher levels of physical activity or lower levels of inactivity. Future research may reveal whether these developments also hold for other countries, and whether these developments continue for the younger generations.

Frailty among elderly people leads to an increased risk for negative health outcomes. To prevent frailty, we need a better understanding of the underlying mechanisms and early detection of individuals at risk. Both may be served by identifying candidate (bio)markers, i.e. biomarkers and markers, for the physical, cognitive, and psychological frailty domains. We used univariate (Rank-ANOVA) and multivariate (elastic net) approaches on the RASIG study population (age range: 35–74 years, n = 2220) of the MARK-AGE study to study up to 331 (bio)markers between individuals with and without frailty for each domain. Biomarkers and markers identified by both approaches were studied further regarding their association with frailty using logistic regression. Univariately, we found lower levels of antioxidants, including β-cryptoxanthin and zeaxanthin, in those who were physically, cognitively or psychologically frail. Additionally, self-reported health was worse in these three frail groups. Multivariately, we observed lower levels of β-cryptoxanthin and zeaxanthin in the cognitively frail. Levels of these carotenoids were inversely associated with the risk of being cognitively frail after adjusting for confounders. Antioxidants and self-reported health are potential (bio)markers to detect persons at risk of becoming frail. The biomarkers identified may indicate the involvement of inflammation in frailty, especially for physical and cognitive frailty.

Background Unhealthy food environments may contribute to unhealthy diets and risk of overweight and obesity through increased consumption of fast-food. Therefore, we aimed to study the association of relative exposure to fast-food restaurants (FFR) with overall diet quality and risk of overweight and obesity in a sample of older adults. Methods We analyzed cross-sectional data of the EPIC-NL cohort (n = 8,231). Data on relative FFR exposure was obtained through linkage of home address in 2015 with a retail outlet database. We calculated relative exposure to FFR by dividing the densities of FFR in street-network buffers of 400, 1000, and 1500 m around the home of residence by the density of all food retailers in the corresponding buffer. We calculated scores on the Dutch Healthy Diet 2015 (DHD15) index using data from a validated food-frequency questionnaire. BMI was categorized into normal weight (BMI Results Relative FFR exposure was not significantly associated with DHD15-index scores in the 400, 1000, and 1500 m buffers (βQ4vsQ1= -0.21 [95 %CI: -1.12; 0.70]; βQ4vsQ1= -0.12 [95 %CI: -1.10; 0.87]; βQ4vsQ1 = 0.37 [95 %CI: -0.67; 1.42], respectively). Relative FFR exposure was also not related to overweight in consecutive buffers (ORQ4vsQ1=1.10 [95 %CI: 0.97; 1.25]; ORQ4vsQ1=0.97 [95 %CI: 0.84; 1.11]; ORQ4vsQ1= 1.04 [95 %CI: 0.90–1.20]); estimates for obesity were similar to those of overweight. Conclusions A high proportion of FFR around the home of residence was not associated with diet quality or overweight and obesity in this large Dutch cohort of older adults. We conclude that although the food environment may be a determinant of food choice, this may not directly translate into effects on diet quality and weight status. Methodological improvements are warranted to provide more conclusive evidence.

Background This study explores whether a sex difference in sensitivity to (strength of the association) and/or in exposure to (prevalence) determinants of gait speed contributes to the observed lower gait speed among older women compared to men. Methods Data from the Longitudinal Aging Study Amsterdam (LASA) were used. In total 2407 men and women aged 55–81 years were included, with baseline measurements in 1992/2002 and follow-up measurements every 3–4 years for 15/25 years. Multivariable mixed model analysis was used to investigate sex differences in sensitivity (interaction term with sex) and in exposure to (change of the sex difference when adjusted) socio-demographic, lifestyle, social and health determinants of gait speed. Results Women had a 0.054 m/s (95 % CI: 0.076 − 0.033, adjusted for height and age) lower mean gait speed compared to men. In general, men and women had similar determinants of gait speed. However, higher BMI and lower physical activity were more strongly associated with lower gait speed in women compared to men (i.e. higher sensitivity). More often having a lower educational level, living alone and having more chronic diseases, pain and depressive symptoms among women compared to men also contributed to observed lower gait speed in women (i.e. higher exposure). In contrast, men more often being a smoker, having a lower physical activity and a smaller personal network size compared to women contributed to a lower gait speed among men (i.e. higher exposure). Conclusions Both a higher sensitivity and higher exposure to determinants of gait speed among women compared to men contributes to the observed lower gait speed among older women. The identified (modifiable) contributing factors should be taken into account when developing prevention and/or treatment strategies aimed to enhance healthy physical aging. This might require a sex-specific approach in both research and clinical practice, which is currently often lacking.

BACKGROUND AND AIMS: It is still unclear whether a healthy diet can prevent heart failure (HF). Therefore, this study aimed to investigate the association between adherence to a Mediterranean-style diet, reflected by modified Mediterranean Diet Scores (mMDS), and the incidence of HF in men and women. METHODS AND RESULTS: This observational study comprised 9316 men and 27,645 women from the EPIC-NL cohort free from cardiovascular disease at baseline. Dietary intakes were assessed using a validated food frequency questionnaire. mMDS was calculated using a 9-point scale based on consumption of vegetables, legumes, fruit, nuts, seeds, grains, fish, fat ratio, dairy, meat and alcohol. HF events were ascertained by linkage to nation-wide registries. Multivariable Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards regression models. Over a median follow-up of 15 years (IQR 14-16), 633 HF events occurred: 144 in men (1.5%) and 489 in women (1.8%). The median mMDS was 4 (IQR 3-5). There was significant effect modification by sex (P-value for interaction

Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5 ), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5 , nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5 , nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m 3 an increase of 5 µg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.

How long does the average person sleep? Here, Kocevska et al. conducted a meta-analysis including over 1.1 million people to produce age- and sex-specific population reference charts for sleep duration and efficiency.We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including >= 100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1-100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40-69 years, 55.5% female) from the United Kingdom and 409,617 people (>= 18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the 'acceptable' sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8-10 h and 18% report daytime sleepiness. In adults (>= 18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6-19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending >= 9 h in bed, whereas poor sleep quality was more frequent in those spending = 41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices.

Background Little is known about the relationship between shift work and perceived health, including potential underlying mechanisms such as unhealthy behaviors. The aim of this study was to investigate whether unhealthy behaviors mediate the relationship between shift work and perceived mental and physical health, taking into account potential differences by level of education. Methods Data from 1633 workers participating in the Doetinchem Cohort Study during 1995–2016 were used. Being engaged in shift work was determined at 1 year preceding the assessment of health behaviors. Mental and physical health were assessed after 5 years of follow-up by the 5-item Mental Health Inventory and the physical functioning scale of the 36-item Short Form Health Survey. Smoking, physical inactivity, alcohol consumption, and overweight were considered as potential mediators and education was treated as moderator. Moderated mediation analyses using generalized estimated equations were performed. Results Shift work was not statistically significantly related to either mental or physical health. Despite this, statistically significant mediation effects of smoking (Beta − 0.09; 95% Confidence Interval − 0.20 - -0.01, respectively B -0.09; 95%CI -0.21 - -0.01) and physical inactivity (B 0.11; 95%CI 0.03–0.23, respectively B 0.08; 95%CI 0.01–0.18) were found in the relationship between shift work and mental or physical health. Direct and indirect effects outweighed each other in the relationship between shift work and mental health, since the direction of these effects was opposite. The relationship between shift work, unhealthy behavior, and health was not different by educational level. Conclusion Shift workers did not report lower mental or physical health than non-shift workers. Though mediation effects of unhealthy behavior were observed in the relationship between shift work and perceived health, these small effects had minor public health relevance.

OBJECTIVES: Older women report lower mental health compared to men, yet little is known about the nature of this sex difference. Therefore, this study investigates time trends and possible risk groups.METHOD: Data from the Doetinchem Cohort Study (DCS) and the Longitudinal Aging Study Amsterdam (LASA) were used. General mental health was assessed every 5 years, from 1995 to 1998 onwards (DCS, n = 1412, 20-year follow-up, baseline age 55-64 years). Depressive and anxiety symptoms were assessed for two birth cohorts, from 1992/1993 onwards (LASA cohort 1, n = 967, 24-year follow-up, age 55-65 years,) and 2002/2003 onwards (LASA cohort 2, n = 1002, 12-year follow-up, age 55-65 years) with follow-up measurements every 3-4 years.RESULTS: Mixed model analyses showed that older women had a worse general mental health (-6.95; -8.36 to 5.53; range 0-100, ∼10% lower), more depressive symptoms (2.09; 1.53-2.63; range 0-60, ∼30% more) and more anxiety symptoms (0.86; 0.54-1.18; range 0-11, ∼30% more) compared to men. These sex differences remained stable until the age of 75 years, where after they decreased due to an accelerated decline in mental health for men compared to women. Sex differences and their course by age were consistent over successive birth cohorts, educational levels and ethnic groups (Caucasian vs. Turkish/Moroccan).CONCLUSION: There is a consistent female disadvantage in mental health across different sociodemographic groups and over decennia (1992 vs. 2002) with no specific risk groups.

The Healthy Aging Index (HAI), an index of physiological aging, has been demonstrated to predicts mortality, morbidity and disability. We studied the longitudinal development of the HAI to identify aging trajectories and evaluated the role of baseline sociodemographic characteristics and lifestyle factors of the trajectories. Four measurements with intervals of 5 years were included from the Doetinchem Cohort Study. The HAI reflects levels of systolic blood pressure, non-fasting plasma glucose levels, global cognitive functioning, plasma creatinine levels and lung functioning. The HAI score ranges from 0 to 10: higher scores indicate a better health profile. Latent class mixture modelling was used to model within-person change and to identify aging trajectories. Area under the curve was calculated per trajectory to estimate total healthy years. In total, 2324 women and 2013 men were included. One HAI trajectory was identified for women, and two trajectories for men, labelled 'gradual' aging (76%) and 'early' aging (24%). Men who were medium/high educated, below 36 years at baseline, complied with guidelines on physical activity and were not obese in any round were associated with increased odds to 'gradual' aging of 1.46 (CI: 1.18-1.81), 1.93 (CI: 1.42-2.62), 1.26 (1.02-1.57) and 1.76 (1.32-2.35), respectively. Between 30 and 70 years of age, men in the 'early' aging trajectory had the least healthy years (29.6 years), followed by women (30.1 years), and 'gradual' aging men (34.7 years). This study emphasizes that 'physiological aging' is not only an issue of older ages. Between 30 and 70 years of age, 'early' aging men and women had approximately five healthy years less compared to 'gradual' aging men. Lifestyle factors (e.g. nutrition and physical activity) seem to play an important role in optimal aging.

Background Low socio-economic position is associated with consumption of lower quality diets, which may be partly explained by the cost of healthier diets. Therefore, we aimed to investigate the mediating role of dietary costs in the association between educational level and diet quality. Methods We used cross-sectional data from Dutch older adults (N = 9399) in the EPIC-NL cohort. Participants provided information about their own and their partners’ highest attained educational level (as proxy for socio-economic position). Dietary behavior was assessed using a food frequency questionnaire from which we derived two diet-quality scores, including the Dutch Healthy Diet index 2015 (DHD15-index) and the Dietary Approaches to Stop Hypertension (DASH) diet. Dietary cost estimates were based on food price data from food stores, and linked to reported consumption of food items. Multiple regression analyses and bootstrapping were used examine the mediating role of dietary cost in the association between educational level and diet quality. Results Mean age of participants was 70 (SD: 10) years and 77% were women. Dietary costs significantly mediated the association between educational level and diet quality, except for high versus middle individual educational level and the DHD15-index. Depending on the dietary and educational indicator, dietary costs explained between 2 and 7% of the association between educational level and diet quality. Furthermore, associations were found to be modified by sex and age. For the DHD15-index, mediation effects were only present in females and adults older than 65 years, and for the DASH diet mediation effects were only present in females and strongest amongst adults older than 65 years compared to adults younger than 65 years. Conclusion Dietary costs seems to play a modest role in explaining educational differences in diet quality in an older Dutch population. Further research is needed to investigate which other factors may explain SEP differences in diet quality.

Background With advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant’s frailty score based on enumeration of immune cell subpopulations. Results In the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16- monocytes, and lower numbers of both CD56+ T cells and late differentiated CD4+ TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty. Conclusions In-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.

Objectives To examine if age-specific anti-Mullerian hormone (AMH) levels are associated with cancer risk; and to investigate if age-related AMH trajectories differ between women who develop cancer and women who do not. More specifically, we examined associations with breast cancer, cancers in other tissues expressing AMH receptor AMHR2, and cancers in non-AMHR2-expressing tissues. Study design We included longitudinal data from 3025 women in the prospective Doetinchem Cohort Study. Cox proportional hazards models were used to assess the association of baseline age-specific AMH tertiles with cancer. We applied linear mixed models to compare age-related AMH trajectories between women who were diagnosed with cancer and women who were not. Main outcome measures Cancer (n = 385; 139 breast cancers, 112 cancers in other AMHR2-expressing tissues, 134 cancers in non-AMHR2-expressing tissues). Results Overall, baseline age-specific AMH levels were not associated with cancer risk, although in women ≤ 40 years an increased risk was suggested for breast cancer (HRT2:T1 = 2.06, 95%CI = 0.95-4.48; HRT3:T1 = 2.03, 95%CI = 0.91–4.50). Analysis of age-related AMH trajectories suggested that AMH levels were higher at younger ages and declined faster in women who were diagnosed with cancer compared with women who were not, but our results did not provide evidence for actual differences in trajectories. Conclusions Our results did not provide evidence for an association between age-specific AMH levels and age-related trajectories and risk of cancer. However, effect estimates for breast cancer were in line with risk-increasing effects found in previous studies.

Introduction: Given its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is correlated with timing of menopause. Accordingly, women with higher AMH levels become menopausal at a higher age. Previous research suggests that a higher age at menopause is associated with a decreased risk of type 2 diabetes (T2D). In contrast, AMH levels are increased in women with polycystic ovary syndrome (PCOS), who have a higher risk of insulin resistance and T2D than women without PCOS. However, it is not clear yet whether AMH actually plays a role in the development of T2D. We aimed to investigate whether plasma AMH levels and age-related AMH trajectories are associated with risk of T2D in women. Hypothesis: Higher age-specific plasma AMH levels are associated with a decreased risk of T2D. Methods: We analyzed longitudinal data from 3104 female participants, aged 20-60 years at recruitment, in the population-based Doetinchem Cohort Study. In total, we analyzed 12460 plasma AMH measurements. We calculated age-specific AMH tertiles, to account for the strong AMH-age correlation. Cox Proportional hazards models adjusted for known risk factors for diabetes were used to assess the relation between age-specific AMH tertiles and T2D. We applied linear mixed models to compare age-related AMH trajectories between T2D cases and non-cases. Results: After a median follow-up of 20 years, 163 incident T2D cases were identified. Higher age-specific AMH levels were associated with a lower risk of T2D (hazard ratio (HR) T2vsT1 = 0.77, 95%CI: 0.53-1.11; HR T3vsT1 =0.62, 95%CI: 0.40-0.94; p for trend = 0.02). These findings were supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages and declined at a slower rate in women who were diagnosed with T2D compared to women who were not. However, differences in trajectories between T2D cases and non-cases were not statistically significant. Conclusions: We observed that women with higher age-specific AMH levels were at a lower risk of T2D. In addition, our longitudinal analyses may suggest that AMH is lower in women who develop T2D compared to women who do not. These findings are in line with previous studies that observed that a higher age at menopause was associated with a decreased risk of T2D.

Aim To investigate the associations between major foods and dietary fibre with subtypes of stroke in a large prospective cohort. Methods and results We analysed data on 418 329 men and women from nine European countries, with an average of 12.7 years of follow-up. Diet was assessed using validated country-specific questionnaires which asked about habitual intake over the past year, calibrated using 24-h recalls. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HRs) for ischaemic and haemorrhagic stroke associated with consumption of red and processed meat, poultry, fish, dairy foods, eggs, cereals, fruit and vegetables, legumes, nuts and seeds, and dietary fibre. For ischaemic stroke (4281 cases), lower risks were observed with higher consumption of fruit and vegetables combined (HR; 95% CI per 200 g/day higher intake, 0.87; 0.82–0.93, P-trend Conclusion Risk of ischaemic stroke was inversely associated with consumption of fruit and vegetables, dietary fibre, and dairy foods, while risk of haemorrhagic stroke was positively associated with egg consumption. The apparent differences in the associations highlight the importance of examining ischaemic and haemorrhagic stroke subtypes separately.

Purpose: A healthy diet may contribute to the primary prevention of heart failure (HF), but evidence is still inconclusive. We aimed to study the association between adherence to the Dutch dietary guidelines and incidence of HF. Methods: We studied 37,468 participants aged 20–70 years and free of HF at baseline from the EPIC-NL cohort. At baseline (1993–1997), data were collected on demographics, lifestyle, and presence of chronic diseases. Dietary intake was assessed using a 178-item validated food frequency questionnaire. Dietary intake data were used to calculate scores on the Dutch Healthy Diet 2015 Index (DHD15-index) measuring adherence to the Dutch dietary guidelines. The DHD15-index is based on the average daily intake of 14 food groups resulting in a total score ranging between 0 and 140, with higher scores indicating better adherence. HF morbidity and mortality during follow-up were ascertained through linkage with national registries. Cox proportional hazards analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between DHD15 adherence and HF risk, adjusting for sociodemographic and lifestyle characteristics. Results: The average score on the DHD15-index was 71 (SD = 15). During a median follow-up of 15.2 years (IQR 14.1–16.5), 674 HF events occurred. After adjustment for demographic and lifestyle characteristics, higher scores on the DHD15-index were associated with lower risk of HF (HRQ4vsQ1 0.73; 95% CI 0.58–0.93; Ptrend 0.001). Conclusion: In a large Dutch population of middle-aged adults, higher adherence to the Dutch dietary guidelines was associated with lower risk of HF.

Aims Early age at menarche has been reported to be associated with increased risks of developing type 2 diabetes (T2D) and coronary heart disease (CHD) in adulthood, but a late menarche has also been found to be associated with an increased risk of CHD. Both T2D and CHD are important risk factors for developing heart failure (HF). We examined the relationship between age at menarche (AAM) and HF incidence in women from the European Prospective Investigation into Cancer and Nutrition – Netherlands (EPIC-NL) cohort study. Methods and results The EPIC-NL cohort comprised 28,504 women aged 20–70 years at baseline (1993–1997). Mean age at menarche was 13.3 (standard deviation 1.6) years. During a median follow-up of 15.2 years HF occurred in 631 women. Cox proportional hazard regression models, stratified by cohort and adjusted for potential confounders, were used to investigate the associations between AAM and HF incidence. After confounder adjustment, each year of older age at menarche was associated with a 5% lower risk of HF (hazard ratio 0.95 (95% CI, 0.91–1.00), p-value 0.048). Further adjusting for body mass index (BMI), prevalent CHD, hypertension, or prevalent T2D as potential mediators between early menarche and risk of HF attenuated the associations between AAM and risk of HF to non-significance. Conclusion Older AAM reduced the risk of HF in this study. BMI, prevalent CHD, hypertension and prevalent T2D seemed to mediate this association. Future research with a longer follow-up should establish whether there is an independent effect of AAM on HF risk. Also, further phenotyping of HF cases is necessary to enable whether the associations differ for the various subtypes of HF.

Aims The benefit an individual can expect from preventive therapy varies based on risk-factor burden, competing risks, and treatment duration. We developed and validated the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model for the estimation of individual-level 10 years and lifetime treatment-effects of cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people. Methods and results Model development was conducted in the Multi-Ethnic Study of Atherosclerosis (n = 6715) using clinical predictors. The model consists of two complementary Fine and Gray competing-risk adjusted left-truncated subdistribution hazard functions: one for hard cardiovascular disease (CVD)-events, and one for non-CVD mortality. Therapy-effects were estimated by combining the functions with hazard ratios from preventive therapy trials. External validation was performed in the Atherosclerosis Risk in Communities (n = 9250), Heinz Nixdorf Recall (n = 4177), and the European Prospective Investigation into Cancer and Nutrition-Netherlands (n = 25 833), and Norfolk (n = 23 548) studies. Calibration of the LIFE-CVD model was good and c-statistics were 0.67–0.76. The output enables the comparison of short-term vs. long-term therapy-benefit. In two people aged 45 and 70 with otherwise identical risk-factors, the older patient has a greater 10-year absolute risk reduction (11.3% vs. 1.0%) but a smaller gain in life-years free of CVD (3.4 vs. 4.5 years) from the same therapy. The model was developed into an interactive online calculator available via www.U-Prevent.com. Conclusion The model can accurately estimate individual-level prognosis and treatment-effects in terms of improved 10-year risk, lifetime risk, and life-expectancy free of CVD. The model is easily accessible and can be used to facilitate personalized-medicine and doctor–patient communication.

Dietary guidelines for pure fruit juice consumption differ between countries, regarding the question whether pure fruit juice is an acceptable alternative for fruit. Currently, little is known about pure fruit juice consumption and the risk of CVD. In this prospective cohort study, we studied the association of pure fruit juice and fruit consumption with the incidence of fatal and non-fatal CVD, CHD and stroke and investigated the differences in association with pure fruit juice consumption between low and high fruit consumers. A validated FFQ was used to estimate dietary intake of 34 560 participants (26·0 % men and 74·0 % women) aged 20–69 years from the European Prospective Investigation into Cancer and Nutrition–Netherlands study. Adjusted hazard ratios (HR) were estimated using Cox regression after average follow-up of 14·6 years. Compared with no consumption, pure fruit juice consumption up to 7 glasses/week – but not consumption of ≥8 glasses – was significantly associated with reduced risk of CVD and CHD, with HR from 0·83 (95 % CI 0·73, 0·95) to 0·88 (95 % CI 0·80, 0·97). Consumption of 1–4 and 4–8 glasses/week was significantly associated with lower risk of stroke with HR of 0·80 (95 % CI 0·64, 0·99) and 0·76 (95 % CI 0·61, 0·94), respectively. Associations did not differ considerably between low and high fruit consumers. The highest three quintiles of fruit consumption (≥121 g/d) were significantly associated with lower incidence of CVD, with HR of 0·87 (95 % CI 0·78, 0·97) and 0·88 (95 % CI 0·80, 0·98). In conclusion, although we observed favourable associations of moderate pure fruit juice consumption with CVD, for now consumption of whole fruit should be preferred because the evidence of the health benefits of fruit is more conclusive.

Context: Anti-Mü llerian hormone (AMH)-based age at menopause predictions remain cumbersome due to predictive inaccuracy. Objective: To perform an individual patient data meta-Analysis, regarding AMH-based menopause prediction. Design: A systematic literature search was performed using PubMed, Embase, and Cochrane databases. Prospective cohort studies regarding menopause prediction using serum AMH levels were selected by consensus discussion. Individual cases were included if experiencing a regular cycle at baseline. Exclusion criteria were hormone use and gynecological surgery. Results: This meta-Analysis included 2596women, and 1077 experiencedmenopause. A multivariable Cox regression analysis assessed time to menopause using age and AMH. AMH predicted time to menopause; however, added value on top of age was poor [age alone: C-statistic, 84%; age + AMH: hazard ratio (HR), 0.66; 95% CI, 0.61 to 0.71; C-statistic, 86%). Moreover, the capacity of AMH to predict early (#45 years) and late menopause (55 years) was assessed. An added effect of AMH was demonstrated for early menopause (age alone: C-statistic 52%; age + AMH: HR, 0.33; 95%, CI 0.24 to 0.45; C-statistic, 80%). A Weibull regression model calculating individual age at menopause revealed that predictive inaccuracy remained present and increased with decreasing age atmenopause. Lastly, a check of nonproportionality of the predictive effect ofAMHdemonstrated a reduced predictive effect with increasing age. onclusion: AMH was a significant predictor of time to menopause and especially of time to early menopause. However, individual predictions of age at menopause demonstrated a limited precision, particularly when concerning early age atmenopause, making clinical application troublesome.

Background: A low vitamin D status has been put forward as a potential risk factor for the development of inflammatory bowel disease (IBD). This study investigated the association between prediagnostic circulating vitamin D concentrations and dietary intakes of vitamin D, and the risk of Crohn’s disease (CD) and ulcerative colitis (UC).Methods: Among 359,728 participants of the European Prospective Investigation into Cancer and Nutrition cohort, individuals who developed CD or UC after enrollment were identified. Each case was matched with2 controls by center, gender, age, date of recruitment, and follow-up time. At cohort entry, blood samples were collected and dietary vitamin D intakes were obtained from validated food frequency questionnaires. Serum 25-hydroxyvitamin D levels were measured using liquid chromatography-tandem mass spectrometry. Conditional logistic regression was performed to determine the odds of CD and UC.Results: Seventy-two participants developed CD and 169 participants developed UC after a median follow-up of 4.7 and 4.1 years, respectively. Compared with the lowest quartile, no associations with the 3 higher quartiles of vitamin D concentrations were observed for CD (p trend = 0.34) or UC (p trend = 0.66). Similarly, no associations were detected when serum vitamin D levels were analyzed as a continuous variable. Dietary vitamin D intakes were not associated with CD (p trend = 0.39) or UC (p trend = 0.83).Conclusions: Vitamin D status was not associated with the development of CD or UC. This does not suggest a major role for vitamin D deficiency in the etiology of IBD, although larger studies are needed to confirm these findings.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Emerging evidence suggests that diet and renal function are related. Little is known, however, about the association of consumption of whole grains, fruit and vegetables with urinary albumin:creatinine ratio (ACR) and changes in estimated glomerular filtration rate (eGFR). We investigated this in a population-based cohort aged 26–65 years. Data were from 3787 participants from the Doetinchem cohort study, who were examined ≥3 times, 5 years apart. Consumption of food groups was assessed at each round with a validated FFQ. GFR was estimated at each round from routinely measured cystatin C and creatinine using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation. ACR was measured at the last round. Generalised estimated equation models were performed to examine associations with changes in eGFR. Linear regression was used to examine associations with ACR. Adjustments were made for covariates related to lifestyle, biological factors and diet. Mean baseline eGFR was 104·5 (sd 13·7) and mean annual decline was −0·95 (sd 0·67) ml/min per 1·73 m2 over a 15-year follow-up. A trend was observed towards slightly less annual decline in eGFR among those with higher consumption of whole grains (P=0·06). This association, however, was attenuated and no longer significant in multivariate models (P=0·29). Consumption of fruit and vegetables was not associated with changes in eGFR and urinary ACR. In conclusion, consumption of whole grains, fruit and vegetables is not associated with changes in eGFR and mean ACR. As this was the first longitudinal study into this association in the general population, and as results are only partially in line with related studies, further research is recommended.

Background Accumulation of problems in physical, psychological, cognitive, or social functioning is characteristic for frail individuals. Using a four-domain approach of frailty, this study explored how sociodemographic and lifestyle factors, life events and health are associated with frailty. Methods The study sample included 4019 men and women (aged 40–81 years) examined during the fifth round (2008–2012) of the Doetinchem Cohort Study. Four domains of frailty were considered: physical (≥4 of 8 criteria: unintentional weight loss, exhaustion, strength, perceived health, walking, balance, hearing and vision impairments), psychological (2 criteria: depressive symptoms, mental health), cognitive (

Guidelines for a healthy diet aim to decrease the risk of chronic diseases. It is unclear as to what extent a healthy diet is also an environmentally friendly diet. In the Dutch sub-cohort of the European Prospective Investigation into Cancer and Nutrition, the diet was assessed with a 178-item FFQ of 40 011 participants aged 20–70 years between 1993 and 1997. The WHO’s Healthy Diet Indicator (HDI), the Dietary Approaches to Stop Hypertension (DASH) score and the Dutch Healthy Diet index 2015 (DHD15-index) were investigated in relation to greenhouse gas (GHG) emissions, land use and all-cause mortality risk. GHG emissions were associated with HDI scores (−3·7 % per sd increase (95 % CI −3·4, −4·0) for men and −1·9 % (95 % CI −0·4, −3·4) for women), with DASH scores in women only (1·1 % per sd increase, 95 % CI 0·9, 1·3) and with DHD15-index scores (−2·5 % per sd increase (95 % CI −2·2, −2·8) for men and −2·0 % (95 % CI −1·9, −2·2) for women). For all indices, higher scores were associated with less land use (ranging from −1·3 to −3·1 %). Mortality risk decreased with increasing scores for all indices. Per sd increase of the indices, hazard ratios for mortality ranged from 0·88 (95 % CI 0·82, 0·95) to 0·96 (95 % CI 0·92, 0·99). Our results showed that adhering to the WHO and Dutch dietary guidelines will lower the risk of all-cause mortality and moderately lower the environmental impact. The DASH diet was associated with lower mortality and land use, but because of high dairy product consumption in the Netherlands it was also associated with higher GHG emissions.

Context Anti-Müllerian hormone (AMH) levels are used worldwide as a screening tool for the duration of the female reproductive lifespan. Although AMH levels are associated with age at menopause, individual predictions of menopause with a single AMH measurement are unreliable. Objective This study investigated whether individual AMH decline patterns can improve the prediction of menopause compared with a single measurement. Design The study population comprised 2434 premenopausal women from the population-based Doetinchem Cohort Study. Participants were followed up every 5 years for a total of 20 years, and AMH was measured in 6699 plasma samples with the picoAMH assay. Longitudinal statistical modeling was combined with time varying Cox modeling, to integrate multiple AMH measurements per woman. Results The mean age at menopause was 50 years, and 7.4% of the women who reached menopause during follow-up did so before age 45 years. For a 25-year-old, the AMH decline rate between ages 20 and 25 years increased the C-statistic of menopause prediction from 0.64 to 0.69. Beyond that age, the AMH decline rate did not improve predictions of menopause or early menopause. For women younger than age 30 years, for whom menopause prediction is arguably most relevant, the models underestimated the risk of early menopause. Conclusion These results suggest that knowledge of the AMH decline rate does not improve the prediction of menopause. Based on the low discriminative ability and underestimation of the risk of early menopause, the use of AMH as a screening method for the timing of menopause cannot currently be advocated.

Background High carbohydrate intake raises blood triglycerides, glucose, and insulin; reduces HDLs; and may increase risk of coronary heart disease (CHD). Epidemiological studies indicate that high dietary glycemic index (GI) and glycemic load (GL) are associated with increased CHD risk. Objectives The aim of this study was to determine whether dietary GI, GL, and available carbohydrates are associated with CHD risk in both sexes. Methods This large prospective study—the European Prospective Investigation into Cancer and Nutrition—consisted of 338,325 participants who completed a dietary questionnaire. HRs with 95% CIs for a CHD event, in relation to intake of GI, GL, and carbohydrates, were estimated using covariate-adjusted Cox proportional hazard models. Results After 12.8 y (median), 6378 participants had experienced a CHD event. High GL was associated with greater CHD risk [HR 1.16 (95% CI: 1.02, 1.31) highest vs. lowest quintile, p-trend 0.035; HR 1.18 (95% CI: 1.07, 1.29) per 50 g/day of GL intake]. The association between GL and CHD risk was evident in subjects with BMI (in kg/m2) ≥25 [HR: 1.22 (95% CI: 1.11, 1.35) per 50 g/d] but not in those with BMI Conclusions This large pan-European study provides robust additional support for the hypothesis that a diet that induces a high glucose response is associated with greater CHD risk.

Purpose The relationship of total, saturated, mono-unsaturated and poly-unsaturated fatty acids (SFA, MUFA, PUFA) with coronary heart disease (CHD) is debated. We hypothesized that the association of dairy-derived FA with CHD may be different than the association of meat-derived FA with CHD. We therefore aimed to directly compare association of FA intakes from dairy and meat with risk of CHD using substitution models. Methods Baseline (1993–1997) FA intake was measured using a validated food frequency questionnaire among 35,767 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort (EPIC-NL). Incident CHD events (n = 2374) were obtained through linkage with national registries during a mean follow-up of 15 years. Association of FA from dairy substituted with FA from meat with CHD risk was estimated through multivariable Cox regression. Results Participants consumed 81.9 (SD 28.7) grams of FA per day, of which 17.9 (SD 5.2) was from dairy and 15.3 (SD 9.5) from meat. Substituting 1 en% of dairy-derived SFA with meat-derived SFA was associated with higher CHD risk (HR 1.06, 95% CI 1.02–1.10), but substituting dairy-derived MUFA or PUFA did not (HRMUFA 1.03, 95% CI 0.97–1.09; HRPUFA 1.17, 95% CI 0.90–1.53). Conclusions Our modelling suggests that substituting dairy SFA with meat SFA is associated with a higher risk of CHD, but substituting dairy MUFA or PUFA with meat FA is not. These results need to be replicated in other cohorts with different fat intakes, preferably with larger variation in the intake of MUFA and PUFA from dairy and meat. Electronic supplementary material The online version of this article (10.1007/s00394-018-1811-1) contains supplementary material, which is available to authorized users.

Background: With aging, the human immune system undergoes several changes. The clinical relevance of these changes, however, is relatively unknown. We investigated immunological aspects of human aging in relation to frailty in the Doetinchem Cohort Study (DCS).Methods: We calculated a frailty index score based on 36 health parameters for each individual in the DCS with data obtained in the period 2008-2016. The frailty index was used to define three health groups ('healthy', 'intermediate', and 'frail'), stratified by age and sex. In a subcohort (n = 289, 60-85 years, selected by balanced random sampling per frailty group), we collected blood samples between October 2016 and March 2017 to determine absolute numbers of leukocyte subsets. In addition, cytomegalovirus serostatus was assessed. C-reactive protein (CRP) levels were longitudinally assessed in four consecutive plasma samples per individual. These samples had been previously collected (1993-2013) as part of the DCS at regular time intervals and spanning a period of > 15 years.Results: We observed higher numbers of myeloid derived neutrophils and monocytes in the frail group compared to the healthy group in both men and women, and, retrospectively, consistently higher CRP concentrations over a period of > 15 years. An increase in CRP concentration with age was found in women, but not in men. Frailty was not associated with cytomegalovirus serostatus or with changes in lymphoid derived T-, B-, or NK-cell numbers.Conclusion: Frail elderly, compared to their age- and sex-matched peers, endure a chronic and stable low-grade inflammation, which is associated with a myeloid cell lineage expansion. These findings could help to monitor clinically significant immunological decline in the elderly.

Background: Pain at any age is related to pain experienced at younger ages, but not much is known on how pain develops over the adult life course. We studied long-term individual trajectories of pain over 15 years of the life course and evaluated the role of baseline sociodemographic factors, lifestyle factors and health characteristics. Methods: Longitudinal data from the Doetinchem Cohort Study was used with 3,485 adults aged 25–71 years at baseline who were measured every 5 years, until the age of 40–86 years. Four measurements of self-reported pain were used to distinguish 15-year trajectories of pain, that were summarized in five pre-definedpatterns. Results: The typical pain trajectory patterns were (prevalence): never pain (32.2%), persistent pain (19.5%), development of pain (19.2%), diminishing pain (11.1%) and fluctuating pain (18.0%). Multinomial logistic regression analyses showed that the trajectory characterized by never pain was more often found among: men, non-smokers, those reporting a normal sleep duration and those without obesity, chronic disease, a poor mental health, a poor perceived health, or musculoskeletal complaints. Conclusions: A substantial part of the population reports pain over a long period of their life course and long-term trajectories of pain may reflect phenotypes that may be relevant to take into account in pain management. Several risk factors, such as short-sleep duration, smoking, obesity and poor perceived or mental health may be relevant in recognizing those with pain, and tackling these may contribute to the prevention of pain over the life course. Significance: Asking adults about pain every 5 years over a 15-year period shows that almost one-third never reported pain and one-fifth persistent pain. “Persistent” and “developing” pain is associated with smoking, obesity and short sleep duration. Long-term pain trajectories may reflect relevant pain phenotypes.

Importance: Soft drinks are frequently consumed, but whether this consumption is associated with mortality risk is unknown and has been understudied in European populations to date. Objective: To examine the association between total, sugar-sweetened, and artificially sweetened soft drink consumption and subsequent total and cause-specific mortality. Design, Setting, and Participants: This population-based cohort study involved participants (n = 451 743 of the full cohort) in the European Prospective Investigation into Cancer and Nutrition (EPIC), an ongoing, large multinational cohort of people from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom), with participants recruited between January 1, 1992, and December 31, 2000. Excluded participants were those who reported cancer, heart disease, stroke, or diabetes at baseline; those with implausible dietary intake data; and those with missing soft drink consumption or follow-up information. Data analyses were performed from February 1, 2018, to October 1, 2018. Exposure: Consumption of total, sugar-sweetened, and artificially sweetened soft drinks. Main Outcomes and Measures Total mortality and cause-specific mortality. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazards regression models adjusted for other mortality risk factors. Results: In total, 521 330 individuals were enrolled. Of this total, 451 743 (86.7%) were included in the study, with a mean (SD) age of 50.8 (9.8) years and with 321 081 women (71.1%). During a mean (range) follow-up of 16.4 (11.1 in Greece to 19.2 in France) years, 41 693 deaths occurred. Higher all-cause mortality was found among participants who consumed 2 or more glasses per day (vs consumers of

Background: Long-term changes in (bio)markers for cognitive frailty are not well characterized. Therefore, our aim is to explore (bio)marker trajectories in adults who became cognitively frail compared to age- and sex-matched controls who did not become cognitively frail over a 15 year follow-up. We hypothesize that those who become cognitively frail have more unfavorable trajectories of (bio)markers compared to controls. Methods: The Doetinchem Cohort Study is a longitudinal population-based study that started in 1987-1991 in men and women aged 20-59 years, with follow-up examinations every 5 years. For the current analyses, we used data of 17 potentially relevant (bio)markers (e.g., body mass index (BMI), urea) from rounds 2 to 5 (1993-2012). A global cognitive functioning score (based on memory, speed, and flexibility) was calculated for each round and transformed into education and examination round-adjusted z-scores. The z-score that corresponded to the 10th percentile in round 5 (z-score = -0.77) was applied as cut-off point for incident cognitive frailty in rounds 2-5. In total, 455 incident cognitively frail cases were identified retrospectively and were compared with 910 age- and sex-matched controls. Trajectories up to 15 years before and 10 years after incident cognitive frailty were analyzed using generalized estimating equations with stratification for sex and adjustment for age and, if appropriate, medication use. Results were further adjusted for level of education, depressive symptoms, BMI, and lifestyle factors. Results: In men, (bio)marker trajectories did not differ as they ran parallel and the difference in levels was not statistically significant between those who became cognitively frail compared to controls. In women, total cholesterol trajectories first increased and thereafter decreased in cognitively frail women and steadily increased in controls, gamma-glutamyltransferase trajectories were more or less stable in cognitively frail women and increased in controls, and urea trajectories increased in cognitively frail women and remained more or less stable in controls. Results were similar after additional adjustment for potential confounders. Conclusions: Out of the 17 (bio)markers included in this explorative study, differential trajectories for three biomarkers were observed in women. We do not yet consider any of the studied (bio)markers as promising biomarkers for cognitive frailty.

Aims: The hypothesis of ‘metabolically healthy obesity’ implies that, in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk. We tested this hypothesis in a large pan-European prospective study. Methods and results: We conducted a case-cohort analysis in the 520 000-person European Prospective Investigation into Cancer and Nutrition study (‘EPIC-CVD’). During a median follow-up of 12.2 years, we recorded 7637 incident coronary heart disease (CHD) cases. Using cut-offs recommended by guidelines, we defined obesity and overweight using body mass index (BMI), and metabolic dysfunction (‘unhealthy’) as >_ 3 of elevated blood pressure, hypertriglyceridaemia, low HDL-cholesterol, hyperglycaemia, and elevated waist circumference. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI) within each country using Prentice-weighted Cox proportional hazard regressions, accounting for age, sex, centre, education, smoking, diet, and physical activity. Compared with metabolically healthy normal weight people (reference), HRs were 2.15 (95% CI: 1.79; 2.57) for unhealthy normal weight, 2.33 (1.97; 2.76) for unhealthy overweight, and 2.54 (2.21; 2.92) for unhealthy obese people. Compared with the reference group, HRs were 1.26 (1.14; 1.40) and 1.28 (1.03; 1.58) for metabolically healthy overweight and obese people, respectively. These results were robust to various sensitivity analyses. Conclusion: Irrespective of BMI, metabolically unhealthy individuals had higher CHD risk than their healthy counterparts. Conversely, irrespective of metabolic health, overweight and obese people had higher CHD risk than lean people. These findings challenge the concept of ‘metabolically healthy obesity’, encouraging population-wide strategies to tackle obesity., European Union (EU) HEALTH-F2-2012-279233, European Research Council (ERC) 268834, Medical Research Council UK (MRC) G0800270 MR/L003120/1 MR/M012190/1, British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), Regional Government of Asturias, Hellenic Health Foundation, German Cancer Aid, German Cancer Research Centre, German Federal Ministry of Education and Research, Cancer Research UK 570/A16491, Regione Sicilia, Associazione Iblea per la Ricerca Epidemiologica (A.I.R.E.) - ONLUS Ragusa, Associazione Volontari Italiani Sangue AVIS Ragusa, Compagnia di San Paolo, Human Genetics Foundation-Torino (HuGeF), British Heart Foundation RG/13/13/30194 RG/08/014/24067, Cancer Research UK 16491, Medical Research Council UK (MRC) MR/L003120/1 G0800270 MC_UU_12015/1, National Institute for Health Research (NIHR) NF-SI-0512-10135 NF-SI-0512-10165, Novo Nordisk Foundation NNF17OC0026936

Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Background Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors. Methods We used data from EPIC-CVD, a case–cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders. Results After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01–1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10–1.42, p Conclusions Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.