The South Carolina Multigenerational Linked Birth Dataset: Developing Social Mobility Measures Across Generations to Understand Racial/Ethnic Disparities in Adverse Birth Outcomes in the US South.

Objectives To describe the creation of a multigenerational linked dataset with social mobility measures for South Carolina (SC), as an example for states in the South and other areas of the country. Methods Using unique identifiers, we linked birth certificates along the maternal line using SC birth certificate data from 1989 to 2014, and compared the subset of records for which linking was possible with two comparison groups on sociodemographic and birth outcome measures. We created four multi-generational social mobility measures using maternal education, paternal education, presence of paternal information, and a summary score incorporating the prior three measures plus payment source for births after 2004. We compared social mobility measures by race/ethnicity. Results Of the 1,366,288 singleton birth certificates in SC from 1989 to 2014, we linked 103,194, resulting in 61,229 unique three-generation units. Mothers and fathers were younger and had lower education, and low birth weight was more common, in the multigenerational linked dataset than in the two comparison groups. Based on the social mobility summary score, only 6.3% of White families were always disadvantaged, compared to 30.4% of Black families and 13.2% of Hispanic families. Moreover, 32.8% of White families were upwardly mobile and 39.1% of Black families were upwardly mobile, but only 29.9% of Hispanic families were upwardly mobile. Conclusions for Practice When states are able to link individuals, birth certificate data may be an excellent source for examining population-level relationships between social mobility and adverse birth outcomes. Due to its location in the Deep South, the multigenerational SC dataset may be particularly useful for understanding racial/ethnic difference in social mobility and birth outcomes.

Geographic Accessibility to Health Services and Neonatal Mortality Among Very-Low Birthweight Infants in South Carolina.

Introduction Mortality for infants born with very-low birthweight (VLBW, 500-1499 grams) is markedly higher than for babies born with normal birthweight (2500-4000 grams). Although these high-risk infants show better outcomes in advanced care settings, only 80 % of VLBW infants born in South Carolina (SC) are delivered in hospitals with a level-III neonatal intensive care unit (NICU). The purpose of this research project was to assess geographic access to delivery hospitals and risk of neonatal death among singleton VLBW infants born in SC. Methods The linked birth and death records of a cross-sectional, population-based study of singleton VLBW infants born in SC between 2010 and 2012 were used (n = 2030). We assessed the impact of travel time from maternal residence to delivery hospital. Logistic regression modeling was performed with adjustments for maternal, newborn, and hospital characteristics. Results The neonatal mortality rate among singleton VLBW infants was 11.03 deaths per 100 live births in 2010-2012. We did not find a significant association between travel time to delivery hospital and neonatal mortality after adjusting for confounders. However, we found that a 1-week increase in gestational age (odds ratio (OR): 0.61) and non-Hispanic black mothers (versus non-Hispanic white mothers) (OR: 0.68) were associated with lower odds of neonatal death, whereas non-NICU admission at birth (OR: 5.90) was associated with increased odds of death. The results of the sensitivity analyses including both singleton and multiple births did not yield significant results for travel time and neonatal mortality in VLBW infants. Discussion Although we found no significant association between travel time and neonatal mortality in singleton VLBW births in SC, we identified significant factors consistent with those found in previous studies that may affect neonatal mortality.

What are the specific disability and limitation types underlying responses to the BRFSS disability questions?

BACKGROUND: Researchers rely on resources such as BRFSS data to understand the health status of people with disability. However, the survey data rely on a limited definition of disability resulting in imprecise inferences about the nature of disability. Understanding how health varies among people with different types of disability is vital to tailoring interventions for improving health and eliminating disparities. OBJECTIVE: The purpose of this study was to utilize state added follow-up questions in the 2011 South Carolina BRFSS to describe the specific health conditions and limitations attributed to their disability and to compare health status across different types of disability. METHODS: Participants reporting a disability were asked to name health condition(s) causing disability and describe their disability-related limitations. Descriptive statistics were calculated using weighted proportions. Logistic regression was used to model the associations of specific health conditions and limitations with the outcomes of self-rated general health and mental health status, controlling for demographic factors. RESULTS: The 5 most commonly reported health condition categories were (weighted percentage): musculoskeletal (68.56%); pulmonary (10.41%); neurologic (8.48%); heart disease (8%) and mental health (7.31%). The 5 most commonly reported limitation categories were: mobility/balance limitations (46.29%); pain (23.22%); breathing problems (12.36%); general weakness/fatigue (9.57%) and limited lifting (8.24%). There was substantial variation in the degree of association between categories of conditions and limitations and the outcomes of self-rated physical and mental health. CONCLUSIONS: Researchers and practitioners should consider variability in the nature of disability when designing interventions to improve the health of people with a disability.

Increases in heroin overdose deaths - 28 States, 2010 to 2012.

Nationally, death rates from prescription opioid pain reliever (OPR) overdoses quadrupled during 1999-2010, whereas rates from heroin overdoses increased by <50%. Individual states and cities have reported substantial increases in deaths from heroin overdose since 2010. CDC analyzed recent mortality data from 28 states to determine the scope of the heroin overdose death increase and to determine whether increases were associated with changes in OPR overdose death rates since 2010. This report summarizes the results of that analysis, which found that, from 2010 to 2012, the death rate from heroin overdose for the 28 states increased from 1.0 to 2.1 per 100,000, whereas the death rate from OPR overdose declined from 6.0 per 100,000 in 2010 to 5.6 per 100,000 in 2012. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians/Alaska Natives. OPR overdose mortality declined significantly among males, persons aged <45 years, persons in the South, and non-Hispanic whites. Five states had increases in the OPR death rate, seven states had decreases, and 16 states had no change. Of the 18 states with statistically reliable heroin overdose death rates (i.e., rates based on at least 20 deaths), 15 states reported increases. Decreases in OPR death rates were not associated with increases in heroin death rates. The findings indicate a need for intensified prevention efforts aimed at reducing overdose deaths from all types of opioids while recognizing the demographic differences between the heroin and OPR-using populations. Efforts to prevent expansion of the number of OPR users who might use heroin when it is available should continue.

Epigenetic modulation of the retinoid X receptor alpha by green tea in the azoxymethane-Apc Min/+ mouse model of intestinal cancer.

We investigated the possible mechanisms of inhibition of colorectal carcinogenesis by green tea (GT) in azoxymethane-treated (AOM) Apc(Min/+) mice. Mice received water or a 0.6% (w/v) solution of GT as the only source of beverage. GT treatment commenced at the 8th week of age and lasted for 8 wk. The treatment caused a statistically significant reduction in the number of newly formed tumors (28%, P < 0.05). Immunohistochemical analysis showed that GT decreased the levels of beta-catenin and its downstream target cyclin D1. To probe a mechanism, we further investigated the expression of retinoic X receptor alpha (RXR alpha) in AOM/Apc(Min/+) tumors. Our results show that RXR alpha is selectively downregulated in AOM/Apc(Min/+) mouse intestinal tumors. In contrast, other retinoic receptors including retinoic acid receptor alpha (RAR alpha), RAR beta, RXR beta, and RXR gamma were all expressed in Apc(Min/+) adenomas. Furthermore, our results show that RXR alpha downregulation is an early event in colorectal carcinogenesis and is independent of beta-catenin expression. GT significantly increased the protein levels of RXR alpha. In addition, RT-PCR analysis showed that GT induced a similar increase in the levels of RXR alpha mRNA. Genomic bisulfite treatment of colonic DNA followed by pyrosequencing of 24 CpG sites in the promoter region of RXR alpha gene showed a significant decrease in CpG methylation with GT treatment. The results suggest that a low concentration of GT is sufficient to desilence RXR alpha and inhibit intestinal tumorigenesis in the Apc(Min/+) mouse.

Bootstrap methods for simultaneous benchmark analysis with quantal response data.

A primary objective in quantitative risk assessment is the characterization of risk which is defined to be the likelihood of an adverse effect caused by an environmental toxin or chemcial agent. In modern risk-benchmark analysis, attention centers on the "benchmark dose" at which a fixed benchmark level of risk is achieved, with a lower confidence limits on this dose being of primary interest. In practice, a range of benchmark risks may be under study, so that the individual lower confidence limits on benchmark dose must be corrected for simultaneity in order to maintain a specified overall level of confidence. For the case of quantal data, simultaneous methods have been constructed that appeal to the large sample normality of parameter estimates. The suitability of these methods for use with small sample sizes will be considered. A new bootstrap technique is proposed as an alternative to the large sample methodology. This technique is evaluated via a simulation study and examples from environmental toxicology.

Green tea selectively targets initial stages of intestinal carcinogenesis in the AOM-ApcMin mouse model.

One of the liabilities of the Apc(Min) mouse as a model for colon cancer is its lack of a robust tumor response in the large bowel. In our protocol, we treated the Apc(Min) mouse with azoxymethane, a colon-selective carcinogen. This protocol induced a 4-fold increase in the number of colon tumors. We utilized this protocol to investigate the possible mechanisms of inhibition of colorectal carcinogenesis by green tea. Mice received water or a 0.6% (w/v) solution of green tea as the only source of beverage. Green tea treatment commenced at the eighth week of age and lasted for either 4 or 8 weeks. Green tea significantly inhibited the formation of new adenomas, but was ineffective against larger tumors. Mechanistically, we investigated the effects of green tea on the expression of biomarkers involved in colon carcinogenesis. Western blotting analysis showed that green tea decreased the total levels of the early carcinogenesis biomarker beta-catenin and its downstream target cyclin D1. In contrast, the expression of COX-2 was not altered. Immunohistochemical analysis showed that green tea inhibited the formation of adenomas overexpressing beta-catenin and cyclin D1, but did not reduce the number of COX-2-expressing adenomas. Our results suggest that green tea specifically targets initial stages of colon carcinogenesis; the time of administration of green tea is pivotal for effective chemoprevention. Beverage levels of green tea do not inhibit the progress of any large adenomas or adenocarcinomas existing prior to the tea administration.

On use of the multistage dose-response model for assessing laboratory animal carcinogenicity.

We explore how well a statistical multistage model describes dose-response patterns in laboratory animal carcinogenicity experiments from a large database of quantal response data. The data are collected from the US EPA's publicly available IRIS data warehouse and examined statistically to determine how often higher-order values in the multistage predictor yield significant improvements in explanatory power over lower-order values. Our results suggest that the addition of a second-order parameter to the model only improves the fit about 20% of the time, while adding even higher-order terms apparently does not contribute to the fit at all, at least with the study designs we captured in the IRIS database. Also included is an examination of statistical tests for assessing significance of higher-order terms in a multistage dose-response model. It is noted that bootstrap testing methodology appears to offer greater stability for performing the hypothesis tests than a more-common, but possibly unstable, "Wald" test.

Common polymorphisms in 5-lipoxygenase and 12-lipoxygenase genes and the risk of incident, sporadic colorectal adenoma.

BACKGROUND: Lipoxygenases (LOX) are major enzymes that metabolize arachidonic acid to hydroxyl-eicosatetraenoic acids and leukotrienes, which have been implicated in inflammation and colorectal cancer risk. Polymorphisms in LOX genes may influence their function and/or expression and, thus, may modify the risk for colorectal adenoma. The authors investigated the associations of 3 polymorphisms (2 in 5-LOX, -1708 guanine-->adenine and 21 cytosine-->thymine; and 1 in 12-LOX, arginine 261 glutamine [Arg261Gln]) in LOX genes with the risk of colorectal adenoma and also explored possible interactions of these polymorphisms with several inflammation-pathway or arachidonic acid metabolism-pathway related factors with the risk of colorectal adenoma. METHODS: By using data from a community-based, case-control study of incident, sporadic colorectal adenoma that included 162 cases and 211 controls, the authors constructed multiple logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) of colorectal adenoma after adjusting for potential confounders. RESULTS: Overall, there were no significant associations of the 2 5-LOX polymorphisms with the risk of colorectal adenoma. However, there was an inverse association between the Arg261Gln polymorphism in 12-LOX and colorectal adenoma (OR, 0.63; 95% CI, 0.40-1.00). A significant interaction also was observed between the 12-LOX polymorphism (Arg261Gln) and the use of nonsteroidal anti-inflammatory drugs (P(interaction) = .02). CONCLUSIONS: The current results suggested that polymorphisms of LOX genes may act independently or with other factors to affect the risk of colorectal adenoma. Further studies will be needed to confirm these findings. Cancer 2007 (c) 2007 American Cancer Society.

Is risk of axillary lymph node metastasis associated with proximity of breast cancer to the skin?

INTRODUCTION: Risk of axillary lymph node metastasis, the most important predictor of disease-free and overall survival in breast cancer patients, is estimated primarily from histologic features of the primary cancer including tumor size, histologic type and grade, and hormone receptor expression. Based upon a clinical impression, and research showing that palpable cancers are more likely to be node positive, we hypothesized that primary breast cancers more proximal to the skin of the breast are more likely to be positive for axillary lymph node metastasis. METHODS: This is a retrospective medical record review of 209 women with stage T1 or T2 (

Permeation and reservoir formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P) across porcine esophageal tissue in the presence of ethanol and menthol.

Environmental influences may affect carcinogen absorption and residency in the tissues of the aero-digestive tract. We quantified the effect of ethanol and menthol on the rates of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P) absorption using a fully validated in vitro diffusion system, capable of accurately and precisely quantifying tobacco carcinogen permeation and reservoir formation in porcine esophageal mucosa. Confocal microscopy was employed to visualize the location of B[a]P in the exposed membranes. Markedly different extents of permeation and reservoir formation for the tobacco carcinogens were recorded in the presence of ethanol and menthol. The water-soluble NNK permeated the membrane rapidly, while the lipophilic B[a]P did not appreciably diffuse through the tissue. Significantly different extents of reservoir formation were observed for the different carcinogens and in the presence of the different penetration-enhancer solvents. Alcohol (at 5% concentration) did not influence the permeation or reservoir formation of NNK. A mentholated donor solution (0.08%) both decreased the flux of NNK and significantly increased the tissue reservoir formation. The magnitude of the reservoir formed by B[a]P was relatively extensive (even though membrane permeation rates were negligible), being greatest in the presence of both ethanol and menthol. This suggests synergy between the two penetration-enhancer species acting on this carcinogen. Confocal microscopy studies confirmed that there was an appreciable intra-cellular, and specifically nuclear, association of the B[a]P species during the reservoir formation process. The aqueous solubility of the diffusing species and the presence of penetration enhancers appeared to be key factors in the absorption and cellular binding processes. The results presented support the hypothesis that the use of mentholated cigarettes, or the concomitant consumption of alcohol while smoking, may have marked effects on the fate of tobacco chemicals. This finding may help to explain elevated rates of esophageal squamous cell carcinoma in African Americans.

Urinary estrogen metabolites, prostate specific antigen, and body mass index among African-American men in South Carolina.

INTRODUCTION: Estrogen metabolites have been linked to risk of breast cancer, and we were interested in whether they are associated with prostate specific antigen (PSA) and other factors associated with prostate cancer. African-American (AA) men in South Carolina have among the highest prostate cancer rates in the world, and thus provide an ideal population in which to investigate this hypothesis. METHODS: We recruited AA men attending prostate cancer screenings in and around Columbia, South Carolina. Because very few men had elevated PSAs, we restricted our study to the 77 men whose PSA was below the cutpoint used by the screening program to indicate need for diagnostic workup. These men provided spot urine samples and answered demographic and lifestyle questions including self-reported body weight, height, exercise, tobacco use, medications, cancer history and age. Levels of urinary 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), and their ratio (2/16) and blood PSA levels were determined. RESULTS: After adjusting for a statistically significant interaction between age and BMI, we found a reduction of 14.2% in 2-OHE1 for each 1.0 ng/ml increase in PSA (p=0.05). For obese AA men only (BMI> or =30 kg/m2), 2-OHE1 increased by 36% for each decade of age (p=0.009). CONCLUSIONS: Estrogen metabolites may be related to PSA level in AA men. Older men with BMIs greater than 30 kg/m2 had an unexpected increase in 2-OHE1, suggesting a dysregulation of this estrogen metabolism pathway. Further studies of estrogen metabolites may provide insights into prostate cancer risk factors.

Multiplicity-adjusted inferences in risk assessment: benchmark analysis with quantal response data.

A primary objective in quantitative risk or safety assessment is characterization of the severity and likelihood of an adverse effect caused by a chemical toxin or pharmaceutical agent. In many cases data are not available at low doses or low exposures to the agent, and inferences at those doses must be based on the high-dose data. A modern method for making low-dose inferences is known as benchmark analysis, where attention centers on the dose at which a fixed benchmark level of risk is achieved. Both upper confidence limits on the risk and lower confidence limits on the "benchmark dose" are of interest. In practice, a number of possible benchmark risks may be under study; if so, corrections must be applied to adjust the limits for multiplicity. In this short note, we discuss approaches for doing so with quantal response data.

Can hyperbaric oxygen therapy reduce breast cancer treatment-related lymphedema? A pilot study.

OBJECTIVE: Arm lymphedema after surgery or radiation for breast cancer is common, causing pain and limitation of activities. Previous reports of hyperbaric oxygen (HBO) therapy for breast edema led us to consider the use of HBO therapy for arm lymphedema. METHODS: Ten healthy postmenopausal women (age 58 +/- 5.7 years) with persistent (9.4 years +/- 9.1 years) arm lymphedema following breast cancer surgery and radiation (n = 10) plus chemotherapy (n = 7) received 20 HBO treatments (90 minutes at 2.0 ATA five times a week for 4 weeks). End points included changes in upper extremity volume, platelet counts, plasma levels of vascular endothelial growth factor (VEGF), and lymph angiogenic-associated vascular endothelial growth factor-C (VEGF-C). Lymphedema volume (LV) was defined as the volume of the unaffected arm subtracted from the volume of the affected arm. RESULTS: We observed a 38% average reduction in hand lymphedema (-7.4 ml, 11.6 SD, range -30-+8 ml, p = 0.076, 95% confidence interval -15.7-0.9 ml) at the end of HBO, which was independent of changes in body weight. For those who benefited (n = 8), the reduction was persistent from the end of treatment to a final measurement an average of 14.2 months after the last HBO treatment. However, total LV did not change significantly. VEGF-C increased from baseline (p = 0.004) before treatment 20, suggesting HBO had begun to stimulate this growth factor. CONCLUSIONS: Future studies should explore the effects of a greater number of HBO treatments on lymphedema, with more patients.

Confidence bands for low-dose risk estimation with quantal response data.

We study the use of simultaneous confidence bands for low-dose risk estimation with quantal response data, and derive methods for estimating simultaneous upper confidence limits on predicted extra risk under a multistage model. By inverting the upper bands on extra risk, we obtain simultaneous lower bounds on the benchmark dose (BMD). Monte Carlo evaluations explore characteristics of the simultaneous limits under this setting, and a suite of actual data sets are used to compare existing methods for placing lower limits on the BMD.