Comparison of subjective cognitive decline and polygenic risk score in the prediction of all-cause dementia, Alzheimer's disease and vascular dementia.

BACKGROUND: Polygenic risk scores (PRS) and subjective cognitive decline (SCD) are associated with the risk of developing dementia. It remains to examine whether they can improve the established cardiovascular risk factors aging and dementia (CAIDE) model and how their predictive abilities compare. METHODS: The CAIDE model was applied to a sub-sample of a large, population-based cohort study (n = 5,360; aged 50-75) and evaluated for the outcomes of all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD) by calculating Akaike's information criterion (AIC) and the area under the curve (AUC). The improvement of the CAIDE model by PRS and SCD was further examined using the net reclassification improvement (NRI) method and integrated discrimination improvement (IDI). RESULTS: During 17 years of follow-up, 410 participants were diagnosed with dementia, including 139 AD and 152 VD diagnoses. Overall, the CAIDE model showed high discriminative ability for all outcomes, reaching AUCs of 0.785, 0.793, and 0.789 for all-cause dementia, AD, and VD, respectively. Adding information on SCD significantly increased NRI for all-cause dementia (4.4%, p = 0.04) and VD (7.7%, p = 0.01). In contrast, prediction models for AD further improved when PRS was added to the model (NRI, 8.4%, p = 0.03). When APOE ε4 carrier status was included (CAIDE Model 2), AUCs increased, but PRS and SCD did not further improve the prediction. CONCLUSIONS: Unlike PRS, information on SCD can be assessed more efficiently, and thus, the model including SCD can be more easily transferred to the clinical setting. Nevertheless, the two variables seem negligible if APOE ε4 carrier status is available.

Prognostic value of post-operative iron biomarkers in colorectal cancer: population-based patient cohort.

BACKGROUND: Post-operative anaemia is linked to iron deficiency. We investigated the prognostic value of post-operative iron biomarkers in colorectal cancer (CRC). METHODS: Ferritin, transferrin, iron, and transferrin saturation (TS%) were measured from blood collected at a single time-point post-surgery in 2769 CRC patients. Associations between iron biomarkers with cancer-specific survival (CSS) and overall survival (OS) were assessed using Cox regression with hazard ratios (HR), stratified by post-operative time of blood collection (<1-month/≥1-month). RESULTS: After a median follow-up of 9.5 years, 52.6% of patients had died. For iron biomarkers assessed <1-month post-surgery, higher compared to normal TS% was associated with shorter CSS (HR [95% CI] = 2.36 [1.25-4.46]), and higher iron levels with better OS (upper vs. median tertile: HR [95% CI] = 0.79 [0.65-0.97]). When assessed ≥1-month post-surgery, elevated ferritin was associated with poor CSS (high vs. normal: HR [95% CI] = 1.44 [1.10-1.87]), and low TS% with worse CSS (low vs. normal: HR [95% CI] = 1.60 [1.24-2.06]). Similar but weaker associations were observed for OS. CONCLUSION: Monitoring of serum ferritin and TS% beyond 1-month post-surgery may be relevant for risk stratification of patients with operable CRC. Future studies should validate our findings.

The Safety Profile of Vitamin D Supplements Using Real-World Data from 445,493 Participants of the UK Biobank: Slightly Higher Hypercalcemia Prevalence but Neither Increased Risks of Kidney Stones nor Atherosclerosis.

Background: Potential calcium-related adverse events of vitamin D supplement use have not been addressed in large-scale, real-world data so far. Methods: Leveraging data from the UK Biobank, encompassing 445,493 individuals aged 40-69, we examined associations of high 25-hydroxyvitamin (25(OH)D) levels ≥ 100 nmol/L and vitamin D supplementation with hypercalcemia (serum calcium > 2.6 mmol/L), kidney stones, and atherosclerosis assessments (pulse wave arterial stiffness index and carotid intima-medial thickness). Regression models were comprehensively adjusted for 49 covariates. Results: Approximately 1.5% of the participants had high 25(OH)D levels, 4.3% regularly used vitamin D supplements, and 20.4% reported regular multivitamin use. At baseline, the hypercalcemia prevalence was 1.6%, and 1.1% was diagnosed with kidney stones during follow-up. High 25(OH)D levels were neither associated with calcium-related adverse events nor atherosclerosis assessments. Vitamin D and multivitamin supplementation were associated with an increased prevalence of hypercalcemia (odds ratios and 95% confidence intervals: 1.46 [1.32-1.62] and 1.11 [1.04-1.18], respectively) but were neither associated with atherosclerosis nor future kidney stones. Conclusions: High 25(OH)D levels observable in routine care were not associated with any adverse outcome. Vitamin D users have a slightly higher prevalence of hypercalcemia, possibly due to co-supplementation with calcium, but without a higher atherosclerosis prevalence or risk of kidney stones.

Mitochondrial DNA abundance in blood is associated with Alzheimer's disease- and dementia-risk.

The mitochondrial cascade hypothesis of Alzheimer's disease (AD) has been portrayed through molecular, cellular, and animal studies; however large epidemiological studies are lacking. This study aimed to explore the association of mitochondrial DNA copy number (mtDNAcn), a marker representative of mtDNA abundance per cell, with risk of incident all-cause dementia, AD, and vascular dementia diagnosis within 17 years and dementia-related blood biomarkers (P-tau181, GFAP, and NfL). Additionally, sex-stratified analyses were completed. In this German population-based cohort study (ESTHER), 9940 participants aged 50-75 years were enrolled by general practitioners and followed for 17 years. Participants were included in this study if information on dementia status and blood-based mtDNAcn measured via real-time polymerase chain reaction were available. In a nested case-control approach, a subsample of participants additionally had measurements of P-tau181, GFAP, and NfL in blood samples taken at baseline. Of 4913 participants eligible for analyses, 386 were diagnosed with incident all-cause dementia, including 130 AD and 143 vascular dementia cases, while 4527 participants remained without dementia diagnosis within 17 years. Participants with low mtDNAcn (lowest 10%) experienced 45% and 65% percent increased risk of incident all-cause dementia and AD after adjusting for age and sex (all-cause dementia: HRadj, 95%CI:1.45, 1.08-1.94; AD: HRadj, 95%CI: 1.65, 1.01-2.68). MtDNAcn was not associated to vascular dementia diagnosis and was more strongly associated with all-cause dementia among women. In the nested case-control study (n = 790), mtDNAcn was not significantly associated with the dementia-related blood biomarkers (P-tau181, GFAP, and NfL) levels in blood from baseline before dementia diagnosis. This study provides novel epidemiological evidence connecting mtDNA abundance, measured via mtDNAcn, to incident dementia and AD at the population-based level. Reduced mitochondrial abundance may play a role in pathogenesis, especially among women.

Gender-specific factors associated with case complexity in middle-aged and older adults-Evidence from a large population-based study.

OBJECTIVES: To investigate gender-specific factors associated with case complexity in a population-based sample of middle-aged and older adults using a holistic approach to complexity. METHODS: Data were derived from the 8-year follow-up home visits of the ESTHER study-a German population-based study in middle-aged and older adults. Cross-sectional analyses were conducted for 2932 persons (aged 57-84). Complexity was assessed by the well-established INTERMED for the elderly interview, which uses a holistic approach to the definition of case complexity. The association between various bio-psycho-social variables and case complexity was analyzed using gender-specific logistic regression models, adjusted for sociodemographic factors (age, marital status, education). RESULTS: Prevalence of complexity was 8.3% with significantly higher prevalence in female (10.6%) compared to male (5.8%) participants (p < 0.001). Variables associated with increased odds for complexity in both, women and men were: being divorced (odds ratio [OR] women: 1.86, 95% CI 1.05-3.30; OR men: 3.19, 1.25-8.12), higher total somatic morbidity (women: 1.08, 1.04-1.12; men: 1.06, 1.02-1.11), higher depression severity (women: 1.34, 1.28-1.40; men: 1.35, 1.27-1.44), and higher loneliness scores (women: 1.19, 1.05-1.36; men: 1.23, 1.03-1.47). Women (but not men) with obesity (Body mass index [BMI] ≥30) had higher odds (1.79, 1.11-2.89) for being complex compared to those with a BMI <25. High oxidative stress measured by derivatives of reactive oxygen metabolites in serum was associated with 2.02 (1.09-3.74) higher odds for complexity only in men. CONCLUSIONS: This study provides epidemiological evidence on gender differences in prevalence and factors associated with case complexity in middle-aged and older adults. Moreover, this study adds to the holistic understanding of complexity by identifying novel variables linked to complexity among middle-aged and older individuals. These factors include loneliness for both genders, and high oxidative stress for men. These findings should be confirmed in future longitudinal studies.

Longitudinal associations of polypharmacy and frailty with major cardiovascular events and mortality among more than half a million middle-aged participants of the UK Biobank.

BACKGROUND: Studies of the associations of polypharmacy and frailty with adverse health outcomes in middle-aged adults are limited. Furthermore, a potentially stronger association of polypharmacy with adverse health outcomes in frail than in non-frail adults is of interest. OBJECTIVE: To evaluate associations of frailty (assessed using a frailty index) and polypharmacy (defined as taking five or more drugs) with major cardiovascular events, cancer incidence, all-cause, cardiovascular disease-specific, and cancer-specific mortality. METHODS: Cox proportional hazards regression models were used to analyze 501,548 participants of the UK Biobank cohort study aged 40-69 years who were followed up for an average of 12 years. RESULTS: The prevalence of pre-frailty and frailty were 43.2 % and 2.3 %, respectively, and that of polypharmacy was 18.3 %. Although strongly associated with each other, frailty and polypharmacy were independently, statistically significantly associated with major cardiovascular events, cardiovascular disease-specific, and all-cause mortality. In addition, the hazard ratios of polypharmacy were stronger among (pre-)frail than non-frail study participants. No profound associations with cancer incidence and cancer mortality were observed. No sex and age differences were observed. CONCLUSIONS: This large cohort study showed that polypharmacy and frailty are independent risk factors for major cardiovascular events, cardiovascular disease-specific and all-cause mortality in both middle-aged (40-64 years) and older people (≥ 65 years). In addition, the hazard ratios of polypharmacy were stronger among (pre-)frail than non-frail study participants. This underlines the need to avoid polypharmacy as far as possible not only in older but also in middle-aged subjects (40-64 years), especially if they are pre-frail or frail.

Addition of inflammation-related biomarkers to the CAIDE model for risk prediction of all-cause dementia, Alzheimer's disease and vascular dementia in a prospective study.

BACKGROUND: It is of interest whether inflammatory biomarkers can improve dementia prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model. METHODS: The Olink Target 96 Inflammation panel was assessed in a nested case-cohort design within a large, population-based German cohort study (n = 9940; age-range: 50-75 years). All study participants who developed dementia over 20 years of follow-up and had complete CAIDE variable data (n = 562, including 173 Alzheimer's disease (AD) and 199 vascular dementia (VD) cases) as well as n = 1,356 controls were selected for measurements. 69 inflammation-related biomarkers were eligible for use. LASSO logistic regression and bootstrapping were utilized to select relevant biomarkers and determine areas under the curve (AUCs). RESULTS: The CAIDE model 2 (including Apolipoprotein E (APOE) ε4 carrier status) predicted all-cause dementia, AD, and VD better than CAIDE model 1 (without APOE ε4) with AUCs of 0.725, 0.752 and 0.707, respectively. Although 20, 7, and 4 inflammation-related biomarkers were selected by LASSO regression to improve CAIDE model 2, the AUCs did not increase markedly. CAIDE models 1 and 2 generally performed better in mid-life (50-64 years) than in late-life (65-75 years) sub-samples of our cohort, but again, inflammation-related biomarkers did not improve their predictive abilities. CONCLUSIONS: Despite a lack of improvement in dementia risk prediction, the selected inflammation-related biomarkers were significantly associated with dementia outcomes and may serve as a starting point to further elucidate the pathogenesis of dementia.

Cancer-specific risk prediction with a serum microRNA signature.

We recently derived and validated a serum-based microRNA risk score (miR-score) that predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow-up in a population-based cohort study from Germany (ESTHER cohort). Here, we aimed to evaluate associations of the CRC-specific miR-score with the risk of developing other common cancers, including female breast cancer (BC), lung cancer (LC), and prostate cancer (PC), in the ESTHER cohort. MicroRNAs (miRNAs) were profiled by quantitative real-time PCR in serum samples collected at baseline from randomly selected incident cases of BC (n = 90), LC (n = 88), and PC (n = 93) and participants without diagnosis of CRC, LC, BC, or PC (controls, n = 181) until the end of the 17-year follow-up. Multivariate logistic regression models were used to evaluate the associations of the miR-score with BC, LC, and PC incidence. The miR-score showed strong inverse associations with BC and LC incidence [odds ratio per 1 standard deviation increase: 0.60 (95% confidence interval [CI] 0.43-0.82), p = 0.0017, and 0.64 (95% CI 0.48-0.84),p = 0.0015, respectively]. Associations with PC were not statistically significant but pointed in the positive direction. Our study highlights the potential of serum-based miRNA biomarkers for cancer-specific risk prediction. Further large cohort studies aiming to investigate, validate, and optimize the use of circulating miRNA signatures for cancer risk assessment are warranted.

Serum 25-Hydroxyvitamin D Status and Vitamin D Supplements Use Are Not Associated with Low Back Pain in the Large UK Biobank Cohort.

Longitudinal studies assessing the association of vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels < 30 nmol/L, and vitamin D supplement (VDS) use with low back pain (LBP) are sparse. This investigation assessed the cross-sectional and longitudinal association of vitamin D status and VDS use with LBP among 135,934 participants from the UK Biobank cohort. Approximately 21.6% of the participants had vitamin D deficiency, while only 4% regularly took VDS. In the month before study enrollment, 3.8% of the population reported experiencing LBP. An additional 3.3% of the population were diagnosed with LBP by their general practitioners for the first time during a median follow-up of 8.5 years. Vitamin D deficiency and VDS use were cross-sectionally associated with LBP in age- and sex-adjusted models, but these associations were not evident in comprehensively adjusted models. In longitudinal analyses, both vitamin D deficiency and VDS use were not associated with LBP in any model after correction for multiple testing. In conclusion, not unexpectedly due to the fact that LBP is multifactorial, our findings provide no evidence for the role of the vitamin D status in the etiology of LBP.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

From a Clustering of Adverse Symptoms after Colorectal Cancer Therapy to Chronic Fatigue and Low Ability to Work: A Cohort Study Analysis with 3 Months of Follow-Up.

In colorectal cancer (CRC) patients, apart from fatigue, psychological and physical symptoms often converge, affecting their quality of life and ability to work. Our objective was to ascertain symptom clusters within a year following CRC treatment and their longitudinal association with persistent fatigue and reduced work ability at the 3-month follow-up. We used data from MIRANDA, a multicenter cohort study enrolling adult CRC patients who are starting a 3-week in-patient rehabilitation within a year post-curative CRC treatment. Participants completed questionnaires evaluating symptoms at the start of rehabilitation (baseline) and after three months. We performed an exploratory factor analysis to analyze the clustering of symptoms at baseline. Longitudinal analysis was performed using a multivariable linear regression model with dichotomized symptoms at baseline as independent variables, and the change in fatigue and ability to work from baseline to 3-month-follow-up as separate outcomes, adjusted for covariates. We identified six symptom clusters: fatigue, gastrointestinal symptoms, pain, psychosocial symptoms, urinary symptoms, and chemotherapy side effects. At least one symptom from each factor was associated with higher fatigue or reduced ability to work at the 3-month follow-up. This study highlights the interplay of multiple symptoms in influencing fatigue and work ability among CRC patients post-rehabilitation.

The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer's disease, and vascular dementia: a UK Biobank based prospective cohort study.

BACKGROUND: Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations. OBJECTIVES: We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. METHODS: With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank. RESULTS: Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07-1.31) for AD; 1.24 (1.08-1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02-1.19) for AD; 1.15 (1.03-1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively. CONCLUSIONS: Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.

Number of medically prescribed pharmaceutical agents as predictor of mortality risk: a longitudinal, time-variable analysis in the EPIC-Heidelberg cohort.

The number of prescribed medications might be used as proxy indicator for general health status, in models to predict mortality risk. To estimate the time-varying association between active pharmaceutical ingredient (API) count and all-cause mortality, we analyzed data from a population cohort in Heidelberg (Germany), including 25,546 participants with information on medication use collected at 3-yearly intervals from baseline recruitment (1994-1998) until end of 2014. A total of 4548 deaths were recorded until May 2019. Time-dependent modeling was used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for all-cause mortality in relation to number of APIs used, within three strata of age (≤ 60, > 60 to ≤ 70 and > 70 years) and adjusting for lifestyle-related risk factors. For participants reporting commonly used APIs only (i.e., API types accounting for up to 80% of medication time in the population) total API counts showed no association with mortality risk within any age stratum. However, when at least one of the APIs was less common, the total API count showed a strong relationship with all-cause mortality especially up to age ≤ 60, with HR up to 3.70 (95% CI 2.30-5.94) with 5 or 6 medications and 8.19 (5.61-11.97) for 7 or more APIs (versus none). Between > 60 and 70 years of age this risk association was weaker, with HR up to 3.96 (3.14-4.98) for 7 or more APIs, and above 70 years it was weakened further (HR up to 1.54 (1.34-1.79)). Multiple API-use may predict mortality risk in middle-aged and women and men ≤ 70 years, but only if it includes at least one less frequently used API type. With advancing age, and multiple medication becomes increasingly prevalent, the association of API count with risk of death progressively attenuates, suggesting an increasing complexity with age of underlying mortality determinants.

Strong associations of serum selenoprotein P with all-cause mortality and mortality due to cancer, cardiovascular, respiratory and gastrointestinal diseases in older German adults.

BACKGROUND: Selenium is an essential trace mineral. The main function of selenoprotein P (SELENOP) is to transport selenium but it has also been ascribed anti-oxidative effects. METHODS: To assess the association of repeated measurements of serum SELENOP concentration with all-cause and cause-specific mortality serum SELENOP was measured at baseline and 5-year follow-up in 7,186 and 4,164 participants of the ESTHER study, a German population-based cohort aged 50-74 years at baseline. RESULTS: During 17.3 years of follow-up, 2,126 study participants (30%) died. The relationship of serum SELENOP concentration with all-cause mortality was L-shaped, with mortality being significantly higher at SELENOP concentrations < 4.1 mg/L, which is near the bottom tertile's cut-off (4.2 mg/L). All-cause mortality of participants in the bottom SELENOP tertile was significantly increased compared to subjects in the top tertile (hazard ratio [95% confidence interval]: 1.35 [1.21-1.50]). SELENOP in the bottom tertile was further associated with increased cardiovascular mortality (1.24 [1.04-1.49]), cancer mortality (1.31 [1.09-1.58]), respiratory disease mortality (2.06 [1.28-3.32]) and gastrointestinal disease mortality (2.04 [1.25-3.32]). The excess risk of all-cause mortality for those in the bottom SELENOP tertile was more than twice as strong in men as in women (interaction of SELENOP and sex; p = 0.008). CONCLUSIONS: In this large cohort study, serum SELENOP concentration was inversely associated with all-cause and cause-specific mortality. Consistent inverse associations with multiple mortality outcomes might be explained by an impaired selenium transport and selenium deficiency in multiple organs. Trials testing the efficacy of selenium supplements in subjects with low baseline SELENOP concentration are needed. TRIAL REGISTRATION: Retrospectively registered in the German Clinical Trials Register on Feb 14, 2018 (ID: DRKS00014028).

Regional and temporal differences in the associations between cardiovascular disease and its classic risk factors: an analysis of 49 cohorts from 11 European countries.

AIMS: The regional and temporal differences in the associations between cardiovascular disease (CVD) and its classic risk factors are unknown. The current study examined these associations in different European regions over a 30-year period. METHODS AND RESULTS: The study sample comprised 553 818 individuals from 49 cohorts in 11 European countries (baseline: 1982-2012) who were followed up for a maximum of 10 years. Risk factors [sex, smoking, diabetes, non-HDL cholesterol, systolic blood pressure (BP), and body mass index (BMI)] and CVD events (coronary heart disease or stroke) were harmonized across cohorts. Risk factor-outcome associations were analysed using multivariable-adjusted Cox regression models, and differences in associations were assessed using meta-regression. The differences in the risk factor-CVD associations between central Europe, northern Europe, southern Europe, and the UK were generally small. Men had a slightly higher hazard ratio (HR) in southern Europe (P = 0.043 for overall difference), and those with diabetes had a slightly lower HR in central Europe (P = 0.022 for overall difference) compared with the other regions. Of the six CVD risk factors, minor HR decreases per decade were observed for non-HDL cholesterol [7% per mmol/L; 95% confidence interval (CI), 3-10%] and systolic BP (4% per 20 mmHg; 95% CI, 1-8%), while a minor HR increase per decade was observed for BMI (7% per 10 kg/m2; 95% CI, 1-13%). CONCLUSION: The results demonstrate that all classic CVD risk factors are still relevant in Europe, irrespective of regional area. Preventive strategies should focus on risk factors with the greatest population attributable risk.

All classic cardiovascular disease (CVD) risk factors are still relevant in Europe, irrespective of regional area. The differences in the associations of CVD risk factors with overt CVD between regions of Europe are generally small. Minor temporal hazard decreases were observed for non-HDL cholesterol and systolic blood pressure, while a minor hazard increase was observed for body mass index.

Subjective cognitive complaints and blood biomarkers of neurodegenerative diseases: a longitudinal cohort study.

BACKGROUND: Subjective cognitive complaints (SCC) have been mostly studied in the context of Alzheimer's disease in memory clinic settings. The potential of combining SCC with genetic information and blood biomarkers of neurodegenerative diseases for risk assessment of dementia and depression in the absence of dementia among community-dwelling older adults has so far not been explored. METHODS: Data were based on a population-based cohort of 6357 participants with a 17-year follow-up (ESTHER study) and a clinic-based cohort of 422 patients. Participants of both cohorts were grouped according to the diagnosis of dementia (yes/no) and the diagnosis of depression in the absence of dementia (yes/no). Participants without dementia included both cognitively unimpaired participants and cognitively impaired participants. Genetic information (APOE ε4 genotype) and blood-based biomarkers of neurodegenerative diseases (glial fibrillary acidic protein; GFAP, neurofilament light chain; NfL, phosphorylated tau181; p-tau181) were available in the ESTHER study and were determined with Simoa Technology in a nested case-control design. Logistic regression models adjusted for relevant confounders were run for the outcomes of all-cause dementia and depression in the absence of dementia. RESULTS: The results showed that persistent SCC were associated both with increased risk of all-cause dementia and of depression without dementia, independently of the diagnostic setting. However, the results for the ESTHER study also showed that the combination of subjective complaints with APOE ε4 and with increased GFAP concentrations in the blood yielded a substantially increased risk of all-cause dementia (OR 5.35; 95%CI 3.25-8.81, p-value < 0.0001 and OR 7.52; 95%CI 2.79-20.29, p-value < 0.0001, respectively) but not of depression. Associations of NfL and p-tau181 with risk of all-cause dementia and depression were not statistically significant, either alone or in combination with SCC, but increased concentrations of p-tau181 seemed to be associated with an increased risk for depression. CONCLUSION: In community and clinical settings, SCC predict both dementia and depression in the absence of dementia. The addition of GFAP could differentiate between the risk of all-cause dementia and the risk of depression among individuals without dementia.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

Medical care and biomarker-based assessment of mortality in two cohorts of patients with chronic coronary syndrome 10 years apart.

BACKGROUND: This study aimed to describe the characteristics and mortality of two cohorts of patients with chronic coronary syndrome (CCS) recruited with identical study designs in the same rehabilitation clinics but approximately 10 years apart. METHODS: The KAROLA cohorts included patients with CCS participating in an inpatient cardiac rehabilitation programme in Germany (KAROLA-I: years 1999/2000, KAROLA-II: 2009-2011). Blood samples and information on sociodemographic factors, lifestyle, and medical treatment were collected at baseline, at the end of rehabilitation, and after one year of follow-up. A biomarker-based risk model (ABC-CHD model) and Cox regression analysis were used to evaluate cardiovascular (CV) and non-CV mortality risk. RESULTS: We included 1130 patients from KAROLA-I (mean age 58.7 years, 84.4% men) and 860 from KAROLA-II (mean age 60.4 years, 83.4% men). Patients in the KAROLA-I cohort had significantly higher concentrations of CV biomarkers and fewer patients were taking CV medications, except for statins. The biomarker-based ABC-CHD model provided a higher estimate of CV death risk for patients in the KAROLA-I cohort (median 3-year risk, 3.8%) than for patients in the KAROLA-II cohort (median 3-year risk, 2.7%, p-value for difference < 0.001). After 10 years of follow-up, 91 (8.1%) patients in KAROLA-I and 45 (5.2%) in KAROLA-II had died from a CV event. CONCLUSIONS: Advances in disease management over the past 20 years may have led to modest improvements in pharmacological treatment during cardiac rehabilitation and long-term outpatient care for patients with CCS. However, modifiable risk factors such as obesity have increased in the more recent cohort and should be targeted to further improve the prognosis of these patients.

Gender-specific association of loneliness and health care use in community-dwelling older adults.

BACKGROUND: Loneliness in older adults is common, particularly in women. In this article, gender differences in the association of loneliness and health care use are investigated in a large sample of community-dwelling older adults. METHODS: Data of 2525 persons (ages 55-85 years)-participants of the fourth follow- up (2011-2014) of the ESTHER study- were analyzed. Loneliness and health care use were assessed by study doctors in the course of a home visit. Gender-specific regression models with Gamma-distribution were performed using loneliness as independent variable to predict outpatient health care use, adjusted for demographic variables. RESULTS: In older women, lonely persons were shown to have significantly more visits to general practitioners and mental health care providers in a three-month period compared to less lonely persons (p = .005). The survey found that outpatient health care use was positively associated with loneliness, multimorbidity, and mental illness in older women but not in older men. Older men had significantly more contact with inpatient care in comparison to women (p = .02). CONCLUSIONS: It is important to consider gender when analyzing inpatient and outpatient health care use in older persons. In older women loneliness is associated with increased use of outpatient services.

Associations of 25-hydroxyvitamin D status and vitamin D supplementation use with mortality due to 18 frequent cancer types in the UK Biobank cohort.

BACKGROUND: Although the associations of serum 25-hydroxyvitamin D (25(OH)D) levels and vitamin D supplementation with total cancer mortality are well-known, evidence regarding the association of 25(OH)D and cancer site-specific mortality is predominantly limited to common cancer types, and most studies on vitamin D supplementation use have limitations on sample size and the adjustment of important confounding factors. METHODS: We used cause-specific Cox regression models adjusted for 48 covariates to assess the associations of vitamin D deficiency, insufficiency, and vitamin D supplementation use with mortality from any cancer and 18 specific cancers in 411,436 United Kingdom Biobank participants, aged 40-69 years. RESULTS: The majority of the study population had either vitamin D deficiency (21.1%) or insufficiency (34.4%). Furthermore, 4.1% and 20.3% of the participants regularly took vitamin D or multivitamin supplements, respectively. During a median follow-up of 12.7 years, vitamin D deficiency was associated with significantly increased mortality from total cancer and four specific cancers: stomach (hazard ratio, 95% confidence interval: 1.42, 1.05-1.92), colorectal (1.27, 1.07-1.50), lung (1.24, 1.10-1.40), and prostate (1.36, 1.06-1.75). Vitamin D insufficiency was associated with increased colorectal (1.14, 1.00-1.30) and lung cancer mortality (1.19, 1.08-1.32). Compared to non-users, vitamin D use was associated with lower lung cancer (0.75, 0.60-0.95) and total cancer mortality. Multivitamin use was associated with lower mortality from melanoma (0.64, 0.43-0.97). CONCLUSION: Vitamin D deficiency and insufficiency were associated with increased mortality from multiple common cancers. The potential to reduce cancer mortality by vitamin D supplementation in populations with low 25(OH)D levels should be further explored.