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Purpose Metabolic syndrome has a high prevalence in the United States. P-wave duration is a valuable indicator for atrial electrical conduction. Abnormalities in atrial electrical conduction can predispose to atrial fibrillation. Our objective was to estimate the effect of metabolic syndrome on P-wave duration in a nationally representative sample. Methods We included 6499 adults who participated in the National Health and Nutrition Examination Survey III (1988–1994). We estimated the effect of metabolic syndrome and its components on P-wave duration after adjusting for confounders such as demographic and lifestyle variables. We stratified the analyses by gender. Results Irrespective of gender, participants with metabolic syndrome had a longer P-wave duration than that of those without it. In addition, we observed a positive linear dose–response relation between metabolic syndrome components and P-wave duration. Conclusions Patients with metabolic syndrome had a longer P-wave duration. They might have been at a higher risk for atrial fibrillation and mortality; they need to be periodically checked by their health care providers. However, the results of this study should be confirmed in prospective studies.

Studies reported a positive relationship between visit-to-visit blood pressure variability (VVBPV) and cardiovascular morbidity and mortality independently of the mean arterial blood pressure across clinical visits. The literature is scarce on the genes and biological mechanisms that regulate long-term VVBPV. We sought to identify biological pathways that regulate visit-to-visit blood pressure variability. We used phenotypic and genotype data from the Women’s Health Initiatives and Cardiovascular Health Studies. We defined VVBPV of systolic and diastolic blood pressure phenotypes as the standard deviation about the participant’s regression line with systolic and diastolic blood pressure regressed separately across visits. We imputed missing genotypes and then conducted a genome-wide association analysis to identify genomic variants related to the VVBPV and detect biological pathways. For systolic VVBPV, we identified a neurological pathway, the GABAergic pathway (P values = 1.1E − 2), and a vascular pathway, the RAP1 signaling pathway (P values = 5.8E − 2). For diastolic VVBPV, the hippo signaling (P values = 4.1E − 2), CDO myogenesis (P values = 7.0E − 2), and O-glycosylation of TSR domain-containing protein pathways (P values = 9.0E − 2) were the significant pathways. Future studies are warranted to validate these results. Further understanding of the roles of the genes regulating the identified pathways will help researchers to improve future pharmacological interventions to treat VVBPV in clinical practice.

The QRS-T angle is a key ECG predictor for ventricular arrhythmia. Lead has a strong relation with cardiovascular diseases; however, no study has been conducted to investigate the association between lead exposure and QRS-T angle. Thus, we explored this association in a population-based representative sample: NHANES III. We used the standard 12-lead ECGs to calculate Spatial QRS-T angles. Blood lead concentration was measured using graphite furnace atomic absorption spectrophotometry method. We conducted multivariate weighted logistic regression to adjust for impaired fasting glucose, hypertension, poverty index, age, race, and smoking status. We found that when the log of blood lead increased by one unit, the odds of an abnormal QRS-T angle increased by 34% among men and 4% among women. We suggest the use of QRS-T angle deviation among those who are exposed to lead to detect individuals at risk for adverse cardiovascular outcomes such as arrhythmias.

Objective Cadmium's effect on QRS|T angle has not been studied. An abnormal QRS|T angle deviation may increase the risk for ventricular dysrhythmias. Methods We calculated the orientation of spatial QRS|T angle using QRS and T amplitudes of leads V2, V5, V6, and AVF from the National Health and Nutritional Examination Survey III. Cadmium concentration was measured in urine. We fit weighted unadjusted and adjusted logistic regressions to calculate odds ratios and their corresponding 95% confidence intervals. Results A unit increase in the logarithm of urinary cadmium increased the odds of QRS|T angle deviation by 30% [1.30 (1.01 to 1.61)]. Conclusions Cadmium exposure was associated with an abnormal QRS|T angle in women but not in men. Women exposed to cadmium should be periodically evaluated to detect QRS|T angle deviation, which can predispose them to ventricular dysrhythmias.

Arkansas (AR) consistently has higher ischemic heart disease (IHD) death rates than the US, which is believed to be due to a higher prevalence in AR of major, modifiable risk factors. We examined the difference in IHD death rates between AR and the US as consequences of differences in the prevalence of nine risk factors between pre-Medicare age group (45-64) and Medicare age group (65-84). We modeled IHD deaths attributable to differential prevalence between AR and the US using mortality data and prevalence data from AR and US for years 2000-2010, and relative risk measures obtained from the INTERHEART and Atherosclerosis Risk in Communities studies. From 2000-2010, our study showed that if we were to reduce the prevalence of significant risk factors to US levels, we would reduce AR IHD deaths by 26.6% in the pre-Medicare age group and 15.9% in the Medicare age group. Most of the increased mortality was explained by higher prevalence of smoking and hypertension in AR. Other socioeconomic factors that contributed to an increased risk of poor health outcomes were education, income, and the lack of health insurance; with AR having worse outcomes than the US for the pre-Medicare age group. The importance of risk factors depended on race, sex, and age. The excess mortality in AR relative to the US for the two age groups can largely be explained by prevalence differences in smoking, hypertension, cholesterol, education and income.

A power calculation for a study with a quantitative outcome requires information on the outcome distribution under the alternative hypothesis. Researchers face challenges when they concisely specify alternative distributions in genetic studies because power depends on genotype frequencies and the average effect of each genotype. In GWAS, investigators evaluate hundreds of thousands of associations; therefore it is unrealistic to specify gene frequencies and gene effects for each test and some simplification is needed. Software packages are available to calculate power, but many of them have limited flexibility and / or may have a steep learning curve. In this review, we describe to researchers and graduate students the essentials of a power calculation for testing for an association between a quantitative trait and genotypes. In addition, we provide them with the codes of the different available software packages—free and commercial—to calculate this power. The calculations can be carried out using virtually any computer language that computes the cumulative distribution function of a non-central F-distribution.

Background: The process by which salt affects the gastric precancerous process has not been adequately studied in humans. Methods: We investigated the effects of salt on gastric inflammation, epithelial damage, the density of Helicobacter pylori infection, and gastric epithelial cell proliferation, all of which may be mediators between salt and gastric precancerous/cancerous lesions. These potential mediators were measured using gastric biopsies as: (a) the density of polymorphonuclear and mononuclear cells (gastric inflammation), (b) mucus depletion (gastric epithelial damage), and (c) the severity of H. pylori infection. Salt intake was measured with spot urine samples (using urinary sodium/creatinine ratios), self-reported frequency of adding salt to food, and as total added salt. Results: The average sodium/creatinine ratio (at baseline and post-treatment at five months) was associated with increased epithelial damage over the 12-year follow-up period among those with a greater severity of chronic inflammation and among those with continued H. pylori infection after treatment at five months. This association was stronger when both severe gastric inflammation and H. pylori infection were present at five months (ß: 1.112, 95% CI: 0.377, 1.848). Conclusion: In humans, salt was associated with an increase in epithelial damage in stomachs with more severe previous H. pylori-induced chronic inflammation.

Gastric cancer is the third leading cause of cancer mortality worldwide. Studies investigating the effect of salt on gastric cancer have mainly used self-reported measures, which are not as accurate as sodium/creatinine ratios because individuals may not know the amount of salt in their food. Using data from a prospective cohort study, we investigated the effect of salt intake on progression to gastric precancerous lesions. Salt intake was estimated by urinary sodium/creatinine ratios, self-reported frequencies of adding salt to food, and total added table salt. We repeated the analyses among groups with and without Helicobacter pylori infection. We did not observe a positive association between salt intake, measured by urinary sodium/creatinine ratio, and overall progression in the gastric precancerous process (adjusted risk ratio (RR): 0.94, 95% confidence interval (CI) 0.76&ndash, 1.15). We did observe an association between salt intake and increased risk for progression to dysplasia or gastric cancer overall (adjusted risk ratio (RR): 1.32, 95% confidence interval (CI): 0.96&ndash, 1.81), especially among those who continued to have H. pylori infection at the five-month follow-up (adjusted RR: 1.53, 95% CI: 1.12&ndash, 2.09), and among those who had persistent H. pylori infection over 12 years (adjusted RR: 1.49, 95% CI: 1.09&ndash, 2.05). Salt intake may increase the risk of gastric dysplasia or gastric cancer in individuals with H. pylori infection.

Background. Gastric cancer is the fourth most common cancer and the third most common cause of cancer deaths worldwide. Morbidity and mortality from gastric cancer may be decreased by identification of those that are at high risk for progression in the gastric precancerous process so that they can be monitored over time for early detection and implementation of preventive strategies. Method. Using machine learning, we developed prediction models for gastric precancerous progression in a population from a developing country with a high rate of gastric cancer who underwent gastroscopies for dyspeptic symptoms. In the data imputed for completeness, we divided the data into a training and a validation test set. Using the training set, we used the random forest method to rank potential predictors based on their predictive importance. Using predictors identified by the random forest method, we conducted best subset linear regressions with the leave-one-out cross-validation approach to select predictors for overall progression and progression to dysplasia or cancer. We validated the models in the test set using leave-one-out cross-validation. Results. We observed for all models that complete intestinal metaplasia and incomplete intestinal metaplasia were the strongest predictors for further progression in the precancerous process. We also observed that a diagnosis of no gastritis, superficial gastritis, or antral diffuse gastritis at baseline was a predictor of no progression in the gastric precancerous process. The sensitivities and specificities were 86% and 79% for the general model and 100% and 82% for the location-specific model, respectively. Conclusion. We developed prediction models to identify gastroscopy patients that are more likely to progress in the gastric precancerous process, among whom routine follow-up gastroscopies can be targeted to prevent gastric cancer. Future external validation is needed.

Background Spatial QRS|T angle is a predictor of cardiovascular events. Those with metabolic syndrome have an increased risk of cardiovascular morbidity and mortality. This study investigated the association between metabolic syndrome and spatial QRS|T angle. Methods We obtained data from the National Health and Nutritional Examination Survey III on 6,249 adults. We calculated spatial QRS|T angle from the standard 12-lead electrocardiogram and classified it as abnormal, borderline, or normal. We identified metabolic syndrome if at least three of the following were present: abdominal obesity, elevated blood pressure, elevated triglycerides, decreased high-density lipoprotein (HDL), and impaired fasting glucose. We used weighted logistic regression to estimate the effect of metabolic syndrome and its components on QRS|T angle while stratifying by gender and adjusting for age, race, smoking status, heart rate, PR, QT, and QRS interval, and QRS amplitude. Results Among men and women, metabolic syndrome, the number of components present, elevated blood pressure, and impaired fasting glucose were positively associated with QRS|T angle. Among women, decreased HDL and abdominal obesity were also positively associated with QRS|T angle. Conclusions This study suggests that persons with metabolic syndrome may be at increased risk for ventricular arrhythmias. The use of spatial QRS|T angle to assess this cardiovascular risk is warranted.

High-normal blood pressure and visit-to-visit blood pressure variability are common in clinical settings. They are associated with cardiovascular outcomes. No population based studies have assessed the association between these two phenomena. Our objective was to test the relationship of high-normal blood pressure with visit-to-visit blood pressure variability.A cross-sectional study.We used data from the cross-sectional Third National Health and Nutrition Examination Survey to test the relationship between high-normal blood pressure and visit-to-visit blood pressure variability; we conducted multivariable regression analyses to evaluate the relationship between these two variables.The analysis included 6,071 participants. The participants' mean age was 37.16 years. The means of visit-to-visit systolic and diastolic blood pressure variability were 5.84 mmHg and 5.26 mmHg. High-normal blood pressure was significantly associated with systolic and diastolic blood pressure variability (p values0.05).High-normal blood pressure is associated with visit-to-visit blood pressure variability. Additional research is required to replicate the reported results in prospective studies and evaluate approaches to reduce blood pressure variability observed in clinical settings among patients with high-normal blood pressure to reduce the subsequent complications of blood pressure variability.

Introduction The 2016 US Surgeon General's Report suggests that the use of electronic nicotine delivery systems (ENDS) is a fetal risk factor. However, no previous study has estimated their effect on adverse pregnancy outcomes. We assessed the prevalence of current ENDS use in pregnant women and explored the effect on birth weight and smallness-for-gestational-age (SGA), correcting for misclassification from nondisclosure of smoking status. Methods We conducted a cohort study with 248 pregnant women using questionnaire data and biomarkers (salivary cotinine, exhaled carbon monoxide, and hair nicotine). We evaluated the association between birth weight and the risk of SGA by applying multivariate linear and log-binomial regression to reproductive outcome data for 232 participants. Participants who did not disclose their smoking status were excluded from the referent group. Sensitivity analysis corrected for misclassification of smoking/ENDS use status. Results The prevalence of current ENDS use among pregnant women was 6.8% (95% CI: 4.4-10.2%); most of these (75%) were concurrent smokers. Using self-reports, the estimated risk ratio of SGA for ENDS users was nearly two times the risk in the unexposed (RR=1.9, 95% CI: 0.6-5.5), and over three times that for ENDS-only users versus the unexposed (RR=3.1, 95% CI: 0.8-11.7). Excluding from the referent group smokers who did not disclose their smoking status, the risk of SGA for ENDS-only use was 5 times the risk in the unexposed (RR=5.1, 95% CI: 1.1- 22.2), and almost four times for all types of ENDS users (RR=3.8, 95% CI: 1.3-11.2). SGA risk ratios for ENDS users, corrected for misclassification due to self-report, were 6.5-8.5 times that of the unexposed. Conclusions Our data suggest that ENDS use is associated with an increased risk of SGA.

Certain viruses naturally infect and cause cancer in chickens and turkeys. Humans are widely exposed. The viruses cause cancer in primates, and transform human cells in vitro, but it is not known if they cause cancer in humans, mainly because of the lack of epidemiologic evidence. We conducted cohort mortality studies of workers in poultry slaughtering/processing plants across the United States, because they have the highest human exposures. An excess of lung cancer and other deaths was recorded in the poultry workers. Here, we report on a case-cohort study of the lung cancer deaths nested within these cohorts, that was conducted to provide epidemiologic evidence linking these viruses with human cancer occurrence, while adjusting for possible confounders, including workplace chemical carcinogens. We obtained interviews for 339 lung cancer deaths and 457 controls, selected from our combined cohorts of 30,411 poultry plant workers and 16,405 non-poultry workers, belonging to United Food & Commercial Workers unions. Data was analyzed by both logistic regression and Cox regression, adjusting for smoking and other confounders. Lung cancer risk was independently associated with tasks or work areas indicative of exposure to both poultry oncogenic viruses and to workplace chemical carcinogens. The study provides an incremental piece of evidence (epidemiologic), indirectly linking the oncogenic viruses of poultry with the occurrence of cancer in humans, and thus may have public health implications, but the limitations highlighted must be considered. Confirmatory studies, particularly molecular studies providing definitive proof of poultry oncogenic retrovirus integration in human DNA are needed, before the findings observed in this study can be put into proper perspective.

We assessed whether the prevalence of recent (within a year) initiation of cigarette smoking was associated with reports of ever using electronic delivery systems (ENDS) in the National Youth Tobacco Survey (NYTS) and whether the association varied by age. Weighted cross-sectional analysis of use of ENDS, cigarette smoking, age at interview and age at initiation of smoking collected systematically through the 2011–2013 NYTS cycles. In multivariate analyses those who ever used ENDS were twice as likely as nonusers of ENDS to have tried cigarette smoking in the last year (multivariate PR: 2.3; 95 % CI 1.9, 2.7). This average hid significant variations by age: a 4.1-fold increase (95 %; 2.6, 6.4) among those 11–13 years of age, compared to a smaller increase among those 16–18 years: 1.4-fold (95 % CI 1.1, 1.8). Use of ENDS by adolescents was associated with initiation of cigarette smoking in the last year. This association was stronger in younger adolescents.

Animal studies showed that the use of metformin after myocardial infarction (MI) resulted in a protective effect on cardiac myocytes. In this study, we examined the effect of metformin in patients with diabetes mellitus (DM) on left ventricular ejection fraction (LVEF) and post-MI mortality. We reviewed charts of patients with MI admitted to the UAMS medical center. Baseline characteristics and 12-month follow up data were collected. Patients were classified into three groups: Control group- no DM (n = 464), Metformin group- DM + MI (n = 88) and No-Metformin group- DM + MI (n = 168). First, we compared Metformin and No-Metformin groups to the Control group. Second, we performed propensity-score matching in patients with DM, and compared Metformin to No-Metformin groups. All-cause 30-day and 12-month mortality was significantly higher in the No-Metformin group compared to controls (13.5 vs 9.3 % p = 0.03 at 30 days, 23.7 vs 15.9 % p = 0.03 at 12 months). However, all-cause 30-day and 12-month mortality were similar in the Controls and Metformin group (9.3 vs 6.8 % p = 0.93 at 30 days, 15.9 vs 11.4 % p = 0.97 at 12 months). Mean LVEF on presentation (45 % in the three groups) and at follow up (47.84, 46.38 and 43.62 % in Control, Metformin, and No-Metformin groups, respectively) were not statistically different. There were no significant differences in regard to re-hospitalization, re-intervention, new stroke, CHF development, new MI, or identifiable arrhythmias. Metformin was an independent predictor of lower 30-day and 12-month all-cause mortality in patients with DM (HR 0.25, p = 0.02 and HR 0.32, p = 0.01, respectively). In the matched analysis, 30-day all-cause mortality was significantly higher in the No-Metformin compared to the Metformin group (21.1 vs 8.8 %, p = 0.05). However the difference in 12-month all-cause mortality did not reach statistical significance (24.6 vs 15.8 %, p = 0.15). This proof-of-concept study shows that use of metformin in patients with DM is associated with lower 30-day all-cause mortality and tendency for a lower 12-month all-cause mortality following MI without discernible improvement in LVEF.

Chronic infections have been shown to enhance atherogenicity. However, the association between chronic hepatitis C (HCV) and coronary heart disease (CHD) remains controversial. We examined the risk for CHD events in patients with HCV with an emphasis on the risk of CHD events with active infection. We conducted a retrospective cohort study using the enterprise data warehouse at the University of Arkansas for Medical Sciences. HCV positive and negative patients were identified based on serology, and incident CHD events were studied. Patient characteristics at entry were compared either by the analysis of variance or F test (continuous variables) or by a chi-square test (categorical variables). The joint effect of risk factors for incident CHD was evaluated using logistic regression. A total of 8,251 HCV antibody positive, 1,434 HCV RNA positive, and 14,799 HCV negative patients were identified. Patients with HCV antibody and RNA positivity had a higher incidence of hypertension, diabetes mellitus, obesity, and chronic lung disease, but lower serum cholesterol levels compared with patients who were HCV negative (p0.001). HCV seropositive patients had a higher incidence of CHD events compared with controls (4.9% vs 3.2%, p0.001). In the HCV cohort, patients with detectable HCV RNA had a significantly higher incidence of CHD events compared with patients who were only HCV antibody positive with no detectable RNA (5.9% vs 4.7%, p = 0.04). In multivariate logistic regression analyses, both HCV antibody positivity (odds ratio 1.32, 95% confidence interval 1.09 to 1.60, p0.001) and HCV RNA positivity (odds ratio 1.59, 95% confidence interval 1.13 to 2.26, p0.001) were independent risk factors for incident CHD events. In conclusion, there is an increased incidence of CHD events in patients with HCV seropositivity and the incidence is much higher in patients with detectable HCV RNA compared with patients with remote infection who are only antibody positive. Lipid profile does not appear to be a good cardiovascular risk stratification tool in patients with HVC.

Epidemiological studies have shown that blood pressure is not a constant variable. Evidence has accumulated showing that the blood pressure variability is associated with organ damage. A substantial increase in the prevalence of the metabolic syndrome has been documented globally. We examined the association of visit-to-visit blood pressure variability with the metabolic syndrome and its components, using data collected in the Third National Health and Nutrition Examination Survey. A multivariable generalized linear model was performed. The metabolic syndrome and its components, particularly hypertension, increased waist circumference and hyperglycemia, were significantly associated with systolic blood pressure variability across study visits (P0.05). After adjusting for the effect of age, gender, race and antihypertensive medication, the multivariable analyses did not show significant relationships between the metabolic syndrome and diastolic blood pressure variability (P-values0.05). Additional research is required to verify the observed results in prospective studies and evaluate approaches to reduce blood pressure variability observed in clinical settings among persons with the metabolic syndrome to reduce its subsequent complications.

Background— The excess stroke mortality in the southeastern states of the United States (stroke-belt states) is well known; however, the factors associated with this pattern have not been fully elucidated. We measured the contribution of several demographic factors by analyzing stroke mortality data (2005–2009) at the census block group (BG) level in the state of Arkansas. Methods and Results— Census BGs were used as proxies for neighborhoods. BGs were stratified using 5 census measures: poverty (percent of population below federal poverty level), population density (population per square mile), education (percent of population aged >25 years who did not graduate from high school), population mobility (percent of population who resided at the same address 1 year ago), and the percent of non-Hispanic blacks (percent of population that is black). Generalized additive models were used to estimate the variation in stroke mortality among BGs and to assess the impact of different demographic variables. From 2005 to 2009, there were 8930 stroke deaths in Arkansas. There was considerable variation in the relative risk even between adjacent BGs within a single county. The geographically weighted regression analyses indicated that 4.5% to 9% of deviance in stroke mortality among BGs could be explained by poverty, education, population density, and population mobility. Race/ethnicity (non-Hispanic blacks) explains Conclusions— Our study shows that primordial risk factors such as poverty and education drive disparities in stroke mortality among neighborhoods in Arkansas.

Objectives: As of October 2015, evidence needed to make a recommendation about the use of electronic nicotine delivery systems (ENDS) for smoking cessation was limited. We used the 2014 Arkansas Behavioral Risk Factor Surveillance System with additional state-specific questions to determine the prevalence of ENDS use, the impact of ENDS use on smoking cessation, and beliefs about ENDS use in Arkansas. Our objectives were to determine if (1) ENDS use was associated with lower odds of quitting smoking, (2) ENDS users believed that ENDS use was not harmful to their health, and (3) ENDS users believed that switching to ENDS reduced their tobacco-related health risks. Methods: We conducted a cross-sectional study of 4465 respondents to the Arkansas Behavioral Risk Factor Surveillance System and used weighted analyses to account for the complex survey design. We used a subset of records formed by (1) formers smokers who quitted smoking in the last 5 years and (2) current smokers to assess the odds of quitting. Results: In 2014, 6.1% (95% confidence interval [CI], 5.0%-7.4%) of Arkansas adults were currently using ENDS. Of the 1083 participants who were current smokers or had quit smoking within the past 5 years, 515 (54.1%) had used ENDS. Of the 515 ENDS users, 404 (80.3%) had continued smoking. ENDS use was significantly associated with reduced odds of quitting smoking (weighted odds ratio = 0.53; 95% CI, 0.34-0.83). Although 2437 of 3808 participants (62.5%) believed that it was harmful for nonsmokers to start using ENDS and 1793 of 3658 participants (47.0%) believed that switching to ENDS did not reduce tobacco-related health risks, only 80 of 165 (41.3%) and 50 of 168 (33.9%) ENDS users shared these same respective beliefs. Conclusions: Most smokers who indicated smoking in the past 5 years and who tried ENDS did not stop smoking. ENDS use was inversely associated with smoking cessation. Tobacco cessation programs should tell cigarette smokers that ENDS use may not help them quit smoking.

Background Driving time to a percutaneous coronary intervention ( PCI )–capable hospital is important in timely treatment of acute myocardial infarction ( AMI ). Our objective was to determine whether driving time from one's residence to a PCI ‐capable hospital contributes to AMI deaths. We conducted a cross‐sectional study of age‐ and sex‐adjusted mortality in census block groups to evaluate this question. Methods and Results We studied all (14 027) AMI deaths that occurred during 2008–2012 in Arkansas to assess the relationship between driving time from the population center of a block group (neighborhood) to the nearest PCI ‐capable hospital. We estimated standardized mortality ratios in block groups that were adjusted for education (population over 25 years of age who did not graduate from high school), poverty (population living below federal poverty level), population density (population per square mile), mobility (population residing at the same address as 1 year ago), black (population that is black), rurality (rural households), geodesic distance, and driving time. The median geodesic distance and driving time were 12.8 miles (interquartile range 3.6–30.1) and 28.3 minutes (interquartile range 9.6–58.7), respectively. Risks in neighborhoods with long driving times (90th percentile) were 26% greater than risks in neighborhoods with short driving times (10th percentile), even after adjusting for education, poverty, population density, rurality, and black race ( P Conclusions AMI mortality increases with increasing driving time to the nearest PCI ‐capable hospital. Improving the healthcare system by reducing time to arrive at a PCI ‐capable hospital could reduce AMI deaths.

Objectives: To determine if driving time to the percutaneous coronary intervention (PCI) capable hospital is an important factor in deaths of patients with acute myocardial infarction (AMI). Methods: We studied the relationship between driving time to the nearest PCI-capable hospital and AMI mortality (2008-2012) in census block groups (BG), N=2147, in the state of Arkansas. Population center of a BG was used as a proxy for an individual’s place of residence. The driving time to the nearest PCI-capable hospital was calculated from the population center of a BG. The risk of AMI death was then calculated using five census measures: poverty (% of population below federal poverty level); population density (population per square mile); education (% of population over 25 years of age that did not graduate from high school); mobility (% of population who resided at the same address 1 year ago) and the percent of non-Hispanic blacks (% of population that is Black); and the calculated driving time to the nearest PCI-capable hospital. Arc GIS was used to calculate the driving time to the nearest PCI-capable hospital. Generalized additive models were used to estimate the variation in AMI mortality among BGs. Findings: During 2008-2012, there were 14,027 AMI deaths in Arkansas. There was considerable variation in the relative risk between BGs and AMI mortality based on the distance to the PCI hospital. The median distance to the nearest PCI-capable hospital was 12.7 miles (Interquartile range 3.5 - 30.1); and the median driving time to the nearest PCI-capable hospital was 28.3 minutes (Interquartile range 9.6-58.7). However, driving time (Range- 58.7 to 149.3 minutes) among residents in BGs (n=536) that are in the fourth quartile was much higher than the optimal timeframe to receive PCI for AMI. The regression analyses indicated that the driving time to the nearest PCI-capable hospital is a significant predictor of AMI mortality (p < 0.0001) in all BGs, after adjusting for education, poverty, race, and population density. Conclusions: Our study shows that the driving time to the nearest PCI-capable hospital is an independent predictor of AMI mortality. Improving health care system by reducing time to arrive at a PCI-capable hospital could reduce AMI deaths in underserved communities.

Probabilistic risk assessment is gaining acceptance as the most appropriate way to characterize and communicate uncertainties in estimates of human health risk and/or reference levels of exposure such as benchmark doses. Although probabilistic techniques are well established in the exposure-assessment component of the National Research Council's risk-assessment paradigm, they are less well developed in the dose-response-assessment component. This paper proposes the use of hierarchical statistical models as tools for implementing probabilistic dose-response assessments, in that such models provide a natural connection between the pharmacokinetic (PK) and pharmacodynamic (PD) components of dose-response models. The results show that incorporating internal dose information into dose-response assessments via the coupling of PK and PD models in a hierarchical structure can reduce the uncertainty in the dose-response assessment of risk. However, information on the mean of the internal dose distribution is sufficient; having information on the variance of internal dose does not affect the uncertainty in the resulting estimates of excess risks or benchmark doses. In addition, the complexity of a PK model of internal dose does not affect how the variability in risk is measured via the ultimate endpoint.

The Mouse Lymphoma Assay (MLA) Workgroup of the International Workshop on Genotoxicity Testing (IWGT), comprised of experts from Japan, Europe, and the United States, met on August 29, 2003, in Aberdeen, Scotland, United Kingdom. This meeting of the MLA Workgroup was devoted to reaching a consensus on the appropriate approach to data evaluation and on acceptance criteria for both the positive and negative/vehicle controls. The Workgroup reached consensus on the acceptance criteria for both the agar and microwell versions of the MLA. Recommendations include acceptable ranges for mutant frequency, cloning efficiency, and suspension growth of the negative/vehicle controls and on criteria to define an acceptable positive control response. The recommendation for the determination of a positive/negative test chemical response includes both the requirement that the response exceeds a defined value [the global evaluation factor (GEF)] and that there also be a positive dose-response (evaluated by an appropriate statistical method).

cDNA arrays allow quantitative measurement of expression levels for thousands of genes simultaneously. The measurements are affected by many sources of variation, and substantial improvements in the precision of estimatedeffects accompany adjustments for these effects. Two generic nuisance variations, one associated with the magnitude of expression and the other associated with array location, are common in data from filter arrays. Procedures, like normalization using lowess regression, are effective at reducing variation associated with magnitude, and they have been widely adopted. However, variation associated with location has received less attention. Here, a simple, but effective method based on localized median is expounded for dealing with these nuisance effects, and its properties are discussed. The proposed methodology handles location-dependent variation ("splotches") and magnitude-dependent variation (background and/or saturation) effectively. The procedure is related to lowess when implemented to adjust magnitude-dependent variation, and it performs similarly. The proposed methodology is illustrated with data from the National Center for Toxicological Research (NCTR), where treatment differences in levels of mRNA from rat hepatocytes were assessed using 3 3 P-labeled samples hybridized to cDNA spotted arrays. Normalizing intensities by the median-of-subsets removes systematic variation associated with the location of a gene on the array and/or the level of its expression. This procedure is easy to implement using iteratively reweighted least-squares algorithms. Although less sophisticated than lowess, this procedure works nearly as well for normalizing intensities based upon their magnitude. Unlike lowess, it can adjust for location-dependent effects.

Individual differences in lung cancer susceptibility should be considered for effective lung cancer prevention. We investigated the CYP2E1, ADH3, and GSTP1 genetic polymorphisms that biotransform xenobiotic carcinogens, and variations of their enzyme activity in Caucasian lung tissues (N=28), and found a variant distribution in pulmonary ADH and CYP2E1 activity. The ADH3*1/*1 subjects (N=8) showed significantly higher ADH activity than ADH3*2/*2 (N=3) subjects (P0.01). On the other hand, we found a 5-fold variation in the pulmonary CYP2E1 activity using a sensitive HLPC/EC based technique. A subject with the CYP2E1-c/t allele showed 2-fold higher CYP2E1 activity than subjects with the c/c allele (N=14). GSTP1 expression comprised 83% of the total pulmonary GSTs. However, neither the GSTP1 polymorphism, nor other lifestyle factors, such as age, gender, smoking status, were found to be associated with pulmonary GST expression. In conclusion, subjects with the ADH3*1 allele showed higher ADH activity and acetaldehyde-DNA adducts in lung than other subjects; thus, the ADH3*1 allele could be considered a risk factor for lung cancer.

The erythrocyte concentrations of the body's chief physiologic methyl donor S-adenosylmethionine (SAM) and of its metabolite and inhibitor S-adenosylhomocysteine (SAH), the plasma concentrations of total homocysteine (tHcy), and the activity of N(5,10) methylenetetrahydrofolate reductase (MTHFR) in lymphocytes were determined in healthy subjects and patients with diabetes mellitus without complications and at various stages of diabetic nephropathy, categorized according to the degree of progression of the disease. These groups were as follows: 1, control; 2, diabetics with no complications; 3, patients with albuminuria; 4, patients with an elevated plasma creatinine; and 5, patients on dialysis. No parameter studied exhibited significant differences between the type 1 and the type 2 diabetics. In control subjects, the blood concentrations of SAM were proportional to the activity of MTHFR; in diabetics, it was not. Consistent with previous observations, progression of nephropathy was accompanied by increased concentrations of tHcy. Increased erythrocyte concentrations of SAH, decreased erythrocyte concentrations of SAM, SAM/SAH ratios, and lymphocyte MTHFR activity also accompanied disease progression. The blood concentrations of SAH paralleled those of tHcy, while the concentrations of SAM showed a bimodal relationship with those of tHcy. These results provide further evidence that alterations in the blood concentrations of SAM and related compounds are abnormal in patients with diabetes, particularly in those with nephropathy. The deficiency of SAM may lead to methyl deficiencies, which may contribute to the high morbidity and mortality in patients with diabetic nephropathy. We have also demonstrated a decrease in lymphocyte MTHFR activity in patients with advanced nephropathy, suggesting that hyperhomocysteinemia in these patients may be due to a generalized metabolic abnormality. Further studies are needed to determine the pathogenesis of these abnormalities and whether they are present in renal failure due to causes other than diabetes or whether they are specific to diabetic nephropathy.

The association between environmental lead exposure and blood pressure variability, an important risk factor for cardiovascular disease, is unexplored and unknown. The objective of the study was to test the hypothesis that lead exposure is associated with blood pressure variability.American participants 17 years of age or older from National Health and Nutrition Examination Survey III were included in the analysis. Participants' blood lead concentrations expressed as micrograms per deciliter were determined. The standard deviations of visit-to-visit systolic and diastolic blood pressure were calculated to determine blood pressure variability. Multivariable regression analyses adjusted for age, gender, race, smoking and socioeconomic status were employed.The participants' mean age and mean blood lead concentration were 42.72 years and 3.44 mcg/dl, respectively. Systolic blood pressure variability was significantly associated with environmental lead exposure after adjusting for the effect of the confounders. The unadjusted and adjusted means of visit-to-visit systolic blood pressure variability and the β coefficient of lead exposure were 3.44, 3.33 mcg/dl, β coefficient = 0.07, P0.01.This study documents a positive linear relationship between environmental lead exposure and systolic blood pressure variability. Screening adults with fluctuating blood pressure for lead exposure could be warranted.

Most estimates of the number of women with breast implants appear to be extrapolations of industry or clinical data. While both provide valuable information, the former about the total number of devices ever produced or sold and the latter about the cumulative number of surgeries performed, neither can be used to directly estimate the prevalence of women with silicone gel or saline implants. In 1989, Market Facts, Inc., conducted a mail survey of 40,000 households chosen as representative of the population of the United States and received responses from 70.7%. Overall, the prevalence was 8.08 per 1,000 women with about 60% of the devices reportedly implanted for cosmetic reasons. The procedure was more common among Whites of the higher socio-economic classes. Based upon the results of this survey, the total number of US women in 1989 with breast implants was estimated to be 815,700 (95% confidence interval: 715,757-924,729).

Evidence has accumulated showing that blood pressure variability is associated with cardiovascular disease. A substantial increase in the prevalence of obesity has been documented globally. Our objective was to examine the relation of total and central obesity on visit-to-visit blood pressure variability.We used data collected from the cross-sectional Third National Health and Nutrition Examination Survey, to examine the association of visit-to-visit blood pressure variability with body mass index and waist circumference.The analysis included 14,988 participants. The participants' mean age was 43.45 years. Visit-to-visit systolic blood pressure variability was associated with a body mass index ≥30 and a large waist circumference (beta coefficients were 0.25 and 0.31, respectively, P-values0.01). Neither the bivariate nor the multivariable analyses showed significant relationships between the obesity indicators and diastolic blood pressure variability.Obesity is associated with visit-to-visit systolic blood pressure variability. Additional research is required to replicate the reported results in prospective studies and evaluate approaches to reduce blood pressure variability observed in clinical settings among obese persons to reduce its subsequent complications.

Many studies have suggested a relationship between certain alleles of the human leukocyte antigen (HLA) and the prevalence of some diseases or the immunological responsiveness to certain antigens. Furthermore, our studies in the past have demonstrated decreased immune function among atomic-bomb survivors who were exposed to high doses of radiation. However, no studies have addressed the possibility of various degrees of radiation-induced immune suppression being dependent on HLA type. To investigate the possibility of differing frequency distributions of HLA type in the Hiroshima atomic bomb survivors, HLA-DQA1 alleles and HLA-DR antigens were typed for 291 survivors in a high-dose group (>1.5 Gy), 339 survivors in an intermediate-dose group (0.005-1.5 Gy), and 388 in a distally exposed control group (

Aims Doxorubicin (DOX), a widely used anticancer agent, can cause an unpredictable cardiac toxicity which remains a major limitation in cancer chemotherapy. There is a need for noninvasive, sensitive and specific biomarkers which will allow identifying patients at risk for DOX-induced cardiotoxicity to prevent permanent cardiac damage. The aim of this study was to investigate whether the expression of specific genes in the peripheral blood can be used as surrogate marker(s) for DOX-induced cardiotoxicity. Methods/Results Rats were treated with a single dose of DOX similar to one single dose that is often administered in humans. The cardiac and peripheral blood mononuclear cells (PBMCs) genome-wide expression profiling were examined using Illumina microarrays. The results showed 4,409 differentially regulated genes (DRG) in the hearts and 4,120 DRG in PBMC. Of these 2411 genes were similarly DRG (SDRG) in both the heart and PBMC. Pathway analysis of the three datasets of DRG using Gene Ontology (GO) enrichment analysis and Ingenuity Pathways Analysis (IPA) showed that most of the genes in these datasets fell into pathways related to oxidative stress response and protein ubiquination. IPA search for potential eligible biomarkers for cardiovascular disease within the SDRG list revealed 188 molecules. Conclusions We report the first in-depth comparison of DOX-induced global gene expression profiles of hearts and PBMCs. The high similarity between the gene expression profiles of the heart and PBMC induced by DOX indicates that the PBMC transcriptome may serve as a surrogate marker of DOX-induced cardiotoxicity. Future directions of this research will include analysis of PBMC expression profiles of cancer patients treated with DOX-based chemotherapy to identify the cardiotoxicity risk, predict DOX-treatment response and ultimately to allow individualized anti-cancer therapy.

Cancer mortality for the period from October 1950 through May 1992 was analyzed in atomic bomb survivors exposed in utero. Risk estimates for this group were also compared to those for survivors who were less than 6 years old at the time of exposure. The cohorts studied include 807 in utero survivors and 5,545 persons exposed during childhood with all members of both groups having estimated doses of at least 0.01 Sv. The comparison group includes 10,453 persons with little (

Imipramine (IMI) was administered s.c. at 0, 5, or 10 mg/kg/day to pregnant rats on gestation days 8-20 to assess possible alterations in postnatal heart and brain development. Maternal weight gain was significantly reduced in a dose-response manner, but litter size and pup weight on postnatal day (PND) 1 were unaffected. On PND 1, litters were culled to 10 pups for analysis on PNDs 4/5, 7/8, 14/15, and 21/22. Pup body weight was not affected at any age measured, but heart weight was significantly reduced at 10 mg/kg IMI on PNDs 4/5 and 7/8. Brain weight was increased in a dose-related pattern on PNDs 4/5 and 7/8 and was significantly higher at 5 mg/kg IMI on PND 14/15. No significant effect was observed in heart or brain protein and DNA content or in cardiac beta-adrenergic receptor concentration. Prenatal IMI exposure had no effect on basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development, but basal brain ODC was lower at 5 mg/kg IMI at all ages measured. Cardiac ODC stimulation by insulin was unaffected by prenatal exposure to IMI, but isoproterenol-stimulated ODC was increased on PND 21/22 at 5 mg/kg IMI. In conclusion, the IMI-related changes in several parameters suggest that when maternal IMI treatment is used, alterations in postnatal heart and brain development must be considered as possible outcomes.

The activities of 23 brain or liver enzymes were studied in 5-6 week old C57BL/6JNctr male and female mice that had been fed ad libitum and standardized for 2 weeks to either (1) 12 hr of light (0600-1800) alternating with 12 hr of darkness (1800-0600) (LD 12:12), (2) staggered sequences of 12 hr of light and 12 hr of dark (SLD 12:12) or (3) continuous illumination (LL 12:12) for 2 weeks. Mice in the LD 12:12 and LL 12:12 experiments were killed at 4 hr intervals along a 24-hr span in order to sample at six different circadian stages. Lighting schedules for mice in the SLD 12:12 experiment were organized such that six different circadian stages were sampled when all mice were killed at one time of day. All 23 enzymes demonstrated a prominent circadian rhythm in at least one of the experiments. Moreover, about two-thirds of the enzymes in LD and SLD 12:12 had a statistically significant fit to a 24-hr cosine curve, while only one-third of the enzymes in LL 12:12 had significant fits to cosine curves. Peak activities of enzymes from mice in LD 12:12 were clustered at the time of transition from light to dark. This was also the trend for the activities of enzymes from mice in SLD 12:12, but resynchronization did not appear completed within the 2-week span. This, along with the observation that mesors (mean 24-hr activity) were reduced and amplitudes altered, indicated that the 2-week standardization period was not sufficient for some enzymes. Times of peak activities, mesors and amplitudes were affected for most enzymes from mice in the LL 12:12 environment. This suggests that individual mice became desynchronized from one another with respect to the original light-dark schedule and that rhythms were altered or lost because individual mice were free running with frequencies different from 24 hr.

Maternal propranolol (PRO) treatment has previously been associated with adverse effects on the fetus and neonate. In the present study, pregnant rats were treated with PRO (25 or 50 mg/kg/day s.c.) on gestation days 8-20 to assess its possible effects on the developing heart. Maternal weight gain and pup weight on postnatal day (PND) 1 were reduced in a dose-dependent manner; litter size was unaffected. Pup body weight and heart weight both showed a dose-related decrease at all ages tested (PNDs 5/6, 8/9, 15/16, and 22/23). Since heart protein, but not DNA, was similarly reduced, the decrease seen in heart weight most likely reflects a decrease in cell size instead of cell number. Basal ornithine decarboxylase (ODC), an enzyme associated with growth and development, was unaffected by maternal PRO treatment. Insulin and isoproterenol stimulation of ODC, suggested markers for testing the function of the sympathetic pathway to the heart and of the heart's ODC response system, respectively, also showed no PRO-related response. In conclusion, prenatal PRO exposure resulted in reduced body weight, heart weight, and heart protein, but had little effect on heart DNA or ODC activity. Since PRO treatment also reduced maternal weight gain, the adverse effects seen in the pups may be due to generalized PRO toxicity. The results suggest that when high PRO doses were used clinically, the careful monitoring of maternal weight gain during pregnancy might be useful in predicting adverse fetal effects.