Polycystic ovary syndrome (PCOS) is a familial disorder characterized by major metabolic consequences related to insulin resistance (IR), including T2DM and metabolic syndrome (MS). There is mounting evidence, which supports association of each of G-174C variant in IL-6 and Pro12Ala variant in PPARλ genes with PCOS-associated biochemical or metabolic features in hyperandrogenic and PCOS adults/adolescents. The major aim of this study was to demonstrate the ability to enroll PCOS probands, who have one or more clinically PCOS-diagnosed woman, and their multigenerational family members for a total sample size of 100-125 to study IR and inflammation markers in such families. Additional important aims were to test for linkage between the IL6 and PPARλ genes loci and for associations between the IL6G-174C SNP and the Pro12Ala PPARλ SNP with IR, MS and its components, serum inflammation levels (IL-6 and CRP) and testosterone in this special population of PCOS families. IR was defined by a HOMA-IR value > 3.9 in adults and HOMA-IR values which are age-gender specific in adolescents. MS was defined according to the ATP III diagnostic criteria in adults and the same criteria, modified for age in adolescents. In total, 101 individuals were recruited from 9 multigenerational extended families; eight of the families were Caucasian and the remaining was African American. No evidence for linkage of each of the IL6 and the PPARγ markers to any of the examined phenotypes was found. However, interesting significant SNP-phenotype associations were found in this population of PCOS families. The Ala12 allele was found to be negatively associated with diastolic blood pressure (DBP) and with fasting glucose. Moreover, the G allele of the IL6 SNP was found to be positively associated with DBP, serum IL6 and testosterone levels. These associations are particularly important because they were adjusted for covariates which are known or were found to be significantly associated with the outcome in our population and were the results of the variance components association test, a test which accounts for family relationships. The findings are of major public health significance, mainly because they are the first to be reported in PCOS extended families.

Current findings related to nicotine addiction and related physiologic-metabolic processes create a biological basis to consider the role of interindividual genetic differences governing smoking behavior. This study examined associations between smoking cessation and a set of potential risk factors measured in a group of adult cigarette smokers participating in a computed tomography (CT) lung cancer screening program. The investigation of non-genetic factors focused on the relationship between CT results and smoking cessation. The investigation of genetic factors attempted to determine genetic influences on the relationship between the dopamine pathway and smoking cessation by examining genetic variation in the dopamine receptor 2 (DRD2: TaqIA, TaqIB, C957T, 141C Ins/Del) and dopamine transporter (SLC6A3). Participants were part of the Pittsburgh Lung Screening Study (PLuSS), a research based low-dose CT screening program containing current and former cigarette smokers, ages 50 to 79. These analyses were restricted to baseline smokers who indicated their smoking status at follow-up. Non-genetic factors were assessed for all eligible members of the cohort; genetic factors were assessed for a subset. A CT scan of the lungs that resulted in a referral was significantly associated with abstinence (for more than 30 days) at one year. The relative risk of being abstinent at one year after receiving a CT referral was 1.39 (95% Confidence Interval (CI): 1.14-1.70). After controlling for the matching variables and other genotypes, the DRD2 TaqIA polymorphism was significantly associated with being abstinent at one year (p=0.01). Compared to participants with the A2A2 genotype, participants who carried at least one variant allele (A1) were less likely to be abstinent (Odds Ratio: 0.47, 95% CI: 0.24-0.94). SLC6A3 genotype was not associated with abstinence at one-year (p=0.757). No significant gene-gene interaction with TaqIA was observed. CT screening can create a teachable moment for smoking interventions. The association between TaqIA and abstinence at one year supports the hypothesis that genetic variation in the dopamine pathway influences smoking cessation. Public Health Significance: Smoking is the leading preventable cause of death in the United States. Identifying genetic variations that influence smoking behaviors could enhance treatment options for smoking cessation. This dissertation identified both non-genetic and genetic influences on smoking cessation. Consideration of those influences in the selection of quitting regimens may improve success rates thereby reducing the morbidity and mortality due to continued cigarette smoking.

In older adults, diabetes is a serious public health problem because of high prevalence as well as its devastating consequences such as functional disability and high mortality. Loss of muscle mass and strength, called sarcopenia, has been considered as a common pathway leading to loss of function and frailty in older adults. We investigated the impact of diabetes on skeletal muscle mass and strength in 3,075 older adults aged 70 to 79, enrolled in the Health, Aging and Body Composition Study. Diabetes was defined not only by self report or medication use, but also by fasting plasma glucose and the result of 75-g oral glucose challenge test. Muscle mass was measured by state of the art techniques such as dual-energy X-ray absorptiometry (DXA) and computed tomography (CT). Muscle strength was assessed quantitatively by isometric and isokinetic dynamometers. Muscle quality was defined as maximal muscle strength per unit muscle mass. In cross-sectional study, we found that muscle strength was significantly lower in men with diabetes and not higher in women with diabetes despite of having greater muscle mass than those without diabetes. Muscle quality was consistently lower in both men and women with diabetes than non-diabetic counterparts in both upper and lower extremities. We also found that longer duration (greater than or equal to 6 yrs) and poor glycemic control (A1c > 8.0 %) were associated with even lower muscle quality. In longitudinal study, older adults with diabetes showed about 50% greater declines in leg muscle strength compared with those without diabetes. Leg muscle quality also declined more rapidly in older adults with diabetes. Skeletal muscle mass, estimated by DXA, declined more rapidly in older adults with diabetes. Interestingly, loss of muscle mass was more pronounced in undiagnosed diabetes. Thigh muscle area by CT declined two times faster in older women with either diagnosed or undiagnosed diabetes than non-diabetic women. The public health importance of these findings is that diabetes is clearly a risk factor for loss of muscle mass and strength in older adults. We need to develop a strategy to prevent rapid loss of muscle mass and strength in this high risk population.

Cardiovascular disease (CVD) is the leading cause of death among women in the US. CVD is still thought to be a mans disease and remains underappreciated by the public and under treated by health-care providers. Yet, unlike men, a large proportion of deaths attributable to CVD occur in asymptomatic women, making early detection and diagnosis difficult. Therefore, both the development of primary CVD prevention strategies to decrease the risk of CVD and screening tools that will aid in the early detection of women who are at increased risk for CVD has major public health implications. Hormone therapy (HT) has been shown to beneficially affect adverse changes to CVD risk factors that occur during menopause; however, HT is no longer indicated for general CVD prevention. Increased physical activity (PA) levels, either separately or as part of a lifestyle intervention, may decrease CVD risk in women; however, previous reports have not adequately accounted for concurrent changes in HT status. Strategies for primary CVD prevention and early detection in postmenopausal women were examined using 508 women from the Woman on the Move through Activity and Nutrition (WOMAN) study. At baseline, PA was found to be related to more favorable lipid and lipoprotein subclass levels; however, some of these associations were influenced by current HT use. Results at 18 months suggested that a lifestyle intervention was effective for general CVD risk factor reduction regardless of HT continuation or discontinuation. Additionally, lifestyle appeared to attenuate increases in lipid levels that resulted from discontinuing HT. Finally, a simple walking endurance test may provide supplemental information when ascertaining CVD risk in women. In the post-WHI era, concern and confusion about the risks associated with HT has left women and health-care providers searching for alternative means to decrease risk of CVD. Findings from the current report suggest that a non-pharmacological approach for CVD risk factor reduction is both safe and effective for primary CVD prevention in postmenopausal women. In light of the current controversies surrounding the use of HT, the promotion of healthy lifestyle behaviors for CVD risk factor reduction has important public health implications.

Changes in nighttime sleep, daytime napping, and fatigue are common complaints in older adults. This study investigated the association between nighttime and daytime sleep, fatigue, and daytime physical function in two cohorts of older adults (75-85 years); The Study of Osteoporotic Fractures (SOF) and the Health Aging and Body Composition Study (Health ABC). In SOF, measured short sleep duration (less than or equal to 6 hours) was associated with slower gait speed and long sleep duration (greater than or equal to 7.5 hours) was associated with longer time to complete 5 chair stands. More wake after sleep onset was associated with slower gait speed, longer time to complete 5 chair stands, lower grip strength and higher odds of Instrumental Activities of Daily Living (IADL) impairment. Women with higher daytime sleep took longer to complete 5 chair stands and had higher odds of IADL impairment. These findings supported the hypothesis that older women with disturbed sleep would have poorer function. In Health ABC, there was a wide range of fatigue symptoms. Compared to self-reported sleep durations of 7 hrs/night, >8 hrs/night was associated with 7% higher fatigue. Awakening during the night or wakening too early in the morning were each associated with 6% higher fatigue. These results remained after multivariate adjustment independent of comorbidity. The association between disturbed nighttime sleep and reported fatigue symptoms suggests that better and more effective behavioral management of sleep may help reduce fatigue in older adults. In the Health ABC ancillary sleep study, 75.7% of the participant's recorded at least one nap/week in their sleep-wake diary. Individuals with more fragmented nighttime sleep, self-reported diabetes, pain, or respiratory symptoms had higher odds of recording a nap. In the group that napped neither sleep duration nor fragmentation the night before the nap was associated with nap duration the next day. Identification of causes and methods to reduce fragmented sleep may help lessen daytime napping in older adults. The public health importance of these findings is that sleep duration and quality are important factors in the daytime function of older adults, and may be important targets for intervention to improve quality of life.

This project examined childhood temperament as a predictor of substance use in early adolescence. Many previous studies of temperament and substance use were cross-sectional, and thus could not address the direction of this relationship. Previous longitudinal studies did not address childhood temperament as a risk factor for substance use. In addition, many studies only considered a small number of covariates of substance use. This study improved on previous studies by collecting childhood temperament data at ages when substance use is rare, and addressing the direction of this relationship. In addition, substance use data were collected in early adolescence and other covariates were analyzed. The data were from a longitudinal, epidemiological study of the effects of prenatal substance use, and included covariates of substance use such as maternal substance use and psychiatric symptoms, child psychiatric symptoms, and family history of substance use problems. Temperament was measured at ages 6 and 10 using the Emotionality, Activity, Sociability, and Shyness Survey (Buss & Plomin, 1984). Substance use outcomes were measured at age 14 with the Health Behavior Questionnaire (Jessor, Donovan, & Costa, 1989), which measures the quantity and frequency of substance use, including cigarettes, alcohol, and marijuana. Increased sociability and increased activity at age 6 predicted ever having tried a cigarette by age 14. This relationship remained significant when controlling for other relevant covariates. Temperament at ages 6 and 10 did not predict alcohol, marijuana, or polysubstance use outcomes, although increased sociability did predict escalation of marijuana use. This project also identified common and unique predictors of the initiation and escalation of use of specific substances. Children with high levels of activity and sociability at age 6 are at increased risk for substance use in early adolescence. The public health importance of these findings is that parents or teachers can easily identify these traits at young ages. Prevention efforts may then be aimed at these children starting in early elementary school in the hopes of reducing and delaying the initiation of their substance use in adolescence. These results may also be used to tailor prevention and intervention efforts to use of specific substances.

Bacterial vaginosis (BV) is one of the most prevalent diseases in women of reproductive age; however, the natural history of BV is poorly understood. We characterized variations in vaginal flora by assessing factors that influence the persistence of BV and BV-associated organisms. In addition, we evaluated the potential impact that prior infection may have on the relationship between douching and BV, and assessed whether condom use may protect against BV. A total of 1199 women enrolled in the Gyn. Infections Follow-through Study were utilized for this study. Women were followed for a median of 3 years, and vaginal microbiology samples were obtained for Gram-stain diagnosis of BV and culture of microflora at baseline and every 6 to 12 months thereafter. After adjusting for confounding factors, only black race (adjusted RR 1.47, 95% CI 1.09, 1.98) and a baseline Gram-stain of BV (adjusted RR 6.60, 95% CI 4.41, 9.87) increased the risk of persistent BV. Other factors, commonly associated with BV in cross-sectional analyses were not associated with persistent BV. In cross-sectional analyses, douching at least once per month was associated with BV among women who had a history of BV, but not among women without prior experience of BV. In prospective analyses, douching only increased the risk of acquisition for BV among women with intermediate flora at baseline (adj. HR 1.5, 95% CI 1.1-2.4), suggesting that douching may lead to BV among women with abnormal flora. Consistent condom use (10 out 10 sexual encounters) was associated with a decreased frequency of BV in case-crossover analyses (adjusted OR = 0.68, 95% CI = 0.49-0.94, p for trend = 0.047). Similar results were seen for carriage of M. hominis (adjusted OR=0.61, 95% CI: 0.41-0.93) and anaerobic Gram-negative pigmented rods (OR=0.65, 95% CI: 0.47-0.91). These results identify women at high risk for persistent infection, and among women with a history of BV douching should be avoided. This study also provided evidence that condoms are protective against BV. Given the high proportion of women with BV, the identification of protective factors is of significant public health importance for reducing the prevalence of BV.

Cardiovascular disease is the leading cause of mortality worldwide, and approximately half of all cardiovascular deaths are attributed specifically to coronary artery disease (CAD). Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) procedures play a prominent role in managing the heavy burden of CAD. The purpose of this dissertation was to evaluate revascularization treatment in patients with multivessel coronary disease. Specifically, predictors of long-term prognosis and factors related to selection of revascularization strategy were investigated in the BARI and BARI 2D cohorts, respectively. In BARI, treatment with CABG was associated with a significantly lower risk of sudden cardiac death, but did not impact any other causes of mortality. Moreover, protection conferred by CABG was observed in patients regardless of diabetes status. Following successful initial PCI in BARI, male gender, proximal LAD disease, and incomplete revascularization were associated with an increased risk of a first subsequent revascularization event but not latter events. Diabetes and extensive CAD, on the other hand, demonstrated an incremental impact on the number of repeat procedures over 10 years of follow-up. Among patients with diabetes and stable CAD in BARI 2D, angiographic features associated with the extent and location of coronary disease greatly influenced the decision to perform CABG over PCI. Geographic region, independent of patient characteristics, was also a driving factor in treatment selection, with a greater propensity to recommend PCI in the US. In all countries of origin, we observed substantial variation across individual clinical sites in this decision-making process. Results in the BARI cohort may have clinical implications on guiding initial revascularization strategy and underscore the importance of intensive management of atherosclerotic risk factors in order to limit disease progression. Our investigation of BARI 2D demonstrate the need for rigorous evaluation of optimal CAD treatment approaches in diabetic patients and factors that guide this decision-making process in current practice. Overall, these findings may be useful for devising long-term treatment strategies that address the chronic, progressive, and systemic nature of coronary disease, which will be of great public health importance as medical advances continue to extend the lives of individuals with CAD.

Among women with pelvic inflammatory disease (PID), prevention of adverse reproductive sequelae is similarly achieved by outpatient and inpatient treatment. It is unknown if outpatient treatment is as effective as inpatient treatment among women in various subgroups based on relevant categories of age, race and clinical presentation, and if there are short-term outcomes of PID treatment that predict pregnancy, recurrent PID and chronic pelvic pain. Women with clinical symptoms of mild-to-moderate pelvic inflammatory disease (n=831) were randomized into the PID Evaluation and Clinical Health trial, a multicenter trial of outpatient versus inpatient treatment. Comparisons between treatment groups during a mean of 84 months of follow-up were made for: pregnancies, live births, time-to-pregnancy, infertility, PID recurrence, chronic pelvic pain, and ectopic pregnancy. Outpatient treatment assignment did not adversely impact the proportion of women having any of the outcomes among women of various races; with or without previous PID; with or without baseline Neisseria gonorrhoeae and/or Chlamydia trachomatis infection; and with or without severe PID. In analyses of the full study cohort irrespective of random assignment, four short-term markers (pelvic tenderness at 5 and 30 days, cervical infection at 30 days, endometritis at 30 days) were evaluated in relation to long-term sequelae. Pelvic tenderness at five days (adjusted HR 1.32, 95% CI: 1.05-1.67) and at thirty days (adjusted HR 2.45; 95% CI: 1.56-3.85) significantly elevated the relative risk for developing chronic pelvic pain; tenderness at 30 days was also significantly associated with recurrent PID (adjusted HR: 2.11; 95% CI: 1.18-3.79). However, pelvic tenderness at five days and at thirty days were poorly predictive of chronic pelvic pain or recurrent PID (positive predictive values 20.5-64.1%). In contrast to pelvic tenderness, cervical infection and endometritis at thirty days were not associated with chronic pelvic pain or recurrent PID. Moreover, none of the short-term markers significantly increased the likelihood of achieving a pregnancy. The public health significance of these findings are that women with pelvic inflammatory disease will not be adversely impacted by outpatient treatment and that no short-term marker of pelvic tenderness or infection can be predict the occurrence of PID-related reproductive morbidities.

Major Depression is a serious mental illness which if left untreated can lead to severe mental and physical debilitation. Major depression often occurs concurrently with many, serious, medical co-morbidities, e.g. diabetes mellitus. Primary care physicians now have to treat more medically complex patients due to the increasing incidence of diabetes mellitus and the increase of screening for major depression in the primary clinic settings. There are little data available about the impact of diabetes mellitus on depression treatment and this report will provide some of this data to the treating clinician. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) was the largest study of major depression in the U.S. to date, with an enrollment of 4041. STAR*D offered a unique opportunity to examine the impact of diabetes on depression and antidepressant treatment. This report focused on the presenting characteristics and treatment outcomes of diabetics from the first STAR*D treatment level. At study entry, diabetics differed on key socio-demographic variables, e.g. race/ethnicity and reported lower physical functioning at baseline across measures of quality of life and depression severity. Diabetics had poorer outcomes, although after adjustment for potential confounders, there was no statistically significant difference in these outcomes. Diabetics received similar treatment regimens as non-diabetic participants and reported fewer side effects at the conclusion of the first treatment level with citalopram. Diabetics also reported a lesser overall impact of side effects than non-diabetics, although these results were limited by a lack of available baseline side effect data for comparison. These findings are of some importance to clinicians. The lack of an independent association of diabetes with major depression treatment response after adjustment for confounding factors implies that clinicians can treat diabetic patients similarly to those without diabetes mellitus for major depression. This is of some public health significance as untreated or poorly treated major depression adversely impacts diabetes disease management, which in turn can lead to the development of life-threatening diabetes complications. The importance of developing MDD treatment modalities that result in sustained remission for individuals with major depression and diabetes mellitus cannot be over-stated.