Includes abstract (p. iii-iv). Includes bibliographical references.

Background Studies suggest antiretroviral therapy (ART) use during pregnancy may be associated with adverse pregnancy outcomes. Given the large numbers of pregnancies exposed to ART, better understandings of potential associations with commonly used ART regimens and adverse pregnancy outcomes is critical. With the number of women on ART initiated before conception rapidly increasing, understanding how current recommended regimens and timing of ART initiation may influence pregnancy outcomes is critically important. Methods This mini-dissertation presents a research protocol (Section A), literature view (Section B) and journalformatted manuscript (Section C) for a study of ART use and birth outcomes among HIV-infected women and a comparator cohort of HIV-uninfected women. Pregnant women seeking care at the Gugulethu MOU, a primary-level antenatal care facility in Cape Town, South Africa were enrolled between March 2013 and August 2015. Pregnancy dating was based on research ultrasound, or last menstrual period/clinical exam where ultrasound was unavailable. Women were followed from their 1st antenatal visit through delivery. Analyses compared birth outcomes (preterm (PTD), low birthweight (LBW) and small for gestational age (SGA) deliveries) between HIV-infected and uninfected women; and between women on ART initiated before conception versus those initiating ART during pregnancy. Results In 1554 women with live singleton births (mean birthweight, 3079g; 21% preterm; 13% LBW; 12% SGA), a higher prevalence of PTD (22% vs 13%, p=0.001) and LBW (14% vs 9%, p=0.030) were observed in the HIV-infected compared to HIV-uninfected women. Adverse birth outcomes (PTD, LBW and SGA) did not vary systematically among the HIV-infected women regardless of ART initiation timing (initiated ART before conception or initiated ART to during pregnancy). The absence of associations between the adverse birth outcomes and timing of ART initiation persisted after adjusting for maternal age, parity, height, CD4 cell count and viral load at 1st visit. Conclusions Levels of adverse birth outcomes, in particular PTD, remain high among HIV-infected women, however our findings from a routine care cohort demonstrate that the timing of initiation of widely used regimens before conception or during pregnancy do not appear to be associated with an increased risk in adverse pregnancy outcomes.

Includes bibliographical references. / The United Nations Millennium Declaration conference held in September of 2000, set key Millennium Development Goals. Millennium Development Goal 4 requires a reduction in the mortality rate of children under the age of five years by two-thirds by the year 2015, from a baseline in 1990. In South Africa, it has been recognised that without a substantial reduction in neonatal deaths, MDG-4 will not be met. This study will focus on the social determinants of health which play a key role in neonatal outcome in South Africa. It will evaluate the effects of these social determinants of health (Primary caregiver's education level, Primary caregiver's age, and Living Standards Measure) on the outcome of neonates admitted to, and operated on, in the general surgery unit of Red Cross War Memorial Children's Hospital (RCWMCH), within the Western Cape, South Africa. This study is based on the hypothesis that there is an association between Neonatal outcome, and a selection of social variables, namely: primary caregiver's level of education, primary caregiver' age, and LSM. The protocol (Part A) describes the sampling methodology that was used during the intervention. This will be followed by a literature review (Part B), Article (Part C), and Appendix (Part D).

Malnutrition is characterized by the insufficient intake of certain nutrients and the inability of the body to absorb or use these nutrients. This health problem continues to be a persistent challenge among children under 5 years of age in developing countries, including Haiti, despite food aid provided. The purpose of this study was to determine the association between dietary habits in children under 5 years of age in Haiti and their malnutrition status. Community organization theory was used to determine the association between determinants of health such as dietary habits, parents' knowledge and experience, cultural eating habits, socioeconomic status, and the outcome of malnutrition status. This study was quantitative using a cross-sectional study design. A total of 113 participants that were parents or legal guardian of children under 5 years of age were used in the data analysis. A chi-square test for association was used for analysis. The results showed a statistically significant association between dietary habits, cultural eating habits, socioeconomic status, and cultural food taboos and moderate malnutrition, with the following Pearson chi-square respectively (113.000), p=0.000; (5.811), p=0.016; (70.236), p=0.000; and (4.181), p= 0.041. There was no statistically significant association between knowledge and experience and moderate malnutrition (p = 0.771). The results of this study could bring positive social change by guiding healthcare practitioners in future practice to have a cultural approach when developing nutrition intervention programs for population in developing countries with diverse cultural background.

Disparities exist between lesbian, gay, and bisexual (LGB) young people and their non-LGB peers, with LGB young people continuing to use alcohol and other drugs into emerging adulthood at higher rates than non-LGB young persons.1–6 Our analyses were conducted with data from two nationally representative studies in the US, the National Longitudinal Study of Adolescent to Adult Health (Add Health) and the National Longitudinal Survey of Youth 1997 (NLSY|97). Using Add Health data, a marginal structural model and structural equation model were used to examine the effect of neighborhood economic advantage (N = 15,101 non-LGB and 5,031 LGB young persons) and neighborhood cohesion (N = 15,097 non-LGB and 5,004 LGB young persons) on the occurrence of alcohol and cannabis use disorders and alcohol use disorder symptoms. With the NLSY|97, logistic regression models assessed the association between parental support and binge drinking among LGB young persons (N = 302 LGB young persons), and whether living in a state with supportive LGB policies modified this association. We found living in a neighborhood with higher levels of neighborhood economic advantage was associated with a lower risk of alcohol [0.81 (0.72-0.90)] and cannabis use disorders [0.88 (075-1.04)]. Neighborhood advantage had a stronger protective effect for LGB [0.75 (0.58-0.96)] than non-LGB [0.99 (0.81-1.21)] young people when examining cannabis use disorders. Higher levels of neighborhood cohesion were mediated by family and school cohesion and were inversely associated with alcohol use disorder symptoms, with a stronger total effect among LGB [-0.05 (-0.10 - -0.01)] than non-LGB [-0.03 (-0.06 – 0.00)] young persons. Higher parental support was inversely associated with binge drinking among LGB young people [0.85 (0.51-1.43)] with a trend toward a more protective effect among LGB persons living in states with supportive LGB-related policies. Our findings contribute to the published literature by extending the research on neighborhood context and substance use outcomes to an LGB population. Building state-level and neighborhood assets has the potential to reduce substance use and abuse among LGB young persons.

Periodontal disease is one of the most prevalent oral pathologies worldwide. Indicators of periodontal disease include deep periodontal pockets, inflammation of gum tissue, and tooth loss. A complex interaction between chronic bacterial infection and inflammatory host response, as well as, genetic and environmental factors drive periodontal disease. Some environmental factors that may contribute to periodontal disease and poor oral health include chronic illness, poor nutrition, poor lifestyle choices, smoking, and excessive alcohol consumption. To date, there has been limited research on the associations of oral health, diet, and the oral microbiome. Even more scarce, is research that includes members of the Black community, who are often disproportionally impacted by illness and disease. Here we investigated the genus-level relative abundance of oral bacteria across different categories of tooth loss, red meat consumption, and smoking status. Our study included saliva samples from 203 women from the Black Women’s Health Study (BWHS). Shotgun sequencing technique was used to identify DNA sequences of the bacteria in our mouth rinse samples. We found that relative abundance of genus Treponema presented as an increasing dose response trend through the highest level of tooth loss. Lactobacillus presented the highest relative abundance when participants had no teeth remaining. We also found genus Capnocytophaga presented highest among those in the lowest quartile of red meat consumption and never smoking status, indicating a potential association with a healthier lifestyle. While this thesis proposes a novel investigation, larger longitudinal studies are needed to further investigate and define the magnitude of the associations between tooth loss, red meat consumption, smoking status, and oral bacterial relative abundance.

Cardiovascular disease (CVD) mortality rates have been declining in the modern era with improved clinical care and better risk factor control. However, CVD remains the leading cause of death in the United States and is projected to affect approximately 45% of the population in the next 15 years. As randomized controlled trials are not always feasible, the use of longitudinal data to identify risk factors and effective treatment for primary and secondary prevention of CVD is essential. The aim of this dissertation was to conduct three studies that assess the risk of second major CVD events after a first CVD event, the effect of moderate alcohol consumption on stroke risk, and the effect of treatment for hypertension using a quasi-experimental design. In study one, I used data from the Framingham Heart Study to describe the risks of five CVD and mortality outcomes after a first major CVD event. I also assessed how the risk of a second CVD event differs from the risk of a first CVD event. I found that those who have experienced a first CVD event have a higher risk of CVD-related mortality and heart failure as a second CVD event compared with the risk of a first major CVD event. I also found that individuals whose first CVD type was myocardial infarction or heart failure had the highest risk of experiencing heart failure as a second event; those whose first CVD type was a stroke had the highest risk of mortality or a recurrent stroke. In study two, I used data from the Veterans Affairs Million Veteran Program to estimate the effect of moderate alcohol consumption on the risk of ischemic and hemorrhagic stroke compared with never drinking, and assessed if primarily drinking wine, beer or liquor is associated with a difference in stroke risk compared with drinking a mixture of beverage types. I observed that moderate alcohol consumption was associated with a reduced risk of stroke; however, stratified analyses by age and number of previous hospital visits provided some evidence that healthy survivor bias and residual confounding may have impacted the observed protective effect. I did not observe a difference in strong risk among those who primarily drink wine or beer, and a slight increase in stroke risk in those who preferred liquor, compared with those who have no beverage preference. In study three, I used Veterans Health Administration electronic health record data and a regression discontinuity design to estimate the effect of eligibility for antihypertensive treatment for patients with stage 1 hypertension, defined using national guidelines, on lowering blood pressure. I found that the blood pressure guidelines were associated with a small increase in antihypertensive treatment initiation and controlled blood pressure within 24 months. I also observed a reduction in blood pressure when estimating the effect of actual treatment among those with hypertension compared with those who were not on treatment.

Coronary heart disease (CHD) is the leading causes of combined morbidity and mortality worldwide. Metabolic syndrome is a cluster of cardiometabolic risk factors that predict cardiovascular disease, including CHD. Psychosocial factors, such as depression and social isolation, are increasingly recognized as risk factors for CHD and metabolic syndrome. However, this recognition is based on research in limited geographical areas, and sub-Saharan Africa is underrepresented in this literature. In addition, the mechanisms explaining the associations between psychosocial risk factors and poor cardiometabolic health are incompletely understood. Both behavioral mechanisms (e.g., physical activity, diet) and biological mechanisms (e.g., inflammation, metabolic changes) have been proposed, but their relative contributions are unknown. This dissertation addresses these gaps. In Studies 1 and 2, we used data from the Nyakabare Parish Social Network Cohort, a cohort of individuals in a rural community in southwestern Uganda in which residents earn income primarily through subsistence farming, animal husbandry, and small-scale enterprise. In Study 1, we estimated the associations between probable depression (as measured by the Hopkins Symptom Checklist for Depression) and each of the five components of metabolic syndrome (i.e., elevated waist circumference, low high-density lipoprotein [HDL] cholesterol, elevated triglycerides, elevated blood pressure, and elevated glycated hemoglobin [HbA1c]), measured approximately two years later, using modified Poisson regression. We found probable depression was not associated with increased risk of any of these outcomes, although contrary to our hypothesis, there was weak evidence of a slight protective association between probable depression and elevated blood pressure (adjusted risk ratio [aRR] = 0.90, 95% confidence interval [CI] = 0.70, 1.15). In Study 2, we estimated the associations between social isolation (vs. social integration, as measured by a composite measure combining marital status, close ties, and community group participation) and the same five components of metabolic syndrome as in Study 1, measured approximately two years later, using modified Poisson regression. We found social isolation was associated with increased risk of elevated blood pressure, specifically in men (aRR = 1.27, 95% CI: 0.93, 1.74). Contrary to our hypothesis, social isolation was associated with reduced risk of elevated waist circumference in both men (aRR = 0.30, 95% CI: 0.12, 0.75) and women (aRR = 0.69, 95% CI: 0.45, 1.06). In a secondary analysis, we found the specific domains of social isolation comprising social isolation affected metabolic syndrome components in unique ways. In Study 3, we used data from the Framingham Heart Study – Offspring Cohort, a cohort of individuals in the United States developed to study risk factors for cardiovascular disease. We assessed the extent to which the components of metabolic syndrome (i.e., elevated waist circumference, low HDL cholesterol, elevated triglycerides, elevated blood pressure, and elevated fasting plasma glucose) mediated the association between probable depression and incident CHD. We used the counterfactual-based inverse odds ratio weighting method to estimate the total effect of probable depression on incident CHD, and decomposed the total effect into natural direct effects (NDE) and natural indirect effects (NIE) through putative mediators. We found probable depression was associated with incident CHD (adjusted hazard ratio [aHR] = 1.45, 95% CI: 0.93, 2.25), and this association was partially mediated by elevated waist circumference (NDE = 1.34, 95% CI: 0.76, 2.32; NIE = 1.08, 95% CI: 0.63, 1.91). Neither metabolic syndrome nor any other component of metabolic syndrome were found to be mediators. Together, these three studies aid in better understanding the etiology of the associations between depression, social isolation, and poor cardiometabolic health. We offer evidence that the associations between depression and the components of metabolic syndrome previously observed in primarily high-income countries and urban areas do not necessarily extend to rural Uganda; that social isolation may affect health differently than depression, with variation by specific domain of social isolation; and that elevated waist circumference is a partial mediator of the association between depression and CHD. Further research is needed in this field, which is currently dominated by associational studies in limited geographical areas.

BACKGROUND: Opioid use has been associated with adverse pregnancy outcomes including neonatal opioid withdrawal syndrome (NOWS) and certain congenital malformations. Less intensively studied in relationship to prescription opioid exposure are stillbirth and ischemic placental disease (IPD), including preeclampsia, placental abruption, and intrauterine growth restriction (IUGR)/being born small for gestational age (SGA), which often result in preterm birth. Little is also known about how NOWS risk varies by the specific prescription opioid used. Given the highly prevalent and growing use of prescription opioid analgesics during pregnancy, a better understanding of their impact on these less studied outcomes as well as the association between NOWS and specific opioid medications is needed. METHODS: Three studies were performed using a cohort derived from the Medicaid Analytic eXtract (MAX), which contains administrative billing data for Medicaid enrollees in 46 states and Washington DC. These studies assessed (1) the association between prescription opioid use leading up to delivery and the risk of stillbirth, (2) the association between prescription opioid use and the risk of ischemic placental disease including pre-eclampsia, placental abruption, intrauterine growth restriction (IUGR) and preterm delivery, and (3) the association between properties of prescription opioid use and risk of NOWS. For Study 1, a case-control approach was utilized, with controls sampled from the cohort at risk to mirror the gestational age at stillbirth observed in the US population. Cases and controls were compared with respect to demographic and clinical characteristics, and odds ratios were calculated based on opioid exposure occurring within 4, 8, and 20 weeks prior to the stillbirth event of control sampling date. Study 2 used a cohort design in which risks of each component of ischemic placental disease were compared between opioid exposed and unexposed women according to timing of exposure during pregnancy (early, late and both early and late). Study 3 compared pregnancies exposed to opioids in the last 90 days before delivery based on characteristics of the opioid used. Relative risks were calculated for NOWS unadjusted, adjusted for characteristics of the medications used (including MMEs), and adjusted for confounding by demographic characteristics and medical history using fine stratification and reweighting of an exposure propensity score. Odds ratios of stillbirth, hazard ratios of ischemic placental disease, and relative risks of NOWS, with their 95% confidence intervals (CI) were estimated overall and within subgroups of interest. Because the analyses relied on administrative claims that require assumptions about timing of pregnancy and may not adequately capture illicit opioid use, other illicit drug use, smoking and obesity, probabilistic bias analyses were employed to estimate the impact of exposure misclassification and unmeasured confounding. RESULTS: Study 1: Among eligible pregnancies in the MAX database, we identified 25,565 stillbirths and 255,650 controls. A small increased risk was observed for exposure in the four weeks prior to delivery (adjusted odds ratio 1.24, 95% CI 1.16 – 1.32), with attenuation of the effect when considering alternate exposure windows of 8 or 20 weeks prior to the stillbirth event or control sampling date. Some differences were observed by specific medication used, with no meaningful increase observed for codeine (aOR 1.09, 95% CI 0.98 – 1.22) and a modest increase for oxycodone (aOR 1.39, 95% CI 1.16 – 1.67). Exploration of the 1.24-fold increase for exposure to any opioid in the four weeks prior to delivery suggests potential for reverse causation whereby medication could have been dispensed after recognition of fetal death, with opioid dispensings in the week of pregnancy loss associated with an aOR of 1.48 (1.34 – 1.63) and dispensings in the 2nd – 4th weeks prior to pregnancy loss associated with an aOR of 1.09 (95% CI 0.97 – 1.23). This could also be compatible with a triggering effect with a specific etiologically relevant window. Study 2: Of 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled by 6.5%. We observed an early exposure aHR of 1.34 (95% CI 1.26–1.43) for placental abruption, 1.21 (1.18–1.23) for preterm delivery, 1.13 (1.09–1.17) for SGA, and 0.95 (0.91–0.98) for preeclampsia. Estimates for late exposure were attenuated for each ischemic placental disease outcome. Exposure both early and late was associated with higher aHRs for placental abruption (1.62, 1.47–1.78), preterm delivery (1.37, 1.33–1.42) and SGA (1.26, 1.19–1.33), but not preeclampsia (0.99, 0.93–1.05). Study 3: We compared 16,202 codeine, 1,244 tramadol, 4,540 oxycodone, 260 methadone, 90 hydromorphone, and 63 morphine users vs. 25,710 hydrocodone users. When compared to hydrocodone users, adjusted relative risk of NOWS was lower for use of weak agonists [codeine (RR 0.57, 95% CI 0.46–0.70) and tramadol (1.06, 0.73–1.56)] and higher for use of strong agonists [oxycodone (1.87, 1.66–2.11), hydromorphone (2.03, 1.09–3.78), morphine (2.84, 1.30–6.22), and methadone (3.02, 2.45–3.73)]. Long half-life opioids had a slightly increased risk compared to short half-life products (1.33, 1.12–1.56). DISCUSSION: Opioid use proximate to delivery does not appear to be a major trigger of stillbirth, although a weak effect cannot be excluded. Prescription opioids may modestly increase risk of placental abruption, preterm birth, and SGA, but they do not appear to be associated with preeclampsia. The risk of NOWS in infants with exposed to opioids during the 90 days before delivery, however, was different based on the type of opioid used. This information may help prescribers with opioid analgesic selection for pain management in late pregnancy. / 2024-05-18T00:00:00Z

The SARS-CoV-2 pandemic has infected millions of people globally and continues to spread rapidly in many countries. As global vaccine access remains limited, SARS-CoV-2 transmission can be reduced through non-pharmaceutical interventions (NPIs), such as social distancing and lockdown measures that limiting human contact by restricting human mobility, and diagnostic testing strategies that rapidly identify and isolate infectious individuals. In this dissertation, I conducted three studies that inform SARS-CoV-2 surveillance and control policies in low- and middle-income countries (LMICs). The first study focuses in South Africa, where there have been multiple lockdowns and COVID-19 resurgences since the start of the pandemic.1 I assessed the association between mobility, as measured by smartphone data, and SARS-CoV-2 case positivity in South African provinces and districts at the ecological-level using regression, cross-correlation and interrupted time series analysis. I found that increases in mobility were positively associated with future COVID-19 incidence aggregated at both the province and district-level, and the association of mobility and COVID-19 incidence remained even when adjusted for district-level confounders. The second and third studies focus on rapid antigen testing (Ag-RDTs) in general LMIC settings. The main outcomes for these two studies include impact, defined as the percentage of infections averted compared to the base case scenario for each use case, and efficiency, defined as the number of tests needed to avert one infection compared to the base case scenario across use cases. In the second study, I quantified impact and efficiency of Ag-RDTs for population-level community testing using a compartmental model in a general population of 10 million people. This study adds to the literature that Ag-RDTs can be a valuable tool for population-level SARS-CoV-2 surveillance and case detection when testing is frequent and widespread, and diagnosis must be accompanied by corresponding reduction in post-diagnosis contacts in order for testing to be effective. I also identified that community testing is most useful when an epidemic is waning or before an epidemic wave, which is when SARS-CoV-2 prevalence and Rt are low. Finally, the third study assessed efficiency and impact of SARS-CoV-2 Ag-RDT testing strategies by comparing eight mathematical models across several scenarios, hereafter referred to as “use cases”. There was a clear trade-off between impact and efficiency; increasing test frequency (and/or more widespread testing of a community) increased impact, but consequently decreased efficiency. Additionally, testing strategies across most scenarios had the greatest impact when Rt and/or infection prevalence were low, but were least efficient. The findings from this dissertation provide further evidence of the importance of public health mitigation and control measures that reduce SARS-CoV-2 spread, such as NPIs and diagnostic testing, particularly in LMICs that have limited access to COVID-19 vaccines. The evidence generated from these studies can be used for future SARS-CoV-2 resurgences, whether from currently circulating variants, emergence of new SARS-CoV-2 variant strains or adaptation for use in future infectious disease outbreaks.