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Background: Increased lung cancer risks for low socioeconomic status (SES) groups are only partially attributable to smoking habits. Little effort has been made to investigate the persistent risks related to low SES by quantification of potential biases., Methods: Based on 12 case-control studies, including 18 centers of the international SYNERGY project (16,550 cases, 20,147 controls), we estimated controlled direct effects (CDE) of SES on lung cancer via multiple logistic regression, adjusted for age, study center, and smoking habits and stratified by sex. We conducted mediation analysis by inverse odds ratio weighting to estimate natural direct effects and natural indirect effects via smoking habits. We considered misclassification of smoking status, selection bias, and unmeasured mediator-outcome confounding by genetic risk, both separately and by multiple quantitative bias analyses, using bootstrap to create 95% simulation intervals (SI)., Results: Mediation analysis of lung cancer risks for SES estimated mean proportions of 43% in men and 33% in women attributable to smoking. Bias analyses decreased the direct effects of SES on lung cancer, with selection bias showing the strongest reduction in lung cancer risk in the multiple bias analysis. Lung cancer risks remained increased for lower SES groups, with higher risks in men (fourth vs. first [highest] SES quartile: CDE, 1.50 [SI, 1.32, 1.69]) than women (CDE: 1.20 [SI: 1.01, 1.45]). Natural direct effects were similar to CDE, particularly in men., Conclusions: Bias adjustment lowered direct lung cancer risk estimates of lower SES groups. However, risks for low SES remained elevated, likely attributable to occupational hazards or other environmental exposures., Competing Interests: Disclosure: The authors do not declare any conflict of interest. J.H., B.K., T. Brüning, and T. Behrens, as staff of the Institute for Prevention and Occupational Medicine (IPA), are employed by the study’s main financing body, the German Social Accident Insurance. IPA is an independent research institute of the Ruhr-University Bochum. The authors are independent of the German Social Accident Insurance in study design, access to the collected data, responsibility for data analysis and interpretation, and the right to publish. The views expressed in this article are those of the authors and not necessarily those of the sponsor. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policies, or views of the International Agency for Research on Cancer/World Health Organization., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In patients with coronary artery disease and concomitant asymptomatic severe carotid stenosis, combined simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) has been widely performed despite lack of evidence from randomized trials. We recently showed that the risk of stroke or death within 30 days was higher following CABG+CEA compared with CABG alone. Here, we report long-term outcomes following CABG with versus without CEA., Methods: The CABACS (Coronary Artery Bypass Graft Surgery in Patients With Asymptomatic Carotid Stenosis Study) is a randomized, controlled, multicenter, open trial. Patients with asymptomatic severe (≥70%) carotid stenosis undergoing CABG were allocated either CABG+CEA or CABG alone, and follow-up was 5 years. Major secondary end points included nonfatal stroke or death, any death and any nonfatal stroke. Due to low recruitment, the study was stopped prematurely after randomization of 127 patients in 17 centers., Results: By 5 years, the rate of stroke or death did not significantly differ between groups (CABG+CEA 40.6% [95% CI, 0.285-0.536], CABG alone 35.0% [95% CI, 0.231-0.484]; P =0.58). Higher albeit statistically nonsignificant rates of nonfatal strokes occurred at any time following CABG+CEA versus CABG alone (1 year: 19.3% versus 7.1%, P =0.09; 5 years: 29.4% versus 18.8%, P =0.25). All-cause mortality up to 5 years was similar in both groups (CABG+CEA: 25.4% versus CABG alone: 23.3%, hazard ratio, 1.148 [95% CI, 0.560-2.353]; P =0.71). Subgroup analyses did not reveal any significant effect of age, sex, preoperative modified Rankin Scale and center on outcome events., Conclusions: During 5-years follow-up, combined simultaneous CABG+CEA was associated with a higher albeit statistically nonsignificant rate of stroke or death compared with CABG alone. This was mainly due to a nonsignificantly higher perioperative risk following CABG+CEA. Since the power of our study was not sufficient, no significant effect of either procedure could be observed at any time during follow-up., Registration: URL: http://www.controlled-trials.com; Unique identifier: ISRCTN13486906.

Background: Reproducible image quality is of high relevance for large cohort studies and can be challenging for magnetic resonance imaging (MRI). Automated image quality assessment may contribute to conducting radiologic studies effectively., Purpose: The aims of this study were to assess protocol repetition frequency in population-based whole-body MRI along with its effect on examination time and to examine the applicability of automated image quality assessment for predicting decision-making regarding repeated acquisitions., Materials and Methods: All participants enrolled in the prospective, multicenter German National Cohort (NAKO) study who underwent whole-body MRI at 1 of 5 sites from 2014 to 2016 were included in this analysis (n = 11,347). A standardized examination program of 12 protocols was used. Acquisitions were carried out by certified radiologic technologists, who were authorized to repeat protocols based on their visual perception of image quality. Eleven image quality parameters were derived fully automatically from the acquired images, and their discrimination ability regarding baseline acquisitions and repetitions was tested., Results: At least 1 protocol was repeated in 12% (n = 1359) of participants, and more than 1 protocol in 1.6% (n = 181). The repetition frequency differed across protocols (P < 0.001), imaging sites (P < 0.001), and over the study period (P < 0.001). The mean total scan time was 62.6 minutes in participants without and 67.4 minutes in participants with protocol repetitions (mean difference, 4.8 minutes; 95% confidence interval, 4.5-5.2 minutes). Ten of the automatically derived image quality parameters were individually retrospectively predictive for the repetition of particular protocols; for instance, "signal-to-noise ratio" alone provided an area under the curve of 0.65 (P < 0.001) for repetition of the Cardio Cine SSFP SAX protocol. Combinations generally improved prediction ability, as exemplified by "image sharpness" plus "foreground ratio" yielding an area under the curve of 0.89 (P < 0.001) for repetition of the Neuro T1w 3D MPRAGE protocol, versus 0.85 (P < 0.001) and 0.68 (P < 0.001) as individual parameters., Conclusions: Magnetic resonance imaging protocol repetitions were necessary in approximately 12% of scans even in the highly standardized setting of a large cohort study. Automated image quality assessment shows predictive value for the technologists' decision to perform protocol repetitions and has the potential to improve imaging efficiency., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19., Patients and Methods: We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19., Results: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease., Conclusions: In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

The current coronavirus disease 2019 (COVID-19) pandemic represents a severe, life-changing event for people across the world. Life changes may involve job loss, income reduction due to furlough, death of a beloved one, or social stress due to life habit changes. Many people suffer from social isolation due to lockdown or physical distancing, especially those living alone and without family. This article reviews the association of life events and social isolation with cardiovascular disease, assembling the current state of knowledge for stroke and coronary heart disease. Possible mechanisms underlying the links between life events, social isolation, and cardiovascular disease are outlined. Furthermore, groups with increased vulnerability for cardiovascular disease following life events and social isolation are identified, and clinical implications of results are presented.

Background: Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events., Methods: In 3281 participants (45-74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed., Results: We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1-Q3, 23-360] versus 8 [0-83], P <0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events. However, CAC progression did not improve models including CAC 5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CAC b =CAC 5y =0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CAC b progressed from 1 to 399 to CAC 5y ≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC 5y =400. Participants with CAC b ≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively)., Conclusions: CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk., (© 2017 The Authors.)

Background: Epidemiologic evidence for work stress as a risk factor for coronary heart disease is mostly based on a single measure of stressful work known as job strain, a combination of high demands and low job control. We examined whether a complementary stress measure that assesses an imbalance between efforts spent at work and rewards received predicted coronary heart disease., Methods: This multicohort study (the "IPD-Work" consortium) was based on harmonized individual-level data from 11 European prospective cohort studies. Stressful work in 90,164 men and women without coronary heart disease at baseline was assessed by validated effort-reward imbalance and job strain questionnaires. We defined incident coronary heart disease as the first nonfatal myocardial infarction or coronary death. Study-specific estimates were pooled by random effects meta-analysis., Results: At baseline, 31.7% of study members reported effort-reward imbalance at work and 15.9% reported job strain. During a mean follow-up of 9.8 years, 1,078 coronary events were recorded. After adjustment for potential confounders, a hazard ratio of 1.16 (95% confidence interval, 1.00-1.35) was observed for effort-reward imbalance compared with no imbalance. The hazard ratio was 1.16 (1.01-1.34) for having either effort-reward imbalance or job strain and 1.41 (1.12-1.76) for having both these stressors compared to having neither effort-reward imbalance nor job strain., Conclusions: Individuals with effort-reward imbalance at work have an increased risk of coronary heart disease, and this appears to be independent of job strain experienced. These findings support expanding focus beyond just job strain in future research on work stress.

Background: Genetic variants of a locus within the chromosome 9p21.3 region are consistently associated with coronary artery disease and coronary artery calcification (CAC). The aim of this study was to examine whether a 9p21.3 common variant interacts with socioeconomic status (SES) to influence CAC and incident coronary events in a population-based cohort., Methods and Results: 9p21.3 single nucleotide polymorphism rs2891168 was genotyped in 4116 participants of the Heinz Nixdorf Recall study. SES indicators (education and income) and CAC were assessed at baseline. Incident coronary events were ascertained over a median follow-up of 9.3 years. Multiple regression models were fitted to estimate genetic effects on log e (CAC+1) and incident coronary events. Genetic effects were highest in the lower income tertile with a 53.1% (95% confidence interval, 30.6%-79.6%; P =1.8×10 - 7 ) increase in CAC and a hazard ratio of 1.44 (95% confidence interval, 1.01-2.07; P =0.049) for incident coronary events per additional risk allele. After including genotype×SES interaction terms in the regression models, genotype×income interactions were observed for CAC (exp[β g×income ]=0.85 [95% confidence interval, 0.74-0.98; P g×income =0.02] per 1000€/mo increase and additional risk allele) and for incident coronary events (hazard ratio g×income =0.69 [95% confidence interval, 0.48-0.98; P g×income =0.04] per 1000€/mo increase and additional risk allele). No interaction was observed using education as SES indicator., Conclusions: A 9p21.3 common variant seems to interact with SES to influence CAC and incident coronary events in a population-based cohort. This supports the hypothesis that better material, psychosocial, and lifestyle conditions enable higher SES groups to reduce the expression of their genetic susceptibility to coronary artery disease., (© 2017 American Heart Association, Inc.)

Background: Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies., Methods: We pooled 14 case-control studies conducted in 1985-2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends., Results: The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women., Conclusions: Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.).

Background and Purpose: Carotid intima-media thickness is a marker for subclinical atherosclerosis that predicts subsequent clinical cardiovascular events. The aim of this study was to identify chromosomal loci with linkage or association to common carotid intima-media thickness., Methods: Nuclear families were recruited using the single parental proband sib-pair design. Genotype data were available for 546 individuals from 132 nuclear families of the Bonn IMT Family Study using the Affymetrix GeneChip Human Mapping 250K Sty chip. Multipoint logarithm of the odds (LOD) scores were determined with the quantitative trait locus statistic implemented in multipoint engine for rapid likelihood. Linkage analysis and family-based association tests were conducted. Data from 2471 German participants from the HNR (Heinz Nixdorf Recall) Study were used for subsequent replication., Results: Two new genomic regions with suggestive linkage (LOD>2) were identified on chromosome 4 (LOD=2.26) and on chromosome 17 (LOD=2.01). Previously reported linkage findings were replicated on chromosomes 13 and 14. Fifteen single nucleotide polymorhisms, located on chromosomes 4, 6, and 9, revealed P<10 -4 in the family-based association analyses. One of these signals was replicated in HNR (rs2416804, 1-sided P=1.60×10 -3 , located in the gene TRAF1)., Conclusions: This study presents the first genome-wide linkage and association study of common carotid intima-media thickness in the German population. Alleles of rs2416804 in TRAF1 were identified as being linked and associated with carotid intima-media thickness. Further studies are needed to evaluate the contribution of this locus to the development of atherosclerosis., (© 2016 American Heart Association, Inc.)

Objectives: The aim of this study was to explore lung cancer risk among firefighters, with adjustment for smoking., Methods: We used pooled information from the SYNERGY project including 14 case-control studies conducted in Europe, Canada, New Zealand, and China, with lifetime work histories and smoking habits for 14,748 cases of lung cancer and 17,543 controls. We estimated odds ratios by unconditional logistic regression with adjustment for smoking and having ever been employed in a job known to present an excess risk of lung cancer., Results: There was no increased lung cancer risk overall or by specific cell type among firefighters (n = 190), neither before nor after smoking adjustment. We observed no significant exposure-response relationship in terms of work duration., Conclusions: We found no evidence of an excess lung cancer risk related to occupational exposure as a firefighter.

Combinations of analgesics with caffeine have been discussed as bearing a risk for headache chronicity. We investigated whether aspirin with caffeine (ASA+) increases headache frequency compared with aspirin alone in migraine, tension-type headache (TTH), and migraine + TTH (MigTTH). The population-based German Headache Consortium Study, which included participants aged 18 to 65 years, collected information about headache and analgesics at baseline (2003-2007, t0, response rate: 55.2%), first follow-up after 1.87 ± 0.39 years (t1, 37.2%), and second follow-up after 3.26 ± 0.60 years (t2, 38.8%). We included participants with headache at t0, aspirin intake, ASA+ or no analgesics at t0 and t2, and known headache frequency. Linear regression was used to estimate changes of headache frequency (Δt2-t0) and 95% confidence intervals depending on analgesic intake, stratified by headache subtypes, adjusting for sex, age, analgesics at t1, changes of headache frequency at t1, drinking, smoking, body mass index, education, headache frequency at t0. Of 509 participants (56.0% women, 42.0 ± 11.8 years [mean ± SD]), 45.2% reported aspirin intake (41.3 ± 10.9 years, 59.6% women, headache days at t0: 2.8 ± 3.1 d/mo, t2: 3.6 ± 4.1 d/mo), 11.8% ASA+ intake (46.0 ± 9.8 years, 73.3%, t0: 4.8 ± 6.1 d/mo, t2: 5.3 ± 5.1 d/mo), and 43.0% no analgesics (41.6 ± 13.1 years, 47.5%, t0: 3.8 ± 6.2 d/mo, t2: 5.3 ± 6.6 d/mo). There was no increase in headache frequency in participants with ASA+ intake compared with aspirin (adjusted, all headache: -0.34 d/mo [95% confidence intervals: -2.50 to 1.82], migraine: -1.36 d/mo [-4.76 to 2.03], TTH: -0.57 d/mo [-4.97 to 3.84], MigTTH: 2.46 d/mo [-5.19 to 10.10]) or no analgesics (all headache: -2.24 d/mo [-4.54 to 0.07], migraine: -3.77 d/mo [-9.22 to 1.68], TTH: -4.68 d/mo [-9.62 to 0.27]; MigTTH: -3.22 d/mo [-10.16 to 3.71]). In our study, ASA+ intake did not increase headache frequency compared with aspirin or no analgesics.

Background: Coronary artery calcification (CAC) is widely regarded as a cumulative lifetime measure of atherosclerosis, but it remains unclear what is the relationship between calcification and traditional risk factors for coronary artery disease (CAD) and myocardial infarction (MI). This study characterizes the genetic architecture of CAC by evaluating the overall impact of common alleles associated with CAD/MI and its traditional risk factors., Methods and Results: On the basis of summary-association results from the CARDIoGRAMplusC4D study of CAD/MI, we calculated polygenic risk scores in 2599 participants of the Dutch and Belgian Lung Cancer Screening (NELSON) trial, in whom quantitative CAC levels (Agatston scores) were determined from chest computerized tomographic imaging data. The most significant polygenic model explained ≈14% of the observed CAC variance (P=1.6×10(-11)), which points to a residual effect because of many as yet unknown loci that overlap between CAD/MI and CAC. In addition, we constructed risk scores based on published single-nucleotide polymorphism associations for traditional cardiovascular risk factors and tested these scores for association with CAC. We found nominally significant associations for genetic risk scores of low-density lipoprotein-cholesterol, total cholesterol, and body mass index, which were successfully replicated in 2182 individuals of the Heinz Nixdorf Recall Study., Conclusions: Pervasive polygenic sharing between CAC and CAD/MI suggests that a substantial fraction of the heritable risk for CAD/MI is mediated through arterial calcification. We also provide evidence that genetic variants associated with serum lipid levels and body mass index influence CAC levels., (© 2015 American Heart Association, Inc.)

Objectives: To investigate the risk of lung cancer among cooks, while controlling for smoking habits., Methods: We used data from the SYNERGY project including pooled information on lifetime work histories and smoking habits from 16 case-control studies conducted in Europe, Canada, New Zealand, and China., Results: Before adjustment for smoking, we observed an increased risk of lung cancer in male cooks, but not in female cooks. After adjusting, there was no increased risk and no significant exposure-response relationship. Nevertheless, subgroup analyses highlighted some possible excess risks of squamous cell carcinoma and small cell carcinoma in female cooks., Conclusions: There is evidence that lung cancer risks among cooks may be confounded by smoking. After adjustment, cooks did not experience an increased risk of lung cancer overall. The subgroup analyses showing some excess risks among female cooks require cautious interpretation.

Background and Purpose: Coronary artery calcification (CAC), a marker of coronary atherosclerosis, predicts stroke in addition to established risk factors. Whether CAC's predictive value can be improved by peripheral atherosclerosis markers, namely carotid intima-media thickness (CIMT) and ankle-brachial index (ABI), was unknown., Methods: A total of 3289 participants of the population-based Heinz Nixdorf Recall study (45-75 years; 48.8% men) without previous stroke or coronary heart disease were evaluated for incident stroke for 9.0±1.9 years. CAC, CIMT, and ABI were examined as stroke predictors., Results: Eighty-four strokes occurred during follow-up. In multivariable Cox proportional hazard regressions, CAC (hazard ratio, 1.45 [95% confidence interval, 1.11-1.88] per SD increase in ln(CAC+1); SD, 2.40), CIMT (1.34 [1.08-1.66] per SD increase; SD, 0.127 mm), and ABI (1.55 [1.32-1.82] per SD decrease; SD, 0.148) were associated with stroke in addition to established risk factors. When combined with each other, ln(CAC+1)'s hazard ratio remained similar when CIMT (1.41 [1.09-1.83]) was inserted into the multivariable model, but slightly decreased when ABI (1.31 [1.01-1.72]) or CIMT and ABI (1.29 [0.99-1.68]) were included. Although CAC alone did not significantly elevate the area under the curve in Harrell's c-statistics (by 0.009; P=0.379) in addition to established risk factors, the combination of CAC and ABI increased area under the curve (by 0.029; P=0.047), as did ABI (by 0.025; P=0.038) but not CIMT (by 0.002; P=0.795) alone. The combination of CAC and ABI also resulted in significant category-free net reclassification and integrated discrimination improvement., Conclusions: CAC, CIMT, and ABI provide complementary information about stroke risk. ABI, which is distinctive in a small subpopulation, had the highest and CIMT, which is distributed across a larger range of values, had the lowest predictive value., (© 2014 American Heart Association, Inc.)

Background and Purpose: Coronary artery calcification (CAC) is a noninvasive marker of plaque load that predicts myocardial infarcts in the general population. Herein, we investigated whether CAC predicts stroke events in addition to established risk factors that are part of the Framingham risk score., Methods: A total of 4180 subjects from the population-based Heinz Nixdorf Recall study (45-75 years of age; 47.1% men) without previous stroke, coronary heart disease, or myocardial infarction were evaluated for stroke events over 94.9 ± 19.4 months. Cox proportional hazards regressions were used to examine CAC as stroke predictor in addition to established vascular risk factors (age, sex, systolic blood pressure, low-density lipoprotein, high-density lipoprotein, diabetes mellitus, smoking, and atrial fibrillation)., Results: Ninety-two incident strokes occurred (82 ischemic, 10 hemorrhagic). Subjects suffering a stroke had significantly higher CAC values at baseline than the remaining subjects (median, 104.8[Q1;Q3, 14.0;482.2] vs 11.2[0;106.2]; P<0.001). In a multivariable Cox regression, log10(CAC+1) was an independent stroke predictor (hazards ratio, 1.52 [95% confidence interval, 1.19-1.92]; P=0.001) in addition to age (1.35 per 5 years [1.15-1.59]; P<0.001), systolic blood pressure (1.25 per 10 mm Hg [1.14-1.37]; P<0.001), and smoking (1.75 [1.07-2.87]; P=0.025). CAC predicted stroke in men and women, particularly in subjects <65 years of age and independent of atrial fibrillation. CAC discriminated stroke risk specifically in participants belonging to the low (<10%) and intermediate (10%-20%) Framingham risk score categories., Conclusions: CAC is an independent stroke predictor in addition to classical risk factors in subjects at low or intermediate vascular risk.

Purpose: We measured extracoronary atherosclerotic plaque burden and its association with cardiovascular risk factors and with coronary atherosclerosis in male marathon runners., Methods: We studied 100 male presumably healthy runners, aged 50-75 yr, who completed at least five marathons during the preceding 3 yr. Presence of plaque in the carotid, abdominal, and lower limb arteries was imaged using B-mode ultrasound. In all runners, traditional cardiovascular risk factors and the electron beam computed tomography-based coronary artery calcium (CAC) score were determined., Results: Ten runners were free from any plaque in the carotid or peripheral arteries. Runners with plaque were older (58±6 vs 54±5 yr, P=0.04), had a higher 10-yr Framingham risk score (7.2±3.8 vs 5.0±1.9, P=0.026), and tended to have a higher prevalence of CAC (76.7% vs 50.0%, P=0.07) compared with those without. Runners with CAC≥100 had larger peripheral artery diameters (aorta and iliac and common femoral arteries) but smaller lumen than runners with CAC<100, indicating atherosclerotic remodeling. A stepwise model selection process to predict CAC on the basis of age and peripheral atherosclerosis yielded a model as follows: log2(CAC+1)=0.181 age (yr)+0.435 maximum carotid plaque thickness (mm)-6.487, with a coefficient of determination of 22.8%. However, positive and negative predictive values were too low to predict CAC≥100 with sufficient accuracy., Conclusions: The prevalence of carotid and peripheral atherosclerosis in marathon runners is high and is related to cardiovascular risk factors and the coronary atherosclerotic burden. Remodeling of peripheral arteries is greatest in runners with the most evidence of atherosclerosis. These data support an increased awareness of atherosclerosis prevalence and cardiovascular risk factors in marathon runners.

Objective: To examine the association between genomewide association study-based diabetes mellitus-related single-nucleotide polymorphisms (SNPs) and coronary artery calcification (CAC), a valid risk factor for coronary heart disease, in a large, unselected, population-based cohort., Methods and Results: We genotyped 11 validated genomewide association study-based diabetes SNPs in 4459 participants of the Heinz Nixdorf Recall Study. We applied generalized linear regression models to explore the impact of the diabetes SNPs on CAC and to jointly model the effect of the SNPs and CAC on diabetes status. We observed a significant association between cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) variant rs564398 and quantitative CAC (P=1.81 x 10(-5) and adjusted P=4.02 x 10(-4); odds ratio for the presence of CAC, 1.12 [95% CI, 1.02 to 1.25]). Moreover, we observed no strong impact of CAC on diabetes risk in the presence of the other genetic variants., Conclusions: We show that a genetic variant near CDKN2A/2B that has been reported to be strongly associated with diabetes is strongly associated with CAC. In contrast, variants near insulin-like growth factor-binding protein 2 (IGFBP2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), solute carreir family 30 (zinc transporter), member 8 (SLC30A8), hematopoietically-expressed homeobox (HHEX), and transcription factor 7-like2 (TCF7L2) were clearly associated with diabetes; no evidence for an association to CAC was observable. This differential association pattern underlines the potential of endophenotypes, such as CAC, to extend the scope of disease outcome associations.

Background: Long-term exposure to particulate air pollution has been associated with increased cardiovascular disease. Biologic pathways for this association are not fully understood., Methods: We examined the association of urban air pollution with atherosclerosis of the peripheral vascular bed, using baseline data (2000-2003) from 4348 participants in a population-based cohort study in the German Ruhr Area. Levels of annual fine particulate matter (PM2.5) exposure, derived from a dispersion and chemistry transport model, were assigned to the participants' home addresses. Residential traffic exposure was assessed by the distance between residence and major roads (federal and state highways). Using multiple regression analyses and controlling for individual level risk factors, we examined the association of PM2.5 and traffic with the ankle-brachial index and prevalence of peripheral arterial disease, defined as an index of less than 0.9 or a history of treatment for peripheral artery disease., Results: Living within 101-200, 51-100, and 50 m of a major road was associated with an adjusted absolute decrease in ankle-brachial index of -0.015 (95% confidence interval [CI] = -0.030 to 0.0), -0.002 (-0.021 to 0.016) and -0.024 (-0.047 to -0.001), respectively. Stronger associations were seen in women, whereas no clear association was found in men. Individuals living within 50 m of a major road had an OR of 1.77 (1.01-2.1) for peripheral arterial disease compared with those living more than 200 m away. Associations with PM2.5 were inconsistent., Conclusions: This study adds to the evidence that long-term residential exposure to traffic is associated with atherosclerosis.

Objectives: Body weight regulation is under complex control involving the central nervous system and peripheral pathways. The beta-adrenoceptor Galphas protein system plays an important role in heart rate regulation and lipid mobilization suggesting a key role for the stimulatory G protein Galphas in body weight regulation., Methods: We sequenced the whole GNAS promoter to identify a functional variant which results in altered Galphas expression. We genotyped 110 participants of a randomized placebo-controlled weight loss trial who were under a low calorie diet and were additionally treated with either placebo or 15 mg sibutramine daily for 54 weeks and associated the respective alleles with regard to treatment outcome using an intention-to-treat analysis., Results: A G>A transition at position -1211 the human GNAS promoter (minor allele frequency=0.36) was identified resulting in altered upstream stimulatory factor 1 transcription factor binding, promoter activity, Galphas expression, and lipolysis. Under a low calorie diet -1211GG genotypes lost significantly more weight compared with A-allele carriers (placebo group: 1211GG, 7.5+/-0.4 versus -1211A, 4.5+/-0.3 kg, P=0.020). Sibutramine was effective only in A-allele carriers whereas GG genotypes showed no additional weight loss under sibutramine but showed the strongest increases in resting heart rate (8.5 bpm; 95% confidence interval: 2.7-14.21 bpm; P=0.005) and systolic blood pressure (9.1 mmHg, 95% confidence interval: 3.1-15.1; P=0.004) compared with placebo., Conclusions: Determination of GNAS promoter alleles may identify obese individuals who lose weight easily under lifestyle changes alone but also those who benefit from adjunct sibutramine therapy.

Background: Long-term exposure to fine-particulate-matter (PM2.5) air pollution may accelerate the development and progression of atherosclerosis. We investigated the associations of long-term residential exposure to traffic and fine particulate matter with the degree of coronary atherosclerosis., Methods and Results: We used baseline data on 4494 participants (age 45 to 74 years) from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study that started in 2000. To assess exposure differences, distances between residences and major roads were calculated, and annual fine particulate matter concentrations, derived from a small-scale dispersion model, were assigned to each address. The main outcome was coronary artery calcification (CAC) assessed by electron-beam computed tomography. We evaluated the association between air pollution and CAC with logistic and linear regression analyses, controlling for individual level risk factors of coronary atherosclerosis. Compared with participants living >200 m away from a major road, participants living within 50, 51 to 100, and 101 to 200 m had odds ratios of 1.63 (95% CI, 1.14 to 2.33), 1.34 (95% CI, 1.00 to 1.79), and 1.08 (95% CI, 0.85 to 1.39), respectively, for a high CAC (CAC above the age- and gender-specific 75th percentile). A reduction in the distance between the residence and a major road by half was associated with a 7.0% (95% CI, 0.1 to 14.4) higher CAC. Fine particulate matter exposure was associated with CAC only in subjects who had not been working full-time for at least 5 years., Conclusions: Long-term residential exposure to high traffic is associated with the degree of coronary atherosclerosis.

Valid incidence rates of uveal melanoma (UM) from German population-based cancer registries are currently not available due to under-reporting. We conducted two case-control studies on UM at a reference centre for eye tumours and show the influence on population-based incidences of UM when data from case-control studies are linked with a cancer registry. The first case-control study (1996-1998) recruited 13 UM cases aged 35-74 years and the second case-control study (2002-2003) recruited 20 UM cases aged 20-74 residing within the population covered by the Münster Cancer Registry. After record linkage, age-truncated and standardized (World Standard Population) incidences with and without the record linkage were compared. Incidence rates based on routine cancer registration increased by a factor of 1.7 (1996-1998, age group 35-74 years) and 3.7 (2002-2003, age group 20-74 years) after record linkage with the case-control data. The supplemented age-standardized incidence of UM is 8.6 per million (20-74 years, 2002-2003) compared with the unsupplemented incidence of 2.3 per million. UM unknown to the registry were less often morphologically verified than those known to the registry. Cancer registries relying on pathology reports underestimate UM incidences if eye-preserving treatments are introduced. Close co-operation between cancer referral centres and cancer registries can substantially improve the completeness of registration.

Objective: A recent cohort study showed an increased risk of testicular cancer among members of the United Brotherhood of Carpenters and Joiners of America. We explored our data of a German population-based case-control study on the etiology of testicular cancer with regard to this association., Methods: The case-control study included 269 testicular cancer cases and 797 controls. We applied conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CIs)., Results: People who worked as cabinetmakers or carpenters had an OR of 0.84 (95% CI = 0.45-1.56). Risks were increased among cabinetmakers who worked at least 15 years ago (OR = 5.81, 95% CI = 1.20-28.09). Ever being employed as a carpenter was associated with a reduced OR of 0.59 (95% CI = 0.24-1.46)., Conclusions: Cabinetmakers may be at an increased risk of testicular cancer.

Over the past few decades, the incidence of cutaneous malignant melanoma has been rising in both sexes in almost all developed countries, notably those with fair-skinned populations. Detailed population-based time trend analyses of skin melanoma incidence and survival in Germany accounting for stage have not been published until now. We analysed skin melanoma data from the population-based Saarland Cancer Registry in Germany from 1970 to 1996. Incidence rates were age-standardized. We estimated 5-year disease-specific survival rates and evaluated the effects of sex, age, calendar period and staging on the prognosis in Cox's proportional hazards models. From 1970-1972 to 1994-1996, melanoma incidence increased 170% from 2.4 to 6.5 per 100 000 person-years among men and 150% from 2.4 to 6.0 per 100 000 person-years among women. Mortality rates peaked in 1988-1990. After 1988-1990, mortality rates declined among women and remained roughly constant among men. The increase in the incidence of localized melanoma and T1-T2 melanoma respectively is driving the overall incidence trend. The improvement of survival over time is most likely due to earlier detection of skin melanoma. In the 1990s, about 30% of all newly diagnosed skin melanoma had stage T3 or T4, implying that further improvement in survival by earlier detection is feasible.

There are few epidemiologic studies dealing with electromagnetic radiation and uveal melanoma. The majority of these studies are exploratory and are based on job and industry titles only. We conducted a hospital-based and population-based case-control study of uveal melanoma and occupational exposures to different sources of electromagnetic radiation, including radiofrequency radiation. We then pooled these results. We interviewed a total of 118 female and male cases with uveal melanoma and 475 controls matching on sex, age, and study regions. Exposure to radiofrequency-transmitting devices was rated as (a) no radiofrequency radiation exposure, (b) possible exposure to mobile phones, or (c) probable/certain exposure to mobile phones. Exposures were rated independently by two of the authors who did not know case or control status. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found an elevated risk for exposure to radiofrequency-transmitting devices (exposure to radio sets, OR = 3.0, 95% CI = 1.4-6.3; probable/certain exposure to mobile phones, OR = 4.2, 95% CI = 1.2-14.5). Other sources of electromagnetic radiation such as high-voltage lines, electrical machines, complex electrical environments, visual display terminals, or radar units were not associated with uveal melanoma. This is the first study describing an association between radiofrequency radiation exposure and uveal melanoma. Several methodologic limitations prevent our results from providing clear evidence on the hypothesized association.

We conducted a case-control study in 12 European study centers to evaluate the role of occupational risk factors among nonsmokers. We obtained detailed occupational histories from 650 nonsmoking cases (509 females/141 males) and 1,542 nonsmoking controls (1,011 females/531 males). On the basis of an a priori definition of occupations and industries that are known (list A) or suspected (list B) to be associated with lung carcinogenesis, we calculated odds ratios (ORs) for these occupations, using unconditional logistic regression models and adjusting for sex, age, and center effects. Among nonsmoking men, an excess relative risk was observed among those who had worked in list-A occupations [OR = 1.52; 95% confidence interval (C) = 0.78-2.97] but not in list-B occupations (OR = 1.05; 95%), CI = 0.60-1.83). Among nonsmoking women, there was an elevation of risk for list-A occupations (OR = 1.50; 95% CI = 0.49-4.53), although this estimate was imprecise, given that less than 1% of cases and controls were exposed. Exposure to list-B occupations was associated with an increase in relative risk (OR = 1.69; 95% CI = 1.09-2.63) in females, but not in males. Women who had been laundry workers or dry cleaners had an OR of 1.83 (95% CI = 0.98-3.40). Our findings confirm that certain occupational exposures are associated with an increased risk for lung cancer among both female and male nonsmokers; however, knowledge on occupational lung carcinogens is biased toward agents to which mainly men are exposed.

We investigated the methods of recruitment, levels and determinants of response, and the calculation method of response proportions in population-based case-control studies in Germany. We identified 26 eligible studies. The pooled analysis showed that the response proportion was 68% among controls and 80% among cases. Response proportions among controls without telephones were about 50% lower than for controls with telephones. We propose a new measure that indicates the efficacy of the recruitment strategy.

In a case-control study of 1,004 lung cancer cases and 1,004 population controls, all nonsmokers (71 cases, 236 controls) were interviewed for their exposure to environmental tobacco smoke. On the basis of indices of duration, we separated intermediate and high exposures from low or no exposure. The odds ratio for high exposure was 2.09 (95% confidence interval = 1.02-4.28). Exposure from the spouse was only weakly associated with lung cancer risk. We found little association for exposure during childhood. High exposure at the work place showed an odds ratio of 1.91. There was little indication of confounding by dietary habits.

Nonsmoking females age 35-65 years from Bremen, Germany (91 women), and Opole, Poland (98 women), were interviewed about their recent passive smoking exposure. We obtained urine samples at the time of interview and determined the concentration of cotinine as an indicator of tobacco smoke exposure. In Poland and in Germany, the vast majority of nonsmoking women are involuntarily exposed to environmental tobacco smoke (ETS). Polish women had slightly higher exposure levels than German women, with overall means of 9.93 and 8.65 ng cotinine/mg creatinine, respectively. Smoking by the husband was the major source of exposure in both study groups. In the Polish group, the work place was also an important source of ETS exposure. The validity of self-reported passive smoking exposure was found to be generally good; it was somewhat better in the German study group. A negative attitude toward tobacco smoke was slightly stronger among the German women. The percentage of women misreporting their active smoking status was low.