Renal Hyperfiltration as a New Mechanism of Smoking-Related Mortality.

INTRODUCTION: Renal hyperfiltration (RHF), an established risk factor for mortality, is prevalent among tobacco smokers. The aim of this study was to assess the mediating role of RHF in the association between smoking and mortality. AIMS AND METHODS: Data of this study were retrieved from the cohort of the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), including 2064 males from Finland. Study participants were followed over a 35-year period. Using classic and counterfactual mediation analysis approaches, we estimated the mediative effect of RHF in the association between smoking and each of the following outcomes: All-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality. RESULTS: The risk of all-cause mortality in smokers was twice that in nonsmokers (hazard ratio [HR], 2.06; 95% confidence interval [CI]: 1.84 to 2.31). Under the counterfactual framework the direct effect of smoking on all-cause mortality, controlled for RHF, corresponded to an HR of 2.00 (95% CI: 1.78 to 2.30). Of the effect of smoking on mortality, 5% (p-value = .016) was mediated by RHF. This finding concerned particularly non-CVD mortality. CONCLUSIONS: RHF mediated the effect of smoking on non-CVD and all-cause mortality, but not on CVD mortality. The generalizability of our study results is however limited by its focus on a Finnish male cohort, underscoring the need for further investigation into RHF's broader implications across diverse populations. IMPLICATIONS: This study elucidates the complex interplay between smoking, renal hyperfiltration (RHF), and mortality, offering novel insights into the mediating role of RHF. Our findings demonstrate that RHF significantly mediates the relationship between smoking and non-cardiovascular disease (non-CVD), but not CVD mortality. This distinction underscores the multifaceted role of RHF beyond its established association with cardiovascular events. By highlighting the specific pathways through which RHF mediates some of the smoking-attributed mortality, this research contributes to our understanding of the mechanisms linking smoking to mortality.

Multiplicative, additive, and interactive associations of 25-hydroxyvitamin D with lung and prostate cancer.

Results regarding the epidemiological association of vitamin D with lung (LCA) and prostate cancer (PCA) are controversial. This study tested whether serum 25-hydroxyvitamin D [25(OH)D] concentrations have interactive epidemiological associations with smoking, the number-one risk factor for LCA, and age, the number-one risk factor for PCA. Also, this study investigated whether the associations of 25(OH)D, smoking, age, alcohol consumption, body mass index, diet (the healthy Nordic diet score), and physical activity with incident LCA and PCA are multiplicative or additive. The study of association types makes it easier to select appropriate statistical methods. The Kuopio Ischaemic Heart Disease Risk Factor Study provided the data of 2578 men with 112 LCA and 300 PCA cases over 35 years by the end of 2019. Serum 25(OH)D did not associate with LCA and PCA or interact with smoking and age. The association of smoking with LCA was additive; 13 extra cases per 1000 men every 10 years. Age and alcohol consumption multiplicatively increased the hazard of LCA (hazard ratio, 95% confidence interval for age >50: 3.56, 1.82-6.17; drink per week: 1.01, 1.00-1.03), whereas adherence to healthy Nordic diet decreased it (per score point: 0.95, 0.89-1.00). The association of age >50 with PCA was additive; 2.5 extra cases per 1000 men every 10 years. To conclude, there was no epidemiological relationship of pre-diagnostic 25(OH)D concentrations with the incidence of LCA and PCA. The respective associations of smoking and age >50 with LCA and PCA were additive rather than multiplicative.

Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque: Individual Participant Data Meta-Analysis of 20 Prospective Studies.

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.

What is the most appropriate follow-up time for detecting the epidemiological relationship between coronary artery disease and its main risk factors: novel findings from a 35-year follow-up study.

BACKGROUND: The aim was to investigate the most appropriate follow-up time to detect the associations of coronary artery disease (CAD) with its traditional risk factors in a long-term prospective cohort study. METHODS: The Kuopio Ischaemic Heart Disease Risk Factors Study provided the study material of 1958 middle-aged men free from CAD at baseline and followed up for 35 years. We performed Cox models adjusted for age, family history, diabetes, obesity, hypercholesterolemia, hypertension, smoking, and physical activity, investigated covariate interactions, and tested Schoenfeld residuals to detect time-dependent covariates. Moreover, we applied a sliding window procedure with a subarray of 5 years to better differentiate between risk factors manifested within years and those manifested within decades. The investigated manifestations were CAD and fatal acute myocardial infarction (AMI). RESULTS: Seven hundred seventeen (36.6%) men had CAD, and 109 (5.6%) men died from AMI. After 10 years of follow-up, diabetes became the strongest predictor of CAD with a fully adjusted hazard ratio (HR) of 2.5-2.8. During the first 5 years, smoking was the strongest predictor (HR 3.0-3.8). When the follow-up time was 8-19 years, hypercholesterolemia predicted CAD with a HR of >2. The associations of CAD with age and diabetes depended on time. Age hypertension was the only statistically significant covariate interaction. The sliding window procedure highlighted the significance of diabetes over the first 20 years and hypertension after that. Regarding AMI, smoking was associated with the highest fully adjusted HR (2.9-10.1) during the first 13 years. The associations of extreme and low physical activity with AMI peaked when the follow-up time was 3-8 years. Diabetes showed its highest HR (2.7-3.7) when the follow-up time was 10-20 years. During the last 16 years, hypertension was the strongest predictor of AMI (HR 3.1-6.4). CONCLUSION: The most appropriate follow-up time for most CAD risk factors was 10-20 years. Concerning smoking and hypertension shorter and longer follow-up times could be considered, respectively, particularly when studying fatal AMI. In general, prospective cohort studies of CAD would provide more comprehensive results by reporting point estimates in relation to more than one timepoint and concerning sliding windows.

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Racial and Ethnic Differences in the Association Between Classical Cardiovascular Risk Factors and Common Carotid Intima-Media Thickness: An Individual Participant Data Meta-Analysis.

Background The major risk factors for atherosclerotic cardiovascular disease differ by race or ethnicity but have largely been defined using populations of European ancestry. Despite the rising prevalence of cardiovascular disease in Africa there are few related data from African populations. Therefore, we compared the association of established cardiovascular risk factors with carotid-intima media thickness (CIMT), a subclinical marker of atherosclerosis, between African, African American, Asian, European, and Hispanic populations. Methods and Results Cross-sectional analyses of 34 025 men and women drawn from 15 cohorts in Africa, Asia, Europe, and North America were undertaken. Classical cardiovascular risk factors were assessed and CIMT measured using B-mode ultrasound. Ethnic differences in the association of established cardiovascular risk factors with CIMT were determined using a 2-stage individual participant data meta-analysis with beta coefficients expressed as a percentage using the White population as the reference group. CIMT adjusted for risk factors was the greatest among African American populations followed by Asian, European, and Hispanic populations with African populations having the lowest mean CIMT. In all racial or ethnic groups, men had higher CIMT levels compared with women. Age, sex, body mass index, and systolic blood pressure had a significant positive association with CIMT in all races and ethnicities at varying magnitudes. When compared with European populations, the association of age, sex, and systolic blood pressure with CIMT was weaker in all races and ethnicities. Smoking (beta coefficient, 0.39; 95% CI, 0.09-0.70), body mass index (beta coefficient, 0.05; 95% CI, 0.01-0.08) and glucose (beta coefficient, 0.13; 95% CI, 0.06-0.19) had the strongest positive association with CIMT in the Asian population when compared with all other racial and ethnic groups. High-density lipoprotein-cholesterol had significant protective effects in African American (beta coefficient, -0.31; 95% CI, -0.42 to -0.21) and African (beta coefficient, -0.26; 95% CI, -0.31 to -0.19) populations only. Conclusions The strength of association between established cardiovascular risk factors and CIMT differed across the racial or ethnic groups and may be due to lifestyle risk factors and genetics. These differences have implications for race- ethnicity-specific primary prevention strategies and also give insights into the differential contribution of risk factors to the pathogenesis of cardiovascular disease. The greatest burden of subclinical atherosclerosis in African American individuals warrants further investigations.

Epidemiological analysis of coronary heart disease and its main risk factors: are their associations multiplicative, additive, or interactive?

OBJECTIVE: The purpose of this study was to discover how considering multiplicative, additive, and interactive effects modifies results of a prospective cohort study on coronary heart disease (CHD) incidence and its main risk factors. MATERIAL AND METHODS: The Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study provided the study material, 2682 Eastern Finnish middle-aged men, followed since the 1980s. We applied multiplicative and additive survival models together with different statistical metrics and confidence intervals for risk ratios and risk differences to estimate the nature of associations. RESULTS: The mean (SD) follow-up time among men who were free of CHD at baseline (n = 1958) was 21.4 (10.4) years, and 717 (37%) of them had the disease and 301 (15%) died for CHD before the end of follow-up. All tested non-modifiable and modifiable risk factors statistically significantly predicted CHD incidence. We detected three interactions: circulating low-density lipoprotein cholesterol (LDL-C) × age, obesity × age, and obesity × smoking of which LDL-C × age was the most evident one. High LDL-C increased the risk of CHD more among men younger than 50 [risk ratio (RR) 2.10] than those older than 50 (RR 1.22). LDL-C status was the only additive covariate. The additive effect of high LDL-C increased almost linearly up to 18 years and then reached a plateau. The simple multiplicative survival model stressed glycemic status as the strongest modifiable risk factor for developing CHD [hazard ratio (HR) for diabetes vs. normoglycemia was 2.69], whereas the model considering interactions and time dependence emphasised the role of LDL-C status (HR for high LDL-C vs. lower than borderline was 4.43). Age was the strongest non-modifiable predictor. CONCLUSIONS: Including covariate interactions and time dependence in survival models potentially refine results of epidemiological analyses and ease to define the order of importance across CHD risk factors. KEY MESSAGESIncluding covariate interactions and time dependence in survival models potentially refine results of epidemiological analyses on coronary heart disease.Including covariate interactions and time dependence in survival models potentially ease to define the order of importance across coronary heart disease risk factors.

How competing risks affect the epidemiological relationship between vitamin D and prostate cancer incidence? A population-based study.

We hypothesized that controversial results regarding the epidemiological relationship between circulating 25-hydroxyvitamin D, 25(OH)D, and risk of prostate cancer (PCA) incidence are partly due to competing risks. To test the hypothesis, we studied associations across 25(OH)D, PCA and death in 2578 middle-aged men belonging to the Kuopio Ischaemic Heart Disease Risk Factor Study. The men were free of cancer at baseline, and the mean (SD) follow-up time was 23.3 (9.1) years. During this period, 296 men had a PCA diagnosis, and 1448 men died without the PCA diagnosis. The absolute risk of developing PCA was highest in the highest 25(OH)D tertile (15%), whereas that of death was highest in the lowest 25(OH)D tertile (67%). A competing risk analysis showed that belonging to the highest 25(OH)D tertile increased the risk of PCA incidence and improved survival with the respective hazard ratios (HR) of 1.35 (95% CI = 1.07-1.70) and 0.79 (95% CI = 0.71-0.89). Adjusting for 10 covariates together with 25(OH)D did not significantly change the results, but the respective adjusted HRs for PCA and death were 1.20 and 0.87. To conclude, the competing risk analysis did not eliminate the direct relationship between 25(OH)D and PCA but rather strengthened it.

Synergic Interaction of Vitamin D Deficiency and Renal Hyperfiltration on Mortality in Middle-Aged Men.

OBJECTIVE: Vitamin D deficiency and renal hyperfiltration (RHF) are prevalent conditions both recently linked with mortality. The two conditions are interrelated, but their combined effect and interaction on mortality have not been studied. The objective of this study was to assess the combined effect and interaction of vitamin D deficiency and RHF on all-cause, cardiovascular (CV), and non-CV mortality in nondiabetic middle-aged men. METHODS: Middle-aged nondiabetic men (n = 1,959) were followed up for a median of 28 years. With adjustment for age, body mass index (BMI), smoking, BMI-smoking interaction, healthy Nordic diet (HND), alcohol consumption, and hypertension, we fitted Cox proportional hazard models to estimate the hazard ratios (HRs) of all-cause-, CV-, and non-CV mortality with respect to vitamin D deficiency and RHF. We evaluated the effect of interaction between RHF and vitamin D on the outcomes on the additive and multiplicative scales. RESULTS: Vitamin D deficiency and RHF, both individually and combined, are associated with a high hazard of mortality. The HRs for all-cause- and non-CV mortality were highest among men with coexisting vitamin D deficiency and RHF (HR, 3.02; 95% CI, 1.90 to 4.79; and HR, 3.63; 95% CI, 2.07 to 6.36; respectively). We found a synergic interaction between vitamin D deficiency and RHF in respect to all-cause (RERI, 1.47; 95% CI, 0.03 to 2.9) and non-CV mortality (RERI, 2.09; 95% CI, 0.02 to 4.16) of type positive multiplicative, positive additive. CONCLUSION: The synergic interaction of vitamin D deficiency and RHF on mortality might have importance in the global burden of the two conditions. Further studies investigating cause-specific mortality are needed to highlight underlying mechanisms by which vitamin D deficiency and RHF interact.

Serum ferritin and incident cardiometabolic diseases in Scottish adults.

BACKGROUND: Iron stores, estimated as ferritin levels, and type 2 diabetes (T2D) have been associated previously, while findings regarding coronary heart disease (CHD) and cerebrovascular disease (CEVD) are still inconclusive. No study has focused on simultaneous evaluation of associations between iron stores and the above cardiometabolic diseases (CMD) in the same population. We aim to evaluate the association between serum ferritin and risk of T2D, CHD and CEVD in Scottish population over a wide range of ferritin levels. METHODS: Longitudinal study in 6,497 participants of the 1995 and 1998 Scottish health surveys, who were followed-up until 2011. Cox regression models were conducted adjusting for age, sex/menopausal status, fibrinogen, GGT levels, smoking, alcohol consumption, total cholesterol, HDL-cholesterol, blood pressure, and BMI. Ferritin was used as continuous (sex/menopausal status-specific Z score) and categorical variable (sex/menopausal status-specific quartiles, quintiles and sextiles). RESULTS: During follow-up, 4.9% of the participants developed T2D, 5.3% CHD, and 2.3% CEVD. By using ferritin quartiles, serum ferritin was positively associated with T2D, CHD and CEVD but only the association with T2D remained after adjustment for covariates [Quartile 4 v. 1: adjusted HR 95% CI 1.59 (1.10-2.34); P = 0.006]. When ferritin sextiles were used (6 v. 1), the ferritin-CEVD association became slightly stronger and significant [adjusted HR 95% CI 2.08 (1.09-3.94); P = 0.024]. CONCLUSIONS: Iron stores relate differently to each CMD. Serum ferritin levels were positively and independently associated with incident T2D, and with incident CEVD if higher cut-off points for high ferritin levels were considered.

Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial: a randomized controlled trial.

BACKGROUND: Vitamin D insufficiency is associated with risks of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited. OBJECTIVES: To investigate the effects of vitamin D3 supplementation on CVD and cancer incidences. METHODS: The study was a 5-year, randomized, placebo-controlled trial among 2495 male participants ≥60 years and post-menopausal female participants ≥65 years from a general Finnish population who were free of prior CVD or cancer. The study had 3 arms: placebo, 1600 IU/day, or 3200 IU/day vitamin D3. Follow-up was by annual study questionnaires and national registry data. A representative subcohort of 551 participants had more detailed in-person investigations. The primary endpoints were incident major CVD and invasive cancer. Secondary endpoints included the individual components of the primary CVD endpoint (myocardial infarction, stroke, and CVD mortality), site-specific cancers, and cancer death. RESULTS: During the follow-up, there were 41 (4.9%), 42 (5.0%), and 36 (4.3%) major CVD events in the placebo, 1600 IU/d (compared with placebo: HR: 0.97; 95% CI: 0.63-1.49; P = 0.89), and 3200 IU/d (HR: 0.84; 95% CI: 0.54-1.31; P = 0.44) arms, respectively. Invasive cancer was diagnosed in 41 (4.9%), 48 (5.8%), and 40 (4.8%) participants in the placebo, 1600 IU/d (HR: 1.14; 95% CI: 0.75-1.72; P = 0.55), and 3200 IU/d (HR: 0.95; 95% CI: 0.61-1.47; P = 0.81) arms, respectively. There were no significant differences in the secondary endpoints or total mortality. In the subcohort, the mean baseline serum 25-hydroxyvitamin D concentration was 75 nmol/L (SD, 18 nmol/L). After 12 months, the concentrations were 73 nmol/L (SD, 18 nmol/L), 100 nmol/L (SD, 21 nmol/L), and 120 nmol/L (SD, 22 nmol/L) in the placebo, 1600 IU/d, and 3200 IU/d arms, respectively. CONCLUSIONS: Vitamin D3 supplementation did not lower the incidences of major CVD events or invasive cancer among older adults, possibly due to sufficient vitamin D status in most participants at baseline.

Economic Recession and the Risk of Cancer: A Cohort Study From Eastern Finland.

BACKGROUND: Little is known about the role of economic recessions in the risk of cancer. Therefore, we evaluated the impact of the severe economic recession in Finland from 1991-1994 on the incidence of all cancers and cancer subtypes among a middle-age and older population. METHODS: From the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), a population-based sample of 1,620 women and men aged 53-73 years were examined from 1998-2001. The cancer-free participants completed a questionnaire on the possible impact of the 1990s recession in Finland on their lives. Incident cases of cancer were obtained through record linkage with the Finnish Cancer Registry. Cox proportional hazards regression was used to estimate hazard ratios (HR) of incident cancer events after adjusting for possible confounders. RESULTS: A total of 1,096 cancer-free participants had experienced socioeconomic hardships due to the recession at the baseline. During 20 years of follow-up, 473 participants developed cancer. After adjustment for age, baseline socioeconomic position, and lifestyle factors, the risk of all cancers was 32% higher among men who experienced socioeconomic hardships compared to those who did not (HR 1.32; 95% confidence interval [CI], 1.00-1.74, P = 0.05). Prostate-genital cancer was 71% higher among men with hardships (n = 103, HR 1.71; 95% CI, 1.06-2.74, P = 0.02). No association was observed between socioeconomic hardships and subsequent risk of total or any subtype of cancer among women. CONCLUSION: The 1990s economic recession was associated with increased risk of all cancers, especially prostate-genital cancer among Finnish middle-age and older men, but no association with cancer was observed in women.

Mortality-based definition of renal hyperfiltration in middle-aged men: a 35-year cohort from Finland.

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.

Long-term changes in sense of coherence and mortality among middle-aged men: A population -based follow-up study.

Sense of coherence (SOC) scale measures one's orientation to life. SOC is the core construct in Antonovsky's salutogenic model of health. It has been shown that weak SOC correlates with poor perceived health, low quality of life, and increased mortality. Some studies have indicated that SOC is not stable across life, but there are no previous studies on how a change of SOC is reflected in mortality. However, there is some evidence that a change in perceived quality of life is associated with mortality. The study explores the association between the change in SOC and mortality using longitudinal data from a cohort of middle-aged Finnish men recruited between 1986 and 1989. Approximately 11 years after the baseline examinations, between 1998 and 2001, 854 men returned the SOC questionnaire a second time. The baseline SOC was adjusted for the regression to the mean phenomenon between the two measurements. The hazard ratios of the SOC difference scores were adjusted for initial SOC age and 12 somatic risk factors of mortality (alcohol consumption, blood pressure, body mass index, cholesterol concentration, physical activity, education, smoking, marital status, employment status, history of cancer, history of cardiovascular disease and diabetes). SOC was not stable among middle-aged Finnish men and a decline in SOC was associated with an increased hazard of all-cause mortality. In the fully adjusted model, a decrease of one standard deviation (SD) of the SOC mean difference increased the mortality hazard by about 35 %, two SDs decrease about 70 %, and 2.5 SDs about 100 %. Strengthening SOC showed a limited association with decreasing mortality hazards in the age-adjusted model. Policies, strategies, or plans, supporting SOC in the middle-age may help to decrease mortality and increase quality of life in later years.

Negative interaction of fatty liver and hypertension on cardiovascular mortality in non-diabetic men: 34 years of follow-up.

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.

Renal hyperfiltration, fatty liver index, and the hazards of all-cause and cardiovascular mortality in Finnish men.

OBJECTIVES: Renal hyperfiltration (RHF) and fatty liver are separately associated with adverse health outcomes. In this study, we investigated the mortality hazard of coexisting RHF and fatty liver. METHODS: Middle-aged men from the Kuopio Ischaemic Disease Risk Factor Study (n=1,552) were followed up for a median of 29 years. Associations among RHF, fatty liver index (FLI) score, age, body mass index, smoking status, alcohol consumption, and hypertension status were assessed using logistic regression. Cox proportional hazards models were used to determine the hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality with respect to RHF and fatty liver. RESULTS: Of the men, 5% had RHF (n=73), whereas a majority had fatty liver (n=848). RHF was associated specifically with smoking, and fatty liver was associated specifically with overweight. The all-cause mortality hazard was highest (HR, 1.96; 95% confidence interval [CI], 1.27 to 3.01) among men with RHF and fatty liver (n=33). Among men with RHF but normal FLI (n=40), the HR of all-cause mortality was 1.67 (95% CI, 1.15 to 2.42). Among men with fatty liver but a normal estimated glomerular filtration rate (n=527), the HR of all-cause mortality was 1.35 (95% CI, 1.09 to 1.66). CVD mortality hazard was associated with RHF, but not fatty liver. We detected no interaction effect between RHF and fatty liver for all-cause (synergy index, 0.74; 95% CI, 0.21 to 2.67) or CVD (synergy index, 0.94; 95% CI, 0.34 to 2.60) mortality. CONCLUSIONS: RHF and fatty liver are independently associated with all-cause and CVD mortality.

Estimating Maximal Oxygen Uptake from the Ratio of Heart Rate at Maximal Exercise to Heart Rate at Rest in Middle-Aged Men.

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 well-trained 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.

Associations of the serum metabolite profile with a healthy Nordic diet and risk of coronary artery disease.

BACKGROUND & AIM: A healthy Nordic diet (HND) rich in wholegrain cereals, berries, vegetables, and fish, has been associated with a lower risk of cardiovascular disease, but the molecular links remain unclear. Here, we present the application of nontargeted metabolic profiling based on liquid chromatography with tandem mass spectrometry (LC-MS/MS) to identify metabolites that would potentially reflect the adherence to HND and their relationship with the risk of coronary artery disease (CAD). METHODS: From a Finnish population-based prospective cohort (Kuopio Ischaemic Heart Disease Risk Factor Study; KIHD), we collected 364 baseline serum samples in 4 groups: 1) 94 participants with high adherence to HND who developed CAD during the follow-up of 20.4 ± 7.6 years (cases), 2) 88 participants with high adherence who did not develop CAD during follow-up (controls), 3) 93 CAD cases with low adherence, and 4) 89 controls with low adherence. RESULTS: Indolepropionic acid, proline betaine, vitamin E derivatives, and medium-chain acylcarnitines were associated with adherence to HND after adjustments for age, waist-to-hip ratio (WHR), physical activity, and total cholesterol. These metabolites also correlated negatively with blood lipid profiles, BMI, insulin, inflammation marker high-sensitivity C reactive protein (hsCRP), smoking, and alcohol consumption, as well as positively with physical activity. Predictors of CAD risk included several lipid molecules, which also indicated lower adherence to HND. But, only the associations with the plasmalogens PC(O-16:0/18:2) and PC(O-16:1/18:2) remained significant after adjusting for age, smoking, systolic blood pressure, LDL cholesterol, and WHR. These plasmalogens did not correlate with any investigated risk factors of CAD at baseline, which may highlight their potential as novel predictors of CAD risk. Interestingly, the metabolic profile predicting CAD risk differed based on the adherence to HND. Also, HND adherence was more distinct within CAD cases than controls, which may emphasize the interaction between HND adherence and CAD risk. CONCLUSIONS: The association between higher adherence to HND and a lower risk of CAD likely involves a complex interaction of various endogenous, plant-, and microbial-derived metabolites.

Cervical Cancer Screening Participation among Women of Russian, Somali, and Kurdish Origin Compared with the General Finnish Population: A Register-Based Study.

Migrant-origin women are less prone to cervical screening uptake compared with host populations. This study examined cervical cancer screening participation and factors associated with it in the Finnish mass screening program during 2008-2012 in women of Russian, Somali and Kurdish origin compared with the general Finnish population (Finns) in Finland. The study population consists of samples from the Finnish Migrant Health and Well-being Study 2010-2012 and Health 2011 Survey; aged 30-64 (n = 2579). Data from the Finnish screening register linked with other population-based registry data were utilized. For statistical analysis we employed logistic regression. Age-adjusted screening participation rates were Russians 63% (95% CI: 59.9-66.6), Somalis 19% (16.4-21.6), Kurds 69% (66.6-71.1), and Finns 67% (63.3-69.8). In the multiple-adjusted model with Finns as the reference; odds ratios for screening were among Russians 0.92 (0.74-1.16), Somalis 0.16 (0.11-0.22), and Kurds 1.37 (1.02-1.83). Among all women, the substantial factor for increased screening likelihood was hospital care related to pregnancy/birth 1.73 (1.27-2.35), gynecological 2.47 (1.65-3.68), or other reasons 1.53 (1.12-2.08). Screening participation was lower among students and retirees. In conclusion, screening among the migrant-origin women varies, being significantly lowest among Somalis compared with Finns. Efforts using culturally tailored/population-specific approaches may be beneficial in increasing screening participation among women of migrant-origin.

Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

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.