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Supplemental digital content is available in the text., Purpose This study aimed to determine whether estimated cardiorespiratory fitness (CRF), fat mass (FM), lean mass (LM), and adiponectin bidirectionally associate with arterial function and structure and if CRF mediates the relationship between cardiometabolic health and arterial outcomes in 9- to 11-yr-old children drawn from the Avon Longitudinal Study of Parents and Children birth cohort, United Kingdom. Methods Brachial artery flow-mediated dilation (FMD), distensibility coefficient (DC), and carotid–radial pulse wave velocity (PWV) were measured by ultrasonography; CRF was measured during the submaximal ergometer test; total FM, trunk FM, and LM were measured by dual-energy x-ray absorptiometry; plasma adiponectin was measured by enzyme assay; and cardiometabolic health was computed based on the International Diabetes Federation criteria for diagnosing metabolic syndrome. We tested bidirectionality by including CRF, FM, LM, and adiponectin as exposures and FMD, DC, and PWV as outcomes, alternatively. Results Among 5566 participants (2816 (51%) girls; median age, 9.75 yr), CRF per body mass0.21 was directly related to DC (β (95% confidence interval) = 0.004 (

Purpose To investigate the association between healthy Nordic diet and risk of type 2 diabetes (T2D) in middle-aged and older men from eastern Finland. Methods A total of 2332 men aged 42–60 years and free of T2D at baseline in 1984–1989 were included. Diet was assessed with 4-day food records at baseline and the healthy Nordic diet score was calculated based on a modified Baltic Sea Diet Score. T2D diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Cox proportional hazards regression and analysis of covariance were used for analyses. Results During the mean follow-up of 19.3 years, 432 men (18.5%) were diagnosed with T2D. The multivariable-adjusted hazard ratio for T2D in the lowest vs. the highest quartile of the healthy Nordic diet score was 1.35 (95% CI 1.03–1.76) (P trend across quartiles 0.028). Lower adherence to healthy Nordic diet was also associated with higher plasma glucose and insulin concentrations. Conclusions In this prospective population-based cohort study among middle-aged and older men from eastern Finland, lower adherence to healthy Nordic diet was associated with higher risk of T2D and higher plasma glucose and serum insulin concentrations.

Aims: Little is known about the effect of economic recessions on cardiovascular disease. Therefore, we investigated the association of the economic recession in Finland in the 1990s with the incidence of cardiovascular disease among middle-aged and older women. Methods: A total of 918 women aged 53–73 years were examined for health and socioeconomic position in 1998–2001, as part of the population-based prospective Kuopio Ischaemic Heart Disease Risk Factor Study. The participants were asked whether Finland’s economic recession in the early 1990s had affected their lives socially or economically. The cohort was followed for 18 years, and incident physician-diagnosed cases of cardiovascular disease were obtained through record linkage with the national hospital discharge registry that covers every hospitalisation in Finland. Cox proportional hazards regression models were used to estimate the risk of cardiovascular disease among those with and without exposure to socioeconomic hardships during the recession, after adjusting for possible confounders. Results: At the baseline, 587 women reported having experienced socioeconomic hardships due to the recession. During the 20 years’ follow-up, 501 women developed cardiovascular disease. After adjustment for age, the risk of cardiovascular disease was 27% higher among women exposed to socioeconomic hardships compared to those who were not (hazard ratio 1.27, 95% confidence interval 1.06–1.53, P=0.012). Further adjustments for overall socioeconomic position at baseline, prior cardiovascular health, and lifestyle factors did not attenuate the association (hazard ratio 1.23, 95% confidence interval 1.02–1.5, P=0.029). Conclusions: The early 1990s economic recession was associated with a subsequently increased risk of cardiovascular disease among Finnish women.

Purpose Atherosclerosis (AS) and osteoporosis (OP) are common causes of morbidity and mortality in postmenopausal women and are connected via an unknown mechanistic link. Metabolite profiling of blood samples may allow the identification of new biomarkers and pathways for this enigmatic association. Patients and methods We studied the difference in 148 metabolite levels from serum samples in postmenopausal women with AS and OP compared with those in healthy participants in this cross-sectional study. Quantitative AS was assessed by carotid artery intima-media thickness (cIMT) and carotid artery calcifications (CACs) by ultrasound, as well as OP by femoral neck (FN) bone mineral density (BMD) and 148 metabolic measures with high-throughput proton (1H) nuclear magnetic resonance (NMR) in serum samples from 280 postmenopausal (PM) women. Subjects were a randomly selected subsample from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The final study population included the following groups: OP with CAC (n=16, group I), non-OP with no CAC (n=59, group II), high cIMT tertile with OP (n=11, group III) and low cIMT tertile without OP (n=48, group IV). Results There were differences in several metabolite levels between groups I and II. The acetate level was lower in group I compared to that in group II (group I mean ± SD: 0.033 ± 0.0070; group II: 0.041 ± 0.014, CI95%: 0.018‒0.15, p=0.014). The result was similar with diacylglycerol (p=0.002), leucine (p=0.031), valine (p=0.022) and several very low-density lipoprotein (VLDL) metabolite levels, which were lower in group I compared to those in group II. However, no associations were found in adjusted analyses with total body (TB) fat mass (FM), age and statin use (p>0.05). Conclusion Our novel study found differences in the metabolite profiling of altered amino acid and lipoprotein metabolism in participants with OP and AS compared with those in healthy women. The causative mechanisms remain unknown and further studies are needed.

Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D., Fumiaki Imamura and colleagues investigate the association between concentrations of fatty acid involved in de-novo lipogensis and incidence of Type 2 diabetes., Author summary Why was this study done? De novo lipogenesis (DNL) is a metabolic pathway involved in the endogenous synthesis of specific fatty acids, such as 16:0, 16:1n7, 18:0, and 18:1n9, and it is linked to the pathophysiology of cardiometabolic diseases, including type 2 diabetes (T2D). Circulating or tissue concentrations of these fatty acids have been investigated for the associations with T2D incidence in epidemiological research. However, published studies reported inconsistent associations inconsistently and were subject to publication bias. Summary evidence is not available to date for the associations between these fatty acids and T2D incidence. An integration of available cohort studies would increase statistical power and allow assessment of generalizability, standardization of analytical strategies, and evidence synthesis with the potential publication bias minimized. What did the researchers do and find? As a part of the Fatty Acids and Outcomes Research Consortium (FORCE), we conducted new individual-participant data analyses of 17 cohort studies of a total of 65,225 adults free of T2D at baseline, among whom 15,383 developed incident T2D over up to 20 years of follow-up. The cohort studies analyzed the associations between fatty acids (16:0, 16:1n7, 18:0, and 18:1n9) and the risk of developing T2D with standardized analytic strategy. In pooled analyses, each of the fatty acids was positively associated with a higher risk of developing T2D. The associations were independent of major risk factors for T2D, such as age, sex, race/ethnicity, socioeconomic characteristics, smoking status, physical activity, and obesity. What do these findings mean? The findings provide the first summary evidence to date for the positive relationships of concentrations of the DNL-related fatty acids with a risk of T2D, indicating the strong relevance of DNL and its determinants to the development of T2D. These fatty acids potentially reflect the status of DNL activity, which may be stimulated or suppressed by a combination of carbohydrate intake, alcohol intake, polyunsaturated fatty acid intake, and other lifestyle and clinical factors. Therefore, the current findings indicate the need for investigation into determinants and consequences of elevated concentrations of these fatty acids. Despite several advantages of our individual-level data analysis in this pooling project, the results cannot establish whether elevated concentrations of these fatty acids caused the development of T2D or whether underlying peripheral or hepatic insulin resistance, for example, may elevate both the fatty acid concentrations and the risk of T2D independently.

Infections are one of the main causes of mortality in elderly due to the decrease of immune response, for which copper (Cu) and zinc (Zn) are claimed to be crucial. High serum copper-to-zinc-ratio (Cu/Zn-ratio) has been reported with infections, but little is known whether it could also predict the incidence of infections. The study cohort consisted of 1975 men aged 42–60 years and free of severe infectious disease at baseline in 1984–1989 from the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. The main outcome was an incident infection leading to hospitalization. Cox proportional hazards regression models were used for statistical analysis. During the average follow-up of 19.2 years, 636 incident first cases of infections were diagnosed. The hazard ratio (HR) of developing an incident infectious disease in the highest compared to the lowest Cu/Zn-ratio quartile after adjustment for age and baseline examination year was 1.35 [95% confidence interval (CI) = 1.07–1.69, P-trend across quartiles = 0.005]. The association was slightly attenuated after additional adjustment for potential confounders (HR = 1.21, 95% CI = 0.96–1.53, P-trend = 0.054). Furthermore, higher serum Cu concentration was associated with higher risk of an incident infection. The multivariable-adjusted HR was 1.39 (95% CI = 1.10–1.75, P-trend = 0.005) in the highest versus the lowest serum Cu quartile. Serum Zn concentration was not associated with the risk (multivariable-adjusted extreme-quartile HR = 0.83, 95% CI = 0.67–1.04, P-trend = 0.218). In conclusion, our data suggest that an increased Cu/Zn-ratio and especially serum Cu concentration are associated with increased risk of incident infections in middle-aged and older men in Eastern Finland.

Purpose High-maternal caffeine intake during pregnancy may be harmful for perinatal outcomes and future child health, but the level of fetal cumulative exposure has been difficult to measure thus far. Here, we present maternal dietary caffeine intake during the last trimester and its correlation to caffeine content in newborn hair after birth. Methods Maternal third trimester diets and dietary caffeine intake were prospectively collected in Kuopio Birth Cohort (KuBiCo) using a 160-item food frequency questionnaire (n = 2840). Newborn hair was collected within 48 h after birth and analyzed by high-resolution mass spectrometry (HRMS) for caffeine (n = 316). Correlation between dietary caffeine intake and neonatal hair caffeine content was evaluated from 203 mother–child pairs. Results Mean dietary caffeine intake was 167 mg/days (95% CI 162–172 mg/days), of which coffee comprised 81%. Caffeine in the maternal diet and caffeine content in newborn hair correlated significantly (r = 0.50; p Conclusion Caffeine exposure, estimated from newborn hair samples, reflects maternal third trimester dietary caffeine intake and introduces a new method to assess fetal cumulative caffeine exposure. Further studies to evaluate the effects of caffeine exposure on both perinatal and postnatal outcomes are warranted, since over 40% of pregnant women consume caffeine more than the current suggested recommendations (European Food Safety Association, EFSA recommendations).

Purpose To investigate associations of total dietary choline intake and its major dietary form, phosphatidylcholine, with type 2 diabetes risk. Methods We included 2332 men aged 42–60 years at baseline in 1984–1989 from the Kuopio Ischaemic Heart Disease Risk Factor Study in eastern Finland. Dietary intakes were assessed with 4-d food recording at baseline. Type 2 diabetes diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Multivariable-adjusted Cox proportional hazards regression models were used for statistical analysis. Results During the mean 19.3-year follow-up, 432 men had type 2 diabetes diagnosis. After multivariable adjustments, those in the highest vs. lowest choline intake quartile had 25% (95% CI 2–43%) lower relative risk (P trend across quartiles = 0.02) and those in the highest vs. lowest phosphatidylcholine quartile had 41% (95% CI 22–55%) lower relative risk (P trend Conclusions Higher choline intake, especially phosphatidylcholine, was associated with lower type 2 diabetes risk among men.

Purpose To investigate the association between healthy Nordic diet and risk of disease death in middle-aged and older men from eastern Finland. Methods A total of 1547 men aged 42–60 years and free of cardiovascular disease (CVD), cancer and type 2 diabetes at baseline in 1984–1989 were included. Diet was assessed with 4-day food records at baseline and the healthy Nordic diet score was calculated based on the Baltic Sea Diet Score. The incidence of death was assessed by a computer linkage to the national cause of death register. Cox proportional hazards regression analyses were used to estimate the associations between the healthy Nordic diet score and mortality. Results During the mean follow-up of 23.6 years (SD 7.0), 576 men died due to disease: 250 due to CVD, 194 due to cancer and 132 due to other diseases. The multivariable-adjusted hazard ratios (95% confidence interval) in the lowest vs. the highest quartile of the healthy Nordic diet score were 1.27 (1.01–1.59) for any disease death (P-trend across quartiles P-trend = 0.049) for CVD death, 1.26 (0.84–1.89, P-trend = 0.316) for cancer death and 1.04 (0.65–1.68, P-trend = 0.563) for other disease deaths. Conclusions In this prospective population-based cohort study among middle-aged and older men, low adherence to a healthy Nordic diet was associated with a higher risk of any disease death, possibly largely attributable to higher CVD mortality.

Atherosclerosis - the pathophysiological mechanism shared by most cardiovascular diseases - can be directly or indirectly assessed by a variety of clinical tests including measurement of carotid intima-media thickness, carotid plaque, ankle-brachial index, pulse wave velocity, and coronary artery calcium. the Prospective Studies of Atherosclerosis (Proof-ATHERO) consortium (https://clinicalepi.i-med.ac.at/research/proof-athero/) collates de-identified individual-participant data of studies with information on atherosclerosis measures, risk factors for cardiovascular disease, and incidence of cardiovascular diseases. It currently comprises 74 studies that involve 106,846 participants from 25 countries and over 40 cities. in summary, 21 studies recruited participants from the general population (n = 67,784), 16 from high-risk populations (n = 22,677), and 37 as part of clinical trials (n = 16,385). Baseline years of contributing studies range from April 1980 to July 2014; the latest follow-up was until June 2019. Mean age at baseline was 59 years (standard deviation: 10) and 50% were female. Over a total of 830,619 person-years of follow-up, 17,270 incident cardiovascular events (including coronary heart disease and stroke) and 13,270 deaths were recorded, corresponding to cumulative incidences of 2.1% and 1.6% per annum, respectively. the consortium is coordinated by the Clinical Epidemiology Team at the Medical University of Innsbruck, Austria. Contributing studies undergo a detailed data cleaning and harmonisation procedure before being incorporated in the Proof-ATHERO central database. Statistical analyses are being conducted according to pre-defined analysis plans and use established methods for individual-participant data meta-analysis. Capitalising on its large sample size, the multi-institutional collaborative Proof-ATHERO consortium aims to better characterise, understand, and predict the development of atherosclerosis and its clinical consequences. (c) 2020 S. Karger AG, Basel, Austrian Science Fund (FWF)Austrian Science Fund (FWF) [P 32488]; Dr.-Johannes-and-Hertha-Tuba Foundation, This work was funded by the Austrian Science Fund (FWF) (P 32488) and the Dr.-Johannes-and-Hertha-Tuba Foundation. Funders of individual studies contributing to the present analysis arelisted onthe Proof-ATHERO webpage(https://clinicalepi.i-med.ac.at/research/proof-athero/studies/).

Background Moderate egg intake has been associated with better cognitive performance in observational studies. This association may be due to the rich content of choline, especially phosphatidylcholine, in eggs because choline has been suggested to have a role in the prevention of cognitive decline. Objectives We investigated the associations of dietary choline intake with the risk of incident dementia and with cognitive performance in middle-aged and older men in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Methods A population-based sample of 2497 dementia-free men aged 42-60 y was examined in 1984-1989. A subset of 482 men completed 5 different cognitive performance tests 4 y later. Dementia and Alzheimer disease diagnoses were retrieved from Finnish health registers. Dietary intakes were assessed with the use of 4-d food records at baseline. Cox regression and ANCOVA were used for the analyses. All analyses were also stratified by the apolipoprotein E phenotype (APOE-e4 compared with other phenotypes). These data were available for 1259 men. Results The mean ± SD total choline intake was 431 ± 88 mg/d, of which 188 ± 63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%; P-trend = 0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations. Conclusion Higher phosphatidylcholine intake was associated with lower risk of incident dementia and better cognitive performance in men in eastern Finland. This trial was registered at clinicaltrials.gov as NCT03221127.

Supplemental Digital Content is available in the text., We examined the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) with the risk of overweight/obesity and elevated blood pressure (BP)/hypertension. We studied 3862 adolescents aged 17.7 years from the Avon Longitudinal Study of Parents and Children, followed-up for 7 years. cfPWV and cIMT were measured by ultrasound. Total and trunk fat mass and lean mass were assessed by dual-energy X-ray absorptiometry. Body mass index and BP were measured. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models, with covariate adjustments. Among 1719 male and 2143 female participants, higher cfPWV at 17.7 years was associated with the risk of elevated systolic BP/hypertension (odds ratio, 1.20 [1.02–1.41]; P=0.026), elevated diastolic BP/hypertension (1.77 [1.32–2.38]; P

Background The American Heart Association's scientific statement on the importance of arterial stiffness recommended that future studies investigate whether increasing arterial stiffness with advancing age results from the age-associated increase in systolic blood pressure (BP). The statement also recommended investigating the natural history of arterial stiffness and BP vis-à-vis the rate at which arterial stiffness and BP increase with age. These questions remain largely unanswered in a population sample of apparently healthy adolescence and young adults. Purpose To investigate whether carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, during adolescence predicts increased systolic and diastolic blood pressure in young adulthood. Methods We studied 3862 British (56% females) participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, Bristol, UK. cfPWV was measured by Vicorder device ultrasound scan, total fat mass and lean mass were measured by dual-energy Xray absorptiometry, and systolic and diastolic BP by Omron BP/pulse monitor. We conducted multivariable linear regression analyses and adjusted for baseline covariates such as age, sex, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, high sensitivity C-reactive protein, fasting blood glucose, fasting insulin concentration, heart rate, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, total fat mass, lean mass and systolic or diastolic BP depending on the outcome. All variables were measured both at age 17.7 and 24.5 years. Results Participants mean (SD) age in years at different time points were [17.72 (0.33) and 24.54 (0.73)]. Over a 7-year follow-up period, cfPWV was directly and independently associated with systolic BP [β = 10.762 (CI: 3.107 to 18.417); p=0.006] and diastolic BP [19.535 (12.879 to 26.191); p Conclusion Our findings showed that increasing arterial stiffness independently predicts higher systolic and diastolic BP with advancing age. Besides, a 0.1 m/s increase in arterial stiffness at age 17.7 years may result in a 1 mmHg increase in systolic BP and a 2 mmHg increase in diastolic BP seven years later. Therefore, public health effort should be targeted at preventing or reducing arterial stiffness during adolescence in order to decrease the risk of elevated BP in later life. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Jenny and Antti Wihuri Foundation and the Finnish Cultural Foundation

Fatty liver disease (FLD) and hypertension are separately associated with cardiovascular (CV) mortality. While the two conditions are established as separate predictors of CV outcomes, FLD and hypertension are interrelated in multiple ways. A biological interaction in respect to CV disease outcomes could exist between FLD and hypertension. In this study, we investigated the joint effect and interaction of FLD and hypertension regarding CV mortality using an interaction framework. Using a population-based cohort, we followed 1,569 middle-aged non-diabetic Finnish men for 34 years. We computed the fatty liver index and considered values ≥60 as indicative of FLD. We defined hypertension as either i) self-reported hypertension and a confirmed use of antihypertension medication, or ii) a mean systolic ≥160 or diastolic ≥105 blood pressure on baseline examination. The choice of the blood pressure measurement threshold to define hypertension was based on a sensitivity analysis. With adjustment for age, body mass index, smoking, and alcohol consumption, separate and combined effects of FLD and hypertension and their interaction at the multiplicative and additive scales regarding all-cause and CV death were assessed using Cox proportional hazards models. Among the men, 372 had FLD and 342 had hypertension. FLD and hypertension coexisted in 134 men. FLD and hypertension associated, independently and combined, with an increased hazard of all-cause and CV deaths. Non-cardiovascular mortality associated with FLD, but not with hypertension. We found a negative interaction between FLD and hypertension regarding the hazard of all-cause (relative excess risk due to interaction [RERI], -0.97; 95% confidence interval [CI], -1.65 to -0.28) and CV mortality (RERI, -1.74; 95% CI, -2.98 to -0.50). The interaction was also found on a multiplicative scale. We found evidence of a negative interaction between FLD and hypertension in respect to CV mortality. Our findings were robust to different definitions of hypertension but were more relevant at high blood pressure thresholds. We thus recommend adjusting for FLD or hypertension when studying the effect of the other condition on mortality or CV diseases in middle-aged men and call for further research on the topic.

Background A temporal association where better arterial function and structure predicts adiponectin level and skeletal muscle mass during childhood remains uninvestigated. Methods We studied 5566 children and adolescents (51% girls) aged 9-11 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, Bristol, UK. Brachial artery endothelial function was determined using flow-mediated dilation (FMD), expressed as the percentage change in diameter from baseline after reactive hyperemia; arterial elasticity as distensibility coefficient (DC) expressed in mean percentage change in cross-sectional area relative to blood pressure (BP); and arterial stiffness by carotid to radial pulse wave velocity (crPWV). Skeletal muscle mass and total fat mass were assessed by dual-energy Xray absorptiometry. We conducted multivariable linear regressions with Sidak correction and adjusted for age, sex, total fat mass, cardiorespiratory fitness, pubertal status, brachial artery diameter, systolic BP, low-density lipoprotein cholesterol, mother’s social-economic class, and time (years) between the measurement of predictors and outcomes. Results FMD (β [95% CI]) = (0.027 [0.007 to 0.047]; P = 0.009) and DC (0.229 [0.088 to 0.369]; P = 0.001) were directly associated with skeletal muscle mass. FMD had a borderline inverse association with adiponectin (-0.004 [-0.008 to Conclusions Better endothelial function and arterial elasticity were associated with higher skeletal muscle mass while arterial stiffness was unrelated to adiponectin and lean mass. Key message Healthy arterial function and structure may enhance muscle growth in children.

Background and objectives Fatty liver disease (FLD) and hypertension are separately associated with cardiovascular (CV) mortality. The two conditions are related in multiple ways. This work aimed to study the joint effect and interaction of FLD and hypertension in respect to overall and CV mortality. Methods The population-based cohort, Kuopio Ischaemic Disease Risk Factor Study, followed 1569 middle-aged non-diabetic Finnish men for 34 years. Considering adjustment for age, body mass index, smoking and alcohol consumption, separate and combined effects of FLD and hypertension and their interaction at the multiplicative and additive scales regarding all-cause and CV death were assessed using Cox proportional hazards models. Results FLD and hypertension coexisted in 8.54% of the men (n = 134). FLD and hypertension associated, independently and combined, with an increased hazard of all-cause and CV deaths. Non-CV mortality associated with FLD, but not with hypertension. We found a negative interaction between FLD and hypertension regarding the hazard of all-cause (relative excess risk due to interaction (RERI), -0.97; 95% confidence interval (CI), -1.65 to -0.28) and CV mortality (RERI, -1.74; 95% CI, -2.98 to -0.5). The interaction was also found on a multiplicative scale. Conclusions We found evidence of a negative interaction between FLD and hypertension in respect to CV mortality. We thus recommend adjusting for FLD or hypertension when studying the effect of the other condition on mortality or CV diseases in middle-aged men.

Background While the impact of low glomerular filtration rate (eGFR) on various outcomes has been extensively studied, the other adverse occurrence, renal hyperfiltration (RHF), remains understudied, poorly defined, and, therefore, its impact on mortality unestablished. Methods Using a population-based subcohort from the Kuopio Ischaemic Disease Risk Factor Study restricted to non-diabetic Finnish men aged 54 or 55 years, we followed up n = 1179 study participants for up to 35 years. We evaluated the hazard of all-cause mortality associated to RHF at different cutoff points defining eGFR. Based on models’ accuracy we suggested an optimal eGFR cutoff point for the definition of RHF. We divided the RHF category to three subgroups and evaluated them in terms of baseline characteristics and mortality hazard. Results The eGFR value of 97 mL/min/1.73 m2 corresponded to the models with the highest accuracy. Overall RHF associated with an increased risk of mortality (hazard ratio [HR] 1.42; 95% confidence interval [CI] 1.21 to 1.67). Moderate RHF associated with a decreased HR of mortality when compared to mild (0.64; 95% CI 0.46 to 0.9) or to extreme RHF (0.61; 95% CI 0.43 to 0.85), suggesting a rather U-shaped relationship between RHF’s eGFR values and mortality hazard. Conclusion The burden of increased eGFR within what is still considered normal eGFR category was highly underestimated. RHF’s eGFR values had a U-shaped association with the risk of overall mortality. A more uniform consensual definition of RHF is needed, as higher to normal eGFR values that are not without consequences.

Background We carried out this study to demonstrate the effects of outcome sensitivity, participant exclusions, and covariate manipulations on results of the epidemiological analysis of coronary heart disease (CHD) and its behaviour-related risk factors. Material and methods Our study population consisted of 1592 54-year-old men, who participated in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. We used the Cox proportional-hazards model to predict the hazard of CHD and applied different sets of outcomes concerning outcome sensitivity and data preprocessing procedures regarding participant exclusions and covariate manipulations. Results The mean follow-up time was 23 years, and 730 men received the CHD diagnosis. Cox regressions based on data with no participant exclusions most often discovered statistically significant associations. Loose inclusion criteria for study participants with any CVD during the follow-up and strict exclusion criteria for participants with no CVD were best in discovering the associations between risk factors and CHD. Outcome sensitivity affected the associations, whereas the covariate type, continuous or categorical, did not. Conclusions This study suggests that excluding study participants who are not disease-free at baseline is probably unnecessary for epidemiological analyses. Epidemiological research reports should present results based on no data exclusions together with results based on reasoned exclusions.

Introduction: Evidence on the associations of fat mass and lean mass with changes in carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT), markers of pre-clinical atherosclerosis, from adolescence through young adulthood is lacking. Previous studies have reported strong associations of body mass index (BMI), a measure of adiposity, with these markers. However, it is unclear if increased BMI in relation to these markers represents a pathological process or physiological adaptation. A knowledge gap also exists on the independent associations of blood pressure (BP) measured from childhood through young adulthood with changes in cfPWV and cIMT between ages 17 and 24.5 years. Hypothesis: We assessed the hypothesis whether lean mass and systolic BP, independent of fat mass, cardiometabolic and lifestyle factors, measured at age 9, 17, and 24.5 years drive a 7-year change in cfPWV and cIMT. Methods: We studied 3863 British children from the Avon Longitudinal Study of Parents and Children's birth cohort (56% females). fat mass and lean mass were measured by dual-energy Xray absorptiometry, systolic and diastolic BP by Omron BP/pulse monitor, cfPWV by Vicorder device, and cIMT by CardioHealth ultrasound scan. All exposures were categorized in tertiles of low, normal, and high, with the low category as the reference group. We conducted linear mixed effect model analyses and adjusted for age, sex, low-density lipoprotein, C-reactive protein, fasting blood glucose, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, time in years between measure at 9 and 24.5 years, and systolic BP, fat mass, and/or lean mass depending on the predictor. Results: Participants mean (SD) age in years at different time points were [9.83 (0.30); 17.72 (0.33); 24.54 (0.73)]. Over a 15-year follow-up period, persistent exposure to high lean mass effect estimate =0.006 (CI 0.001 - 0.010, p=0.022), high systolic BP 0.013 (0.009 - 0.017, p Conclusion: For the first time, we showed in a healthy cohort that persistent exposure to higher lean mass and BP from childhood independently drives arterial wall adaptation in early adulthood. These arterial changes are likely normal responses to growth and maturation rather than subclinical signs of arterial diseases. Thus, cumulative exposure to high BMI in relation to higher cfPWV and cIMT may not indicate a deleterious effect of adiposity.

Background: Epidemiologic studies suggest inverse associations between consumption of egg, a major source of dietary cholesterol, and stroke. However, the evidence of the relation remains limited, especially among carriers of apolipoprotein E4 (apoE4), which influences cholesterol metabolism. Objective: The aim of this study was to investigate associations of egg and cholesterol intakes with risk of stroke and with the major stroke risk factor, blood pressure, inmiddle-aged and older men from eastern Finland and whether apoE phenotype could modify these associations. Methods: A total of 1950 men aged 42-60 y in 1984-1989 were included at the baseline examinations of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on apoE phenotype were available for 1015 men. Dietary intakes were assessed with 4-d food records at baseline and incident stroke events were assessed by record linkage to hospital discharge registries. Cox proportional hazards regression analyses were used to estimate associations with stroke risk. Associations with baseline blood pressure were evaluated with ANCOVA. Results: During the mean +/- SD follow-up of 21.2 +/- 7.2 y, there were 217 incidences of any stroke: 166 of ischemic stroke and 55 of hemorrhagic stroke. Comparing the highest egg intake quartile with the lowest, the multivariable-adjusted HRs were 0.81 for total stroke (95% CI: 0.54, 1.23; P-trend = 0.32), 0.84 for ischemic stroke (95% CI: 0.53, 1.34; P-trend = 0.44), and 0.75 for hemorrhagic stroke (95% CI: 0.32, 1.77; P-trend = 0.40). The respective HRs for the highest cholesterol intake quartile compared with the lowest were 0.86 (95% CI: 0.57, 1.32; P-trend = 0.42), 0.74 (95% CI: 0.46, 1.20; P-trend = 0.32), and 1.10 (95% CI: 0.45, 2.66; P-trend = 0.75). Diastolic blood pressure was 1.6 mm Hg (P-trend = 0.04) lower in the highest egg intake quartile compared with the lowest, but there were no associations with systolic blood pressure or with cholesterol intake. ApoE phenotype (32% had apoE4 phenotype) did not modify the associations. Conclusion: Neither egg nor cholesterol intakes were associated with stroke risk in this cohort, regardless of apoE phenotype. This trial was registered at www.clinicaltrials.gov as NCT03221127.

ObjectiveLong-chain omega-3 polyunsaturated fatty acids (PUFA) from fish have been inversely associated with coronary heart disease (CHD) risk. Fish may also contain methylmercury, which has been associated with higher CHD risk and may diminish the cardioprotective effect of long-chain omega-3 PUFA. We investigated the associations of serum long-chain omega-3 PUFA and hair mercury with the odds for myocardial ischaemia during exercise.MethodsA total of 2199 men from the Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42–60 years were studied in 1984–89. Of the 2199 men, 342 had history of CHD. The men performed a maximal symptom-limited exercise stress test using an electrically braked bicycle ergometer. ORs for exercise-induced myocardial ischaemia were estimated with logistic regression.ResultsIn the multivariable analysis, those in the highest versus lowest serum long-chain omega-3 PUFA quartile had 33% lower odds of myocardial ischaemia (OR 0.67, 95% CI 0.51 to 0.87, p-trend=0.006). The association was stronger among those with CHD history (OR 0.10, 95% CI 0.03 to 0.39, p-trend ConclusionHigher circulating concentrations of the long-chain omega-3 PUFAs, a marker for fish consumption, were associated with lower occurrence of exercise-induced myocardial ischaemia, but only among men with CHD history. Hair mercury concentration was directly associated with the occurrence of exercise-induced myocardial ischaemia in the entire study population.

Background Previous studies investigating protein intake in relation to mortality have provided conflicting results. Objective We investigated the associations of dietary protein and protein sources with risk of disease death in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Methods The study population consisted of 2641 Finnish men, aged 42-60 y at baseline in 1984-1989. We estimated protein intakes with 4-d dietary records at baseline and collected data on disease deaths from the national Causes of Death Register. Cox proportional hazards regression models were used to estimate HRs and 95% CIs. Results During the average follow-up of 22.3 y, we observed 1225 deaths due to disease. Higher intakes of total protein and animal protein had borderline statistically significant associations with increased mortality risk: multivariable-adjusted HR (95% CI) in the highest compared with the lowest quartile for total protein intake = 1.17 (0.99, 1.39; P-trend across quartiles = 0.07) and for animal protein intake = 1.13 (0.95, 1.35; P-trend = 0.04). Higher animal-to-plant protein ratio (extreme-quartile HR = 1.23; 95% CI: 1.02, 1.49; P-trend = 0.01) and higher meat intake (extreme-quartile HR = 1.23; 95% CI: 1.04, 1.47; P-trend = 0.01) were associated with increased mortality. When evaluated based on disease history at baseline, the association of total protein with mortality appeared more evident among those with a history of type 2 diabetes, cardiovascular disease, or cancer (n = 1094) compared with those without disease history (n = 1547) (P-interaction = 0.05 or 0.07, depending on the model). Intakes of fish, eggs, dairy, or plant protein sources were not associated with mortality. Conclusions Higher ratio of animal to plant protein in diet and higher meat intake were associated with increased mortality risk. Higher total protein intake appeared to be associated with mortality mainly among those with a predisposing disease. This trial was registered at clinicaltrials.gov as NCT03221127.

In the vitamin D intervention study VitDbol (NCT02063334) blood samples were drawn directly before an oral bolus (2000 μg vitamin D3) and 24 h later. The focus of phase II of VitDbol was the transcriptome-wide analysis of the effects of vitamin D gene expression in human peripheral blood mononuclear cells (PBMCs). All five participants responded in an individual fashion to the bolus by increases in serum levels of the vitamin D metabolites 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). RNA sequencing identified 15.040 commonly expressed genes in PBMCs, 702 (4,7%) of which were significantly (p

Healthy Nordic diet has been beneficially associated with CHD risk factors, but few studies have investigated risk of developing CHD. We investigated the associations of healthy Nordic diet with major CHD risk factors, carotid atherosclerosis and incident CHD in middle-aged and older men from eastern Finland. A total of 1981 men aged 42–60 years and free of CHD at baseline in 1984–1989 were investigated. Diet was assessed with 4-d food recording and the healthy Nordic diet score was calculated based on the Baltic Sea Diet Score. Carotid atherosclerosis was assessed by ultrasonography of the common carotid artery intima–media thickness in 1053 men. ANCOVA and Cox proportional hazards regression analyses were used for analyses. Healthy Nordic diet score was associated with lower serum C-reactive protein (CRP) concentrations (multivariable-adjusted extreme-quartile difference 0·66 mg/l, 95 % CI 0·11, 1·21 mg/l) but not with serum lipid concentrations, blood pressure or carotid atherosclerosis. During the average follow-up of 21·6 years (sd 8·3 years), 407 men had a CHD event, of which 277 were fatal. The multivariable-adjusted hazard ratios in the lowest v. the highest quartile of the healthy Nordic diet score were 1·15 (95 % CI 0·87, 1·51) for any CHD event (Ptrend 0·361) and 1·44 (95 % CI 0·99, 2·08) (Ptrend 0·087) for fatal CHD event. We did not find evidence that adherence to a healthy Nordic diet would be associated with a lower risk of CHD or with carotid atherosclerosis or major CHD risk factors, except for an inverse association with serum CRP concentrations.

Predictive models are commonly used in epidemiological studies to estimate risks of illnesses. For knowledge-based models, the logic behind is clear, whereas for automatically generated data-driven models, it is not always transparent how they work. In this study, we applied an evolutionary approach to design a Fuzzy Logic Rule-based model that is easily interpretable compared to many other data-driven models. We utilized a high-dimensional epidemiological data collected within the Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study in 1984–1989 to train the model and predict cardiovascular death for middle-aged men by 2016. In multiple runs of 5-fold cross-validation, we evaluated the model performance and showed that it could achieve higher true positive rate (TPR) than Random Forest and provide more stable results than Decision Tree. Also, the presented approach proved its effectiveness for high-dimensional samples: on the set of 653 predictors, we obtained 68% accuracy on average, whereas on the reduced set of 100 predictors, we could improve this result only up to 70%. Furthermore, this study introduces the most important predictor variables used in the generated Fuzzy Logic Rule-based model.

OBJECTIVE The aim of the study was to investigate the association between sense of coherence (SOC) and all-cause mortality in the general adult population. METHODS We conducted a systematic review and meta-analysis of prospective cohort studies. We searched eight electronic bibliographic databases for eligible studies. A random effects model and the restricted maximum likelihood method were used to calculate the pooled effect size. RESULTS Eight studies were eligible for the meta-analysis. The studies included 48,138 participants, of whom 5307 died during a median follow-up of 14.1 years (range, 8-29.5 years). Their age ranged from 20 to 80 years, and 53% of them were men. In the meta-analysis model of crude values, the risk of all-cause mortality for individuals with a weak SOC (lowest tertile) was 1.30 (95% confidence interval [CI] = 1.09-1.55, p = .003, I = 78.84%) compared with individuals with a strong SOC (highest tertile). In the model adjusted for age, the risk remained almost the same (risk ratio = 1.26, 95% CI = 1.15-1.38, p < .001, I = 69.59%). In the model adjusted for several other risk factors for mortality, the risk was still 1.17 (95% CI = 1.07-1.27, p < .001, I = 57.85%). CONCLUSIONS This meta-analysis shows that a weak SOC is associated with an increased risk of all-cause mortality in the general adult population. Future studies are needed to further develop assessment tools for SOC with good psychometric properties and to determine the disease processes that mediate the association of SOC with mortality.

The infants of mothers with elevated depressive symptoms (EDS) postpartum appear to be at increased risk of somatic health problems during their first 12 months of life in low- and lower-middle-income countries. However, in higher-income countries, knowledge of this association is scarce. We sought to examine whether maternal reports of infant health problems, adherence to vaccination schedules and analgesic supply to the infant during the first 12 months of life differ between mothers with and without postpartum EDS. Altogether, 969 women who were enrolled in the Kuopio Birth Cohort study (www.kubico.fi) during 2012?2017 were included in this investigation. Depressive symptoms were measured with the Edinburgh Postnatal Depression Scale during pregnancy (1st and/or 3rd trimester) and at eight weeks postpartum. Infant health data were collected as a part of a 12-month online follow-up questionnaire for mothers and were based on self-reports of either maternal observations or physician-determined diagnoses. Postpartum EDS were associated with a 2- to 5-fold increased likelihood of abnormal crying and paroxysmal wheezing (based on parental observations), as well as gastroesophageal reflux and food allergy (based on physician-determined diagnoses). Mothers with postpartum EDS also supplied their infants with analgesic medication for longer periods. Adherence to vaccination schedules was similar between the examined groups. In conclusion, infants of mothers with postpartum EDS may be more likely to experience health problems or to be perceived by their mother as having health problems, and thus receive more medications.

Recent dairy product studies have suggested that fermented rather than non-fermented dairy products might provide benefits on cardiovascular health, but the evidence is inconclusive. Therefore, we investigated whether fermented and non-fermented dairy products have distinct associations with the risk of incident CHD in a population with high dairy product intake. The present study included a total of 1981 men, aged 42–60 years, from the Kuopio Ischaemic Heart Disease Risk Factor Study, with no CHD at baseline. Dietary intakes were assessed with instructed 4-d food records. We used Cox’s proportional hazards regression model to estimate the associations with the risk of CHD. Fatal and non-fatal CHD events were ascertained from national registries. During a mean follow-up of 20·1 years, 472 CHD events were recorded. Median intakes were 105 g/d for fermented (87 % low-fat products) and 466 g/d for non-fermented dairy products (60 % low-fat products). After adjusting for potential confounders, those in the highest (v. lowest) intake quartile of fermented dairy products had 27 % (95 % CI 5, 44; P-trend=0·02) lower risk of CHD. In contrast, those in the highest intake quartile of non-fermented dairy products had 52 % (95 % CI 13, 104; P-trend=0·003) higher risk of CHD. When analysed based on fat content, low-fat (P-trend=0·03), but high-fat fermented dairy and low-fat or high-fat non-fermented dairy products had no association. These results suggest that fermented and non-fermented dairy products can have opposite associations with the risk of CHD.

Background There remains a dearth of life-course studies analyzing childhood environment and late-life chronic illness. In particular, few have addressed possible early-life predictors of dementia. This study examines relationships between childhood stress and later-age dementia, specifically Alzheimer's disease (AD). Methods We used data from 2682 men in the population-based Kuopio Ischemic Heart Disease Risk Factor Study who participated in extensive baseline health examinations and interviews between 1984 and 1989, when they were between 42 and 61 years of age. Childhood events were documented in these structured interviews. We created a composite childhood stress variable that included living in custody or an orphanage, experience of crisis in childhood, having problems with teachers and emigrating because of war. Data on incident cases of dementia, including AD, were obtained through 2014 via national health register linkages. Risk of developing dementia was estimated using Cox regression adjusting for age, education, income and prior/existing diseases at baseline. Results Childhood stress was associated with increased risk of dementia (HR = 1.86, 95% CI: 1.12-3.10). Associations remained statistically significant after adjustment for age, education, income and other covariates (HR = 1.93, 95% CI: 1.14-3.25). Associations were marginally significant with AD, with HRs of similar magnitude. Conclusions Childhood stress plays an important role in late-life dementia risk among men. Support systems should be developed for children suffering from stressful conditions. Further research examining childhood social and environmental effects on later morbidity, in diverse populations, is necessary to develop a holistic understanding of life-course disease burden.

The cardioprotective properties of linoleic acid (LA), a major n-6 (ω-6) polyunsaturated fatty acid (PUFA), have been recognized, but less is known about its associations with other causes of death. Relatively little is also known about how the minor n-6 PUFAs-γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA)-relate to mortality risk.We investigated the associations of serum n-6 PUFAs, an objective biomarker of exposure, with risk of death in middle-aged and older men and whether disease history modifies the associations.We included 2480 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y at baseline in 1984-1989. The stratified analyses by baseline disease status included 1019 men with a history of cardiovascular disease (CVD), cancer, or diabetes and 1461 men without a history of disease.During the mean follow-up of 22.4 y, 1143 deaths due to disease occurred. Of these, 575 were CVD deaths, 317 were cancer deaths, and 251 were other-cause deaths. A higher serum LA concentration was associated with a lower risk of death from any cause (multivariable-adjusted HR for the highest compared with the lowest quintile: 0.57; 95% CI: 0.46, 0.71; P-trend 0.001) and with deaths due to CVD (extreme-quintile HR: 0.54; 95% CI: 0.40, 0.74; P-trend 0.001) and non-CVD or noncancer causes (HR: 0.48; 95% CI: 0.30, 0.76; P-trend = 0.001). Serum AA had similar, although weaker, inverse associations. Serum GLA and DGLA were not associated with risk of death, and none of the fatty acids were associated with cancer mortality. The results were generally similar among those with or without a history of major chronic disease (P-interaction 0.13).Our findings showed an inverse association of a higher biomarker of LA intake with total and CVD mortality and little concern for risk, thus supporting the current dietary recommendations to increase LA intake for CVD prevention. The finding of an inverse association of serum AA with the risk of death needs replication in other populations.

Background Depression is a major public health challenge worldwide, and polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, have been found to inversely associate with the risk of depression. However, only few cross-sectional studies have investigated the association between dihomo-γ-linolenic acid (DGLA), an n-6 PUFA with anti-inflammatory effects, and depression. The aims of the present study were to examine an association between serum DGLA and the risk of depression, and to study whether the potential association is mediated via inflammation. Methods A 20-year prospective Kuopio Ischaemic Heart Disease Risk Factor (KIHD) follow-up study was conducted from 1984 to 1989 with 2179 middle-aged and older Finnish men (42–60 years old at baseline). The baseline concentrations of serum fatty acids, including DGLA, were determined. A hospital discharge diagnosis of depression was used as the main outcome and obtained from linkage to National Hospital Discharge Register. Serum C-reactive protein (CRP) levels were measured to assess inflammation. Results An inverse association between serum DGLA concentration and incidence of depression was found after adjustment for several potential confounders (Hazard ratio HR 0.53, CI 0.36–0.79, P=0.002). The association between DGLA and depression was not dependent on inflammation (P-interaction=0.618). Limitations Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting. Conclusions Higher serum DGLA concentrations may predict lower risk of develop depression in elderly men. Further studies are warranted to address potential mechanisms as mechanism behind this association remains unclear., final draft, peerReviewed

Stroke is a leading cause of morbidity and mortality. The role of PUFA in reducing the risk of stroke is uncertain. The concentrations of PUFA in the human body are determined both by dietary intake and by activities of desaturase enzymes. Desaturase enzymes have been associated with chronic diseases, but little is known about their association with stroke risk. We investigated the associations of Δ-6-desaturase (D6D) and Δ-5-desaturase (D5D) activities with stroke risk factors and risk of stroke among 1842 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42–60 years and free of CVD at baseline in 1984–1989. ANCOVA and Cox regression models were used for the analyses. Whole serum desaturase activities were estimated as product:precursor ratios – γ-linolenic acid:linoleic acid for D6D and arachidonic acid:dihomo-γ-linolenic acid for D5D. Higher D6D activity was associated with higher systolic and diastolic blood pressure, BMI, serum insulin and TAG concentrations and worse homoeostatic model assessment (HOMA) indices. In contrast, higher D5D activity was associated with lower systolic and diastolic blood pressure, BMI, serum insulin, LDL-cholesterol, TAG and C-reactive protein concentrations, higher HDL-cholesterol concentration, and better HOMA indices. During the mean follow-up of 21·2 years, 202 stroke cases occurred. Neither D6D activity (multivariable-adjusted extreme-quartile hazard ratios (HR) 1·18; 95 % CI 0·80, 1·74) nor D5D activity (HR 1·06; 95 % CI 0·70, 1·60) were associated with stroke risk. In conclusion, higher D5D activity was favourably associated and higher D6D activity unfavourably associated with several stroke risk factors, but not with the risk of incident stroke.

ObjectiveFatty liver disease (FLD) has been associated with extrahepatic morbidity outcomes. However, reports on the association of FLD, assessed using fatty liver index (FLI), with mortality outcomes have been inconsistent. Our objective was to examine the effect of metabolic factors (blood pressure, insulin, fasting glucose, lipoproteins) on the associations of FLI with mortality outcomes among middle-aged men.Study designProspective cohort study.MethodsOur subjects were 1893 men at baseline from 1984 to 1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study cohort. Multivariable Cox regression models were used to analyse the association of baseline FLI, with the HRs for all-cause, disease, cardiovascular, non-cardiovascular and cancer mortality outcomes.ResultsThe mean FLI in the FLI categories were 16.2 in the low and reference category (FLIConclusionHigh FLI (FLD) is associated with increased risks of mortality outcomes. The FLI-CVD mortality association can be largely explained by metabolic factors. Persons with FLD should be monitored for metabolic deterioration and extrahepatic morbidity to improve their prognoses.

Objective Peripartum depression (PPD) pertaining to depression in pregnancy and postpartum is one of the most common complications around childbirth with enduring adverse effects on mother and child health. Although psychiatric symptoms may improve or worsen over time, relatively little is known about the course of PPD symptoms and possible fluctuations. Methods We applied a person-centered approach to examine PPD symptom patterns across pregnancy and childbirth. 824 women were assessed at three time points: first trimester (T1), third trimester (T2), and again at eight weeks (T3) postpartum. We assessed PPD symptoms, maternal mental health history, and childbirth variables. Results Growth mixture modeling (GMM) analysis revealed four discrete PPD symptom trajectory classes including chronic PPD (1.1%), delayed (10.2%), recovered (7.2%), and resilient (81.5%). Delivery complications were associated with chronic PPD but also with the recovered PPD trajectory class. History of mental health disorders was associated with chronic PPD and the delayed PPD class. Conclusion The findings underscore that significant changes in a woman's depression level can occur across pregnancy and childbirth. While a minority of women experience chronic PDD, for others depression symptoms appear to significantly alleviate over time, suggesting a form of recovery. Our findings support a personalized medicine approach based on the woman's symptom trajectory. Future research is warranted to identify the mechanisms underlying modifications in PPD symptoms severity and those implicated in recovery.

AimsAveraged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.Methods and resultsAn individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration ( n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.ConclusionAveraged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.

Various data-driven models are often involved in epidemiological studies, wherein the availability of data is constantly increasing. Accurate and, at the same time, interpretable models are preferable from the practical point of view. Finding simple and compact dependences between predictors and outcome variables makes it easier to understand necessary interventions and preventive measures. In this study, we applied a Fuzzy Logic-based model, which meets these requirements, to predict the coronary heart disease (CHD) progression during a 30-year follow-up. The Fuzzy Logic-based model was automatically designed with an ad hoc Genetic Algorithm using the data from the Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, a Finnish cohort of 2682 men who were middle-aged at baseline in 1980s. Using cross-validation, we found out that the sample from the KIHD study is heterogeneous and after filtering out 10% of outliers, the predictive accuracy increased from 65% to 73%. The generated rule bases include 19 fuzzy rules on average with maximum 7 variables in one rule from the initial set of 638 predictor variables. The selected predictors of CHD progression are informative and diverse representing physical aspects, behavior, and socioeconomics. The Fuzzy Logic-based model creates a comprehensive set of predictors that enables us to better understand the complexity of illnesses and their progression. Moreover, the Fuzzy Logic-based model has potential to provide tools to analyse and deal with heterogeneity in large cohorts.

Postmenopause is associated with elevated levels of follicle stimulating hormone (FSH) compared to premenopause. There is evidence to suggest that high levels of FSH may influence lipid levels; however, the association between FSH and lipid levels in postmenopausal women has been largely unexplored. OBJECTIVE: The purpose of this study was to evaluate the relation between FSH and lipid levels in postmenopausal women from the Kuopio Ischaemic Heart Disease Risk Factor Study. METHODS: Postmenopausal women (n=588) aged 53–73 and not using hormone therapy were included. The relation between FSH and total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) was evaluated using linear regression, adjusting for estradiol, body mass, smoking and other hormonal and lifestyle factors. The relation between FSH, dyslipidemia and abnormal lipid levels were also evaluated. RESULTS: FSH was positively and linearly associated with TC (p=0.001) and LDL-C (p=0.01) in all participants, with stronger relations seen in younger compared to older postmenopausal women. FSH was less strongly associated with HDL-C and TG. FSH was not associated with dyslipidemia; however, higher FSH was associated with increased risk of high TC (p=0.02) and high LDL-C (p=0.03). CONCLUSIONS: These data suggest that higher FSH in postmenopausal women is related to higher levels of both TC and LDL-C.

Purpose: To estimate the maximum mass-specific oxygen uptake (VO2max) from the ratio of the heart rate at maximal exercise (HRmax) to heart rate at rest (HRrest) in middle-aged men. VO2max is an essential measure of cardiorespiratory fitness, but it is difficult to utilize in clinical practice. The proportionality factor HRmax to HRrest is known to approximate 15 in young welltrained adults. Presumably, the same value is inaccurate for middle-aged men. Materials and Methods: Six-hundred thirty-four men belonging to the Kuopio Ischaemic Heart Disease Risk Factor Study. Their mean age, body mass index (BMI), the daily total physical activity (TPA), VO2max, HRmax, and HRrest were: 49.4±6.4 years, 26.3±3.2 kg/m2, 48.5±10.1 metabolic equivalent hours per day, 33.7±7.6 mL/min/kg, 170.1±15.4 beats/min, and 63.3±10.8 beats/min. They included never-smokers 38%, former smokers 29%, and current smokers 33%. Results: The proportionality factor HRmax to HRrest in around 50-year-old men approximated 12. One year in age, one step change in BMI (normal weight, overweight, obese), smoking status (never, former, current), and TPA (moderately active, active, highly active) reduced the proportionality factor by 0.1, 0.6, 0.4, and 0.1, respectively. The proportionality factor in obese or current smoking middle-aged men was one point lower compared to normal weight or never-smoking peers. This corresponds to approximately 10 years in chronological age. Conclusions: In around 50-year-old men with no cardiovascular diseases, bronchial asthma, or cancer, the HRmax to HRrest ratio should be multiplied by approximately 12 to estimate VO2max. BMI and smoking status can be considered in calculations to improve accuracy.

Background Observational studies on the association of chronic hepatitis C with coronary atherosclerosis have shown varying results and previous related reviews have been inconclusive. By careful outcome classification and further data syntheses, we aimed to clarify current evidence on the association between hepatitis C infection and coronary atherosclerosis. Methods Through systematic searches of PubMed and Scopus, related published observational studies were identified. These were narrowed by review of abstract, full review and quality assessment to yield eligible studies. These were used in qualitative and quantitative syntheses. Results The initial search identified 274 unique publications, which were narrowed to 15 by means of preliminary reviews, and narrowed further to 10 by quality assessment. The endpoints assessed varied, representing different attributes of the disease. The 10 studies were used in the subsequent meta-analyses. The risk of a person with chronic hepatitis C developing coronary atherosclerosis is about triple the risk in uninfected persons (OR = 3.06, 95% CI = 1.99–4.72). Coronary atherosclerosis in persons with chronic hepatitis C is also more severe. The pooled risk of coronary atherosclerosis-related events in persons with chronic hepatitis C was null (OR = 1.10 95% CI = 0.80–1.52). Conclusion The current evidence indicates that hepatitis C virus or factors associated with HCV infection are apparently associated with increased risk of occurrence of coronary atherosclerosis and probably, increased severity of coronary atherosclerosis. Evidence of association with coronary atherosclerosis-related events is yet indeterminate.

Long-chain n-3 PUFA from fish and exercise capacity are associated with CVD risk. Fish, especially large and old predatory fish, may contain Hg, which may attenuate the inverse association of long-chain n-3 PUFA with CVD. However, the associations of long-chain n-3 PUFA or Hg exposure with exercise capacity are not well known. We aimed to evaluate the associations of serum long-chain n-3 PUFA EPA, docosapentaenoic acid (DPA) and DHA and hair Hg with exercise cardiac power (ECP, a ratio of VO2max:maximal systolic blood pressure (SBP) during an exercise test), a measure for exercise capacity. For this, data from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study were analysed cross-sectionally in order to determine the associations between serum long-chain n-3 PUFA, hair Hg and ECP in 1672 men without CVD, aged 42–60 years. After multivariate adjustments, serum total long-chain n-3 PUFA concentration was associated with higher ECP and VO2max (P trend across quartiles=0·04 and P trend=0·02, respectively), but not with maximal SBP (P trend=0·69). Associations were generally similar when EPA, DPA and DHA were evaluated individually. Hair Hg was not associated with ECP, VO2max or maximal SBP. However, the associations of total long-chain n-3 PUFA (P interaction=0·03) and EPA (P interaction=0·02) with higher VO2max were stronger among men with lower hair Hg. Higher serum long-chain n-3 PUFA concentration, mainly a marker for fish consumption in this study population, was associated with higher ECP and VO2max in middle-aged men from eastern Finland., published version, peerReviewed

Fish intake and the long-chain omega-3 polyunsaturated fatty acids (PUFAs) in fish have been suggested to lower the risk of cognitive decline. We assessed whether serum long-chain omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are associated with performance on neuropsychological tests in an older population and whether exposure to methylmercury, mainly from fish, or apolipoprotein-E4 (Apo-E4) phenotype can modify the associations.A total of 768 participants from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study were included. Cognitive function was measured using five neuropsychological tests: the Trail Making Test, the Verbal Fluency Test, the Selective Reminding Test, the Visual Reproduction Test and the Mini Mental State Exam. Multivariate-adjusted analysis of covariance and linear regression were used to analyze the cross-sectional associations.We found statistically significant associations between serum EPA+DPA+DHA and better performance in the Trail Making Test and the Verbal Fluency Test. The individual associations with EPA and DHA were similar with the findings with EPA+DPA+DHA, although the associations with DHA were stronger. No associations were observed with serum DPA. Pubic hair mercury content was associated only with a worse performance in the Trail Making Test, and mercury had only little impact on the associations between the serum PUFAs and cognitive performance. Apo-E4 phenotype did not modify the associations with PUFAs or mercury.Higher serum long-chain omega-3 PUFA concentrations were associated with better performance on neuropsychological tests of frontal lobe functioning in older men and women. Mercury exposure or Apo-E4 phenotype had little impact on cognitive performance.

Objectives Little is known about the role of cardiorespiratory fitness (CRF) and leisure-time physical activity (LTPA) with the risk of lung cancer. Previous research shows that maintaining a sufficient amount of physical activity may have a protective effect against cancer. The aim of this study is to examine the associations of CRF, LTPA and lung cancer among middle-aged Finnish men. Design Prospective cohort study. Methods In a population-based cohort study of 2305 men from Eastern Finland with no history of cancer at baseline. CRF and LTPA data was collected at baseline, 73 cases of lung cancer occurred during an average follow-up of 20-years. Results In a multivariate adjusted model, every 3.8 mL/kg/min (1 SD) increase of CRF was related to a 31% decrease in lung cancer risk across all VO2max quartiles. Furthermore, a 2.8-fold (95% CI 1.14–7.22, p = 0.024) increased risk of lung cancer among men in the lowest quartile (≤20.3 mL/kg/min) of CRF as compared those in the highest quartile (>35.1 mL/kg/min). In a multivariate adjusted model LTPA was not associated to lung cancer. Conclusions In middle-aged men with no history of lung cancer, increasing levels of CRF serves as a protective factor against lung cancer. Increasing CRF may reduce the risk of lung cancer. Furthermore, CRF is a better predictor of lung cancer than LTPA.

Background The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. Design Meta-analysis of individual participant data. Method From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. Results Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. Conclusions The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.

Background: A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child. Methods: KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omits; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics. Discussion: This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.