Osteoporosis has affected millions of patients worldwide and is a continuing concern for the increasing ageing population. It is a skeletal disease due to abnormal bone growth and resorption, characterized by low bone mass. Onset could be due to genetics and family history or acquired risk factors like lifestyle, diet, and exercise. As a result, it is important to try to understand the mechanisms of the onset of low bone mineral density so that effective treatment plans and prevention methods can be determined. The purpose of this study is to compare how the genetic makeup of an individual interacts with one’s environment in the determination of bone mineral density (BMD) and the onset of osteoporosis. This study focused on comparing biochemical markers of osteogenic cells and their mineralization potential between primary and secondary cultures of mesenchymal stem cells (MSC) that were harvested from pelvic bone-marrow remains of patients undergoing hip replacement. We hypothesized that the primary cultures grown out directly after being acquired; should be impacted more directly by comorbidities present at the time of collection while the secondary cultures expanded from the initial marrow stromal cells should show less impact of comorbidities and reflect more closely genetic aspects that affect BMD. It was found that while the secondary cultures overall produced greater values for DNA, ALP, calcium, hydroxyproline, and protein, when samples were normalized the values between the primary and secondary cultures did not show significant differences. This data appeared however to validate our hypothesis since the overall increased growth and mineralization of the secondary cultures showed a loss in their overall correlation to the environmental impacts of smoking and BMI that were observed in the primary cultures. The second hypothesis explored the specific correlations between the biochemical markers as indices of osteogenic potential of the cultures (DNA, ALP, calcium, hydroxyproline, and total protein) in relation to each other. The hypothesis was mostly supported with positive correlations, between all the features except for that between hydroxyproline and calcium which showed a negative correlation. Overall, this study demonstrates that although the normalized values between the primary and secondary cultures did not show significant different osteogenic features; it did show the correlations to comorbidities identified in primary cultures were lost upon expansion following sub cultivation. Further studies with larger sample sizes are needed which will provide a more statistically significant conclusion, allowing for further analysis when comparing genetic and environmental effects.

Includes bibliographical references (leaves 68-72 ).

BACKGROUND Endocrine disrupting chemicals (EDCs) pose significant risks to public health because of their ubiquitous nature throughout the environment. Concern regarding these toxic substances is well-justified, with past research highlighting links to male, female, and even transgenerational health defects with increased exposure to these chemicals. Recent studies have revealed that the average American women uses 12 personal care products (PCPs) every day, suggesting females are particularly susceptible to the adverse health outcomes associated with PCP-related EDC exposures (Taylor et al., 2017). OBJECTIVES The purpose of this study is to characterize the role and significance of EDCs found in PCPs by assessing implications of exposure on female reproductive health outcomes. This study also seeks to explore public perceptions of PCP dangers in order to contextualize findings regarding body burden of chemical toxicants from different bioassays. METHODS One component of this project involves a review of publications highlighting the relationship between EDCs and PCPs and how successfully these findings have been communicated to the general public to influence their awareness of the dangers of endocrine disruption (Aims 1A-1C). The second involves the creation of a novel PCP exposure assessment through survey analysis of pre-existing PCP surveys (Aim 2). The last objective centers around an analysis of bioassay-based EDC exposure assessments at the level of the kidney (Aim 3A) and uterus (Aim 3B) from urine and menstrual effluent samples, respectively. RESULTS A scoping review regarding the nature of the relationship between PCPs and EDCs was completed - yielding a total of 255 journal articles included in analysis (Aim 1A). Urinary biomonitoring studies of EDCs populated the majority of this review, and measurable levels of EDCs were highest in this type of bioassay over other types of biological media. Published literature detailing the public’s awareness of EDCs suggests that people are less concerned with the health implications of repeated exposure from PCP usage than they are with environmental health concerns like air and water pollution (Aim 1B). Identification of resources available to consumers for assessment of PCP safety was completed successfully (Aim 1C). Tools at the public’s disposal include webpages, documentaries, and mobile applications. Exploration of 29 PCP questionnaires from outside resources facilitated the expansion of an 18-question cosmetic questionnaire into a 134-question PCP questionnaire to be used in future studies (Aim 2). Analysis of urinary biomonitoring data was unable to be completed because of legal and logistical setbacks in the sharing of the dataset among multiple different institutions (Aim 3A). Analysis of preliminary menstrual effluent biomonitoring data yielded 9,321 metabolites, but results from further confirmatory testing of 68 toxicants are still pending (Aim 3B). CONCLUSION Taken together, the findings suggest that urinary assessments are a preferable method for scientists to use in bioassays to characterize relative amounts of EDCs within PCPs. While biomonitoring studies are valuable in conveying information regarding sociodemographic contributors towards heightened exposure and associated adverse health outcomes, a lack of awareness among the public suggests that additional efforts must be undertaken to stress the potential implications of these toxicants on environmental health – particularly in females. Continued looks at PCP usage patterns and EDC exposure assessments in different biological media like menstrual blood are important next steps for further analysis, and implementation of the expanded PCP Questionnaire and use of the PCP Chemical Library may be of use for this process.

There is limited data regarding human immunodeficiency virus (HIV) prevalence among transgender individuals. Further complicating the absence of knowledge, transgender women are often conflated with men who have sex with men (MSM). Approximately half of transgender men and women who live with HIV are from the Southern region of the United States (US). While transgender women are more likely to contract HIV compared to transgender men, approximately two-thirds of transgender individuals have not tested for HIV, likely leading to underreporting. Among the 14% of transgender women diagnosed with HIV/AIDS in the US, 44% are Black, (despite representing only 25% of the population in the US), and 26% are Latinx, which is four times the prevalence rate of White transgender women (7%). Pre-exposure prophylaxis (PrEP) is an HIV prevention method in which individuals at risk for HIV can take a daily pill to reduce the risk of contracting HIV. Previous PrEP research has been conducted among transgender women and men, Black and Latinx MSM, and cisgender women. However, there is limited research on barriers to PrEP adoption among Black or Latinx transgender women and men. This study aims to evaluate barriers to PrEP interest and adoption to better address issues faced by Black and Latinx transgender men and women. A meta-analysis of HIV prevalence among transgender women identified a need for HIV prevention as transgender women are at high risk for HIV. In a study with a sample of 233 transgender women in the US, only 13.7% were aware of PrEP (Wilson et al., 2016). Among studies including Black and Latinx transgender women, barriers to PrEP adoption included: medical mistrust, lack of knowledge (e.g., side effects), PrEP stigma among community members and doctors, perceived/actual discrimination regarding having sex with men by providers and advertisements, concerns regarding interactions with hormone therapy, and objections by romantic partners. Social support following PrEP use disclosure is associated with greater self-esteem for one’s transgender identity and greater likelihood of PrEP use. Among black and Latinx trans men, barriers to PrEP included lack of support from family and discrimination. Other barriers that Black and Latinx cisgender women face, which may be applicable to Black or Latinx transgender women and men, are lower educational attainment, income, decreased access to healthcare services, medical mistrust, language barriers, racial bias from medical providers, and lack of social support. Awareness of PrEP has been lower among those who are less educated and whose primary care providers are unaware that they have sex with men. One study showed that those with lower income and less than a high school education were associated with poorer medication adherence and greater risk of death even when controlling for HIV treatment. In another study examining potential barriers to PrEP acceptability and adherence, efficacy and side effects were notable barriers to PrEP initiation among 78% of MSM and transgender women participants, which were more commonly reported among Black compared to White participants. Given the dearth of research among Black and Latinx trans men and women regarding barriers to PrEP adoption, it is essential to evaluate systemic and interpersonal barriers to PrEP access that are unique to Black and Latinx transgender communities.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Smoking is the primary known risk factor in the development of COPD. Noxious particle or gas exposure to cells in the lungs leads to a chronic and sometimes irreversible state of airway inflammation, resulting in airflow limitation, hyper production of mucous, and destruction of distal lung tissue including gas exchange surfaces. COPD patients often develop dyspnea (difficult or labored breathing) and can become hospitalized during acute exacerbations. Current treatment options for COPD include exercise therapy, oxygen therapy, and multiple drugs with bronchodilation activity. These therapies aim to reduce dyspnea and exacerbation frequency. Steroid resistance in COPD patients has made treatment of underlying chronic inflammation difficult. Multiple targeted non-steroidal anti-inflammatory drugs (NSAIDs) are under investigation as potential therapeutic options. To this point, there is no approved treatment which adequately combats chronic inflammation in COPD. Mesenchymal stromal/stem cells (MSCs) have become increasingly of interest in recent years as a potential therapeutic option for multiple different diseases in the body due to their demonstrated anti-inflammatory, immunomodulatory, tissue regenerative, and trophic signaling capacities. In the search for better ways to treat COPD, researchers have turned to MSC therapy as a potential solution. Preclinical studies demonstrated an ability of transplanted MSCs to ameliorate alveolar destruction and suppress inflammation in rodent models of COPD. Phase I clinical studies have identified safety, tolerability, and feasibility of MSC therapy in COPD, and preliminary findings suggest potential anti-inflammatory capacities which allow for improved lung function and quality of life. Many questions are still left unanswered in the study of MSC therapy in COPD, including the proper cell source and delivery route, and whether MSC-derived products might deliver equal or better results than transplanted cells. Currently, there is much optimism surrounding MSC therapy in COPD, as it has demonstrated a potential to relieve chronic inflammation through a multitude of signaling pathways as well as aid in regeneration of lung tissue. Further research is needed to uncover the optimal mechanism of MSC therapy in COPD and whether it will become a new standard of care.

Recent epidemiological evidence suggests that up to 15% of worldwide tuberculosis (TB) cases may be attributable to tobacco smoking. The aim of the studies reported here was to gain insights into the effects of exposure to cigarette smoke on human cells that form part of the innate immune system of host defence in the lung. The experiments on the pulmonary effects of cigarette smoke confirm that exposure has a significant effect upon innate host defences. Significant reductions in the production of key cytokines implicated in defences against mycobacteria were observed, not attributable to impairment of mycobacterial uptake by cigarette smoke extract exposure. Furthermore, control of intracellular mycobacterial growth was impaired by cigarette smoke extract exposure.

Includes bibliographical references (leaves 67-81).

Includes abstract. / Includes bibliographical references (leaves 91-122). / This study assessed the ability of 0.8 mM ferulic acid (FA), in combination with vitamins C and E, to reduce the effect of UVA-induced photodamage in human epidermal (HaCaTs) and dermal skin cells (primary human fibroblasts (HFbs) and murine 3T3 cells). Pretreatment with the FA and vitamins C and E (vEC) combination solution reduced UVAinduced ROS in human fibroblasts while pre-treatment with vEC individually led to a reduction in HaCaTs.

Includes abstract. / Includes bibliographical references (leaves 82-96). / Efavirenz (EFV) is used in first-line antiretroviral (ARV) therapy of HIV-infected patients, and is principally metabolised by CYP1A2, CYP2A6, CYP2B6, CYP3A4/5 and the drug transporter ABCB1. Genetic variability in the above genes may contribute to differences in EFV plasma concentrations which affect the levels of viral suppression as well as development of side effects in patients. The aim of this project was to evaluate the effects of the different genetic polymorphisms on EFV plasma concentration levels in HIV/AIDS patients receiving first-line antiretroviral treatment (ART) containing EFV.

Background and Purpose: With the introduction of potent antiretroviral therapy (ART) leading to longevity, cardio-metabolic diseases are emerging health concerns in people living with HIV. This thesis aims to 1) to quantify the burden of metabolic syndrome (MS), which is a constellation of cardio-metabolic risk factors, in people living with HIV infection (PLWHIV) from a global perspective; and in ≥18-year-old PLWHIV receiving HIV-care in the Western Cape, South Africa to 2) determine the MS prevalence and the agreement between the popular MS diagnostic criteria, 3) assess the distribution of cardio-metabolic risk factor clustering by adiposity levels, 4) determine the optimal waist circumference (WC) thresholds, and 5) HbA1c to define abdominal obesity and dysglycaemia, respectively, for the purpose of MS screening in South African PLWHIV. Methods: A systematic review with meta-analysis was conducted to determine the MS prevalence globally. The main study comprised a representative cross-sectional study of PLWHIV receiving HIV-care at 17 public healthcare clinics across the Western Cape, South Africa. Results: The global prevalence of MS was 16.7%-31.3% by different diagnostic criteria with substantial heterogeneity not explained by major study characteristics. The prevalence was higher in women than in men (International Diabetes Federation [IDF]-2005, 23.2% vs. 13.4%, p=0.030), in antiretroviral therapy (ART) versus non-ART users (Adult Treatment Panel III [ATPIII]-2001, 18.4% vs. 11.8%, p=0.001), and varied significantly by participant's age, duration of HIV diagnosis, CD4 count level, ART regimens. In the study conducted in the Western Cape (N=748, median age 38 years), MS prevalence among PLWHIV was 28.2% (JIS-2009), 26.5% (IDF-2005), and 24.1% (ATPIII-2005), which was higher in women, participants with longer duration of diagnosed HIV infection, ART users not receiving 1st line regimen (all p≤0.039). There was a good agreement between sets of the criteria that was not affected by HIV-related factors (all kappa ≥0.81). Cardio-metabolic risk factors clustered across all categories of adiposity levels: 11.7% of normal-weight, and 15.1% of obese PLWHIV had two or more factors, and this distribution was not affected by HIV-specific features. The optimal WC thresholds for abdominal obesity were 92 cm (sensitivity 64%, specificity 64%) in women and 87 cm (sensitivity 48%, specificity 85%) in men, which differed from the internationally recommended 80 cm (women) and 94 cm (men). The optimal HbA1c thresholds to define oral glucose tolerance test diagnosed dysglycaemia was 5.75% (39.3 mmol/mol) (sensitivity 52%, specificity 85%), similar to the threshold of 5.7% (39 mmol/mol) recommended by the American Diabetes Association. The MS prevalence by the JIS was 28.2% and 29.7% using glucose-defined and HbA1c-defined dysglycaemia, with a good agreement between the original and modified criteria (kappa=0.81). Conclusions: The high prevalence of cardio-metabolic risk factor clustering in PLWHIV highlights the need for effective management strategies. Optimal performance of MS criteria in South African PLWHIV requires the use of the African-population-specific WC thresholds, while using HbA1c to diagnose dysglycaemia could be both effective and more practical than blood glucose defined dysglycaemia. However, these findings need to be confirmed and the effects of their introduction in routine care on healthcare behaviour and patient outcomes assessed through impact and implementation studies.