Exposure to noise and ototoxic chemicals in the Australian workforce.

OBJECTIVE: To determine the current prevalence of exposure to workplace noise and ototoxic chemicals, including co-exposures. METHOD: A cross-sectional telephone survey of nearly 5000 Australian workers was conducted using the web-based application, OccIDEAS. Participants were asked about workplace tasks they performed and predefined algorithms automatically assessed worker's likelihood of exposure to 10 known ototoxic chemicals as well as estimated their full shift noise exposure level (LAeq,8h) of their most recent working day. Results were extrapolated to represent the Australian working population using a raked weighting technique. RESULTS: In the Australian workforce, 19.5% of men and 2.8% of women exceeded the recommended full shift noise limit of 85 dBA during their last working day. Men were more likely to be exposed to noise if they were younger, had trade qualifications and did not live in a major city. Men were more likely exposed to workplace ototoxic chemicals (57.3%) than women (25.3%). Over 80% of workers who exceeded the full shift noise limit were also exposed to at least one ototoxic chemical in their workplace. CONCLUSION: The results demonstrate that exposures to hazardous noise and ototoxic chemicals are widespread in Australian workplaces and co-exposure is common. Occupational exposure occurs predominantly for men and could explain some of the discrepancies in hearing loss prevalence between genders.

Type 2 diabetes and leucocyte DNA methylation: an epigenome-wide association study in over 1,500 older adults.

AIMS/HYPOTHESIS: Development of type 2 diabetes depends on environmental and genetic factors. We investigated the epigenome-wide association of prevalent diabetes with DNA methylation (DNAm) in peripheral blood. METHODS: DNAm was measured in whole blood with the Illumina Infinium HumanMethylation450 BeadChip in two subsamples of participants from the ESTHER cohort study. Cohort 1 included 988 participants, who were consecutively recruited between July and October 2000 and cohort 2 included 527 randomly selected participants. The association of DNAm with prevalent type 2 diabetes at recruitment was estimated using median regression analysis adjusting for sex, age, BMI, smoking behaviour, cell composition and batch at 361,922 CpG sites. RESULTS: Type 2 diabetes was prevalent in 16% of the participants, and diabetes was poorly controlled in 45% of the diabetic patients. In cohort 1 (discovery) DNAm at 39 CpGs was significantly associated with prevalent diabetes after correction for multiple testing. In cohort 2 (replication) at one of these CpGs, DNAm was still significantly associated. Decreasing methylation levels at cg19693031 with increasing fasting glucose and HbA1c concentrations were observed using restricted cubic spline analysis. In diabetic patients with poorly controlled diabetes, the decrease in estimated DNAm levels was approximately 5% in comparison with participants free of diagnosed diabetes. CONCLUSIONS/INTERPRETATION: Cg19693031, which is located within the 3'-untranslated region of TXNIP, might play a role in the pathophysiology of type 2 diabetes. This result appears biologically plausible given that thioredoxin-interacting protein is overexpressed in diabetic animals and humans and 3'-untranslated regions are known to play a regulatory role in gene expression.

Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites.

Understanding the role of epigenetic modifications, e.g. DNA methylation, in the process of aging requires the characterization of methylation patterns in large cohorts. We analysed >480 000 CpG sites using Infinium HumanMethylation450 BeadChip (Illumina) in whole blood DNA of 965 participants of a population-based cohort study aged between 50 and 75 years. In an exploratory analysis in 400 individuals, 200 CpG sites with the highest Spearman correlation coefficients for the association between methylation and age were identified. Of these 200 CpGs, 162 were significantly associated with age, which was verified in an independent cohort of 498 individuals using mixed linear regression models adjusted for gender, smoking behaviour, age-related diseases and random batch effect and corrected for multiple testing by Bonferroni. In another independent cohort of 67 individuals without history of major age-related diseases and with a follow-up of 8 years, we observed a gain in methylation at 96% (52%, significant) of the positively age-associated CpGs and a loss at all (89%, significant) of the negatively age-associated CpGs in each individual while getting 8 years older. A regression model for age prediction based on 17 CpGs as predicting variables explained 71% of the variance in age with an average accuracy of 2.6 years. In comparison with cord blood samples obtained from the Ulm Birth Cohort Study, we observed a more than 2-fold change in mean methylation levels from birth to older age at 86 CpGs. We were able to identify 65 novel CpG sites with significant association of methylation with age.

Self-reported smoking, serum cotinine, and blood DNA methylation.

BACKGROUND: Epigenome-wide profiling of DNA methylation pattern with respect to tobacco smoking has given rise to a new measure of smoking exposure. We investigated the relationships of methylation markers with both cotinine, an established marker of internal smoking exposure, and self-reported smoking. METHODS: Blood DNA methylation levels across the genome and serum cotinine were measured in 1000 older adults aged 50-75 years. Epigenome-wide scans were performed to identify methylation markers associated with cotinine. The inter-dose-response relationships between the number of cigarettes smoked per day, cotinine concentration, and DNA methylation were modeled by restricted cubic spline regression. RESULTS: Of 61 CpGs that passed the genome-wide significance threshold (p<1.13×10(-7)), 40 CpGs in 25 chromosomal regions were successfully replicated, showing 0.2-3% demethylation per 10ng/ml increases in cotinine. The strongest associations were observed for several loci at AHRR, F2RL3, 2q37.1, 6p21.33, and GFI1 that were previously identified to be related to self-reported smoking. One locus at RAB34 was newly discovered. Both cotinine and methylation markers exhibited non-linear relationships with the number of cigarettes smoked per day, where the highest rates of increase in cotinine and decreases in methylation were observed at low smoking intensity (1-15 cigarettes/day) and plateaued at high smoking intensity (>15-20 cigarettes/day). A clear linear relationship was observed between cotinine concentration and methylation level. Both cotinine and methylation markers showed similar accuracy in distinguishing current from never smoker, but only methylation markers distinguished former from never smoker with high accuracy. CONCLUSIONS: Our study corroborates and expands the list of smoking-associated DNA methylation markers. Methylation levels were linearly related to cotinine concentration and provided accurate measures for both current and past smoking exposure.

Age-specific influence of wheezing phenotypes on pre-adolescent and adolescent health-related quality of life.

INTRODUCTION: Asthma is associated with diminished health-related quality of life (HRQoL). Particularly in adolescence, asthma may be under-diagnosed and undertreated or poorly managed. Therefore, we aimed to determine the association between childhood wheezing phenotypes rather than asthma and adolescent HRQoL in children aged 10-17 yr. METHODS: We analyzed the data from two prospective population-based cohort studies (n = 604 and n = 1804) conducted in southern Germany with baseline assessments in 2000 and 2006 and follow-ups at frequent intervals. Parent-reported wheeze was categorized into never, early transient, persistent, and late-onset wheeze. We assessed child-reported HRQoL in seven scales using the validated KINDL-R. Multivariate linear regression models were computed. RESULTS: Participants with late-onset wheeze had significantly lower values in all HRQoL scales, but physical well-being compared to never wheezers. Early transient wheeze was negatively associated with three HRQoL scales only (family, school, and total). These effects were confined to the oldest age group (≥13.5 yr) in one study. Persistent wheeze was not associated with HRQoL. CONCLUSIONS: In teenagers, late-onset wheezers seem to be particularly vulnerable for impairments in psychosocial aspects of health-related quality of life. They may therefore require particular attention with regard to education about asthma management and potentially family-based psychosocial intervention.

Infant atopic eczema and subsequent attention-deficit/hyperactivity disorder--a prospective birth cohort study.

BACKGROUND: Comorbidity between childhood atopic eczema (AE) and attention-deficit/hyperactivity disorder (ADHD) has been observed, but temporal relationships remain unclear. METHODS: We analyzed data of a population-based, prospective birth cohort study among 770 children included at baseline in 2000/2001 with follow-up up to age 11. Information on age at diagnosis of AE, rhinoconjunctivitis, and ADHD was obtained by questionnaires administered to parents and for AE also to caring physicians. Adjusted relative risks (aRR) with 95% confidence intervals (95% CI) were modeled with a modified Poisson regression. RESULTS: Early AE up to age 4 yr was reported for 14.8% of the children by the parents and for 26.0% by the physicians with only fair agreement between these reports (kappa = 0.36). Based on parental reports, the association of early AE with early ADHD was strong (aRR: 5.17, 95% CI: 2.18; 12.28), but absent for late ADHD [aRR: 0.50 (0.13; 2.02)]. The association of late AE with late ADHD [aRR: 3.03 (0.75; 12.29)] was not statistically significant. This pattern was independent of the presence of rhinoconjunctivitis. CONCLUSIONS: The observed comorbidity between AE and ADHD may indicate vulnerability to develop ADHD symptoms in response to AE symptoms or through a common underlying mechanism. This vulnerability seems to decrease with time since AE onset and may be greater in early life. These temporal relationships should be considered in future research investigating mechanisms linking both diseases and in clinical efforts to screen for and prevent ADHD symptoms in children with AE.

Process review of a departmental change from conventional coronary artery bypass grafting to totally arterial coronary artery bypass and its effects on the incidence and severity of postoperative stroke.

BACKGROUND: We evaluated the process of changing from conventional coronary artery bypass grafting (CABG) to totally arterial off-pump coronary artery bypass (TOPCAB) at a single heart center in Germany. METHODS: We (1) used multivariate statistical methods to assess real-time monitoring of OPCAB effects, (2) conducted a case review to assess preventable deaths and identify areas of improvement, (3) conducted a team survey, and (4) evaluated benchmarking results. RESULTS: All surgeons and assistants (n = 18) at this center were involved and were guided by the department head and one of the consultants, who was trained in this procedure in 2004 at the Leuven OPCAB school. The frequency of OPCAB operations increased abruptly in 2005 from 5% to 43% and then increased gradually to 67% (n = 546) by 2008 (total, 1781 OPCAB cases and 1563 on-pump cases). The in-hospital and 30-day mortality rates for OPCAB surgeries (n = 10 [0.6%] and 21 [1.2%], respectively) were lower than for on-pump surgeries (n = 27 [1.7%] and 26 [1.7%], respectively). Stroke rates were also lower for OPCAB surgeries (7 cases [0.4%] versus 15 cases [1%]). The lower risk of stroke in the OPCAB group was significant (P < .05) after risk adjustment. Monitoring curves and case reviews demonstrated a preventable death percentage of at least 30%. The attitude of the team was mostly positive because of the promising results (eg, fewer strokes, increasing TOPCAB popularity, and a top national rank). CONCLUSIONS: The change from conventional CABG to TOPCAB was effective in decreasing the incidence and severity of stroke, in developing a team routine and a positive team attitude, and in producing excellent benchmarking results. The presence of a training and communication deficiency at the beginning of the study suggested an area for further improvement. After 6 years TOPCAB had largely replaced conventional CABG.

The late impact of surgical skills and training on the subcoronary implantation of the Freestyle stentless bioprosthesis.

BACKGROUND AND AIM OF THE STUDY: Recent data have demonstrated an impact of higher postoperative mean pressure gradient (MPG) across the subcoronary Freestyle stentless bioprosthesis on the mid-term quality of life, but not on that of survival. Thus, the question remains that, with a prolonged follow up, would an effect on duration of survival also evolve? METHODS: Between 1996 and 2006, a total of 939 patients underwent aortic valve replacement (AVR) for aortic stenosis with the Freestyle stentless bioprosthesis, using the subcoronary technique. A follow up was conducted by mailed questionnaires, and completed by telephone interviews in September 2008. The follow up was 99% complete and totaled 3,468 patient-years (pt-yr); the mean follow up time was 7.7 years (range: 7.3-8.1 years). The maximum follow up was 11.9 years. RESULTS: Actuarial survival rates at five and 10 years were 73 +/- 2% and 35 +/- 4%, respectively. The cut-off gradient was identified at a postoperative MPG of 20 mmHg, where a gradient >20 mmHg had a negative impact on survival rate (p = 0.008), as indicated by the greatest fall of deviance in the Akaike information criterion. Risk factors also affecting survival rate included atrial fibrillation, diabetes, higher serum creatinine levels, greater age, left ventricular ejection fraction < or = 40%, liver insufficiency, lower body mass index, chronic obstructive pulmonary disease, and peripheral arterial disease. Risk factors for MPG >20 mmHg were a smaller valve size, a higher preoperative gradient, individual surgeons and lesser cumulative experience, and early adopters (surgeons) of the subcoronary stentless valve implantation technique. CONCLUSION: A higher MPG impedes long-term survival, with the cut-off being at 20 mmHg. A higher MPG was largely influenced by the individual surgeons and their cumulative experience of using the subcoronary technique. Late adopters of the technique profited from the observations of early adopters. The standardization of a surgical technique and the identification of common pitfalls were key to optimizing the surgical outcome after stentless valve implantation.

The Freestyle stentless bioprosthesis in more than 1000 patients: a single-center experience over 10 years.

BACKGROUND AND AIM: Early and mid-term clinical outcomes after aortic valve replacement (AVR) with stentless bioprostheses in a large cohort of patients are presented. METHODS: Between April 1996 and November 2005, 1014 patients underwent AVR with the stentless Medtronic Freestyle bioprosthesis, with 168 using the full-root technique. The mean age was 73+/-3 (range: 20 to 90) years. Follow-up included 2953 patient-years and was 95% complete for adverse events. RESULTS: Operative mortality was 3.4% (N=34). Overall survival was 46+/-9% at nine years and similar to age- and gender-matched German general population. Freedom from prosthetic valve endocarditis, major bleeding, neurological events, and reoperation after nine years was 97+/-6%, 92+/-7%, 70+/-16%, and 92+/-9%, respectively. Freedom from structural valve deterioration was 97+/-5% at 9 years. During the learning phase, mean transprosthetic gradients of 23.5+/-3.0 mmHg and 24.8+/-3.1 mmHg were observed for valve sizes 21 and 23 mm, respectively, 10 days after subcoronary implantation in 1997, which could be lowered to 16+/-2.1 mmHg and 14.9+/-0.9 mmHg in 2005, respectively, with increasing experience of the surgeons. During the follow-up period, mean gradients dropped on average by 15 mmHg in patients presenting higher gradients at discharge. CONCLUSIONS: The Freestyle stentless bioprosthesis showed encouraging midterm durability with low rates of valve-related morbidity, and can be safely implanted without increased operative risk even during the learning phase. Special training of the surgeons is recommended to achieve optimal hemodynamic performance.

Inter-rater Agreement Between Exposure Assessment Using Automatic Algorithms and Using Experts.

Objectives: To estimate the inter-rater agreement between exposure assessment to asthmagens in current jobs by algorithms based on task-based questionnaires (OccIDEAS) and by experts. Methods: Participants in a cross-sectional national survey of exposure to asthmagens (AWES-Asthma) were randomly split into two subcohorts of equal size. Subcohort 1 was used to determine the most common asthmagen groups and occupational groups. From subcohort 2, a random sample of 200 participants was drawn and current occupational exposure (yes/no) was assessed in these by OccIDEAS and by two experts independently and then as a consensus. Inter-rater agreement was estimated using Cohen's Kappa coefficient. The null hypothesis was set at 0.4, because both the experts and the automatic algorithm assessed the exposure using the same task-based questionnaires and therefore an agreement better than by chance would be expected. Results: The Kappa coefficients for the agreement between the experts and the algorithm-based assessments ranged from 0.37 to 1, while the agreement between the two experts ranged from 0.29 to 0.94, depending on the agent being assessed. After discussion by both experts the Kappa coefficients for the consensus decision and OccIDEAS were significantly larger than 0.4 for 7 of the 10 asthmagen groups, while overall the inter-rater agreement was greater than by chance (P < 0.0001). Conclusions: The web-based application OccIDEAS is an appropriate tool for automated assessment of current exposure to asthmagens (yes/no), and requires less time-consuming work by highly-qualified research personnel than the traditional expert-based method. Further, it can learn and reuse expert determinations in future studies.

Impact of valve prosthesis-patient mismatch estimated by echocardiographic-determined effective orifice area on long-term outcome after aortic valve replacement.

BACKGROUND: The impact of valve prosthesis-patient mismatch on long-term outcome after aortic valve replacement estimated by various variables such as projected indexed effective orifice area and internal geometric orifice area obtained from in vivo or in vitro published data is still controversial. METHODS: The effective orifice area was measured by echocardiography in 533 patients. The mean age of the patients was 71 +/- 9 years; mean follow-up time was 4.7 +/- 2.2 years. The impact of severe (indexed effective orifice area

Concomitant aortic valve replacement and coronary bypass: the effect of valve type on the blood flow in bypass grafts.

OBJECTIVE: In cases of aortic valve replacement, the downstream flow profile and turbulence in the ascending aorta differ according to the prosthetic aortic valve implanted. The objective of this work is to study the influence of prosthetic valve type on the flow in the bypass grafts implanted to the ascending aorta in cases of concomitant aortic valve replacement and coronary artery bypass. METHODS: The study is conducted on 456 patients receiving concomitant aortic valve replacement and coronary bypass vein grafts anastomosed to the ascending aorta. The patients included in the study received a total number of 725 vein grafts, 249 biological aortic valves and 207 mechanical aortic valves. Intraoperative transit time flow measurement was done for all bypass grafts and a multiple regression model was calculated for the factors influencing the flow in the bypass grafts. RESULTS: The mean flow in vein grafts in patients receiving biological valves was 49.79+/-26.88 ml/min, while in patients receiving mechanical valves it was 46.54+/-26.68 ml/min. The multiple regression model revealed that receiving a mechanical valve is an independent risk factor for lower flow in the vein grafts. CONCLUSIONS: The type of the aortic valve implanted and consequently the downstream flow profile in the ascending aorta do affect the flow in the vein grafts in cases of concomitant aortic valve replacement and coronary bypass. Receiving a mechanical aortic valve is an independent risk factor for lower flow in the vein grafts.

Body mass index: a risk factor for 30-day or six-month mortality in patients undergoing aortic valve replacement?

BACKGROUND AND AIM OF THE STUDY: In recent studies, the impact of a low or high body mass index (BMI) on outcome after cardiac surgery has been the subject of controversy. A retrospective study was conducted to determine the influence of BMI on 30-day and six-month mortality after aortic valve replacement (AVR). METHODS: A multivariable logistic regression was performed on data from 1,241 consecutive patients (mean age 69 +/- 11 years) who underwent AVR either with (n = 514; 41%) or without coronary artery bypass grafting CABG between 2000 and 2003. A wide spectrum of periprocedural variables was collected, including laboratory data as markers for nutritional status and comorbidity. Patients were followed up for six months after AVR (99% complete). RESULTS: Mortality rates after 30 days and after six months were 3.9% (n = 49) and 7.6% (n = 94), respectively. A low BMI was identified as an independent risk factor for 30-day (OR (odds ratio) 0.87; CI (confidence interval) 0.8-0.94) and six-month mortality (OR 0.91; CI 0.86-0.96). The relationship between the logit function and BMI was linear; however, a BMI value of 24 was considered an appropriate cut-off point. Both models containing the BMI linearly or dichotomic were equivalent. As patients with a lower BMI differ in their preoperative risk profile compared to those with a higher BMI, a saturated propensity score estimating the propensity towards having a BMI < 24 was calculated. The propensity score was not significant in the final models for 30-day and six-month mortality (0.24 and 0.73, respectively), and the OR for BMI remained largely unaltered (0.89 and 0.91, respectively). CONCLUSION: A BMI < 24 is predictive of an increased risk of mortality after AVR, independently of malnutrition, advanced heart disease, or valve size. Further studies are required to investigate the role of adipose tissue in extreme situations and chronic disease. It is mandatory to include BMI in outcome studies after AVR.

Current determinants of 30-day and 3-month mortality in over 2000 aortic valve replacements: Impact of routine laboratory parameters.

OBJECTIVE: Haematological and biochemical measurements are performed routinely before surgery to exclude organ malfunction and blood cell and coagulation abnormalities. We aimed to test routinely obtained laboratory data as factors predicting operative risk. METHODS: Between 1996 and 2003, 2198 patients underwent aortic valve replacement (AVR) (908 of them with concomitant CABG) in our institute. The mean age of the study population was 69+/-11 years (range 13-91, 43% female). Clinical and laboratory parameters based on the consolidated data mart set were evaluated by multiple logistic regression analysis. RESULTS: The overall operative mortality (within 30 days) was 3.8% and the mortality after 3 months was 5.9%. In addition to clinical characteristics, the following laboratory values were identified as independent predictors of 30-day mortality: fasting blood glucose, antithrombine III, partial thromboplastine time and creatinine kinase. As independent predictors of 3-month mortality, the following laboratory values were indentified: fasting blood glucose, serum creatinine, antithrombine III, partial thromboplastine time, lactate dehydrogenase, sodium concentration and serum proteins. The discriminative power of the models increased if laboratory parameters were included in addition to preoperative clinical characteristics (from 0.75 to 0.79 and from 0.75 to 0.78 for 30-day and 3-month mortality, respectively). The discriminative power using the logistic EuroScore was lower (0.71 and 0.7, for 30-day and 3-month mortality, respectively). CONCLUSIONS: Laboratory parameters as objective markers for organ function and nutritional status are useful data for the prediction of 30-day and 3-month mortality after aortic valve replacement. Using modern methods of information technology, these valuable data which are stored electronically in most hospitals, can be used efficiently for research and quality control.

Epigenome-wide search for association of serum 25-hydroxyvitamin D concentration with leukocyte DNA methylation in a large cohort of older men.

AIM: We aimed for an epigenome-wide identification of vitamin D-associated CpG sites in leukocyte DNA. MATERIALS & METHODS: Infinium HumanMethylation450BeadChip measurements in 402 Caucasian older men were evaluated for significant association with 25-hydroxy-vitamin (25(OH)D) using Spearman's correlation and median regression to adjust for confounding variables. A cross-validation approach as well as a bootstrapping procedure were implemented to determine the replicability of significant associations. Multiple testing was corrected for by Benjamini-Hochberg or Bonferroni. RESULTS: Although in the screening subcohorts significant associations of DNAm with 25(OH)D were observed in the validation cohorts these associations were not replicated after adjustment for potential confounders. At none of the 361,945 CpGs a significant association of DNAm with 25(OH)D was found in all 100 random bootstrap samples, but in comparison at 462 CpGs for the well-established association with age. CONCLUSION: Leukocyte DNAm was not associated with 25(OH)D levels after validation and consideration of confounders.

Breast cancer risk and the interaction between adolescent body size and weight gain in later life: A case-control study.

BACKGROUND: While the breast cancer risk associated with increasing adult BMI in postmenopausal women can be explained by increases in concentrations of endogenous estrogens the biologic mechanisms behind the inverse association between adolescent BMI and breast cancer risk are still a subject of controversial debate. METHODS: We investigated the association of breast cancer with body size and changes in body size across life time estimated by age-specific BMI Z scores and changes in BMI Z scores from teenage years to middle age in an age-matched population-based case-control study of 2994 Australian women. Logistic regression adjusted for the matching factor age and further potential confounders was used. RESULTS: Adolescent body leanness in postmenopausal women and excess adult weight gain in all study participants were associated with an increased breast cancer risk with an odds ratio [95% confidence interval] of 1.29 [1.08,1.54] and 1.31 [1.09,1.59], respectively. Interaction analyses restricted to postmenopausal women revealed an increased risk of breast cancer in those who were lean during adolescence and gained excess weight during adulthood (odds ratio [95% confidence interval]: 1.52 [1.19,1.95]) but not in women who were lean during adolescence and did not gain excess weight during adulthood (1.20 [0.97,1.48]) and not in women who were not lean during adolescence and but gained excess weight during adulthood (1.10 [0.95,1.27]) compared to postmenopausal women who were neither lean during adolescence nor gained excess weight. CONCLUSION: In postmenopausal women adolescent leanness was only associated with increased breast cancer risk when excess weight was gained during adulthood.

Smoking-Associated DNA Methylation Biomarkers and Their Predictive Value for All-Cause and Cardiovascular Mortality.

BACKGROUND: With epigenome-wide mapping of DNA methylation, a number of novel smoking-associated loci have been identified. OBJECTIVES: We aimed to assess dose-response relationships of methylation at the top hits from the epigenome-wide methylation studies with smoking exposure as well as with total and cause-specific mortality. METHODS: In a population-based prospective cohort study in Germany, methylation was quantified in baseline blood DNA of 1,000 older adults by the Illumina 450K assay. Deaths were recorded during a median follow-up of 10.3 years. Dose-response relationships of smoking exposure with methylation at nine CpGs were modeled by restricted cubic spline regression. Associations of individual and aggregate methylation patterns with all-cause, cardiovascular, and cancer mortality were assessed by multiple Cox regression. RESULTS: Clear dose-response relationships with respect to current and lifetime smoking intensity were consistently observed for methylation at six of the nine CpGs. Seven of the nine CpGs were also associated with mortality outcomes to various extents. A methylation score based on the top two CpGs (cg05575921 and cg06126421) showed the strongest associations with all-cause, cardiovascular, and cancer mortality, with adjusted hazard ratios (95% CI) of 3.59 (2.10, 6.16), 7.41 (2.81, 19.54), and 2.48 (1.01, 6.08), respectively, for participants with methylation levels in the lowest quartile at both CpGs. Adding methylation at those two CpGs into a model that included the variables of the Systematic Coronary Risk Evaluation chart for fatal cardiovascular risk prediction improved the predictive discrimination. CONCLUSION: The novel methylation biomarkers are highly informative for both smoking exposure and smoking-related mortality outcomes. In particular, these biomarkers may substantially improve cardiovascular risk prediction. Nevertheless, the findings of the present study need to be further validated in additional large longitudinal studies. CITATION: Zhang Y, Schöttker B, Florath I, Stock C, Butterbach K, Holleczek B, Mons U, Brenner H. 2016. Smoking-associated DNA methylation biomarkers and their predictive value for all-cause and cardiovascular mortality. Environ Health Perspect 124:67-74; http://dx.doi.org/10.1289/ehp.1409020.

Stentless bioprostheses in small aortic roots: impact of patient-prosthesis mismatch on survival and quality of life.

BACKGROUND AND AIM OF THE STUDY: Although stentless bioprostheses offer hemodynamic advantages, prosthetic valves of smaller size may provide less reduction of left ventricular hypertrophy and, therefore, affect survival and quality of life. METHODS: A total of 303 patients (mean age 75 +/- 7 years) who underwent aortic valve replacement with the stentless Freestyle bioprostheses were followed up. The impact of projected indexed effective orifice area (IEOA) on survival and quality of life (QoL) was determined multivariately by Cox regression and logistic regression analysis. RESULTS: Independent predictors of survival time were diabetes mellitus (p < 0.001), atrial fibrillation (p = 0.004), male gender (p = 0.015), peripheral vascular disease (p = 0.039), and patient-prosthesis mismatch (PPM, defined as projected IEOA < 0.75 cm2/m2) in patients with aortic regurgitation (p = 0.017). A history of congestive heart failure (p = 0.016), small body mass index (p = 0.01), age > 75 years (p = 0.002) and small projected IEOA (p = 0.016) were identified as predictors of impaired QoL. CONCLUSION: PPM and small projected IEOA were identified as independent risk factors for impaired mid-term survival and QoL. As the occurrence of PPM was rare in total root replacements, and the implantation procedure did not increase the operative risk in the present patient population, the recommendation is made to consider this implantation technique if a small projected IEOA is expected.

Current determinants of operative mortality in 1400 patients requiring aortic valve replacement.

BACKGROUND: Determinants of operative mortality after aortic valve replacement vary with a changing patient population due to advances in operative management and increasing life expectancy. In order to predict current groups of high risk patients, a statistically valid large study population base recruited over a short period of time is required. METHODS: Between January 1996 and June 2001, 1408 aortic valves were replaced in 1400 patients (572 of them with simultaneous coronary artery bypass grafting). The data were analyzed by multivariate logistic regression to evaluate the operative risk. Mean age of the study population was 68 +/- 11 years (range 19 to 90 years old, 44% female). RESULTS: Overall operative mortality (within 30 days) was 3.8%. Independent predictive factors for operative mortality were previous bypass surgery, emergency operation, simultaneous mitral valve replacement, renal dysfunction, more than 80 years old, simultaneous bypass surgery in female patients with a body mass index greater than 29 kg/m(2), and height smaller than 1.57 m for patients more than 71 years old. Simultaneous coronary artery bypass grafting in general (p = 0.6), previous aortic valve replacement (p = 0.59), and implantation of stented bioprostheses (p = 0.39) or stentless bioprostheses (p = 0.7) were not identified as independent risk factors. CONCLUSIONS: Certain groups of patients with a high operative risk were identified: patients more than 80 years old, women with a body mass index greater 29 kg/m(2) undergoing simultaneous coronary artery bypass surgery, and "small" patients more than 71 years old.

Risk in elderly patients after stentless versus stented aortic valve surgery.

Recent studies suggest that the hemodynamic advantage of stentless bioprostheses over the stented type improves long-term survival after aortic valve replacement, but the more complex and time-consuming implantation technique may increase the risks of operative death and postoperative complications. Between April 1996 and June 2001, 519 patients with a mean age of 76 +/- 5 years underwent aortic valve replacement using a stentless (Medtronic Freestyle, n = 277) or stented bioprosthesis (Medtronic Mosaic, n = 242). Multiple logistic regression analysis considering different patient populations revealed no increased risk of operative death, postoperative complications, or neurological impairment after implantation of a stentless bioprosthesis. Survival curves in respect of 367 patients who underwent aortic valve replacement up to September 2000 and were followed up for 3 years were not different (p = 0.98). As the patients were elderly, improved survival due to implantation of a stentless valve could not be demonstrated within this time span.