Electronic Nicotine Delivery System (ENDS) Device Types and Flavors Used by Youth in the PATH Study, 2016-2019.

The evolving electronic nicotine delivery system (ENDS) marketplace and recent regulatory actions may influence youth ENDS device preferences. Using data from Waves (W) 4, 4.5, and 5 (2016-2019) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study, this study estimated the prevalence of open and closed system primary ENDS use by youth (12-17 years) current (past 30-day) ENDS users, and compared demographics, tobacco use characteristics, and patterns of ENDS use, including flavors, by device type. Among current ENDS users, closed system use was significantly higher than open system use in W4.5 (68.3% vs. 31.7%) and W5 (60.5% vs. 39.5%). In W5, closed system users were more likely to have a regular ENDS brand, believe their ENDS had nicotine, and use tobacco and mint or menthol flavors in the past 30 days compared to open system users. In W5, users of closed systems were less likely to use fruit, non-alcoholic drink, and candy, desserts, or other sweets flavors in the past 30 days than users of open systems. Youth were more likely to use closed over open system ENDS in 2017-2019. Differences were observed between device types, particularly with flavor use, reflecting recent changes in flavored product availability.

Changes in Biomarkers of Tobacco Exposure among Cigarette Smokers Transitioning to ENDS Use: The Population Assessment of Tobacco and Health Study, 2013-2015.

Limited data are available for how biomarkers of tobacco exposure (BOE) change when cigarette smokers transition to using electronic nicotine delivery systems (ENDS). Using biomarker data from Waves 1 (2013-2014) and 2 (2014-2015) of the PATH Study, we examined how mean BOE concentrations, including metabolites of nicotine, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC) and metals, changed when 2475 adult smokers transitioned to using ENDS or quit tobacco products. Exclusive smokers who transitioned to dual use had a significant decrease in NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol), but not nicotine metabolites, most PAHs, metals, or VOCs. Exclusive smokers who became dual users had significant reductions in total nicotine equivalents, NNAL, and 2CyEMA (acrylonitrile metabolite), but only in those who reduced cigarettes per day (CPD) by >=50%. Smokers who transitioned to exclusive ENDS use had significant reductions in most TSNAs, PAHs, and VOCs; however, nicotine metabolites did not decrease in dual users who became exclusive ENDS users. Smokers who quit tobacco use had significant decreases in nicotine metabolites, all TSNAs, most PAHs, and most VOCs. Cigarette smokers who became dual users did not experience significant reductions in most BOEs. Reductions were impacted by changes in CPD. However, transitioning from smoking to no tobacco or exclusive ENDS use was associated with reduced exposure to most BOEs measured. Future analyses could incorporate additional waves of PATH data and examine changes in biomarker exposure by ENDS device type and CPD.

Cigarette Smoking Reduction and Health Risks: A Systematic Review and Meta-analysis.

INTRODUCTION: Studies have shown the health benefits of cigarette smoking cessation. However, the literature remains unclear about the relationship between smoking reduction and health risks. This comprehensive review and meta-analysis updates previous reviews with the newest estimates. AIMS AND METHODS: We conducted a systematic review and meta-analysis evaluating the association between smoking reduction and some health risks in observational studies. We defined the following smoking categories: heavy smokers smoked ≥15-20 cigarettes per day (CPD), moderate smokers smoked 10-19 CPD, and light smokers smoked <10 CPD. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random-effect models. RESULTS: We identified 19 studies including four case-control and 15 cohort studies. Compared with continuing heavy smokers, we found decreased lung cancer risk for those who reduced CPD by more than 50% (RR = 0.72, 95% CI: 0.52, 0.91), from heavy to moderate (RR = 0.66, 95% CI: 0.46, 0.85), and from heavy to light (RR = 0.60, 95% CI: 0.49, 0.72). We also found lower risk of cardiovascular disease (CVD) for those who reduced from heavy to light smoking (RR = 0.78, 95% CI: 0.67, 0.89) but not those who reduced by more than 50% and reduced smoking from heavy to moderate. We did not find any significant difference in all-cause mortality, all-cancer risks, and smoking-/tobacco-related cancer risk among those who reduced. CONCLUSIONS: Substantial smoking reduction may decrease lung cancer risk but results on CVD (coronary heart disease and stroke combined) risk were mixed. The relationships between smoking reduction and other endpoints examined were not significant. IMPLICATIONS: This meta-analysis helps clarify our understanding of various smoking reduction levels on some health risks. While smoking reduction may decrease risks of lung cancer, the relationships between smoking reduction and other endpoints, including all-cause mortality and cardiovascular disease, remain unclear. Although smoking reduction may decrease lung cancer risks, the magnitude of lung cancer risk remain high. Among smokers, complete cessation remains the most effective approach for cancer and CVD prevention.

Tobacco Product Use and Associated Factors Among Middle and High School Students - United States, 2019.

PROBLEM/CONDITION: Tobacco use is the leading cause of preventable disease, disability, and death in the United States. Most tobacco product use begins during adolescence. In recent years, tobacco products have evolved to include various smoked, smokeless, and electronic products. PERIOD COVERED: 2019. DESCRIPTION OF SYSTEM: The National Youth Tobacco Survey (NYTS) is an annual, cross-sectional, school-based, self-administered survey of U.S. middle school (grades 6-8) and high school (grades 9-12) students. A three-stage cluster sampling procedure is used to generate a nationally representative sample of U.S. students attending public and private schools. NYTS is the only nationally representative survey of U.S. middle and high school students that focuses exclusively on tobacco use patterns and associated factors. NYTS is designed to provide national data on tobacco product use and has been conducted periodically during 1999-2009 and annually since 2011. Data from NYTS are used to support the design, implementation, and evaluation of comprehensive tobacco use prevention and control programs and to inform tobacco regulatory activities. Since its inception in 1999 through 2018, NYTS had been conducted via paper and pencil questionnaires. In 2019, NYTS for the first time was administered in schools using electronic data collection methods. CDC's Office on Smoking and Health, in collaboration with the U.S. Food and Drug Administration's (FDA's) Center for Tobacco Products, analyzed data from the 2019 NYTS to assess tobacco product use patterns and associated factors among U.S. middle and high school students. Overall, 19,018 questionnaires were completed and weighted to represent approximately 27.0 million students. On the basis of self-reported grade level, this included 8,837 middle school questionnaires (11.9 million students) and 10,097 high school questionnaires (15.0 million students); 84 questionnaires with missing information on grade level were excluded from school-level analyses. RESULTS: In 2019, an estimated 53.3% of high school students (8.0 million) and 24.3% of middle school students (2.9 million) reported having ever tried a tobacco product. Current (past 30-day) use of a tobacco product (i.e., electronic cigarettes [e-cigarettes], cigarettes, cigars, smokeless tobacco, hookahs, pipe tobacco, and bidis [small brown cigarettes wrapped in a leaf]) was reported by 31.2% of high school students (4.7 million) and 12.5% of middle school students (1.5 million). E-cigarettes were the most commonly cited tobacco product currently used by 27.5% of high school students (4.1 million) and 10.5% of middle school students (1.2 million), followed in order by cigars, cigarettes, smokeless tobacco, hookahs, and pipe tobacco. Tobacco product use also varied by sex and race/ethnicity. Among current users of each tobacco product, the prevalence of frequent tobacco product use (on ≥20 days of the preceding 30 days) ranged from 16.8% of cigar smokers to 34.1% of smokeless tobacco product users. Among current users of each individual tobacco product, e-cigarettes were the most commonly used flavored tobacco product (68.8% of current e-cigarette users). Among students who reported ever having tried e-cigarettes, the three most commonly selected reasons for use were "I was curious about them" (55.3%), "friend or family member used them" (30.8%), and "they are available in flavors, such as mint, candy, fruit, or chocolate" (22.4%). Among never users of each individual tobacco product, curiosity and susceptibility (a construct that can help to identify future tobacco product experimentation or use) was highest for e-cigarettes (39.1% and 45.0%, respectively) and cigarettes (37.0% and 45.9%, respectively). Overall, 86.3% of students who reported contact with an assessed potential source of tobacco product advertisements or promotions (going to a convenience store, supermarket, or gas station; using the Internet; watching television or streaming services or going to the movies; or reading newspapers or magazines) reported exposure to marketing for any tobacco product; 69.3% reported exposure to e-cigarette marketing and 81.7% reported exposure to marketing for cigarettes or other tobacco products. Among all students, perceiving no harm or little harm from intermittent tobacco product use (use on some days but not every day) was 28.2% for e-cigarettes, 16.4% for hookahs, 11.5% for smokeless tobacco products, and 9.5% for cigarettes. Among current users of any tobacco product, 24.7% reported experiencing cravings to use tobacco products during the past 30 days and 13.7% reported wanting to use a tobacco product within 30 minutes of waking. Moreover, 57.8% of current tobacco product users reported they were seriously thinking about quitting the use of all tobacco products and 57.5% reported they had stopped using all tobacco products for ≥1 day because they were trying to quit. INTERPRETATION: In 2019, approximately one in four youths (23.0%) had used a tobacco product during the past 30 days. By school level, this represented approximately three in 10 high school students (31.2%) and approximately one in eight middle school students (12.5%). Since 2014, e-cigarettes have been the most commonly used tobacco product among youths. Importantly, more than half of current youth tobacco product users reported seriously thinking about quitting all tobacco products in 2019. However, established factors of use and initiation, including the availability of flavors, exposure to tobacco product marketing, curiosity and susceptibility, and misperceptions about harm from tobacco product use, remained prevalent in 2019 and continue to promote tobacco product use among youths. PUBLIC HEALTH ACTION: The continued monitoring of all forms of youth tobacco product use and associated factors through surveillance efforts including NYTS is important to the development of public health policy and action at national, state, and community levels. Everyone, including public health professionals, health care providers, policymakers, educators, parents, and others who influence youths, can help protect youths from the harms of all tobacco products. In addition, the comprehensive and sustained implementation of evidence-based tobacco control strategies, combined with FDA's regulation of tobacco products, is important for reducing all forms of tobacco product use among U.S. youths.

e-Cigarette Use Among Youth in the United States, 2019.

Importance: The prevalence of e-cigarette use among US youth increased from 2011 to 2018. Continued monitoring of the prevalence of e-cigarette and other tobacco product use among youth is important to inform public health policy, planning, and regulatory efforts. Objective: To estimate the prevalence of e-cigarette use among US high school and middle school students in 2019 including frequency of use, brands used, and use of flavored products. Design, Setting, and Participants: Cross-sectional analyses of a school-based nationally representative sample of 19 018 US students in grades 6 to 12 participating in the 2019 National Youth Tobacco Survey. The survey was conducted from February 15, 2019, to May 24, 2019. Main Outcomes and Measures: Self-reported current (past 30-day) e-cigarette use estimates among high school and middle school students; frequent use (≥20 days in the past 30 days) and usual e-cigarette brand among current e-cigarette users; and use of flavored e-cigarettes and flavor types among current exclusive e-cigarette users (no use of other tobacco products) by school level and usual brand. Prevalence estimates were weighted to account for the complex sampling design. Results: The survey included 10 097 high school students (mean [SD] age, 16.1 [3.0] years; 47.5% female) and 8837 middle school students (mean [SD] age, 12.7 [2.8] years; 48.7% female). The response rate was 66.3%. An estimated 27.5% (95% CI, 25.3%-29.7%) of high school students and 10.5% (95% CI, 9.4%-11.8%) of middle school students reported current e-cigarette use. Among current e-cigarette users, an estimated 34.2% (95% CI, 31.2%-37.3%) of high school students and 18.0% (95% CI, 15.2%-21.2%) of middle school students reported frequent use, and an estimated 63.6% (95% CI, 59.3%-67.8%) of high school students and 65.4% (95% CI, 60.6%-69.9%) of middle school students reported exclusive use of e-cigarettes. Among current e-cigarette users, an estimated 59.1% (95% CI, 54.8%-63.2%) of high school students and 54.1% (95% CI, 49.1%-59.0%) of middle school students reported JUUL as their usual e-cigarette brand in the past 30 days; among current e-cigarette users, 13.8% (95% CI, 12.0%-15.9%) of high school students and 16.8% (95% CI, 13.6%-20.7%) of middle school students reported not having a usual e-cigarette brand. Among current exclusive e-cigarette users, an estimated 72.2% (95% CI, 69.1%-75.1%) of high school students and 59.2% (95% CI, 54.8%-63.4%) of middle school students used flavored e-cigarettes, with fruit, menthol or mint, and candy, desserts, or other sweets being the most commonly reported flavors. Conclusions and Relevance: In 2019, the prevalence of self-reported e-cigarette use was high among high school and middle school students, with many current e-cigarette users reporting frequent use and most of the exclusive e-cigarette users reporting use of flavored e-cigarettes.

Methylmercury exposure, genetic variation in metabolic enzymes, and the risk of glioma.

Methylmercury (MeHg) is an environmental neurotoxin with human exposure mainly from dietary intake of contaminated fish. Exposure to MeHg has been implicated in neurological damage, but research on its role in cancers, specifically glioma, is limited. In a glioma case-control study, we examined associations between toenail mercury (Hg) and glioma risk. We also examined genetic polymorphisms in 13 genes related to MeHg metabolism for association with glioma risk; genetic associations were also studied in the UK Biobank cohort. Median toenail Hg in cases and controls, respectively, was 0.066 µg/g and 0.069 µg/g (interquartile range (IQR): 0.032-0.161 and 0.031-0.150 µg/g). Toenail Hg was not found to be significantly associated with glioma risk (Odds Ratio: 1.02; 95% Confidence Interval: 0.91, 1.14; p = 0.70 in analysis for ordinal trend with increasing quartile of toenail MeHg). No genetic variant was statistically significant in both of the studies; one variant, rs11859163 (MMP2) had a combined p-value of 0.02 though it was no longer significant after adjustment for multiple testing (Bonferroni corrected p = 1). This study does not support the hypothesis that exposure to MeHg plays a role in the development of glioma at levels of exposure found in this study population.

Frequency of Use Among Middle and High School Student Tobacco Product Users - United States, 2015-2017.

Tobacco product use during adolescence increases the risk for lifelong nicotine addiction and immediate adverse health effects (1,2). During 2011-2017, current use of cigarettes, cigars, smokeless tobacco, and pipe tobacco decreased significantly among middle and high school students, but current use of e-cigarettes increased significantly from 1.5% to 11.7% (3). In 2017, an estimated 19.6% of high school students (2.95 million) and 5.6% of middle school students (0.67 million) were current users of any tobacco product; e-cigarettes were the most commonly used tobacco product for both middle (3.3%) and high (11.7%) school students (3). The Food and Drug Administration (FDA) and CDC analyzed combined data from the 2015-2017 National Youth Tobacco Surveys (NYTS) to determine past 30-day (current) frequency of use of cigarettes, e-cigarettes, cigars, smokeless tobacco, and hookahs among U.S. high school and middle school students. During 2015-2017, the proportion of students currently using tobacco products who used a product for ≥20 of the past 30 days ranged from 14.0% of cigar smokers to 38.7% of smokeless tobacco users among high school students and from 13.1% of e-cigarette users to 24.5% of hookah smokers among middle school students. Among current users, use of two or more tobacco products ranged from 76.7% (e-cigarettes) to 90.9% (hookahs) among those using the product ≥20 of the preceding 30 days, from 68.0% (e-cigarettes) to 84.2% (hookahs) among those using the product for 6 to 19 of the preceding 30 days, and from 48.8% (e-cigarettes) to 77.2% (cigarettes) among those using the product for 1 to 5 of the preceding 30 days. Sustained implementation of proven tobacco control strategies focusing on all types of tobacco products, in coordination with the regulation of tobacco products by FDA, are needed to reduce tobacco product initiation and use among U.S. youths.

Smokeless tobacco use and circulatory disease risk: a systematic review and meta-analysis.

Objective: Smokeless tobacco use is a public health issue throughout the world, but reviews and analyses of circulatory disease risks associated with smokeless tobacco use may be outdated or incomplete. This study provides a thorough and comprehensive review and meta-analysis of circulatory disease risks in high-income countries, including recently published study estimates. Methods: We conducted a systematic review of studies of circulatory disease risks associated with smokeless tobacco use in Europe and North America that were identified from electronic databases and reference lists. Study estimates were extracted by region, smokeless tobacco use status, cigarette smoking status, and circulatory condition and combined in meta-analysis using a random-effects model. We used the Newcastle-Ottawa scale to assess study quality and risk of bias. Results: We identified 17 relevant cohort studies, two pooled analyses, five case-control studies and one cross-sectional analysis. We found increased risk of heart disease (relative risk (RR) 1.17, 95% CI 1.09 to 1.27) and stroke (RR 1.28, 95% CI 1.01 to 1.62) among US smokeless tobacco users compared with non-users. Increased circulatory disease risk was not observed among Swedish smokeless tobacco users. Conclusion: US smokeless tobacco users were found to have increased risk of heart disease and stroke.

Toenail selenium, genetic variation in selenoenzymes and risk and outcome in glioma.

BACKGROUND: Selenium is an essential trace element obtained through diet that plays a critical role in DNA synthesis and protection from oxidative damage. Selenium intake and polymorphisms in selenoproteins have been linked to the risk of certain cancers though data for glioma are sparse. METHODS: In a case-control study of glioma, we examined the associations of selenium in toenails and genetic variants in the selenoenzyme pathway with the risk of glioma and patient survival. A total of 423 genetic variants in 29 candidate genes in the selenoenzyme pathway were studied in 1547 glioma cases and 1014 healthy controls. Genetic associations were also examined in the UK Biobank cohort comprised of 313,868 persons with 322 incident glioma cases. Toenail selenium was measured in a subcohort of 300 glioma cases and 300 age-matched controls from the case-control study. RESULTS: None of the 423 variants studied were consistently associated with glioma risk in the case-control and cohort studies. Moreover, toenail selenium in the case-control study had no significant association with glioma risk (p trend = 0.70) or patient survival among 254 patients with high grade tumors (p trend = 0.70). CONCLUSION: The present study offers no support for the hypothesis that selenium plays a role in the onset of glioma or patient outcome.

E-cigarette and Smokeless Tobacco Use and Switching Among Smokers: Findings From the National Adult Tobacco Survey.

INTRODUCTION: Assessing the extent that cigarette smokers use or switch to e-cigarettes and smokeless tobacco can help inform the population health impact of these products. This study estimated the prevalence of e-cigarette and smokeless tobacco use and switching among current and recent former adult cigarette smokers. METHODS: Data from the 2012-2013 (n=8,891) and 2013-2014 (n=11,379) National Adult Tobacco Survey were analyzed in 2016. Response rates for this telephone survey were 44.9% and 36.1%, respectively. Tobacco product use was assessed by smoking status. RESULTS: Current e-cigarette use increased for all groups, with a greater increase among recent quitters, 9.1% (95% CI=7.1%, 11.1%) in 2012-2013 and 15.8% (95% CI=13.7%, 17.9%) in 2013-2014, than smokers with an unsuccessful quit attempt, 10.4% (95% CI=9.1%, 11.7%) in 2012-2013 and 14.8% (95% CI=13.5%, 16.1%) in 2013-2014, or smokers with no quit attempt, 5.9% (95% CI=4.8%, 6.9%) in 2012-2013 and 10.7% (95% CI=9.4%, 12.0%) in 2013-2014. Between 2012-2013 and 2013-2014, current use of smokeless tobacco remained steady for recent quitters (4.6% to 4.7%, p=0.92) and smokers with no quit attempt (4.0% to 4.3%, p=0.97), and decreased in smokers with an unsuccessful quit attempt (5.7% to 3.8%, p=0.004). More recent quitters completely switched to e-cigarettes in the past year (15.3% in 2012-2013, 25.7% in 2013-2014) than to smokeless tobacco (4.6% in 2012-2013, 4.5% in 2013-2014). CONCLUSIONS: Current and recent former adult smokers are more likely to use e-cigarettes than smokeless tobacco. Current e-cigarette use was most prevalent among unsuccessful quitters and recent quitters, who were substantially more likely to report complete switching to e-cigarettes than smokeless tobacco.

Metabolomic Profiling of Serum Retinol in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

The role of retinol in the prevention of multifactorial chronic diseases remains uncertain, and there is sparse evidence regarding biological actions and pathways implicated in its effects on various outcomes. The aim is to investigate whether serum retinol in an un-supplemented state is associated with low molecular weight circulating metabolites. We performed a metabolomic analysis of 1,282 male smoker participants based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We examined the association between 947 metabolites measured by ultra-high performance LC-MS/GC-MS and retinol concentration (from HPLC) using linear regression that estimated the difference in metabolite concentrations per unit difference in retinol concentration as standardized ß-coefficients and standard errors (SE). We identified 63 metabolites associated with serum retinol below the Bonferroni-corrected P-value (p < 5.3 × 10-5). The strongest signals were for N-acetyltryptophan (ß = 0.27; SE = 0.032; p = 9.8 × 10-17), myo-inositol (ß = 0.23; SE = 0.032; p = 9.8 × 10-13), and 1-palmitoylglycerophosphoethanolamine (ß = 0.22; SE = 0.032; p = 3.2 × 10-12). Several chemical class pathways were strongly associated with retinol, including amino acids (p = 1.6 × 10-10), lipids (p = 3.3 × 10-7), and cofactor/vitamin metabolites (3.3 × 10-7). The strongest sub-pathway association was for inositol metabolism (p = 2.0 × 10-14). Serum retinol concentration is associated with circulating metabolites in various metabolic pathways, particularly lipids, amino acids, and cofactors/vitamins. These interrelationships may have relevance to the biological actions of retinol, including its role in carcinogenesis.

Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

BACKGROUND: Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and other outcomes. Epidemiological studies have reported on the importance of vitamin D in cancer prevention and treatment. The discovery of vitamin D-associated metabolites through agnostic metabolomics analyses offers a new approach for elucidating disease aetiology and health-related pathway identification. METHODS: Baseline serum 25-hydroxy-vitamin D [25(OH)D] and 940 serum metabolites were measured in 392 men from eight nested cancer case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers (aged 50-69 years). The metabolomic profiling was conducted using mass spectrometry. We used linear regression to estimate the standardized beta-coefficient as the effect metric for the associations between metabolites and 25(OH)D levels. RESULTS: A majority of the metabolites associated with 25(OH)D were of lipid origin, including 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) [beta-estimate 0.38 per 1 standard deviation (SD) increment], stearoyl-arachidonoyl-glycerophosphoethanolamine (GPPE) (-0.38 per SD) and two essential fatty acids: eicosapentaenoate (EPA; 0.17 per SD) and docosahexaenoate (DHA; 0.13 per SD). Each of these lipid metabolites was associated with 25(OH)D at the principal components corrected P-value of 3.09 × 10-4 CONCLUSIONS: The large number of metabolites, particularly lipid compounds, found to be associated with serum 25(OH)D provide new biological clues relevant to the role of vitamin D status and human health outcomes. The present findings should be re-examined in other metabolomics studies of diverse populations.

Association between serum 25-hydroxyvitamin D and serum sex steroid hormones among men in NHANES.

BACKGROUND: Recent literature suggests that high circulating vitamin D may increase prostate cancer risk. Although the mechanism through which vitamin D may increase risk is unknown, vitamin D concentration could influence circulating sex steroid hormones that may be associated with prostate cancer; an alternate explanation is that it could be associated with prostate-specific antigen (PSA) concentration causing detection bias. OBJECTIVE: We examined whether serum vitamin D concentration was associated with sex steroid hormone and PSA concentrations in a cross-sectional analysis of men in the National Health and Nutrition Examination Surveys (NHANES). DESIGN: Testosterone, oestradiol, sex hormone-binding globulin (SHBG), androstanediol glucuronide, and 25-hydroxyvitamin D (25(OH)D) were measured in serum from men aged 20 and older participating in NHANES III (n = 1315) and NHANES 2001-2004 (n = 318). Hormone concentrations were compared across 25(OH)D quintiles, adjusting for age, race/ethnicity, body fat percentage, and smoking. PSA concentration was estimated by 25(OH)D quintile in 4013 men from NHANES 2001-2006. RESULTS: In NHANES III, higher testosterone (quintile (Q) 1 = 17·2, 95% confidence interval (CI) = 16·1-18·6; Q5 = 19·6, 95% CI = 18·7-20·6 nmol/l, P-trend = 0·0002) and SHBG (Q1 = 33·8, 95% CI = 30·8-37·0; Q5 = 38·4, 95% CI = 35·8-41·2 nmol/l, P-trend = 0·0005) were observed with increasing 25(OH)D. Similar results were observed in NHANES 2001-2004. PSA concentration was not associated with serum 25(OH)D (P-trend = 0·34). CONCLUSION: Results from these nationally representative studies support a positive association between serum 25(OH)D and testosterone and SHBG. The findings support an indirect mechanism through which vitamin D may increase prostate cancer risk, and suggest the link to prostate cancer is not due to PSA-detection bias.

Serum vitamin D, vitamin D binding protein, and lung cancer survival.

OBJECTIVES: Vitamin D may prolong cancer survival by inhibiting tumor progression and metastasis, however, there are limited epidemiologic studies regarding the association between circulating 25-hydroxyvitamin D (25(OH)D) and lung cancer survival. The aim of this study was to examine the relationship between serum 25(OH)D and lung cancer specific survival and to evaluate whether vitamin D binding protein (DBP) concentration modified this association. MATERIALS AND METHODS: 25(OH)D and DBP were measured in fasting serum samples from 500 male lung cancer cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer related death according to quartiles of season-specific 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. RESULTS: Comparing highest to lowest quartiles, serum 25(OH)D (HR=1.18; 95% CI: 0.89-1.56) and DBP (HR=0.95; 95% CI: 0.71-1.26) were not associated with lung cancer survival and DBP concentration did not modify the association with 25(OH)D (p for interaction=0.56). There was suggestion of an association between higher serum 25(OH)D and better survival from adenocarcinoma (HR=0.64; 95% CI: 0.17-2.45) and small cell carcinoma (HR=0.55; 95% CI: 0.21-1.45), but these estimates were based on a relatively small number of cases. CONCLUSION: Serum 25(OH)D was not associated with overall lung cancer survival regardless of DBP concentration, however, these findings should be examined in other studies that include women and subjects with higher 25(OH)D levels.

Transfer of residents to hospital prior to cardiac death: the influence of nursing home quality and ownership type.

OBJECTIVES: We hypothesised that among nursing home decedents, nursing home for-profit status and poor quality-of-care ratings, as well as patient characteristics, would lower the likelihood of transfer to hospital prior to heart disease death. METHODS: Using death certificates from a large metropolitan area (Tampa Florida Metropolitan Statistical Area) for 1998-2002, we geocoded residential street addresses of heart disease decedents to identify 2172 persons who resided in nursing homes (n=131) at the time of death. We analysed decedent place of death as an indicator of transfer prior to death. Multilevel logistic regression modelling was used for analysis. Cause of death and decedent characteristics were obtained from death certificates. Nursing home characteristics, including state inspector ratings for multiple time points, were obtained from Florida's Agency for Healthcare Administration. RESULTS: Nursing home for-profit status, level of nursing care and quality-of-care ratings were not associated with the likelihood of transfer to hospital prior to heart disease death. Nursing homes >5 miles from a hospital were more likely to transfer decedents, compared with facilities located close to a hospital. Significant predictors of no transfer for nursing home residents were being white, female, older, less educated and widowed/unmarried. CONCLUSIONS: In this study population, contrary to our hypotheses, sociodemographic characteristics of nursing home decedents were more important predictors of no transfer prior to cardiac death than quality rankings or for-profit status of nursing homes.

Serum vitamin D, vitamin D binding protein, and risk of colorectal cancer.

BACKGROUND: We previously reported a positive association between serum 25-hydroxyvitamin D (25(OH)D) and colorectal cancer risk. To further elucidate this association, we examined the molar ratio of 25(OH)D to vitamin D binding protein (DBP), the primary 25(OH)D transport protein, and whether DBP modified the association between 25(OH)D and colorectal cancer risk. METHODS: In a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, controls were 1∶1 matched to 416 colorectal cancer cases based on age and date of blood collection. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free, unbound circulating 25(OH)D. RESULTS: Comparing highest to lowest quartiles, DBP was not associated with colorectal cancer risk (OR = 0.91; 95% CI: 0.58, 1.42, p for trend  = 0.58); however, a positive risk association was observed for the molar ratio of 25(OH)D:DBP (OR = 1.44; 95% CI: 0.92, 2.26, p for trend  = 0.04). In stratified analyses, the positive association between 25(OH)D and colorectal cancer was stronger among men with DBP levels above the median (OR = 1.89; 95% CI: 1.07, 3.36, p for trend  = 0.01) than below the median (OR = 1.20; 95% CI: 0.68, 2.12, p for trend  = 0.87), although the interaction was not statistically significant (p for interaction  = 0.24). CONCLUSION: Circulating DBP may influence the association between 25(OH)D and colorectal cancer in male smokers, with the suggestion of a stronger positive association in men with higher DBP concentrations. This finding should be examined in other populations, especially those that include women and non-smokers.

Reproductive factors and risk of primary brain tumors in women.

Gender-specific incidence patterns and the presence of hormonal receptors on tumor cells suggest that sex hormones may play a role in the onset of primary brain tumors. However, epidemiological studies on the relation of hormonal risk factors to the risk of brain tumors have been inconsistent. We examined the role of reproductive factors in the onset of glioma and meningioma in a case-control study conducted in the Southeastern US that included 507 glioma cases, 247 meningioma cases, and 695 community-based and friend controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) adjusting for age, race, US state of residence, and education. An older age at menarche was associated with an increased risk of glioma (≥ 15 vs. ≤ 12 years: OR 1.65; 95% CI 1.11-2.45), with a stronger association observed in pre-menopausal (OR 2.22; 95% CI 1.12-4.39) than post-menopausal (OR 1.55; 95% CI 0.93-2.58) women. When compared to controls, meningioma cases were more likely to have undergone natural menopause (OR 1.52; 95% CI 1.04-2.21) whereas glioma cases were less likely to be long term users of oral contraceptives (OR 0.47; 95% CI 0.33-0.68). Increasing parity was not related to the risk of either tumor. Current findings are consistent with a limited role for hormones in the onset of brain tumors in women. Results contribute to a growing body of evidence that a later age at menarche increases the risk of glioma in women.

Inherited variation in the PARP1 gene and survival from melanoma.

We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p = 0.005, eleven cohorts) and MSS (HR = 1.20 per allele, 95% CI 1.01-1.39, p = 0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS.

An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study.

An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization.

Circadian pathway genes in relation to glioma risk and outcome.

PURPOSE: There is growing evidence that circadian disruption may alter risk and aggressiveness of cancer. We evaluated common genetic variants in the circadian gene pathway for associations with glioma risk and patient outcome in a US clinic-based case-control study. METHODS: Subjects were genotyped for 17 candidate single nucleotide polymorphisms in ARNTL, CRY1, CRY2, CSNK1E, KLHL30, NPAS2, PER1, PER3, CLOCK, and MYRIP. Unconditional logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95 % confidence intervals (CI) for glioma risk under three inheritance models (additive, dominant, and recessive). Proportional hazards regression was used to estimate hazard ratios for glioma-related death among 441 patients with high-grade tumors. Survival associations were validated using The Cancer Genome Atlas (TCGA) dataset. RESULTS: A variant in PER1 (rs2289591) was significantly associated with overall glioma risk (per variant allele OR 0.80; 95 % CI 0.66-0.97; p trend = 0.027). The variant allele for CLOCK rs11133391 under a recessive model increased risk of oligodendroglioma (OR 2.41; 95 % CI 1.31-4.42; p = 0.005), though not other glioma subtypes (p for heterogeneity = 0.0033). The association remained significant after false discovery rate adjustment (p = 0.008). Differential associations by gender were observed for MYRIP rs6599077 and CSNK1E rs1534891 though differences were not significant after adjustment for multiple testing. No consistent mortality associations were identified. Several of the examined genes exhibited differential expression in glioblastoma multiforme versus normal brain in TCGA data (MYRIP, ARNTL, CRY1, KLHL30, PER1, CLOCK, and PER3), and expression of NPAS2 was significantly associated with a poor patient outcome in TCGA patients. CONCLUSION: This exploratory analysis provides some evidence supporting a role for circadian genes in the onset of glioma and possibly the outcome of glioma.