Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration: A Coordinated Meta-Analysis of 8 Cohort Studies.

BACKGROUND: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aß) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. METHODS: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aß42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. RESULTS: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (ß 0.11; 95% CI: 0.05-0.17). CONCLUSIONS: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.

In-depth immune cellular profiling reveals sex-specific associations with frailty.

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.

Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (ß ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (ß = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (ß = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (ß = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (ß = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

The relationship between fermented food intake and mortality risk in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort.

The objective of the present study was to investigate the relationship between total and subtypes of bacterial fermented food intake (dairy products, cheese, vegetables and meat) and mortality due to all causes, total cancer and CVD. From the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort, 34 409 Dutch men and women, aged 20-70 years who were free from CVD or cancer at baseline, were included. Baseline intakes of total and subtypes of fermented foods were measured with a validated FFQ. Data on the incidence and causes of death were obtained from the national mortality register. Cox proportional hazards models were used to analyse mortality in relation to the quartiles of fermented food intake. After a mean follow-up of 15 (sd 2·5) years, 2436 deaths occurred (1216 from cancer and 727 from CVD). After adjustment for age, sex, total energy intake, physical activity, education level, hypertension, smoking habit, BMI, and intakes of fruit, vegetables and alcohol, total fermented food intake was not found to be associated with mortality due to all causes (hazard ratio upper v. lowest quartile (HR(Q4 v. Q1)) 1·00, 95% CI 0·88, 1·13), cancer (HR(Q4 v. Q1) 1·02, 95% CI 0·86, 1·21) or CVD (HR(Q4 v. Q1) 1·04, 95 % CI 0·83, 1·30). Bacterial fermented foods mainly consisted of fermented dairy foods (78 %) and cheese (16%). None of the subtypes of fermented foods was consistently related to mortality, except for cheese which was moderately inversely associated with CVD mortality, and particularly stroke mortality (HR(Q4 v. Q1) 0·59, 95% CI 0·38, 0·92, P trend= 0·046). In conclusion, the present study provides no strong evidence that intake of fermented foods, particularly fermented dairy foods, is associated with mortality.

Quantifying the contributions of behavioral and biological risk factors to socioeconomic disparities in coronary heart disease incidence: the MORGEN study.

Quantifying the impact of different modifiable behavioral and biological risk factors on socioeconomic disparities in coronary heart disease (CHD) may help inform targeted, population-specific strategies to reduce the unequal distribution of the disease. Previous studies have used analytic approaches that limit our ability to disentangle the relative contributions of these risk factors to CHD disparities. The goal of this study was to assess mediation of the effect of low education on incident CHD by multiple risk factors simultaneously. Analyses are based on 15,067 participants of the Dutch Monitoring Project on Risk Factors for Chronic Diseases aged 20-65 years examined 1994-1997 and followed for events until January 1, 2008. Path analysis was used to quantify and test mediation of the low education-CHD association by behavioral (current cigarette smoking, heavy alcohol use, poor diet, and physical inactivity) and biological (obesity, hypertension, diabetes, and hypercholesterolemia) risk factors. Behavioral and biological risk factors accounted for 56.6 % (95 % CI 42.6-70.8 %) of the low education-incident CHD association. Smoking was the strongest mediator, accounting for 27.3 % (95 % CI 17.7-37.4 %) of the association, followed by obesity (10.2 %; 95 % CI 4.5-16.1 %), physical inactivity (6.3 %; 95 % CI 2.7-10.0 %), and hypertension (5.3 %; 95 % CI: 2.8-8.0 %). In summary, in a Dutch cohort, the majority of the relationship between low education and incident CHD was mediated by traditional behavioral and biological risk factors. Addressing barriers to smoking cessation, blood pressure and weight management, and physical activity may be the most effective approaches to eliminating socioeconomic inequalities in CHD.

Differences in the Mediating Role of HL in Socioeconomic Inequalities in Health Across Age Groups: Results from the Dutch Doetinchem Cohort Study.

BACKGROUND: Although it is known that health literacy (HL) plays an explanatory role in educational inequalities in health, it is unknown whether this role varies across age groups. OBJECTIVE: The purpose of this study was to investigate whether the mediating role of HL in educational inequalities in four health outcomes varies across age groups: age 46 to 58 years, age 59 to 71 years, and age 72 to 84 years. METHODS: We used data from the Dutch Doetinchem Cohort Study, which included 3,448 participants. We included years of education as predictor, chronic illness prevalence and incidence, mental and self-perceived health as outcomes, and HL, based on self-report, as mediator. We used multiple-group mediation models to compare indirect effects across age groups. KEY RESULTS: In the complete sample without age stratification, HL partly mediated the effect of education on all health outcomes except for incidence of chronic diseases. These indirect effect estimates were larger for subjective (self-perceived health, proportion mediated [PM] = 37%, and mental health, PM = 37%) than for objective health outcomes (prevalence of chronic disease, PM = 17%). For the prevalence of chronic disease, the indirect effect estimate was significantly larger among individuals age 46 to 58 years compared to individuals age 59 to 71 years and for incidence of chronic disease also compared to individuals age 72 to 84 years. All other indirect effect estimates did not differ significantly between age groups. Using an alternative cut-off point for HL or adjusting for cognitive functioning did not meaningfully change the results. CONCLUSIONS: Overall, we found that the explanatory role of HL in educational inequalities in mental and subjective health was stable but that it varied across age groups for chronic diseases, where it was largest among individuals age 46 to 58 years. Future studies may investigate the benefits of starting to intervene on HL from a younger age but means to improve HL may also benefit the subjective health of older adults with lower education. [HLRP: HL Research and Practice. 2023;7(1):e26-e38.] Plain Language Summary: This study examined age-group differences in the mediating role of HL in the relationship between education and health. Overall, we found that the explanatory role of HL in educational inequalities in mental and subjective health was stable but that it varied across age groups for chronic diseases, where it was largest among individuals age 46 to 58 years compared to individuals age 59 to 71 years and individuals age 72 to 84 years.

Sources of dietary protein and risk of hypertension in a general Dutch population.

Evidence suggests a small beneficial effect of dietary protein on blood pressure (BP), especially for plant protein. We examined the relationship between several types of dietary protein (total, plant, animal, dairy, meat and grain) and the risk of hypertension in a general population of 3588 Dutch adults, aged 26-65 years, who were free of hypertension at baseline. Measurements were done at baseline and after 5 and 10 years of follow-up. Hazard ratios (HR), with 95 % CI, for incident hypertension were obtained in tertiles of energy-adjusted protein, using time-dependent Cox regression models. Models were adjusted for age, sex, BMI, education, smoking, baseline systolic BP, dietary confounders and protein from other sources (if applicable). Mean BP was 118/76 mmHg at baseline. Protein intake was 85 (sd 22) g/d (approximately 15 % of energy) with 62 % originating from animal sources. The main sources of protein were dairy products (28 %), meat (24 %) and grain (19 %). During the follow-up, 1568 new cases of hypertension were identified (44 % of the participants). Energy-adjusted intake of total protein, plant protein and animal protein was not significantly associated with hypertension risk (all HR approximately 1·00, P>0·60). Protein from grain showed a significant inverse association with incident hypertension, with a HR of 0·85 (95 % CI 0·73, 1·00, P trend = 0·04) for the upper tertile ( ≥ 18 g/d) v. the lower tertile ( < 14 g/d), whereas dairy protein and meat protein were not associated with incident hypertension. In conclusion, higher intake of grain protein may contribute to the prevention of hypertension, which warrants confirmation in other population-based studies and randomised controlled trials.

The association of pure fruit juice, sugar-sweetened beverages and fruit consumption with asthma prevalence in adolescents growing up from 11 to 20 years: The PIAMA birth cohort study.

Pure fruit juice is comparable to sugar-sweetened beverages (SSBs) with respect to its sugar and fructose content. However, it also contains favorable components like polyphenols. From this perspective, pure fruit juice is more comparable with whole fruit. SSBs have been associated with higher asthma risk, while whole fruit consumption has been associated with lower prevalence of asthma (symptoms). Associations with pure fruit juice have been rarely studied. Therefore, we studied the associations of consumption of pure fruit juice, SSBs and whole fruit with asthma prevalence in 3046 children of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort growing up from 11 to 20 years. Consumption of pure fruit juice, SSBs and fruit was self-reported at the ages of 11, 14, 17 and 20 years. Presence of asthma was defined based on parental reports of asthma diagnosis ever, and wheezing and asthma medication in the last 12 months. Odds ratios (OR) were estimated using generalized linear mixed models accounting for correlation between repeated measurements within subjects. No associations were found between pure fruit juice, SSBs and fruit consumption and the overall prevalence of asthma from 11 to 20 years. An earlier reported association of low pure fruit juice consumption with higher asthma prevalence at the age of 11 years in the PIAMA population was confirmed, but no associations were found at the ages of 14, 17 and 20 years.

Long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in a large pooled European cohort: ELAPSE study.

Ambient air pollution is an established risk factor for premature mortality from chronic cardiovascular, respiratory and metabolic diseases, while evidence on neurodegenerative diseases and psychiatric disorders remains limited. We examined the association between long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in seven European cohorts. Within the multicenter project 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE), we pooled data from seven European cohorts from six countries. Based on the residential addresses, annual mean levels of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), ozone (O3), and 8 PM2.5 components were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and mortality from dementia, psychiatric disorders, and suicide. Of 271,720 participants, 900 died from dementia, 241 from psychiatric disorders, and 164 from suicide, during a mean follow-up of 19.7 years. In fully adjusted models, we observed positive associations of NO2 (hazard ratio [HR] = 1.38; 95 % confidence interval [CI]: 1.13, 1.70 per 10 µg/m3), PM2.5 (HR = 1.29; 95 % CI: 0.98, 1.71 per 5 µg/m3), and BC (HR = 1.37; 95 % CI: 1.11, 1.69 per 0.5 × 10-5/m) with psychiatric disorders mortality, as well as with suicide (NO2: HR = 1.13 [95 % CI: 0.92, 1.38]; PM2.5: HR = 1.19 [95 % CI: 0.76, 1.87]; BC: HR = 1.08 [95 % CI: 0.87, 1.35]), and no association with dementia mortality. We did not detect any positive associations of O3 and 8 PM2.5 components with any of the three mortality outcomes. Long-term exposure to NO2, PM2.5, and BC may lead to premature mortality from psychiatric disorders and suicide.

Preventing heart failure: a position paper of the Heart Failure Association in collaboration with the European Association of Preventive Cardiology.

The heart failure epidemic is growing and its prevention, in order to reduce associated hospital readmission rates and its clinical and economic burden, is a key issue in modern cardiovascular medicine. The present position paper aims to provide practical evidence-based information to support the implementation of effective preventive measures. After reviewing the most common risk factors, an overview of the population attributable risks in different continents is presented, to identify potentially effective opportunities for prevention and to inform preventive strategies. Finally, potential interventions that have been proposed and have been shown to be effective in preventing heart failure are listed.

Pain over the adult life course: 15-year pain trajectories-The Doetinchem Cohort Study.

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.

DNA methylation and exposure to ambient air pollution in two prospective cohorts.

Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes. This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available. Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation. Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses.

Effectiveness of customary use of phytosterol/-stanol enriched margarines on blood cholesterol lowering.

Postlaunch monitoring of functional foods can encompass monitoring of effectiveness under conditions of customary use. To this end, the effectiveness of phytosterol/-stanol enriched margarine consumption in free-living conditions was investigated with data from the Dutch "Doetinchem cohort study". In total, 4,505 subjects (aged 26-70 years) were examined in 1994-1998 and re-examined during 1999-2003. A general and a food frequency questionnaire and non-fasting blood samples for total and HDL cholesterol determination were obtained. Subjects were stratified into phytosterol/-stanol enriched margarine users (n = 84) and non-users (n = 4,421) based on the re-examination data, as these margarines were available on the Dutch market from 1999 onwards. Mean spontaneous daily use (g +/- SD) of phytosterol-containing margarine (n = 71) was 15 +/- 8 and of phytostanol-containing margarine (n = 13) 9+/-6. After five years, total blood cholesterol had increased with 0.26 mmol/l in non-users while it had not significantly changed in users. The difference in total blood cholesterol change in users versus non-users was -0.30 mmol/l (p < 0.001). The beneficial effect of the phytosterol/-stanol enriched margarine, used under customary conditions can be characterized as a stabilization of cholesterol levels. This is the first report finding a modest beneficial effect on blood cholesterol level under customary conditions thereby partly confirming findings from clinical trials.

Obesity and Age-Related Changes in Markers of Oxidative Stress and Inflammation Across Four Generations.

OBJECTIVE: The prevalence of obesity increases with age and is higher in each younger generation (unfavorable generation shift). This may influence patterns of oxidative stress and inflammation. Age-related changes and generation shifts in markers of oxidative stress and inflammation were investigated, specifically addressing the role of body mass index (BMI). METHODS: Four generations (aged 26-35, 36-45, 46-55, and 56-65 at baseline) (N = 5,155) were examined every 5 years for 15 years between 1993 and 2012. Random coefficient analyses were used to study age-related changes and generation shifts in BMI, γ-glutamyltransferase (GGT), uric acid (UA), and C-reactive protein (CRP). RESULTS: Levels of BMI, UA, and CRP increased in all generations up to age 75, whereas GGT increased up to age 55. No consistent generation shifts were observed for GGT, UA, and CRP (P ≥ 0.05). Participants with a stable BMI (change ≤1 kg/m(2) /15 years) had either no or small increases with age in GGT, UA, and CRP, whereas participants with increasing BMI (increase >1 kg/m(2) /15 years) had much larger increases (P < 0.01). CONCLUSIONS: The unfavorable age-related changes in obesity-related biochemical markers, particularly among individuals with increasing BMI, show the importance of maintaining a healthy weight to improve population levels of oxidative stress and inflammation.

Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors.

Coronary artery disease is among the leading causes of death worldwide. Clinical trials show a protective effect of statins against the sequelae of coronary artery disease. The mean risk reductions for subjects using statins compared with placebo found in these trials is about 30%. These are average reductions for all patients included in the trials. Important factors in interpreting the variability in the outcome of drug therapy include the patient's health profile, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. This review aims to give an overview of the known polymorphisms (Cholesteryl Ester Transfer Protein polymorphism, Stromelysin-1 polymorphism, -455G/A and TaqI polymorphisms of the beta-fibrinogen gene, apoE4, Asp(9)Asn mutation in the lipoprotein lipase gene, the -514 CT polymorphism in the hepatic lipase gene and the ACE deletion type gene) that have an influence on the effects of statins in the general population. The expectation is that in the future a subject's genotype may determine whether he will be treated with statins or not. Determining the genotype will not deny therapy to a subject, but will help in deciding the therapy that will suit the patient best.

Total cholesterol concentration and mortality at a relatively young age: do men and women differ?

OBJECTIVE: To investigate the relation between total cholesterol concentration and mortality from coronary heart disease, cardiovascular diseases, non-cardiovascular causes, and all causes. DESIGN: Population based cohort study. SUBJECTS: 23,000 men and 26,000 women aged 30-54 years examined between 1974 and 1980. MAIN OUTCOME MEASURES: Mortality for the above mentioned end points for fifths of cholesterol distribution, and relative risks estimated by using Cox's proportional hazard (survival) analysis. Adjustment was made for age, smoking, systolic blood pressure, and body mass index. RESULTS: Mortality from coronary heart disease in men was five times higher than that in women. A strong positive association between total cholesterol concentration and mortality from coronary heart disease and cardiovascular diseases was observed in both men and women. The relative risk for the highest compared with the lowest fifth of the cholesterol distribution was for mortality from coronary heart disease (3.0 (95% confidence interval 1.8 to 5.1) in men and 3.8 (1.1 to 13.1) in women) and for mortality from cardiovascular disease (2.8 (1.8 to 4.2) in men and 2.9 (1.4 to 6.0) in women). No increase of non-cardiovascular mortality at low cholesterol concentration was observed. All cause mortality was significantly higher in the highest compared with the lowest fifth of the cholesterol distribution: relative risk 1.6 (1.3 to 2.0) in men and 1.5 (1.1 to 1.9) in women. CONCLUSION: Total cholesterol concentration is a strong predictor of mortality from coronary heart disease, cardiovascular diseases, and all causes in women as well as in men. Low cholesterol concentrations are not associated with increased mortality from non-cardiovascular causes.

Intake of dietary phylloquinone and menaquinones and risk of stroke.

BACKGROUND: Dietary vitamin K intake is thought to decrease the risk of cardiovascular disease (CVD) by reducing vascular calcification, although vitamin K is also involved in coagulation. Studies investigating the association between phylloquinone intake and risk of stroke are scarce, and the relation with menaquinones has not been investigated to date. METHODS AND RESULTS: We investigated the association between intake of phylloquinone and menaquinones and stroke in a prospective cohort of 35,476 healthy subjects. Information on occurrence of stroke was obtained by linkage to national registries, and stroke was further specified into ischemic and hemorrhagic stroke. Vitamin K intake was estimated using a validated food-frequency questionnaire. Multivariate Cox proportional hazards models adjusted for cardiovascular risk factors, lifestyle, and other dietary factors were used to estimate the associations. During a follow-up of 12.1 ± 2.1 years, 580 incident cases of stroke were identified, 163 of which were hemorrhagic and 324 were ischemic. Phylloquinone intake was not associated with risk of stroke with a hazard ratio (HR) of 1.09 (95% CI: 0.85 to 1.40, P(trend) 0.41) for the highest versus lowest quartile. For intake of menaquinones similar results were found, with an HR(Q4 versus Q1) of 0.99 (95% CI: 0.75 to 1.29, P(trend) 0.82). When specifying hemorrhagic and ischemic stroke or menaquinone subtypes, no significant associations were detected. CONCLUSION: In our study, neither dietary phylloquinone nor dietary menaquinones intake were associated with stroke risk.

Ten year course of low back pain in an adult population-based cohort--the Doetinchem cohort study.

BACKGROUND: The long-term course of long-standing low back pain is largely unknown since long-term data are scarce. OBJECTIVE: We examined the course of self-reported low back pain in the prospective population-based Doetinchem cohort over a period of 10years. METHODS: Between 1993 and 2007, around 5700 randomly selected men and women in four age groups of originally 20-29, 30-39, 40-49, 50-59years were measured three times. Logistic regression analysis was used to study the association of sociodemographic (gender, age, education, work status) and lifestyle characteristics (BMI, smoking, physical activity) with persistent and new episodes of long-standing low back pain. RESULTS: The prevalence of long-standing low back pain is quite stable over a 10year period, approximately 20% on population level. On individual level, around 30% of the population was completely free of low back pain during the entire period, 6% can be characterized as persistent back pain sufferers. Individuals with persistent and a varying pattern have a more unhealthy lifestyle (BMI and smoking) than those without low back pain. Age, smoking, obesity and not having a paid job are associated with 10-year persistent back pain in the general population, whereas age and not having a paid job are associated in those with long-lasting back pain at baseline. New episodes of long-standing back pain are relatively frequent among women and smokers. CONCLUSIONS: Low back pain in the population is characterized as very dynamic which challenges epidemiological studies highly. Long-term information on the course of back pain is needed to define severe subgroups.