School of Public Health (ETDs)
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Item Salient beliefs, preferences and intention to use HIV pre- exposure prophylaxis among pregnant and breastfeeding women in Zambia(University of the Witwatersrand, Johannesburg, 2024) Hamoonga, Twaambo EuphemiaPregnant and breastfeeding women living in sub-Saharan Africa are at substantial risk for HIV infection, and maternal seroconversion may affect the quality of life for the mother, and is a risk for vertical transmission of HIV. Despite the adoption of PrEP into national guidelines for HIV prevention, its uptake in antenatal and postnatal settings in Zambia remains low. We used an exploratory sequential mixed methods design to explore facilitators and barriers to uptake of PrEP among pregnant and breastfeeding women (18 years or older) not living with HIV in Zambia. We purposively recruited 24 women for the qualitative component and conveniently selected 389 women for the quantitative component of the study at Chipata Level 1 Hospital in Lusaka. For qualitative data, Nvivo was used for data management and data was analysed using thematic analysis. Quantitative data was analysed using chi-square test, pearson correlation coefficient (r) and logistic regression analysis using Stata v.16. Findings from our qualitative study showed that women had positive attitudes and favourable intentions to use PrEP. Most women felt that people who are important to them, especially their male partners, would not support PrEP use during pregnancy and breastfeeding. The anticipated disapproval from partners made women believe that PrEP use would not entirely be under their control, with some reporting that they would not use PrEP if their partners disapproved. Women also cited rude health care provider attitude as a potential barrier to uptake. Some women preferred receiving PrEP from a health facility for fear of stigma in the community while others preferred community-based delivery as an avenue for creating PrEP awareness. This paper was published in Frontiers in Reproductive Health In our second paper, we determined intention to use PrEP during pregnancy and breastfeeding and also identified salient beliefs associated with it. Participants had positive attitude and favourable intention to use PrEP during pregnancy and breastfeeding (mean = 6.65, SD = 0.71 and mean = 6.01, SD = 1.36), respectively. They felt that people who are important to them would approve of their use of PrEP (mean = 6.09, SD = 1.51) and also believed that they would be able to use PrEP if they desired (mean = 6.52, SD = 1.09). All salient beliefs positively and significantly predicted intention to use PrEP during pregnancy and breastfeeding: attitude (β = 0.24, p<0.01); subjective norms (β = 0.55, p<0.01); and perceived behavioural control (β = 0.22, p < 0.01). This paper was published in Global Public Health. The third paper discusses findings from a discrete choice experiment (DCE) on preferences for PrEP service delivery among pregnant and breastfeeding women. In this study, waiting time, travel time, health care provider attitude and amount of PrEP supply at each refill were important considerations likely to influence PrEP use during pregnancy and breastfeeding (all p<0.01). Women expressed strong preference for 3-month’s supply of PrEP compared to other attribute levels (β= 1.69, p<0.01). They were willing to wait for 5 hours at the facility, walk for more than an hour to a facility dispensing PrEP, encounter a health care provider with a negative attitude as long as they received PrEP enough for 3 months. This paper is under review in Frontiers in Reproductive Health. The overall contribution of this PhD research to the body of knowledge on HIV prevention strategies is the ability to identify beliefs about PrEP and how each salient belief influences intention to use PrEP during pregnancy and breastfeeding. It is also one of the first to estimate the benefit (value or satisfaction) that women derive from different attributes of PrEP service delivery for pregnant and breastfeeding populations interested in using PrEP. This information could provide guidance on specific beliefs and service delivery attributes of PrEP that women prefer the most and therefore need to be prioritized if PrEP uptake is to improve in antenatal and postnatal settingsItem Adolescent health in rural South Africa: building an evidence-base to inform a health promotion intervention supporting healthier lifestyles(University of the Witwatersrand, Johannesburg, 2024) Seabi, Tshegofatso Martha; Kahn, Kathleen; Wagner, Ryan GBackground Low- and middle-income countries (LMICs), including South Africa, face the persisting double burden of malnutrition, with undernutrition and overnutrition coexisting within the population. This issue is particularly pronounced among rural adolescents, who experience limited access to healthcare services, inadequate infrastructure, poverty, and a scarcity of nutritious foods. Addressing this double burden of malnutrition is essential for improving the health outcomes of rural adolescents and breaking the intergenerational cycle of malnutrition. Community health worker-led interventions have shown promise in promoting healthier lifestyles in this population, making it crucial to understand the feasibility and acceptability of such interventions. Aim This thesis aims to provide context-specific information on the changing distribution of Body Mass Index (BMI) and views on obesity among rural South African adolescents to inform the development of a targeted behaviour change intervention. Furthermore, it seeks to determine the feasibility, acceptability, and overall experience of implementing a complex intervention aimed at promoting healthier lifestyles in this population. Methods Using a mixed methods approach focusing on adolescents 12-20 years of age living in rural South Africa. This work is nested within the MRC/Wits rural public health and health transitions research unit (Agincourt) Health and Demographic Surveillance System, which is where the sample was drawn and provided explanatory variables such as SES. This work includes data from two studies with comparable measures, conducted in 2007 (n= 1309) and in 2018 (n=518), this study analysed comprehensive data on the prevalence and trends of BMI, including both undernutrition and overweight/obesity, among rural adolescents in 2007 and 2018. This was done through weight and height measures. Growth z-scores were used to determine stunting, underweight and overweight and overweight/obesity was generated using the 2007 WHO growth standards for adolescents aged up to 17 years and adult cut-offs of BMI of <=18.5 for underweight and =>30 kg/m2 for overweight and obese respectively for adolescents 18 to 20 years. Qualitative data was collected in the form of focus group discussions and in-depth interviews. Pre-intervention, three focus group discussions were held with male (n = 16) and female adolescents (n = 15) focusing on obesity to capture views, attitudes and perceptions surrounding obesity. Post-interventions, six focus group discussions were held with male and female adolescents. In-depth interviews were conducted with adolescents (n=20), parents (n=5) and CHWs (n=3), focusing on the feasibility and acceptability of the health promotion intervention. All qualitative data were analysed using inductive thematic analysis. Results This study found that there is a persistent double burden of malnutrition amongst rural adolescents. The pattern of underweight and overweight/obesity remains similar between 2007 and 2018, with an increase in overweight and obesity, and a decrease in underweight observed across different age and gender groups throughout this period. The prevalence of stunting and underweight, particularly in males in both 2007 and 2018 was substantial although lower in the later year. Adolescents expressed conflicting views of obesity, highlighting their knowledge of the cause and long-term consequences of obesity. In regard to the intervention, participants expressed support for the CHWs and the community-based intervention guided by them. The findings demonstrated the feasibility of providing the intervention to adolescents in a rural context, with modifications needed to ensure participant uptake, such as changes to the time and location. Responses from participants show how the intervention, which included dietary and quantity modifications, was acceptable to adolescents. The gathered information in this study serves as a foundation for developing a health promotion intervention tailored to the specific needs and circumstances of rural adolescents, considering both undernutrition and overweight and obesity. Conclusion This research provides valuable context-specific insights into the burden of malnutrition and perceptions of obesity among rural South African adolescents, considering the complexities of the double burden of malnutrition. The findings contribute to the development of tailored health promotion interventions that address both undernutrition and overweight/obesity in this population. Understanding the feasibility and acceptability of such interventions is vital for successful implementation and sustainability in rural communities.Item Attrition in the dental therapy profession: an exploration of the contributing factors(University of the Witwatersrand, Johannesburg, 2024) Sodo, Pumla Pamella; Jewett, SaraBackground: A new type of oral health profession called dental therapy was introduced to address the growing need for affordable and accessible oral healthcare services, especially among marginalised communities. Extensive global research has demonstrated that dental therapists provide cost-effective and high-quality services, effectively addressing the issue of limited access to basic oral health services. The introduction of dental therapy into the South African healthcare system took place in 1977, however, disparities in accessing basic oral healthcare persist, particularly among some population groups where the highest prevalence of oral diseases has been reported. Despite being established over four decades ago, the number of registered dental therapists remains low, and there have been reports of attrition within this professional group. This PhD aimed to explore the factors contributing to attrition in the dental therapy profession. The first objective was to determine South African dental therapists' attrition rate and demographic profile over 42 years (1977-2019). The second objective explored factors contributing to attrition, while the third objective explored the applicability of the Hertzberg Two-Factor Theory in the context of dental therapy attrition in South Africa. Methods: This was a concurrent mixed methods study, involving registered graduate dental therapists, former dental therapists, and key stakeholders. The conceptual framework that guided the study was derived from Hertzberg's Two-Factor Theory. Data sources included the HPCSA registry and primary data collected using a quantitative survey investigating job satisfaction and intention to leave among registered graduate dental therapists and qualitative in-depth interviews with former dental therapists and key stakeholders to gain insights into their perspectives on attrition in the dental therapy profession. The attrition rate was determined by using the formula (Attrition Rate = Number of dental therapists who left the profession divided by the total number of dental therapists registered during the period of interest, multiplied by 100). Quantitative data was analysed in STATA version 15 using descriptive and inferential statistics, and qualitative data was analysed using thematic analysis. Findings: A total of 1232 dental therapists were registered with HPCSA over 42 years, with only 714 registered in 2019, two-thirds of whom were Africans. The attrition rate over the 42 years was 40%, while it reduced to 9% during the 10 years from 2010 to 2019. Of the 200 registered dental therapists who took part in the survey, 74.5% being Africans, approximately 51.5% expressed their intention to leave the profession and a notable 69.5% reported job dissatisfaction. In logistic regression analysis, job satisfaction correlated positively with several factors, including qualification from UKZN (AOR= 2.28, CI: 1.06-4.91), post-graduation job availability (AOR=3.87, CI: 1.73-8.69), awareness of postgraduate opportunities (AOR=2.28, CI: 1.05-4.96), and feeling valued (AOR= 6.91, CI: 1.45-26.36). Conversely, job satisfaction was negatively associated with becoming aware of the scope of work only after enrolment (AOR= 0.31, CI: 0.21-0.81). Job satisfaction was inversely correlated with the intention to leave; satisfied individuals had significantly lower odds of intending to leave (AOR= 0.25, CI: 0.11-0.57). In-depth interviews with 14 former dental therapists identified diverse reasons for enrolling in dental therapy and a shared enthusiasm for the dental therapy profession. Most reasons they cited for attrition, such as inadequate remuneration, job scarcity, poor working conditions, lack of career advancement opportunities, and policy implementation gaps aligned with Herzberg's Two-Factor Theory. One novel factor contributing to attrition not covered by the theory was a lack of professional identity. The 12 key stakeholders who were interviewed echoed similar factors contributing to the attrition of dental therapists. To address limitations in moving from a description of factors to recommendations on how to address system-level challenges, I adapted a framework that is a combination of Herzberg's Two-Factor Theory and the Human Resources for Health System Development framework. This new framework addresses multifaceted issues affecting dental therapists, covering production, deployment, and retention. Conclusion: This study sheds light on challenges within South Africa's dental therapy profession, highlighting their profound implications for both the profession and the broader healthcare system. Despite comparable attrition rates to other mid-level health professionals, there were alarmingly high job dissatisfaction levels and intentions to leave the profession, demanding immediate attention and intervention. Identifying key factors contributing to attrition and the novel insight into the lack of professional identity collectively highlight the multifaceted nature of the issue. To address these challenges, embracing a comprehensive human resource retention framework is imperative. This study emphasizes the urgent need for proactive measures to ensure the sustainability and contentment of dental therapists, ultimately benefiting the healthcare system and the communities it serves. Addressing these factors will lead to increased retention rates and improved access to basic oral health services nationwideItem Exploring the relationship between orphanhood status, living arrangements and sexual and reproductive health outcomes among female adolescents in Southern Africa(University of the Witwatersrand, Johannesburg, 2024) Shoko, Mercy; Kahn, Kathleen; Ginsburg, CarrenAdolescent Sexual and Reproductive Health (ASRH) is high on the global development agenda. Among the respective research conducted is the various social contexts that may contribute to adverse SRH outcomes, including the overlapping issues of orphanhood and living arrangements. These are crucial given that the presence or absence of parents emerges as critical for the sexual and reproductive well-being of adolescents. While orphanhood, particularly in the context of the HIV epidemic in Southern Africa, receives considerable attention, this study highlights a noteworthy gap in the literature – the limited focus on living arrangements and its influence on ASRH, often overshadowed by orphanhood. This research is important given the evidence suggesting that the African traditional kinship care systems offer support for orphans. However, recent research also highlights the crucial role of biological parents in providing effective care and support for adolescents. The study aims to contribute by exploring the relationship between orphanhood status, living arrangements, and ASRH in Southern Africa. Utilising cross-sectional Demographic and Health Survey (DHS) data, the analysis delves into key dimensions of SRH, including sexual debut, HIV knowledge, and adolescent fertility, which are all critical links to HIV risk. The findings underscore a significant association between non-coresidency with parents, whether due to orphanhood or separate living arrangements, and a heightened risk of adverse SRH outcomes. This suggests that interventions aimed at addressing adolescent SRH in Southern Africa should encompass a holistic understanding of parental presence or absence. The study emphasises the complex interplay between orphanhood, parental absence, and various individual, household, and geographic factors that collectively contribute to the vulnerability of female adolescents in the context of ASRH. Despite that the results suggest that the data on orphanhood and living arrangements may be of acceptable quality, the study recognises the potential for detailed insights through future research employing longitudinal data. Such an approach could offer a more nuanced and comprehensive understanding of ASRH over time, subsequently informing targeted policies and interventions in the unique socio-cultural context of Southern AfricaItem The development of a competency-based programme for management of disease outbreaks(University of the Witwatersrand, Johannesburg, 2024) Engelbrecht, LinettePurpose: The purpose of this study was to develop, a competency-based programme for the management of disease outbreaks. Method: The study utilized an exploratory sequential mixed method approach, using both qualitative and quantitative methods to develop a competency-based program. This study was conducted in South Africa, Gauteng, whilst the country was experiencing the third COVID-19 wave (May 2021 – October 2021), the fourth COVID-19 wave (December 2021– April 2022), and the fifth (May 2022 – July 2022), as well as the post-pandemic phase. The study was conducted in three phases namely: Phase One: Exploratory phase, Phase Two- Development of the programme Phase Three- Validation of the programme. In phase one, a scoping review on the existing literature was conducted using the Joanna Briggs Institute methodological approach. Following this were individual in-depth interviews with purposively sampled healthcare professionals as well as professional nurses. Through reflexive thematic analysis themes were identified for inclusion in the Delphi-survey in the next phase. For the second phase, a Delphi-survey was developed based on the data from phase one. The Delphi-survey consisted of two rounds whereby categories were identified to be included in the competency-based curriculum. A curriculum, consisting of ten modules was developed using the Backward design. In phase three the curriculum matrix was validated by experts. Results: A total of 62 publications were included in this study. Three categories and eight sub-categories were identified as needs of nurses during disease outbreaks. In-depth interviews with healthcare professionals resulted in the development of eight themes and 21 sub themes (challenges) of nurses. The in-depth interviews with nurses resulted in the development of 11 themes (challenges) of nurses. The results of the scoping review and in- depth interviews were used to develop a Delphi-survey. Experts in this two-round Delphi survey validated the domains and statements. The results of the Delphi-survey was used to develop a curriculum matrix consisting of ten modules, which was validated by three experts. Conclusion: A competency- based curriculum was developed based on the challenges nurses experienced working through the COVID-19 pandemic. This program could contribute to the development of disease outbreak competent nursesItem Community-orientated primary health care: Exploring the interface between community health workers, the healthcare system and communities in South Africa(University of the Witwatersrand, Johannesburg, 2024) Malatji, Hlologelo; Goudge, Jane; Griffiths, FrancesBackground: To achieve universal health coverage, low and middle income countries (LMICs) are extending primary health care (PHC) services using community health worker (CHW) programmes. However, CHWs are marginalized within the healthcare system. Community-orientated primary health care (COPC) and supportive supervision are two interventions being used to strengthen CHW programmes. Primary aim: To understand whether and how the COPC and supportive supervision approaches strengthen CHW programmes in South Africa. Methods: Data was collected between 2016 and 2019 using qualitative methods in nine PHC facilities in rural and semi-urban areas of Mpumalanga and Gauteng provinces, South Africa. Purposive and snowball sampling techniques were used to recruit participants. The participants included: CHWs, supervisors, facility staff members and community members. Data was collected using focus group discussions, individual interviews and observations, and was analysed thematically. Findings: In line with the COPC approach, there were efforts to engage communities in the implementation of the CHW programmes but community members prioritised other challenges such as lack of housing and running water. In some facilities, in-service training increased CHWs knowledge and skills but challenges such as lack of supervision, lack of resources and outsourced employment without benefits demotivated the CHWs (Paper 1 / Objective 1, Published). In response to challenges, in the semi-urban sites, CHWs unionised to present their grievances to government. This resulted in an increase in stipend but not permanent government employment. During the height of the COVID-19 pandemic, when decision- makers recognised the essential role of CHWs higher remuneration was secured. CHWs in rural areas were not active in demanding permanent employment (Paper 2 / Objective 2, Published). Supportive supervision provided by a nurse mentor over 14 months, (1) trained CHWs and their supervisors resulting in increased knowledge and new skills, (2) addressed their fears of learning and failing and (3) established operational systems to address inefficiencies in CHW core activities (household registration and medication delivery). The intervention was disrupted by union activities. The communities’ demonstrated little interest in the functioning of CHW programmes (Paper/ Objective 3, Published). Conclusion: Both the COPC approach and supportive supervision can reduce marginalisation of CHW within the health systemItem Characterisation of emission and exposure to diesel engine exhaust from trackless mobile machinery in underground South African Platinum Mines: Evaluating strategies to prevent and control exposure(University of the Witwatersrand, Johannesburg, 2024) Manyike-Modau, Amukelani Portia; Brouwer, DerkBackground: Mining remains one of the major economic drivers in South Africa, as is evident through continued focus on long-term investments in mining and the mechanisation of mining operations. Mechanisation uses diesel-powered machinery; such machinery offers greater versatility than electric and battery-operated vehicles due to their ability to cover greater distances and move between different working sections (1). Diesel powered machines are most preferred because of their high energy efficiency and low carbon monoxide and carbon dioxide emissions compared to gasoline equipment (2). Using diesel-powered machines in mechanised mining has introduced a new risk to mine workers working in confined spaces underground. Diesel engine exhaust (DEE) can increase significantly due to wear or breakdown of the engine components and after-treatment systems. The impact on emissions varies depending on the engine type, age, and state of wear and tear (3). Significant evidence demonstrates a correlation between DEE exposure and respiratory outcomes in mine workers. DEE is a known carcinogen. In 2012, the International Agency for Research on Cancer (IARC) classified DEE as being carcinogenic to humans (class I) when inhaled, based on sufficient evidence that exposure is associated with an increased risk for lung cancer (4). There has been an incredible drive to manage diesel Particulate matter (DPM) in the South African mining industry (SAMI). The approach, however, has been focused on monitoring personal exposure to DPM rather than a multifaceted approach that includes eliminating or reducing the pollutant at the source. Efforts should be made to ensure that management plans for engineered solutions and risk-based approaches are in place when monitoring DPM (5). As a result, research in the mining domain has focused on developing integrated control strategies/solutions to prevent exposure to diesel engine exhaust. South Africa shares the same concern with other countries regarding the DPM challenges in mining operations. The South African legal framework requires the employer to conduct a risk assessment and implement measures to prevent employees from overexposure to harmful airborne pollutants (MHSA 1996). Therefore, without local guidelines and regulations, SAMI can use the available scientific knowledge to control the exposure of DPM to employees and to ensure continuous monitoring of employees while working at the mines. Currently, no specific systems guide sets standards or limits for personal or occupational exposure or tailpipe emissions of DPM (6,7). Further, even though enough knowledge is The Occupational Cancer Research Centre Report published in 2017 presented different control strategies for DPM following the hierarchy of control principles (8). These ranged from the proactive (most effective) to reactive (less effective) controls and included the following controls: elimination using alternative energy such as electric or battery-powered machines, substitution such as replacing, repowering, or engine rebuilds, and this would typically include retrofitting the engines with engine after-treatment systems; Engineering controls which may include retrofitting the engines with after-treatment technologies, improving general ventilation systems, idling technologies, installation of protective cabs; Administrative controls which may include preventative maintenance, idling policies, operator training and planned schedule for the site such as planning the number of machines required to operate in a working place; and lastly the use of personal protective equipment such as respirators. These controlscan be implemented in a multifaceted approach to reduce or prevent employees from being overly exposed (3,8,9). Diesel emission is a complex mixture and may require multiple control strategies to minimise employee exposure. In the study conducted by Bugarski et al, 2009, they highlighted different monitoring and control strategies ranging from emissions monitoring, including undiluted emissions measurements, i.e., Both ‘tailpipe output’ and ‘engine out’ (upstream of after- treatment systems), and the installation of after-treatment strategies and higher tier standard engine emissions. The control strategies can help identify and distinguish between engine maintenance issues and emission control device failures and assist in estimating ventilation requirements (10). In addition, in a study by Hines in 2019, significant improvements were achieved in reducing tailpipe emissions (reduction at source) by implementing an emission- based maintenance (EBM) program. This has resulted in a reduction of Carbon Monoxide (CO) by more than 80% and DPM by more than 47% on personal exposure, showing the direct impact the EBM has on reducing exposure of DPM to employees working underground. The study successfully reduced tailpipe emissions by introducing the EBM program at the mines. Further, fuel usage was also reduced by 7-20%, showing that when machines are well maintained, there are improvements in efficiencies and even utilisation and availability of machines for production (11). Objective: The overarching aim of the research project was to determine the characteristics of diesel engine exhaust emissions at the source (aerodynamic size fractions) and evaluate how maintenance, maintenance plus installation of diesel particulate filters (DPF), and ventilation will impact the levels of DEE at the source and in the workplace. Methods: A quantitative, quasi-experimental study, designed with an intervention component, was conducted in two Platinum underground mines in South Africa. DEE was measured at the source, and DPM was personally exposed to employees. DPM dispersion modelling was conducted underground, and different control strategies were evaluated to determine their role in reducing the pollutant underground. Results: The concentration of median particles significantly decreased post the interventions, achieving an efficacy of 90-96% and 20-40% (p-value=0.001) for the machines that underwent maintenance plus installation of the DPF and machines that underwent maintenance only, respectively. Most particles emitted were in the ultrafine aerodynamic range, with a diameter between ≥0.01<0.1μm and an aerodynamic fine size of ≥0.1<1μm. Conclusion: A combination of control strategies (maintenance, retrofitting of machines with DPF, and ventilation) has shown great potential to reduce DEE in underground mines. Therefore, focused effort is required to implement integrated strategies to prevent or minimise exposure to DEE. Future studies to link dispersion models with real-time monitors are recommended to improve DEE's risk-based managementItem Trend of Pre-antiretroviral Therapy HIV-1 Drug Resistance in Kilombero and Ulanga Antiretroviral Cohort, South-Western Tanzania, for over 15 years (2005-2020)(University of the Witwatersrand, Johannesburg, 2024) Ntamatungiro, Alex; Kagura, JulianaIntroduction Pre-treatment HIV drug-resistance (PDR) may result in increased risk of virological failure and subsequently acquisition of new HIV drug resistant mutations. With recent increase in antiretroviral therapy (ART) coverage and periodic modifications of the guidelines for HIV treatment, monitoring changes in levels of PDR is critical, particularly in under-sampled areas, such as rural Tanzania. This PhD project aimed to determine the trend and patterns of PDR in the Kilombero and Ulanga antiretroviral cohort (KIULARCO), analyse the impact of recent HIV-1 infection, and dolutegravir rollout in rural Tanzania. Methods The study comprised a systematic review and meta-analysis of primary studies about prevalence of PDR among ART-naive people living with HIV (PLHIV) (³15 years old), published between 2017 and 2022. The data had to be in one or several of the countries of Eastern Africa, namely, Ethiopia, Kenya, Malawi, Rwanda, Mozambique, Tanzania, and Uganda. Thereafter, cross- sectional analyses of data on newly HIV-1-diagnosed ART-naïve adults (aged ≥ 15 years), enrolled in the on-going prospective clinic-based observational rural antiretroviral cohort- KIULARCO focusing on various aspects of PDR. Multivariate logistic regressions were used to determine the factors associated with recent HIV-1 infection, and viral suppression at 12-months in patients initiating dolutegravir-based ART in the KIULARCO. Results Overall, the pooled prevalence estimate of any PDR was 10.0% (95% CI: 7.9%–12.0%, I2 =88.9%) among 22 studies in the general adults’ population, which was higher than the previously reported prevalence of 8.7% using data available until 2016 in the Eastern Africa region. PDR was mainly driven by non-nucleoside reverse transcriptase inhibitors (NNRTI); whereas the pooled prevalence of PDR to nucleoside reverse transcriptase inhibitors (NRTI) was 2.6% (95% CI: 1.8%–3.4%, I2=69.2%). Remarkably, PDR to NRTIs in a sub-population of recently HIV-1 infected PLHIV in the KIULARCO was high at 12.5%. Also, there was a notable tendency to an increasing prevalence of PDR to NRTI, with the overall prevalence of 2.1% in the first five-year period (2005-2009) of the ART program in Tanzania, and 3.4 % in the most recent period (2019-2022). Moreover, there was no PDR to the dolutegravir co-administered NRTI in those with viremia ≥50 copies/mL, at one year, in patients initiating dolutegravir-based ART in the KIULARCO 2 years after dolutegravir roll. Notably, dolutegravir-based ART was associated with >2 times the odds of viral suppression compared to NNRTI-based ART with an adjusted odds ratio (aOR) of 2.10 (95% CI 1.12-3.94). Conclusions There is notable level of PDR to NRTI among general adults’ population in Eastern Africa region, that was high among recently HIV-1 infected PLHIV in a representative rural Sub-Saharan Africa setting. Hence, routine surveillance of pre-existing resistance to the DTG co-administered NRTI remains particularly important, in resource-limited settings, to prevent risk of failure of newer antiretroviral agents such as dolutegravir, which would be detrimental to Tanzania and other low- and middle-income countries for the aim to “end AIDS by 2030”. Our results underline the benefit of programmatic uptake of dolutegravir -based ART in low- and middle-income countries.Item The in vitro diffusion across exercised porcine skin of various formulations of compounds used topically in the treatment of skin afflictions(University of the Witwatersrand, Johannesburg, 2023) Elonga, Jessica; Eyk, VanIntroduction and Aim: Skin afflictions have been treated with topically applied active compounds since the ancient Greek era. Topical compounds mostly avoid first-pass metabolism and move directly into the local region of the skin or mucous membranes to exert their therapeutic effects. In this study, the aim was to investigate the in vitro diffusion characteristics of active compounds commonly used in topical formulations, such as caffeine, theophylline, retinol, L-carnitine, and Co-enzyme Q10 across porcine skin, used as a model for human skin. These compounds were tested alone and in combination within different topical formulations (liquid, gel, and cream) to investigate skin permeation, skin accumulation and effect on skin integrity. Methods: Method development and validation were performed to detect and quantitate all compounds tested by using a RP C18 HPLC system. Mobile phases included the following: caffeine and theophylline (Methanol:water [40:60], 20oC), retinol (Methanol:water [95:5], 20oC), L-carnitine (Sodium Phosphate buffer (pH 3.0):Methanol [99:1], 40oC) and Co-enzyme Q10 (Methanol:2-propanol [40:60], 25oC). All analyses were performed at 1 ml/min and injection volume of 20 μl. In vitro diffusion studies were performed using a PermeGear 7-in- line flow-through system. Either caffeine (2.5%), theophylline (2%), retinol (0.3%), L-carnitine (2%) or Coenzyme Q10 (0.5%) in various formulations alone, and in combinations were loaded into the donor compartments and PBS (pH 7.4) was pumped through the acceptor chambers at 1.5 ml/h (32°C, over 4 hours and 24 hours). The fluid collected (every 30 min or 2 hours) was analysed by RP HPLC. Skin accumulation for each compound was performed after completion of each experiment and skin integrity was established by measuring tissue resistance. Results: HPLC methods were found to be sensitive and valid for linearity, precision, accuracy and robustness. Retention times were as follows: caffeine 2.57±0.02 min, theophylline 2.18±0.03 min, retinol 2.91±0.02 min, L-carnitine 3.0±0.009 min and Co-enzyme Q10 3.15 ±0.003 min. From the in vitro diffusion studies of active compounds alone, caffeine within all formulations had the highest diffusion rate compared to theophylline and L-carnitine (caffeine>theophylline>L-carnitine). Retinol and Co-enzyme Q10 did not diffuse across the skin within a 24-hour time-period. In combination with Co-enzyme Q10, the diffusion of caffeine increased from both gel and cream formulations (p<0.05), while retinol increased the diffusion of theophylline from a liquid formulation (p<0.05). Theophylline increased the diffusion of L-carnitine from both liquid and gel formulations (p<0.05). Liquid and gel formulations without compounds, decreased the skin’s integrity after 24 hours and 2 hours, respectively. After 24 hours, the skin’s integrity decreased after exposure to all compounds tested (liquid and gel formulations), while the cream formulation mostly kept the integrity of the skin intact. Caffeine accumulated much more in the skin (>13%) compared to all the other compounds (<2.5%) for all three different formulations tested (caffeine>>L- carnitine>theophylline>retinol>Co-enzyme Q10). Combination studies mostly caused a decrease in accumulation of all compounds within the skin, except the following: retinol increased theophylline accumulation from a gel formulation and vice versa, Co-enzyme Q10 increased caffeine accumulation from all formulations and L-carnitine’s accumulation mostly increased when combined with other compounds. Conclusion: Caffeine was found to diffuse across and accumulate within the skin to a higher extent as compared to all the other compounds due to its ideal physicochemical characteristics. Very lipophilic compounds like retinol and Co-enzyme Q10 only accumulated to some degree in the skin. The findings indicated that the preferable combinations to increase efficacy, would be Co-enzyme Q10 in combination with caffeine, especially from a cream formulation, retinol in combination with theophylline (gel) and any of the compounds combined with L-carnitine (gel and cream). Cognisance must however be taken about possible systemic side effectsItem Assessing the potential interaction between CBD and TBR1 CBD and T-box domain(University of the Witwatersrand, Johannesburg, 2024) Blignaut, Chanel; Sylvia, Fanucchi; Adeyemi, SamsonIn 2020, Cannabidiol (CBD) emerged as the most commonly used recreational substance among pregnant women and was perceived as a natural and safer option for alleviating pregnancy- related symptoms, yet its potential effects on foetal neurodevelopment remain uncertain. With varied results from existing literature on the association between prenatal cannabis use and Autism Spectrum Disorder (ASD) development, this study focuses on filling these knowledge gaps. It investigates the potential interaction of CBD with the T-box domain of TBR1, a transcription factor implicated in ASD. CBD may cross the placenta and distribute throughout the developing foetal organs, including the brain, where it may interact with TBR1. This study's objective is to lay the groundwork for future research into the impact of CBD binding on TBR1 functionality, whose dysregulation is implicated in ASD. The study aims to use in vitro and in silico methods to identify and characterise the interaction between CBD and TBR1 T-box Domain. Initially, predictive models were utilised to determine the structure of the TBR1 T-box domain and its binding domains. Subsequently, the ADMET properties of CBD are assessed to determine its potential interaction with TBR1 T-box domain within the body. Through the optimisation of the TBR1 T-box domain and CBD structures, induced fit docking and molecular dynamics simulations, the study aims to predict the potential interaction sites, dynamics and stability of this interaction. The study confirms the computational results using in vitro methodologies. After expressing and purifying the TBR1 T-box domain, a pull-down assay (PDA), thermal shift assay (TSA) and Time-resolved Fourier-transformed infrared spectroscopy (TR-FTIR) are used to evaluate the potential binding, stability and physiochemical properties of the interaction. Computational analysis, using Maestro Schrödinger Induced Fit Protocol, predicts that CBD binds stably within a hydrophobic pocket of TBR1 T-box domain, away from its DNA-interacting residues. Pose 2 and 3 from molecular docking shows the highest binding affinity and molecular dynamics simulations, using Maestro Schrödinger Desmond Molecular Dynamics System, reveal that the TBR1 T-box domain stabilises upon interaction with CBD. Specifically, the interaction is facilitated by hydrophobic interactions and hydrogen bond formation with residues Ser238, Pro335, Thr360, Glu363 and Asn240. Experimental validation through PDA and TSA provided inconclusive results, but TR-FTIR confirmed the dynamic nature of the CBD-TBR1 interaction, characterised by time-dependent spectral changes. While the results do not directly indicate an impact of CBD on TBR1 functionality, further DNA binding studies are necessary for confirmation. This study suggests caution in using CBD during pregnancy due to its complex and largely unexplored interaction with TBR1, underscoring the need for more comprehensive research to conclusively understand its influence on neurodevelopmental disorders and its therapeutic potential