The HIV pandemic has posed an unprecedented challenge to the global health, devastating communities and reinforcing the historical problems that link ill-health with poverty. Sound evidence for public health decision-making is needed as antiretroviral programmes are being rolled out in developing countries. This thesis discusses the effectiveness of Highly Active Antiretroviral Therapy (HAART) in resource-limited countries from the Antiretroviral Therapy in Lower Income Countries (ART-LINC), a network of HIV/AIDS treatment programmes and cohorts in Africa, South America, and Asia. The objectives of this project were to document the effectiveness of HAART in these settings, defined by changes in immunologic and virologic markers within 6 months of treatment; assess factors associated with 6-month response to therapy; and to assess the association of 6 month response with long-term outcomes. In the first article, the evidence supporting effectiveness of HAART is reviewed, focusing on aspects of immunologic and virologic responses to therapy. Despite the lack of a standardized definition of immunologic and virologic response, we conclude that around one third of the patients who start HAART show a response pattern where either immunologic or virologic response is not achieved, a condition referred to as discordant response. The second and third articles provide a picture of the association between HAART and 6-month response in resource-limited countries. Overall, the effectiveness of HAART in these settings is similar to that reported in resource-rich countries. Finally, we assessed the association between immunologic and virologic discordant responses at 6 months and mortality in ART-LINC. We found that the hazard of death for those showing discordance at 6 months was similar to that reported in resource-rich countries. However, we found that early mortality was high in Africa and Asia, and a significant proportion of patients that did not have access to laboratory measurements were also at greater risk of death. This is the first report on the association of discordant responses and mortality in lower income countries, which provides important evidence for public health decision making in the context of antiretroviral rollout.

Each year, in the United States, 235,000 individuals sustain a traumatic brain injury requiring hospitalization. Patient outcome from severe traumatic brain injury is improved with intensive care management of pathophysiological processes developing in the days following the injury. An important secondary complication of traumatic brain injury is fever, which is known to worsen neurologic outcome. Our institution has recently developed an approach to combat fever through the prophylactic use of intravascular cooling catheters, a treatment termed controlled normothermia. We have recently demonstrated that controlled normothermia reduces both core and brain temperature and can improve the intracranial milieu that may facilitate recovery. A major drawback to the systematic use of controlled normothermia is an increased risk of infection, or delayed diagnosis of infection by masking of fevers. In the current study, we evaluated whether controlled normothermia, the prophylactic use of intravascular cooling catheters in severe traumatic brain injury, is associated with increased infection rates during the intensive care stay. Utilizing a matched cohort study and data from the Brain Trauma Research Centers database, a retrospective study was performed. The data was taken from the Brain Trauma Research Centers traumatic brain injury registry, and was matched on age, gender, and Glasgow Coma Score. After analysis, the results of the study indicated fewer infections in the controlled normothermia group; the rates of bloodstream infections were statistically lower in the controlled normothermia group. The current study demonstrates that prophylactic use of intravascular cooling catheters in severe traumatic brain injury is not associated with an increased risk of infection. The public health significance is that these results lend further support to the concept of controlled normothermia as a treatment for severe traumatic brain injury. Further study may prove that controlled normothermia is effective in improving neurologic outcomes from traumatic brain injury, which remain the leading cause of death under age 45 in the United States.

Obesity is one of the major risk factors of atherosclerosis and arterial stiffness. Recent evidence suggests detrimental effect of fat mass rather than overall body mass. Abdominal fat has been indicated to have more negative impact than other fat depots. We evaluated the impact of regional fat distribution on atherosclerosis and compared the variances explained by 11-different adiposity measures on atherosclerosis and arterial stiffness among bi-racial women in menopausal transition. All analyses were cross-sectional. In the first analysis, adjusted for age, race, menopausal status, insulin, systolic blood pressure (SBP), triglycerides, height, high-density lipoprotein (HDL) and smoking; proportions of total (p= 0.03) and trunk fats (p= 0.03) were positively associated with common carotid adventitial diameter (AD). In contrast, proportion of leg fat was negatively associated with AD (p= 0.03). SBP attenuated the significant associations of total and regional fat distribution with carotid IMT. In the second analysis, adjusted for age, race, menopausal status, height, SBP, low-density lipoprotein (LDL), HDL and insulin; waist circumference (WC) explained 25.2% of variance in IMT and 27.0% of variance in AD, while proportion of trunk fat explained 22.7% of variance in IMT and 25.1% of variance in AD, and area of visceral adipose tissue (VAT) explained 22.7% of variance in IMT and 25.8% of variance in AD. When adjusted for age, race, menopausal status, height, SBP, insulin and C-reactive protein; WC, proportion of trunk fat and VAT explained comparable proportions of the variance in carotid-femoral pulse wave velocity (cfPWV) (WC, 9.0% of variance; proportion of trunk fat, 9.9%; and VAT, 10.3%). After adjusting for above mentioned variables, only proportion of total fat remained positively associated with cfPWV (p= 0.04). Overall, our findings provide evidence for differential role of regional fat distribution on atherosclerosis but not on arterial stiffness. Moreover, WC seems to be as good as computed tomography (CT) and dual-energy x-ray absorptiometry (DXA) measures of fat in explaining variability on atherosclerosis and arterial stiffness. Given the cost, difficulty in maintenance and exposure to radiation associated with CT and DXA, the use of WC in future research may have great public health significance.

Objectives: Although prior research has shown that self-efficacy (SE), the belief that one has the ability to create change through behaviors, is associated with better clinical outcomes for Type 2 diabetes (DM) and coronary artery disease separately (CAD), little research has examined the role of SE in patients with both DM and CAD. The goal of this cross-sectional analysis was to describe the association between SE and glycosylated hemoglobin (HbA1c), systolic blood pressure (SBP), and low density lipids (LDL) in patients with comorbid CAD and DM. In addition, this analysis examined the demographic and clinical factors that are associated with SE in the management of DM and CAD. Methods: Bivariate and multivariate analyses were conducted with 1,447 patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study who completed a self-efficacy assessment. Only patients recruited at U.S. sites were included in the analyses. The majority of the patients were White non-Hispanic, male, and had a post high school education. The average age at enrollment was 63 years. The models were adjusted for sex, age, race/ethnicity, and education. Results: Better HbA1c was positively associated with SE, even after adjusting for race/ethnicity, age, sex, and education. Better SBP was positively associated with SE, however this association was only marginally significant when adjusting for race/ethnicity, age, sex, and education. LDL was not associated with SE. Hispanic ethnicity, history of congestive heart failure, number of hypertension drugs, probable neuropathy, and insulin use were factors negatively associated with SE. A post high school education and history of cancer were positively associated with SE. Conclusions: Psychosocial factors, such as self-efficacy, are of public health significance because they play a considerable role in the management of diabetes and cardiovascular disease. Self-efficacy was positively associated with better cardiac and diabetic factors in the BARI 2D population. Literacy skills, cardiac history, number of medications, and neuropathy are several other factors doctors should take into consideration when assessing and building up patients confidence in being able to manage their medical conditions.

Childhood maltreatment (CM) is associated with negative physical, psychological, and social outcomes throughout life. Among the important psychosocial outcomes for female victims of CM is the risk for subsequent violent victimization during adulthood. Few studies have examined the risk and protective factors associated with revictimization and following CM. Additionally, although both CM and adult violent victimization (AVV) are associated with factors that impact womens socioeconomic status, there is a paucity of research explicitly examining socioeconomic outcomes, such as neighborhood characteristics, among victimized women. Racial and socioeconomic differences exist in the prevalence of both CM and AVV, yet little data exists to show demonstrate, how those factors impact the CM-AVV relation. This study examined the role of race in the association between CM and AVV and related socioeconomic outcomes among adult women. The goals were to; 1) Characterize the association between CM and AVV; 2) Examine whether there are racial differences in the association between CM and AVV; and 3) Determine whether victimization history is associated with the characteristics of the neighborhood in which one resides. Women (n=477) participating in a longitudinal study of the effects of prenatal exposure to alcohol and marijuana were interviewed about their history of exposure to CM and AVV. Other measures included demographic characteristics, social support, substance use, depression and anxiety, and household environment. The results demonstrated an increased likelihood of experiencing AVV among women who reported a history of CM; regardless of the type of maltreatment experienced. Baseline illicit drug use partially mediated the CM-AVV relation. The risk of AVV associated with CM was not different by race; however, baseline marijuana use was found to mediate the CM-AVV relation for Caucasian women only. Victimization was not associated with neighborhood-level characteristics. There are several important public health implications of this study. When all forms of CM exposure are considered there is a substantial increase in the odds of experiencing AVV, both intimate partner violence and non-intimate partner violence. This study also suggests that approaches to prevent revictimization should differ depending on race, and that drug interventions may be more relevant for Caucasian women.

Type 1 diabetes (T1D) is associated with numerous complications. These include renal and cardiovascular disease which are the leading causes of morbidity and mortality in T1D. Renal complications also increase the risk for cardiovascular disease. Early detection and treatment of their risk factors may help to prevent or at least delay these complications. This dissertation examines potential risk factors for altered measures of pulse wave analysis (PWA), which have been linked to cardiovascular events and mortality in other populations. It also examines how PWA measures relate to prevalent cardiovascular and renal complications in T1D. Prospective analyses of potential risk factors for increased arterial stiffness indices, augmentation index (AIx) and augmentation pressure (AP), and decreased estimated myocardial perfusion, i.e. subendocardial viability ratio (SEVR), showed autonomic neuropathy, smoking history, low HDL cholesterol and poorer glycemic control, to be associated with altered PWA measures 18 years later. Next, cross-sectional analyses between PWA measures and prevalent CVD showed AP and SEVR to be significantly related to coronary artery disease and coronary artery calcification, respectively, although age was the major predictor of both. AP was also higher, although not significantly, and SEVR significantly lower in those with peripheral vascular disease. Finally, SEVR, but not AIx nor AP, was significantly associated with the presence of microalbuminuria (MA), and preferentially entered multivariate models over brachial blood pressure measures. SEVR was also related to degree of albuminuria in those within the normo- and MA range, and was significantly associated, multivariately, with low renal function. This dissertation thus yields significant Public Health findings by identifying factors (AN, smoking, glycemic control, lipid levels) that may delay increased arterial stiffness (AIx and AP) and decreased myocardial perfusion (SEVR). As it additionally shows that these same PWA measures are altered in the presence of CVD and renal damage in T1D a potential role for PWA measures, especially SEVR, in risk stratification and early intervention for T1D complications is apparent.

The introduction and widespread use of highly active antiretroviral therapy (HAART) in the past decade has changed the profile of HIV/AIDS epidemic. Marked decreases in mortality and morbidity have been reported in low- and high-income settings. Recently, significant relative increases in non-AIDS-associated conditions in HIV-infected individuals have been reported in developed countries. In Brazil, where access to HAART has been universal for all eligible patients since 1996, a steep decrease in mortality among HIV/AIDS patients has also been documented, but the rates have been stable since 1999. So far, no data have been available about the pattern of non-HIV-related mortality in these patients. In these studies, we assessed temporal changes in causes of death among HIV-infected patients in Brazil. In the first paper using Brazilian national mortality data, we demonstrate that, between 1999 and 2004, the odds of having conditions not usually considered to be related to HIV-infection among individuals who had HIV/AIDS listed on their death certificate significantly increased over time. Specific diseases that increased were cardiovascular diseases and diabetes mellitus. In the second paper, we studied temporal trends in cause of death in a cohort of HIV-infected patients in Rio de Janeiro. Results showed an increase of non-AIDS causes of death and a decrease of AIDS causes of death in HIV-infected patients, which appeared to be driven by an aging of the population. This cohort study was facilitated by a linkage algorithm that was developed to recover vital status from patients lost to follow-up. In a third paper that validated the algorithm, sensitivity and specificity were found to be 95% and 100%, respectively. In addition, the use of the algorithm led to a 50% increase in the observed mortality rate. These findings have major public health and programmatic implications for developing countries that are scaling-up access to antiretroviral therapy. In the HAART era, HIV infection has become a manageable disease and is now associated with an increase in chronic illness. Public health measures that are not normally targeted to this population need to be included in their regular care, such as smoking cessation, lipid-lowering drugs, and hypertension control.

There are many advantages to using locally produced health information, such as its cultural appropriateness, geographic specificity, and flexibility. The Indian Supercourse is an online repository of lectures in Epidemiology, written by authors in India, on topics of particular interest to teachers and students in India. The purpose of this dissertation is to describe the planning, development and evaluation of the Indian Supercourse Network. The Indian Supercourse Network has 6,000 faculty members in India, and more than 200 epidemiology lectures written by authors in India. Evaluation of the Indian Supercourse Network included an assessment of utilization of these educational materials in India using page views measured by web statistics analysis software. The main hypothesis compared page views from India, between the Indian Supercourse and the Main Supercourse. The results of the Wilcoxon Rank-Sum test showed that there were significantly more page views from India to the Indian Supercourse as compared to the Main Supercourse (p < 0.0001). This means that users in India prefer to use the Indian Supercourse more than the Main Supercourse. This may be because information in the Indian Supercourse is more pertinent to the epidemiology education needs of users in India. In contrast, there were significantly more page views from non-Indian countries to the Main Supercourse as compared to the Indian Supercourse (p < 0.0001). Interestingly, there was no significant difference (p = 0.0642) in total page views from all countries considered together, between the Indian Supercourse and the Main Supercourse. Public Health Significance In India, there is a lack of an adequate system for formal epidemiology education. The Indian Supercourse has made epidemiology education available to everyone interested in learning epidemiology in India. The results of this study have shown that the Indian Supercourse is being utilized by people in India. Information contained on the Indian Supercourse website can eventually be disseminated across the digital divide via low-bandwidth methods and the postal system in India.

HHV-8 seropositivity was associated with prevalent prostate cancer among African-Caribbean Tobago men (Odds ratio [O.R.] = 2.24; 95% confidence interval [C.I.], 1.29-3.90). To understand this association, HHV-8 seropositivity among African-Caribbean Tobago women, modes of HHV-8 sexual transmission, the natural history of HHV-8 seropositivity, and the relationship between HHV-8 and incident prostate cancer were examined. A cross-sectional study was conducted in 213 Tobago women, ages 18-65 years. Age-specific rates were compared to those previously observed in men. Logistic regression analyses were performed to determine the association between HHV-8 seropositivity and sexual behaviors among women. A 9-year prospective cohort study was conducted among 407 Tobago men at risk for incident prostate cancer, ages 40-81 years. HHV-8 seroconversion and seroreversion rates and their 95% C.I. were calculated using a Poisson distribution. A case-cohort study was conducted among 90 and 407 Tobago men, ages 40-81 years, with incident prostate cancer and at risk for incident prostate cancer, respectively. Cox proportional hazards modeling for case-cohort design was used to examine the association between baseline HHV-8 seropositivity and incident prostate cancer. All serum/plasma were tested for HHV-8 seropositivity by immunofluorescence assay. Among women, HHV-8 seroprevalence was 14.1%, with no difference with men of similar age (p-value = .741). There was a significant but minimal association between HHV-8 seropositivity and age less than and equal to 17 years at first sexual intercourse among women (O.R. = 2.51, 95% C.I. = 1.09-5.78). Among men at risk for incident prostate cancer, HHV-8 seroconversion and seroreversion rates were 0.5 (95% C.I., 0.22-0.99) and 2.52 (95% C.I., 1.09-4.96) per 100 person-years, respectively. There were inverse associations between baseline HHV-8 seropositivity and screen-detected incident prostate cancer when age and baseline prostate cancer screening results (Hazard ratio [H.R.] = 0.454, 95% C.I., 0.221 0.933) and age (H.R. = 0.517, 95% C.I., 0.262 1.020) were considered. Sexual activity may not be the predominant mode of HHV-8 transmission among women. HHV-8 is probably acquired at younger ages, less than 40 years among men. HHV-8 seropositivity may not be related to prostate cancer incidence. The public health significance of these studies is to reduce HHV-8 infection and prostate cancer in Tobago.

Examination of the prevalence of subclinical cardiovascular disease (SCD) may help us to delineate future trends of coronary heart disease (CHD) mortality. There are substantial differences in the prevalence of SCD in different population groups. Identification of explaining factors for the difference in SCD rates across different population groups can provide new preventive strategies for reducing CHD morbidity or mortality. Based on this, the EBCT and Risk Factor Assessment among Japanese and U.S. Men in the Post World War II Birth Cohort (ERA-JUMP) Study is an ongoing population-based-cross-sectional study to examine differences in SCD rates across Japanese, Japanese American, and U.S. white men, and Korean men aged 40-49 years. As a part of the ERA-JUMP study, the present study demonstrated that: 1) among middle-aged men, Koreans in South Korea had a significantly higher level of carotid intima-media thickness than the Japanese in Japan. Middle-aged Korean men may continue to be at more increased risk for CHD than Japanese men at least over the near future. 2) Of polyunsaturated fatty acids, the proportion of linoleic acid was significantly and inversely associated with unfavorable levels of lipoprotein subclasses in three population groups of Japanese, Japanese American, and white men; an inverse association of docoxahexaenoic acid occurred only in white men. 3) Associations between pulse wave velocity (PWV) and cardiovascular risk factors were segmental-specific among white men. Brachial-ankle PWV had a mixed characteristic of stiffness of the central and peripheral arteries, compared to carotid-femoral PWV having a characteristic of the central arteries. Public health importance of these findings is that: First, we can provide scientific information imperative to addressing a health-related problem (i.e., increasing risk for cardiovascular disease in South Korea). Second, the promotion of enriched intakes of linoleic acid (e.g., sunflower, corn, safflower oils) and fish-derived n-3 fatty acids (e.g., mackerel or salmon) should be addressed to public in habitual diet in the prevention of CHD by establishing practical guidelines. Finally, incorporation of both measures of brachial-ankle PWV and carotid-femoral PWV into the assessment of arterial stiffness should be considered when screening a high-risk group for cardiovascular disease.