Despite extensive research demonstrating that moderate lifestyle changes can reduce risk for Type 2 diabetes and cardiovascular disease these two chronic conditions continue to account for an overwhelming amount of morbidity and mortality worldwide. Translation of successful prevention and risk reduction research into real world settings faces many challenges, while strategies for implementation are lacking. For many reasons, the primary care practice venue provides an ideal environment for provision of prevention services on a permanent basis. The dissertation consists of three related projects; the first two examined the main components of diabetes prevention and cardiovascular disease risk reduction while the third investigated the relationship between perception of disease risk and lifestyle intervention performance. Because current practices of prevention screening are often haphazard and tend to overlook those in greatest need, the first project focused on risk identification through prevention screening in a systematic manner. Feasibility in the primary care practice setting as well as differences between those invited to attend prevention screening and those not invited was examined. The second project investigated the effectiveness and feasibility of provision of a lifestyle change intervention in a primary care practice setting. The successful lifestyle intervention utilized in the Diabetes Prevention Program was modified for delivery in a group rather than individual setting. The effectiveness of the intervention was evaluated through risk assessment measures collected before and after participation in the intervention. Finally, motivation for making lifestyle changes remains a mystery and varies considerably from one individual to another. It has been hypothesized that perceived risk, i.e., the probability of developing a disease or condition may influence an individuals health behavior. Utilizing a modified version of the Risk Perception Survey for Developing Diabetes (RPS-DD) the final project examined baseline differences in responses as well as the relationship between perception of risk and subsequent performance in the group lifestyle intervention. Differences in risk perception before and after participation were also examined. The projects are significant from a public health perspective in that they seek to begin to establish a foundation for implementation of diabetes prevention and cardiovascular risk reduction for the general population.

Background: Polycystic ovary syndrome (PCOS) is a common complex hormonal disorder. Many PCOS symptoms may have implications on bone mineral density (BMD). One way to analyze BMD is quantitated computed tomography (QCT), which may have advantages over other BMD analysis methods. The study analyzed descriptive characteristics of a group of PCOS cases and controls; considered the determinants of BMD (as measured by QCT) from the literature in PCOS cases and controls; and adjusted for these variables via multivariate logistic regression to determine if PCOS case status is an independent predictor of lumbar BMD after controlling for these factors. Methods: The study used women from the third implementation of the University of Pittsburgh Cardiovascular Health and Risk Management study (CHARM III). Descriptive information was gathered by survey and clinical visits and blood samples were taken to measure hormones and other biological factors. Lumbar BMD was measured by QCT in a subset of women. Students T-Test, the Mann-Whitney U-Test and X2 tests were used to evaluate descriptive characteristics of PCOS cases and controls. BMD measures between PCOS case and controls were compared using Students T-test. Lumbar BMD comparisons between PCOS cases and controls were also stratified by factors determined from the literature to affect BMD, including age, ethnicity, menstrual period status, BMI, and menstrual history. Correlations of BMD with hormones in cases and controls were considered. Multivariate linear regression models were used to assess the effect of PCOS case-control status on lumbar BMD after controlling for these factors associated with BMD. Results: There was no significant BMD difference between PCOS cases and controls for any univariate comparisons, nor for any multivariate adjusted compositions. Conclusion: The deleterious effects of middle age and approaching menopause and the protective effects of heavy BMI in controls may mediate some protective effects of PCOS case status on BMD in this group. Statement of Public Health Significance: The current study is one of only a few to use QCT to measure BMD in women with PCOS. Results from this study can serve as the basis of comparison for other studies that use QCT methods to assess BMD.

Cardiovascular diseases are a leading cause of morbidity and mortality. To facilitate early treatment and prevention, the relationship between risk markers and measures of subclinical disease should be determined. This dissertation examines how putative markers of risk, including traditional cardiovascular risk factors, rheumatoid arthritis and negative affect, are associated with measures of subclinical cardiovascular disease and vascular health. First, the relationship of traditional risk factors with carotid artery intima-media thickness (IMT) is evaluated in 453 healthy middle-aged women. It is unknown whether segment-specific associations exist when accounting for the interdependence across IMT locations. Results show unique positive associations between common carotid IMT and weight, bifurcation IMT and smoking and systolic blood pressure, and internal carotid IMT and apoprotein B. Second, it is postulated that the evaluation of carotid diameters augments knowledge of associations between rheumatoid arthritis and IMT and plaque. In 93 middle-aged patients, diagnosis of rheumatoid arthritis is associated with larger lumen and interadventitial diameters compared to 93 matched healthy women; whereas plaque prevalence is not statistically different and carotid IMT is similar, showing potential influences of vascular adaptation. Positive associations are demonstrated between carotid measures and rheumatoid arthritis medications, hypothyroidism and inflammatory markers. Third, associations between negative psychosocial indices and brachial artery flow-mediated dilation (FMD) are examined in 332 healthy older men and women. It is not known whether a link exists when considering multiple measures of negative affect in a large sample of both sexes. After controlling for traditional cardiovascular risk factors, FMD is inversely associated with hostility and general anger scores for men, and anger suppression in women. As demonstrated in this dissertation, associations between cardiovascular health and risk markers are evident early in the disease process. When evaluating cardiovascular disease risk, including co-morbid conditions and psychosocial symptoms along with traditional risk factors is of public health relevance. Additionally, the implications of appropriate statistical methods, the effects of vascular adaptation, and the importance of including women in epidemiologic research are illustrated. In conclusion, evaluating associations between markers of risk and subclinical cardiovascular disease and vascular health provides insight into the broader epidemic of cardiovascular disease.

Factors such as mammographic breast density and angiogenesis may be related to breast cancer development, though numerous questions about the etiologic mechanisms remain. Percent density is positively associated with breast cancer risk, yet is negatively associated with another breast cancer risk factor, body mass index (BMI). Vascular endothelial growth factor (VEGF) is a primary regulator of angiogenesis, yet its relationship to breast cancer risk is unclear. We evaluated the longitudinal association between BMI and breast density in the Study of Women's Health Across the Nation (SWAN) Mammographic Density Substudy (N=834). Using adjusted random intercept models, changes in BMI were not associated with changes in dense breast area (Beta=-0.0105, p=0.34), but were strongly negatively associated with changes in percent density (Beta=-1.18, p<0.001). Thus, effects of changes in anthropometry on percent breast density may reflect effects on non-dense tissue, rather than on the dense tissue where cancers arise. Breast density was measured from routine screening mammograms which were not timed with SWAN visits. We developed a method to align the off-schedule mammogram data to the study visit times using linear interpolation with multiple imputation. Our method was shown to be valid, with an average bias for dense breast area of 0.11 cm2. In the random intercept models, use of a simple matching algorithm to estimate breast density produced different (Beta=-0.0155, p=0.04), and likely incorrect, results. Our linear interpolation with multiple imputations method may be applicable to other longitudinal datasets with important data collected off-schedule. In a separate case-control study, the Mammograms and Masses Study (MAMS), we evaluated the association between serum VEGF levels and breast cancer (N=407). Geometric mean VEGF levels were higher among cases (331.4 pg/mL) than controls (291.4 pg/mL; p=0.21). In a multivariable logistic regression model, VEGF greater than or equal to 314.2 pg/mL was positively associated with breast cancer (odds ratio 1.37, 95% confidence interval 0.88-2.12), albeit non-significantly. Higher levels of VEGF may increase breast cancer risk. We have identified roles for anthropometry and angiogenesis in breast carcinogenesis. Enhancing knowledge of breast cancer etiology is a significant contribution to public health and may lead to improved opportunities for prevention or early detection.

Experimental evidence suggests that omega-6 (n-6) fatty acids have mammary tumor promoting effects whereas omega-3 (n-3) fatty acids inhibit tumor growth. These two families of fatty acids may influence breast cancer development by impacting prostaglandin E2 (PGE2) formation and consequently estradiol synthesis. Whether this effect on estrogen production can be observed in the circulation or in breast tissue, as reflected on a mammogram, is unknown. Therefore, using fatty acids in erythrocytes as a biomarker of recent dietary intake, we sought to establish the relationship between the n-6 and n-3 fatty acids with both serum estradiol and mammographic breast density, two well-established modifiable breast cancer risk factors. We hypothesized that n-6 fatty acids are positively related and n-3 fatty acids negatively related to both risk factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit PGE2 formation, therefore we further hypothesized that estradiol levels would be lower among NSAID users. NSAID data was not available at the time of mammogram; hence the relationship between NSAID use and mammographic density could not accurately be assessed. To test our hypotheses we conducted several investigations ancillary to the Mammograms and Masses Study (MAMS), a case control study of the determinants of mammographic breast density. Participants were eligible for this compilation of studies if they were breast cancer-free, postmenopausal and not taking exogenous hormones. We observed significantly lower levels of serum estradiol among current users of NSAIDs as compared to non-users of NSAIDs. Further, as hypothesized, estradiol concentration decreased with increasing erythrocyte composition of total n-3 fatty acids and rose with increasing erythrocyte composition of total n-6 fatty acids. However, these findings were noted only among non-users of NSAIDs and not among NSAID users. No relationship was observed between any of the n-6 or n-3 fatty acids measures and mammographic breast density. In summary, lowering consumption of n-6 fatty acids, increasing n-3 intake, or taking a NSAID may result in reduced estradiol synthesis and potentially breast cancer risk. Further research is needed to validate our results. If confirmed, these findings could have a substantial impact on public health as it could lead to the development of chemopreventive guidelines, and ultimately prevent the development of estrogen-dependent breast cancer.

Accelerometers are reliable, valid, and versatile tools for measuring physical activity for research studies. However, compliance to protocols of accelerometer use by participants of research studies is crucial in order to ensure the most accurate measure of their physical activity. It is possible that aging effects on physical and cognitive health will limit the ability of an older adult to be compliant with wearing an accelerometer. Unfortunately, research investigations into the factors that predict compliance to accelerometer protocols in older adults are nonexistent. We used data from the study entitled Environmental Correlates of Physical Activity Among Older Adults: A Healthy Aging Network Research Collaboration to investigate compliance to an accelerometer protocol in a cohort of 201 individuals 65 years of age and older in Allegheny county, Pennsylvania. We had two main hypotheses: (a) Compliance generally decreases with age among older adults and (b) the effect of age on compliance will be attenuated when controlling for demographic variables, cognitive and physical functioning, and walking behavior. The results show that 89.90% (n=178) of participants had at least four valid days of accelerometer wear and therefore met the valid person criteria and 50.00% (n=99) of participants had seven valid days of accelerometer wear and therefore met the compliant person criteria based on the accelerometer protocol. The best multivariate logistic regression model to predict being a valid person included IADL (p=0.002) score and a constant (p<.001) while the best multivariate logistic regression model to predict being a compliant person included Modified Guralnik Lower Body Score (p=0.008), White race (p=0.018), and a constant (p=0.036). While we hypothesized that compliance would decrease with advancing age in older adults, this analysis found no significant relationship between age and compliance. The results of this analysis did, however, show that several characteristics were associated with compliance, which supports the idea that compliance to an accelerometer protocol is influenced by certain characteristics among older adults. This research has public health significance because participants with characteristics associated with lower compliance will be consistently excluded from analyses involving measures of physical activity with accelerometers until compliance is increased to acceptable levels.

Poisoning is the leading cause of injury hospitalization among women of reproductive age and the third leading cause of injury hospitalization during pregnancy. The California Patient Discharge Dataset and Vital Statistics-Patient Discharge Database were utilized to identify cases of acute poisoning hospital discharges. Studies were conducted to determine the epidemiology of acute poisoning hospital discharges in women of reproductive age and during pregnancy and to investigate the effects of acute poisoning during pregnancy on birth outcomes. Pregnancy was associated with a lower risk for acute poisoning hospital discharge (OR=0.89, p=0.0007). Acute poisoning hospital discharges were greatest among young black women, and in women with substance abuse and mental health problems, regardless of pregnancy status. Analgesic and psychiatric medications were most commonly implicated in acute poisoning hospital discharges among women of reproductive age and during pregnancy. The majority of poisonings among women of reproductive age and among pregnant women were self-inflicted. Adverse birth outcomes associated with acute poisoning include preterm delivery (PTD), respiratory distress, cesarean delivery, and other cardiac congenital anomalies. Infants born to women delivering at their poisoning hospitalization exhibited higher rates of respiratory distress and PTD. In the later-delivery group, infants born to women with an acute poisoning during pregnancy were at a greater risk of PTD and other cardiac congenital anomalies. Adverse birth outcomes associated with intentional acute poisoning include PTD and low birth weight (LBW). Infants born to women that were discharged for an intentional acute poisoning hospital discharge within the first nine weeks of gestation exhibited higher rates of LBW. Among women who were discharged between gestational weeks 10 and delivery, intentional acute poisoning was associated with higher rates of circulatory system congenital anomalies. Although the etiologies of the reported adverse outcomes are speculative, it can be suggested that substance abuse or other risk-taking behaviors associated with acute poisoning may confound the relationship between poisoning and congenital anomalies. The public health significance of this dissertation is that these results provide public health practitioners the information necessary to design programs to reduce the burden of poisonings in women and their infants.

Osteoporosis is a common senile condition with major public health impact in both genders of all races. Very little is known about the natural history and etiology of bone loss, and trabecular and cortical volumetric bone mineral density (vBMD) in men, especially in men of African heritage. This research project was to evaluate age-related patterns and potential correlates for the rate of decline in areal BMD (aBMD) at the proximal femur, and vBMD at the radius and tibia in a cohort of Afro-Caribbean men aged 40 and above from the Tobago Bone Health Study. We also investigated the genetic associations of variants in a gene involved in the bone mineralization process, ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1), with bone loss, aBMD and vBMD. In longitudinal analyses, a significantly greater rate of bone loss was observed in men aged 40-45 than those aged 45-49 and 50-54. Thereafter, the rate of bone loss accelerated with advancing age. The rate of bone loss was also comparable with those observed in Caucasian men. Additionally, we identified low body mass index, weight loss, prostate cancer, and treatment for prostate cancer with androgen deprivation (ADT) as potential determinants for accelerated bone loss. In cross-sectional analyses of vBMD, we observed an early decline of trabecular vBMD before age 50 and with a slower decline thereafter into 7th decade. Cortical vMBD, however, appeared to decrease with advancing age in a linear fashion. Correlates of vBMD included weight, diabetes, prostate cancer, ADT, cigarette smoking and bone chewing. In genetic association study, several variants in the ENPP1 gene were strongly associated with bone loss, aBMD or vBMD. More associations were found with cortical vBMD than with the other phenotypes. Our findings have important public health relevance as they increase our understanding of vBMD and age-related bone loss in an under-studied population. We have also identified a novel association of ENPP1 gene variants with bone loss and BMD in this population of African heritage. Additional research is needed to better understand the factors related to BMD and bone loss in populations of African ancestry, especially the apparent early loss of bone mass.

Background: Interstitial Cystitis (IC) is a poorly understood condition of urinary bladder characterized by pelvic pain, urinary frequency, urgency and nocturia in the absence of other obvious pathology. The public health significance of IC is related to its profound impact on patients physical and emotional Quality of Life (QOL). The actual prevalence rate is unknown, and estimates range widely from 67/100,000 to 575/100,000. The majority of IC cases are females in the midlife age. This research addressed 1) the extent to which socio-demographic and clinical factors affect both symptom severity and QOL in IC patients, 2) the impact of symptom severity on QOL and 3) the efficacy of a combination of oral and intravesical Pentosan Polysulfate Sodium (PPS) as a new therapeutic option for IC. Methods: Forty one women with IC (age 20-71 years) were studied. Demographic, reproductive and clinical characteristics as well as QOL measures were evaluated in a cross-sectional design to assess the first two aims. To examine the third aim, participants were randomized to receive either a combination of oral plus intravesical PPS (treatment group) or oral PPS plus intravesical placebo (placebo group) in a clinical trial design. The main outcomes were the changes in subjective and objective measures of symptom severity, QOL and sexual functions. Results: Unmarried patients reported more severe symptoms compared to married patients. Being unemployed, obese, currently unmarried and never pregnant were associated with a decrement in at least one QOL domain. Moreover, symptom severity was associated with worse QOL on 4 domains, (p<0.05). On the other hand, the results from the clinical trial showed a greater significant reduction in symptom severity among the treatment group compared to the placebo group (46% reduction vs. 24% reduction respectively, p=0.04) and significant improvement in all QOL domains in the treatment group compared to the baseline (p<0.05). Conclusion: Being unmarried and symptom severity are important factors that may disturb the QOL in IC patients. Moreover, the use of intravesical PPS simultaneously with oral PPS is an effective therapeutic option. The findings of this research will open a new option for IC patients to reduce their devastating symptoms and to improve their quality of life.

Chronic Hepatitis C Virus (HCV) infection is prevalent in approximately 3.2 million people in the United States. Understanding mechanisms of HCV treatment response and conditions seen in people with HCV such as steatosis and Insulin Resistance (IR) are important to preventing excess morbidity and mortality and improving HCV treatment outcomes. Host genetic factors may be important with respect to these issues. The purpose of this research was to investigate host genetic relationships with 28 day viral decline after treatment initiation, steatosis and insulin resistance and to examine these associations separately in African Americans and Caucasian Americans infected with HCV genotype-1. Data from the Study of Viral Resistance of Antiviral Therapy of Chronic Hepatitis C (Virahep-C) were used. Virahep-C was designed to understand the mechanisms of resistance to antiviral therapy for chronic HCV genotype-1 patients. The studies reported in this dissertation included up to 194 Caucasian Americans (CA) and 180 African Americans (AA) who agreed to participate in the Virahep-C genetics ancillary study. In longitudinal analyses of 28 day treatment induced viral decline, polymorphisms in Myxovirus resistance 2 (MX2), Oligoadenylate synthetase-like (OASL), Signal transducer and activator of transcription 1 and 2 (STAT1 and STAT2) were significantly associated with viral decline. Additionally, significant Protein Kinase (PKR) haplotype associations with viral decline were observed among AAs. In cross-sectional analyses, significant associations between selected genetic variants and either steatosis or IR were observed in Interleukin-10 (IL10), Leptin Receptor (LEPR), Interleukin-6 (IL6) and Transforming Growth Factor Beta 1 (TGF-â1) for both conditions. Statistically significant interactions were observed between IL10, LEPR and TGF-â1 polymorphisms and HOMA2-IR scores when examining steatosis. Statistically significant associations were observed for Adiponectin Receptor 1 (ADIPOR1) polymorphisms and 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (HMGCS2) polymorphisms and steatosis or IR. Overall, these findings suggest that host genetic factors are associated with treatment induced 28 day viral decline, steatosis and IR. Understanding the biological mechanisms that contribute to these findings has significant public health implications because it could help establish new therapies and interventions to prevent HCV related morbidity and mortality. Results may also contribute to understanding the mechanisms of treatment response, steatosis and IR.