BACKGROUND: In the United States, chronic hepatitis C virus (HCV) infection afflicts approximately 3.2 million persons and is the leading indication of liver transplantation. Therapies for chronic HCV are not completely effective and African Americans are significantly less responsive to therapy than Caucasian Americans. Studies suggest that lipoproteins and cholesterol metabolism play a role in biological mechanisms of the HCV life cycle. This dissertation characterizes the serum lipid profile in a cohort with genotype 1 chronic HCV infection, the predominant HCV genotype in the United States. STUDY POPULATION: Participants for this study were from the Virahep-C study, a prospective study of resistance to antiviral therapy involving 401 treatment naïve people with chronic hepatitis C (genotype 1) infection who underwent combination pegylated interferon alfa-2a + ribavirin therapy for up to 48 weeks. Included in this dissertation analysis were 330 participants who had serum lipid profile data before starting therapy. RESULTS: Before treatment, HCV viral level was directly associated with triglyceride levels, liver fat was directly and inversely related to triglycerides and high density lipoprotein cholesterol, respectively, and severe fibrosis was associated with lower of total and high density lipoprotein cholesterol levels. Over the course of therapy, all lipid profile measures changed during 6 months of treatment, and post-treatment, changes were limited to 6 month virological responders. For some lipid profile measures, changes during 6 months of treatment differed by race and were related to the amount of interferon taken. Lastly, components of the lipid profile were significant predictors of sustained virological response in univariable and multivariable analyses. CONCLUSIONS: This dissertation highlights the importance of the lipid profile in relation to aspects of liver disease, potential mechanisms of HCV eradication attributed to antiviral therapy, and virological response to therapy. The findings are of public health significance as they may highlight opportunities for new therapeutic targets and intervention studies to improve virological response, as well as elucidate factors involved in the racial disparity in treatment efficacy.

Salmonella enterica is a major cause of disease in the United States and world-wide. This pathogens increasing antibiotic resistance over the past decades has exacerbated its public health burden. To combat the rise in antibiotic resistance, it is necessary to understand how resistance spreads through the bacterial population. This requires study of the genes that determine resistance and also of the genetic relatedness of the isolates bearing those genes. In this dissertation, three studies are presented. The aim of the first study was to examine the utility of multilocus sequence typing (MLST), which indexes sequence changes in housekeeping genes, for investigating genetic relatedness in S. enterica. MLST was shown to be a stable genetic typing method for S. enterica that is useful for long-term and global epidemiologic studies. The aim of the second study was to examine the mechanisms of dissemination of antibiotic resistance genes mediated by a genetic structure called an integron, in a genetically diverse, global collection of S. enterica. Integrons are able to create variable collections of resistance genes and may be disseminated by horizontal gene transfer or by clonal expansion. Using MLST to determine genetic relatedness, the second study indicated that both of these mechanisms are important forces in the dissemination of integron mediated antibiotic resistance in S. enterica. The investigation of integrons revealed three integrons not previously reported in S. enterica. The aim of the third study was to characterize those integrons, which contained novel aggregates of resistance genes, making them capable of conferring resistance to multiple antibiotics. One of these integrons was found in two genetically unrelated strains, reinforcing this structures potential for contributing to horizontal gene transfer of antibiotic resistance in S. enterica. Validation of MLST as a typing method for S. enterica has importance for public health because it facilitates large scale and global studies of this organism by providing a basis for assessing genetic relatedness of diverse isolates. An understanding of the patterns of dissemination of integrons has public health significance because it enhances the ability to accomplish surveillance for changes in antibiotic resistance.

Allegheny County (AC) has limited information on asthma morbidity. In order to improve upon the sensitivity of asthma, a cross sectional study from January 1, 2002 through December 31, 2005 was conducted to determine whether the data received for emergency room visits from a large regional medical center might be a good predictor for quantifying asthma cases for surveillance. An electronic medical record (EMR) abstract using the Council for State and Territorial Epidemiology (CSTE) Asthma Surveillance case definition of an ICD 9 coded physician diagnosis for primary and secondary asthma (n= 18,284), and primary asthma (n = 5,100) were used to define asthma. The analysis used data from a subset of six hospitals from a large regional medical center covering approximately 60% of adult ED visits in AC that use electronic data for reporting. A secondary analysis of the physician diagnosed primary asthma cases (n= 180) was applied against the CSTE Clinical and Laboratory case definition. Statistical software was used to validate these data abstracted from the EMR. Once these data were validated for accuracy, a fourth dataset of any primary asthma emergency room visits (n= 10,183) were used to test the relationship between asthma morbidity and exposure to ozone. Recent studies have linked asthma hospitalizations in several cities to ozone action days. However, data on the effects of ozone as they relate to asthma emergency room (ER) visits have not been well studied. Electronic medical records from the six hospitals representing the large metropolitan medical center in Allegheny County, PA were obtained on individuals with asthma based on the ICD-9 discharge diagnosis of (493.0-493.9) for the respective time period. Data on ozone, PM2.5, and temperature were obtained for same period. A case crossover methodology using conditional logistic regression as the statistical estimator was conducted to assess the relationship between levels of ozone and PM 2.5 and increases in asthma ER visits. A time stratified sampling strategy was employed assuming a 3:1 case-control ratio. A total of 6,979 individuals were included in the study, with a mean age of 39.25 ±21.0. The mean ozone exposure for this period was 40.6 ppb (range: 0-126). The effect estimates for year-round data was greatest for a 2-day lag adjusted for temperature (OR= 1.02 (95% CI= 1.01-1.04) (p<.05). For each 10-ppb increase in 24-hour maximum ozone, a 2% increase was noted in asthma ER visits. These results indicate that asthma ED visits may be an additional source of information for use in environmental public health tracking.

Preterm premature rupture of the fetal membranes (PPROM) is one of the most significant causes of preterm birth. PPROM is complicated by infection of the placenta and membranes (chorioamnionitis) in about half the cases, increasing the likelihood of adverse infant outcomes. Because stress has been associated with both preterm birth and altered immune function, we hypothesized that stress would increase the risk of chorioamnionitis among women with PPROM who were not actively infected upon presentation. Stress was measured by both physiological [salivary cortisol and serum Corticotropin Releasing Hormone (CRH) levels] and psychological (stress questionnaires: the Psychiatric Epidemiology Research Questionnaire, the Daily Hassles Scale, the 14-item Perceived Stress Scale, and the Interpersonal Support Evaluation List) means. Logistic regression was used to determine the association between stress and the development of chorioamnionitis and between stress and a composite adverse neonatal outcome (death or abnormal cranial ultrasound finding). Linear regression was used to assess the association between stress and latency (time from rupture of membranes until delivery). A one SD increase in mean salivary cortisol concentration was associated with a 3-fold increased odds of developing chorioamnionitis (OR 3.17, 95% CI 0.88-11.46), and an 8.6 fold increased odds of adverse neonatal outcomes (OR 8.62, 95% CI 0.99-75.03). A 1 SD increase in CRH was associated with a 33% increased odds of chorioamnionitis (OR 1.33, 95% CI 0.50-3.53) and a 3.5 fold increased odds of adverse neonatal outcomes (OR 3.45, 95% CI 0.55-21.56). Stress batteries were not associated with the development of either chorioamnionitis or adverse neonatal outcomes. There was little relationship between either physiologic or psychological measures of stress and latency. Physiologic measures of stress in women with PPROM may be associated with an increased risk of adverse obstetric and neonatal outcomes, specifically the development of chorioamnionitis and the composite newborn outcome of death or abnormal cranial ultrasound findings. Since prematurity is the most important causes of death and disability among children in developed countries, our finding is of significant public health importance. If a role for stress in the etiology of PPROM-associated chorioamnionitis is confirmed, then stress-reduction techniques may reduce adverse neonatal outcomes.

Background: Increases in the prevalence of overweight and obesity states, and in their associated adverse health outcomes, have been well described in the general population. However, in type 1 diabetes (T1D), a disease traditionally characterized by a lean phenotype, time trends in overweight and obesity and the role of adiposity on complications in TID have not been well investigated. We therefore investigated time trends in overweight and obesity and the association of adiposity with mortality and coronary artery calcification (CAC), a subclinical marker of coronary artery disease in the Pittsburgh Epidemiology of Diabetes Complications cohort of childhood onset T1D. Methods: Participants were first seen in 1986-1988 and followed biennially thereafter. Mortality was censored at January 1, 2007. Body mass index (BMI) was defined as kg/m² and Waist circumference (WC) was measured. CAC, visceral adiposity (VAT) and subcutaneous adiposity (SAT) by electron beam tomography. Free fatty acids (FFA) were determined by in vitro colorimetry. Results: After 18 years of follow-up, the prevalence of overweight increased by 47%; the prevalence of obesity increased 7-fold. BMI demonstrated a quadratic relationship with mortality. Adjustment for waist circumference eliminated the increased risk in the obese. Weight gain was positively related to intensive insulin therapy and inversely with mortality. There was a positive relationship between the presence of CAC and adiposity measures, however the degree of CAC was not associated with any adiposity measure, except negatively with SAT in women. Finally, FFA were not associated with any adiposity measure and showed no association with CAC. Conclusion: Adiposity is increasing in T1D and shows a complex association with coronary artery disease and mortality. These results have great public health significance by suggesting that avoidance of overweight, per se, in type 1 diabetes should not be a major priority; rather attention should focus on maximizing glucose control even though it may result in weight gain.

Osteoporosis is commonly considered a womens health problem, but is also a significant health concern for older men. Less is known about the predictors of osteoporosis and bone mineral density (BMD) in men. The aging of the population and expected increase in osteoporosis prevalence makes understanding the determinants of BMD of great public health importance. Genetics is an important determinant of BMD, but little is known about specific loci associated with BMD in men and even less is known about the genetic influences on volumetric BMD (vBMD). With this in mind, we investigated 4108 single nucleotide polymorphisms (SNPs) in 383 candidate genes for their association within a population of older Caucasian men. In addition, we investigated 148 of these SNPs in 28 WNT pathway genes for gene-gene interactions and gene-environment interactions with physical activity and body weight. We identified several SNPs that were associated with lumbar spine and femoral neck integral vBMD and explained 3.5% and 1.7% of the phenotypic variation in these traits, respectively. SNPs in two genes, adenomatous polyposis coli (APC) and the homeo box A gene cluster (HOXA) were associated with integral vBMD at both the femoral neck and lumbar spine. Analysis of cortical and trabecular vBMD at the femoral neck identified SNPs that explained 1.8% and 4.0% of the phenotypic variance, respectively. None of the SNPs for cortical vBMD were associated with trabecular vBMD. Statistically significant gene-gene and gene-environment interactions were also identified. Of note, statistically significant interaction effects of SNPs in the low density lipoprotein receptor-related protein 5 and physical activity level on integral vBMD at the femoral neck and lumbar spine were identified. Although additional work is needed to confirm and extend these findings we identified a number of novel associations for vBMD in older Caucasian men. Our results suggest the presence of genetic loci that are skeletal-site specific and specific to either cortical or trabecular bone. Additionally, these findings underscore the importance of evaluating genetic variation in the context of other genes and environmental factors.

Injury during the perinatal period can have significant health effects on the pregnant woman, the fetus, and the child; therefore, injuries during pregnancy and during labor and delivery in the form of birth trauma were the focus of this dissertation. Through a three papers format, this dissertation addressed three unique research questions that fell under the overarching theme of injury during the perinatal period. The first paper tested the association between injury during pregnancy and nervous system birth defects through a case control study and the utilization of the Texas Birth Defects Registry. The second paper applied an underutilized semi-automated method of sensitivity analysis to determine the effect of misclassification of injury during pregnancy on the association tested in the first paper. The third paper primarily determined the rate of birth trauma overall and specific types of birth trauma in the United States through the utilization of the HCUP Kids Inpatient Database. Through sophisticated statistical analyses it was determined that there is was an association between injury during pregnancy and nervous system birth defects among breech presentation infants, but no association among normal presentation infants or among the entire study population, even when accounting for exposure misclassification. Additionally, it was found that the national rate estimate of birth trauma in the United States for 2003 was 29 per 1,000 in-hospital births. This rate is higher than a majority of previously published studies; therefore, the occurrence and subsequent burden of birth trauma is higher than previously thought. The public health significance of this dissertation was to determine if injury during pregnancy could account for some of the 65-70% of unknown causes of birth defects, to determine where in the range of 0.2-37 per 1,000 births the rate of birth trauma actually falls, and to further explore an area of maternal and child health and injury research that is inadequately studied. Therefore, the results of this dissertation suggest that strategies to prevent injuries during pregnancy and birth trauma should be explored, implemented, and subsequently evaluated for effectiveness to reduce maternal, fetal, and infant morbidity and mortality.

The number of Americans over 65 years of age has increased rapidly in recent years. This population of older Americans will increase even more as the Baby Boomers begin reaching 65 in the year 2010. One of the greatest challenges in public health today is the increasing number of older adults who suffer disproportionately from chronic diseases and disability. Chronic diseases can be addressed by modifying risk factors and are not an inevitable consequence of aging. There is a great need to design community based multiple risk factor interventions that emphasize disease prevention. The Center for Healthy Aging recruited a population of healthy, at risk, older adults in southwestern Pennsylvania for a randomized community based intervention program. The program targeted adults aged ≥65, based upon "10 Keys"™ to Healthy Aging. The intervention evaluated (1) Brief Education and Counseling Intervention or (2) Brief Education and Counseling Intervention plus a Physical Activity and Dietary intervention for individuals with hypertension. Recruitment strategies included a direct mail campaign using voter registration lists and telephone follow-up. Health assessment data was collected at six month intervals through 24 month follow-up. Health behavior counseling and the Prevention in Practice Report were provided to participants in both programs as tools to advocate behavior change. A total of 951 households responded (8.2% response rate) and 541 participants from 444 households were randomized. After 24 months adherence to the "10 Keys"™ improved significantly in a number of areas. There was, however, no difference between the two groups in physical activity or changes in performance based measures related to physical activity. This prevention program resulted in significant reduction in key risk factors, immunization and screening over 2 years to established prevention guidelines for older adults. Further public health research is needed on the use of health advisors/health counselors to maximize public health prevention in individuals over 65. Empowering individuals regarding their own risk factor status for screenings, immunizations, and lifestyle changes could successfully impact the quality of health in community settings.

Mycoplasma genitalium (Mg), a sexually transmitted bacterium, may cause female reproductive morbidities, including pelvic inflammatory disease (PID). As the clinical and risk profile of women with Mg is not well understood, we examined the characteristics of Mg among women. Data from 586 women with clinically suspected PID enrolled in the PID Evaluation and Clinical Health Study were analyzed. Clinical, demographic, sexual and behavioral characteristics were compared between women positive and negative for Mg in the cervix and/or endometrium by polymerase chain reaction (PCR), and between Mg positive and Chlamydia trachomatis (Ct) and/or Neisseria gonorrhoeae (Gc) (Ct/Gc) positive women. Mg positive women had similar clinical characteristics as women without Mg and as women with Ct. Compared to women with Gc, women with Mg had lower pelvic pain scores (p=0.01), and were less likely to have cervicitis (p=0.001), erythrocyte sedimentation rate >15mm/hr (p=0.002), white blood cell count >10,000mm3 (p=0.02), and oral temperature >38.3°C (p=0.08). Age <25 years (AOR 2.7, 95% CI 1.5-5.2), douching (AOR 2.3, 95% CI 1.3-4.1), and smoking (AOR 1.8, 95% CI 1.0-3.2) were associated with Mg. The demographic, sexual and behavioral characteristics were similar between Mg positive women and Ct/Gc positive women. Since Mg is associated with PID, Mg may affect pregnancy, yet the consequences of prenatal Mg are unknown. Therefore, we next conducted a nested case-control study to examine the relationship between Mg and spontaneous abortion (SAB) among women enrolled in the Early Pregnancy Study, a study of violence and SAB among pregnant women presenting at an Emergency Department. Mg was measured by PCR in urine from 82 women who experienced a SAB and 134 control women. Characteristics of cases and controls were compared and the relationship between Mg and SAB was evaluated. Mg was not associated with SAB but was associated with nulliparity (AOR 3.4, 95% CI, 1.0-11.6), self-reported difficulty conceiving (AOR 4.8, 95% CI 0.9-25.7), and history of PID (AOR 3.9, 95% CI 0.9-16.1) and Ct (AOR 3.0, 95% CI 0.8-10.5). This dissertation yields significant public health findings by describing the clinical picture of Mg-PID, identifying women at risk, and examining the consequences of prenatal Mg.

This dissertation took steps towards filling major research gaps in lesbian health in the form of three manuscripts evaluating epidemiologic evidence for health disparities. Although the health disparities explored were not closely related, each was based upon analysis of data collected as part of the ESTHER (Epidemiologic STudy of HEalth Risk in Women) Project, a large cross-sectional study examining risk factors for coronary heart disease (CHD) among lesbian and heterosexual women living in the Pittsburgh, Pennsylvania area. Data were collected between 2003 and 2006, and these analyses were completed in 2009. The first manuscript examined differences in complementary and alternative medicine (CAM) use between lesbian and heterosexual women. Lesbians were more likely to have used CAM in their lifetime and within the past 12 months when compared to heterosexual women. Among women who had used CAM within the past 12 months, the types of CAM reported did not vary by sexual orientation. The second manuscript investigated the association between lesbian sexual orientation, sexual abuse history, and adulthood obesity. Lesbian sexual orientation and a history of childhood sexual abuse (CSA) perpetrated by a family member were each independently associated with current adulthood obesity. The third manuscript explored potential differences in the prevalence and associated factors of polycystic ovary syndrome (PCOS) by sexual orientation. A small sample size limited the power of the analysis to confirm statistical difference in PCOS prevalence or associated factors; however, meaningful trends were observed. If the observed trends are reflective of the larger population, lesbians may exhibit differences in PCOS determinate factors, have higher rates of PCOS, and may be more likely to be diagnosed with PCOS compared to heterosexual women. The public health significance of this dissertation was to explore potential health-related differences that may exist between heterosexual and lesbian women in the areas of CAM, obesity, and PCOS research. Findings contributed to the literature on health disparities and provided further support for a greater focus on lesbian health, including public health training, education, screenings, and interventions to better serve the lesbian population.