4. Electronic Theses and Dissertations (ETDs) - Faculties submissions

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The constitutionality of COVID 19 Vaccination Policies and its implications on the right to freedom of religion in South Africa
(University of the Witwatersrand, Johannesburg, 2024) Karuaihe, Janee Raahua Siegfried
Covid-19 was declared by the World Health Organisation (WHO) as a disease affecting people over a large geographical area. It caused severe illness to millions of people around the world and the death of over four million people. This impact on people had a direct effect on employers, employees and the workplace. Religions and those practicing their religion weren’t spared from the impact of Covid-19. To control the impact of Covid-19 on the workplace, employers were obligated to take steps to keep the workplace safe and to ensure that businesses can reopen in a manner that would ensure the safety of employees and the public. One of the measures taken by employers to ensure the safety of the workplace was the introduction of vaccination policies. These policies varied from workplace to workplace, but a consistent feature was that employees were required to be vaccinated to return to the workplace. If such workplace were to be implemented without exception, it would fail to recognise the fact that certain religious practices and certain people who practice various religions do not permit vaccines, and where they do, only certain vaccines are allowed. As there is no specific legislation governing the implementation of vaccination policies in the workplace, many employees across South Africa believed these policies unjustifiably limited rights protected by the Constitution, including the right to religion. The courts have accepted that vaccination policies may have the effect of limiting rights that are protected in terms of the Bill of Rights. Still, such limitations may be justified where the employer takes steps and introduces such a policy where necessary to ensure the safety of the workplace.
In Silico Exploration of Endocannabinoid Receptor–CB1 and CB2–Interactions Comparing Cannabidiol and Cannabidiol Diacetate: A Comprehensive Computational Study
(University of the Witwatersrand, Johannesburg, 2024-09) Soobben, Marushka; Achilonu, Ikechukwu Anthony; Sayed, Yasien
In the rapidly evolving field of cannabinoid research, acetylated phytocannabinoids such as cannabidiol diacetate (CBDDA) have shown prominence due to its enhanced effects compared to its natural counterpart, cannabidiol (CBD). Despite the growing popularity in the consumption of acetylated phytocannabinoids, in-depth research on its pharmacological impact, especially on CB1 and CB2 receptors, remains scarce. With rising reports of adverse reactions to acetylated phytocannabinoids, a molecular understanding of their interaction with endocannabinoid receptors (CBRs) is imperative. This study aimed to fill this knowledge gap by analysing receptor interactions of CBDDA in comparison with receptor interactions of CBD. The study showed that CBDDA forms stronger interactions with CBRs than CBD. Recognised for its heightened potency, the potential of CBDDA as a biopharmaceutical product was examined. CBR interactions with known endocannabinoids, agonists and inverse agonists validated the computational models used to determine the difference in conformational dynamics upon ligand binding. In this work, bioinformatics, molecular docking, and molecular dynamics (MD) simulations were used to determine the structural differences of CBRs when bound to CBD/CBDDA. Simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and water environment successfully mimicked physiological conditions. Subsequent high-throughput virtual screening (HTVS) was conducted using CBDDA as a reference where ligands 142730975 and 21568811 were identified as the top scoring hits for CB1 and CB2 receptors, respectively. The identification of these ligands via HTVS highlights the therapeutic potential of targeting CBRs and the biopharmaceutical potential of CBDDA. This study elucidates the specific interactions of CBD and CBDDA with CB1 and CB2 receptors, laying a foundation for assessing the safety and efficacy of acetylated phytocannabinoids. Overall, the differential interaction of CBDDA compared to CBD with CBRs suggests that acetylation changes the conformational dynamics of CBRs thereby potentially affecting signalling. The identification of ligands 142730975 and 21568811 as strong interactors with the receptors may provide valuable leads for the development of new cannabinoid-based therapies.
Realising the right to healthcare: the legislative frameworks pertaining to private health establishments and private healthcare funding models in South Africa
(University of the Witwatersrand, Johannesburg, 2024) Labuschagne-Kom, Lindsie; Mahery, Prinslean; Martin, Blake
The Universal Declaration of Human Rights recognises access to healthcare as a fundamental human right and is guaranteed by the South African Constitution. An analysis of this right reveals that it comprises of two main components, namely financing and delivery of healthcare services. These are fulfilled by the government in the public sector and by private healthcare funders and private health establishments in the private sector. However, an analysis reveals that access to healthcare is substantively inequitable due to the fragmentation of the health system and unveils significant inefficiencies in the private sector that impeded realisation of this right. This dissertation examines the cause of this fragmentation and the inefficiencies within the private healthcare funders and private health establishments market. It investigates how these issues can be resolved to realise the right to healthcare. This study applied a qualitative desktop review of governmental policies, direct and incidental legislation, and multidisciplinary fields of academic reviews such as competition, healthcare, constitutional law and international policies to evaluate the effect of historical, contemporary and prospective policies and legislation, on access to healthcare. This analysis reveals that access to healthcare was historically manipulated to achieve political ideology through a legislative framework that provided the foundation for private funding models and private health establishments to flourish. This occurred at the expense of the public sector and embedded the fragmentation and inefficiencies in the health system. Notwithstanding the enactment of the Constitution, which envisioned a transformed and equal society, access to healthcare remains substantively inequitable. This is due to governmental failings to regulate these stakeholders. Given this state of affairs, the government intends to enact legislative reform through the National Health Insurance Bill to meet its constitutional mandate to realise the right to healthcare. An analysis of the Bill’s framework, however, reveals that it will have a cascading effect with the collapse of the private healthcare funders and private health establishment markets. This will ultimately cause a regression in access to healthcare and impede the practical realisation of this right. An investigation into alternative mechanisms to fulfil the right to healthcare reveals that incorporation and collaboration with private healthcare funders and private health establishments is a pragmatic alternative to the National Health Insurance Bill that will aid with the practical realisation and vindication of this right. These findings indicate the need for government to improve its stewardship of the health system and provide pragmatic solutions to reform the legislative and regulatory frameworks governing these stakeholders to resolve inefficiencies and to foster collaboration to fulfil the right to healthcare.
The price effects of a hospital merger: a case study of the Mediclinic Southern Africa (Pty) Limited (Mediclinic) and Matlosana Medical Health Services (Pty) Limited (MMHS) merger
(University of the Witwatersrand, Johannesburg, 2024) Laurence, Marcelle; Mncube, Liberty
This study evaluates the assessment conducted in the prohibited Mediclinic Southern Africa (Pty) Ltd and Matlosana Medical Health Services (Pty) Ltd (MMHS) proposed merger. The study employs a qualitative approach, centred on a case study methodology, to assess the theories of harm discussed. It aims to provide insights into the adequacy and outcome of the competition authorities’ assessment drawing comparisons to international literature and policy implications. It uses economic theory to analyse and show the significance of robust and nuanced regulatory frameworks in healthcare merger evaluation.
Assessing the inter-annual and inter-seasonal climate-induced variation in caseload of respiratory diseases
(University of the Witwatersrand, Johannesburg, 2024-06) Motlogeloa, Ogone
In South Africa, acute upper respiratory diseases pose a significant public health challenge, influenced heavily by climatic factors. Recognizing the critical need for detailed seasonal analysis. This thesis delves into the inter-annual and inter-seasonal impacts of climate on disease caseloads, offering four pivotal contributions to health biometeorology. The first contribution refines the understanding of the acute upper respiratory disease season in South Africa, previously recognized as the winter months of May to September. This research provides a more granular analysis by pinpointing specific onset timings and fluctuations within the season that are crucial for optimizing healthcare responses, particularly in vaccination schedules. The second contribution is an in-depth analysis of climatic variables affecting acute upper respiratory disease prevalence. Utilizing Spearman's correlation analyses and the Distributed Lag Non-linear Model across Johannesburg, Cape Town, and Gqeberha, this study identifies negative correlations between temperature and disease cases, pinpointing significant risk thresholds most prevalent during the winter peak. The third contribution investigates the impact of extreme climate events (ECEs) over twelve years, elucidating how, while individual ECEs influence medical aid claims and disease incidence, it is the broader seasonal patterns that predominantly dictate acute upper respiratory disease prevalence. The fourth contribution offers a nuanced exploration of the climate-health nexus, demonstrating that routine weather variations play a more significant role in the peak transmission of acute upper respiratory viruses than extreme events. This thesis elucidates the substantial yet nuanced influence of climate on respiratory health in South Africa. By specifying the disease season with greater precision and clarifying the relationship between temperature variations and disease prevalence, the research provides essential data for health practitioners to plan targeted interventions. This study moves beyond the focus on extreme weather events to expose the subtler, yet more consistent, impact of seasonal climate shifts on health outcomes, enriching our understanding and serving as a vital reference for enhancing disease preparedness in an era marked by climatic uncertainty.
Immunomodulation of the innate immune system: The role of vitamin D in the context of monocytes and macrophages
(University of the Witwatersrand, Johannesburg, 2024-07) Mol, Bronwyn Ashleigh; Gentle, Nikki; Meyer, Vanessa
Macrophages are widely distributed cells of the innate immune system with essential roles in homeostasis and disease. Despite concerted efforts, several aspects of macrophage origin, biology, and functionality remain poorly understood. To gain a deeper understanding of these cells, a physiologically relevant, but practical model is required. In vitro, macrophages are principally generated from primary monocytes and monocyte-like cell lines through a natural process referred to as monocyte-to-macrophage differentiation. Monocyte-like cell lines have several practical advantages over the use of primary monocytes with the most commonly employed monocyte-like cell lines being THP-1 and U937 cells. Despite their frequent use, no standardised protocol is employed in the differentiation of monocyte-like cell lines to macrophages. Naturally, this results in large discrepancies and a lack of comparability between studies. Furthermore, many of these protocols are not physiologically relevant and produce macrophages that are not responsive to downstream stimuli. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active form of vitamin D3, is a recognised immunomodulator that shows pronounced genomic and non-genomic effects in immune cells. It is also reported as an inducer of monocyte-to-macrophage differentiation, though heavily debated, and a potential macrophage polarisation agent. Despite this, there is relatively little information concerning the role of 1,25(OH)2D3 in monocyte-to-macrophage differentiation and macrophage biology. This study aimed to develop a more physiologically relevant differentiation protocol for the monocyte-like THP-1 and U937 cell lines. This model was then used to investigate the role of 1,25(OH)2D3 in monocyte-to-macrophage differentiation and macrophage biology. Assessment of morphological features and the macrophage markers, CD11b and CD14, indicated that in both THP-1 and U937 cells, differentiation induced using a combination of 5 nM of phorbol 12-myristate 13-acetate (PMA) and 10 nM 1,25(OH)2D3 over 96 hours produced the most mature macrophages. It was observed that 1,25(OH)2D3 alone was not capable of inducing differentiation, yet when combined with PMA, greatly enhanced macrophage features. THP-1 cells are the most widely employed monocyte-like cell line, and are proposed to be the most reflective of primary monocytes. In this study these cells were shown to be more responsive to the effects of 1,25(OH)2D3 than their U937 counterparts. As such, RNA-sequencing was used to explore the efficacy of the proposed differentiation protocols and the influence of 1,25(OH)2D3 on macrophage biology in THP-1 cells. Differential gene expression analysis confirmed that the most effective differentiation protocol was the combination of 5 nM PMA with 10 nM 1,25(OH)2D3 when considering macrophage associated features including transcription factor usage, adhesion, phagocytosis, and cytokine and cytokine receptor expression. This protocol also produced THP-1-derived macrophages that showed increased expression of genes considered to be primary macrophage markers. These results also suggested that THP-1 cells differentiated with neither PMA nor PMA with 1,25(OH)2D3 were likely to represent fully polarised macrophages. 1,25(OH)2D3 treatment of THP-1 monocytes and THP-1-derived macrophages produced distinct gene expression profiles with considerably less overlap than expected. Though 1,25(OH)2D3 treatment often affected similar biological processes in both cell types, the genes within these processes found to be differentially expressed in each cell line were often distinct. For example, in THP-1- derived macrophages, but not THP-1 monocytes, 1,25(OH)2D3 treatment resulted in the increased expression of genes encoding numerous antibacterial peptides, several small GTPases and their regulators. Additionally, several type I interferon response related proteins showed decreased expression, while expression of cytokines and cytokine receptors was variable. This, taken together with the morphological work, indicates two potential roles for 1,25(OH)2D3 in macrophages. Firstly, a protective role as it suggests the potential to prime an antibacterial response, while still balancing inflammatory responses and protecting against autoinflammation induced by aberrant type I interferon response. Secondly, a potential role in determining the morphological features, clearly demonstrated through microscopy, and further suggested by the differential expression of a variety of small GTPases and their regulators.
Detecting Disease in Citrus Trees using Multispectral UAV Data and Deep Learning Algorithm
(University of the Witwatersrand, Johannesburg, 2024-06) Woolfson, Logan Stefan; Adam, Elhadi
There is a high prevalence, in South Africa, of fruit tree related diseases infesting lemon trees, subsequently affecting overall crop yield and quality. Ultimately, the income for the farmers is significantly diminished and limits the supply of nutritional food crops for the South African population, who already suffer from a high incidence of malnutrition. Currently, there are various methods utilized to detect diseases in fruit trees, however they pose limitations in terms of efficiency and accuracy. By employing the use of drones and machine learning methods, fruit tree diseases could be detected at an earlier stage of development and with a much higher level of accuracy. Consequently, the chances of remedying the trees before the disease spreads is greatly improved, and the supply of nutritious fruit within South Africa is increased. This research report’s aim is to investigate the effectiveness of a deep learning algorithm for detecting and classifying diseases in lemon orchards using multispectral drone imagery. This entails assessing the performance of a pretrained ResNet-101 model, fine-tuned with additional sample images, in accurately identifying and classifying diseased lemon trees, specifically those affected by Phytophthora root rot. The methodology involves the utilization of a pretrained ResNet-101 model, a deep learning architecture, and the retraining of its layers with an augmented dataset from multispectral aerial drone images of a lemon orchard. The model is fine-tuned to enhance its ability to discern subtle spectral variations indicative of disease presence. The selection of ResNet-101 is grounded in its proven success in image recognition tasks and transfer learning capabilities. The results obtained demonstrated an impressive accuracy of 80%. The deep learning algorithm exhibited notable performance in distinguishing root rot-affected lemon trees from their healthy counterparts. The findings indicate the promise of utilizing advanced deep learning methods for timely and effective disease detection in agricultural farmlands, facilitating orchard management.
Knockdown of long non-coding RNA PANDA improves the cytotoxic effects of cisplatin in oesophageal squamous cell carcinoma cell lines
(University of the Witwatersrand, Johannesburg, 2024-11) Moonsamy, Sasha Sarasvathee Keshnee; Mavri-Damelin, Demetra; Jivan, Rupal
Oesophageal cancer is one of the leading causes of cancer death worldwide, of which oesophageal squamous cell carcinoma (OSCC) is the major subtype in southern and eastern Africa. Cisplatin is a well-established drug used to treat multiple cancers, including OSCC. Drug resistance is a major impediment to continued cisplatin therapy in numerous cancers. LncRNA P21-associated non-coding RNA DNA damaged activated RNA (PANDA) is known to function in cell cycle regulation in response to DNA damage and is upregulated in OSCC. We aim to determine lncRNA PANDA expression in South African-derived OSCC cells and establish whether down-regulation of this lncRNA can be used to supplement cisplatin therapy. In this study, MTT assays were performed to determine the EC50 concentrations of cisplatin in OSCC (WHCO1, WHCO5, and SNO) cells and HEK293 cells as a non-cancer control. The cytotoxic effects of cisplatin were exerted in all cell lines, with WHCO5 and SNO appearing more responsive to cisplatin than WHCO1 and HEK293. RT-PCR was used to detect if lncRNA PANDA is expressed in untreated and cisplatin-treated cells and was detected in all cell lines. Knockdown of lncRNA PANDA by siRNA was assessed with RT-PCR. Phase contrast microscopy was used to assess whether siRNA reagents altered cell morphology at 5, 24, and 48 hours post treatment. No significant alterations in cell morphology were observed in WHCO1, WHCO5, SNO, and HEK293 cells. MTT assay evaluation after 48 hours of cisplatin exposure, with or without siRNA for lncRNA PANDA, showed a significant reduction in EC50 concentrations in WHCO5, SNO, and HEK293 cell lines, suggesting that knockdown of lncRNA PANDA may improve cisplatin cytotoxicity in some cell lines. However, the EC50 values were higher with lncRNA PANDA knockdown in the WHCO1 cell line, suggesting that not all OSCC cell types may be responsive to this approach. In conclusion, lncRNA PANDA is expressed in response to cisplatin-induced DNA damage, and the down regulation of lncRNA PANDA improves the cytotoxic effects of cisplatin; however, further investigations are warranted in OSCC.
Caregiver capabilities and socio-economic disparities in children’s health-related quality of life
(University of the Witwatersrand, Johannesburg, 2024) Turner, Georgia
This study investigates the relationship between children’s health-related quality of life and the associated contextual factors. Furthermore, this study analyses the socio-economic disparities that exist amongst children and what particular social determinants of health are influencing their health and wellbeing. Using an OLS regression as well as the Blinder-Oaxaca decomposition, the results show how children with a lower socio-economic status experience a lower HRQOL as opposed to those with a higher socio-economic status. Furthermore, this paper reports new research on the association of caregiver’s capabilities and children’s HRQOL which represents an important explanation for children’s health-related quality of life. Caregivers’ capabilities are a set of tools that enables parents to manage work, life and parenting effectively. The results provide evidence how important these capabilities are as it contributes to a better health related quality of life in their children. The findings show how a higher socio-economic status is associated with better caregiver capabilities. This is an important finding in the South African context, as exorbitant social inequalities exist, and hence, improving adult capabilities could potentially result in not only aiding to narrow the socio-economic disparity gap, but also improving the overall quality and health of children. This also leads to the premise of a bi-directional association whereby improving caregivers’ socio-economic status may likely also improve their capabilities.
Novel antiangiogenic peptide targeted therapeutic nanosystem for non-small-cell lung carcinoma
(University of the Witwatersrand, Johannesburg, 2023) Ngema, Lindokuhle Malibongwe; Choonara, Yahya Essop; Marimuthu, Thashree; Adeyemi, Adebawole
Lung cancer is the leading cause of cancer deaths globally, with nearly 1.8 million deaths and 2.2 million incidences recorded annually. Primarily, non-small-cell lung carcinoma (NSCLC) is the most commonly diagnosed type of lung cancer, which makes up approximately 85% of all reported lung cancer cases. Currently, the management of NSCLC is a global challenge, and although, various treatment protocols are available, such as surgery, radiotherapy, and chemotherapy, the survival outcomes remain poor. Combination chemotherapy is the current first-line treatment for NSCLC, however, it presents with a myriad of drawbacks, including non-specificity, high dosage, and detrimental side effects, resulting in patients intolerability to the regimen. Consequently, a new therapeutic approach is greatly needed and warrants the design of biocompatible targeted drug delivery nanosystems that can halt tumor proliferation and metastasis by targeting key molecules and deliver drugs directly to tumors, with limited side effects and toxicity to healthy cells. Tumor targeted drug delivery nanosystems such as magnetic nanoparticles (MNPs) modified with biomolecules and functionalized with homing peptides are of great interest for potential application as a potent nanomedicine in NSCLC management. Accordingly, the present study set to develop novel targeted paclitaxel (PTX) delivery nanosystems from the amenable superparamagnetic iron oxide nanoparticles (SPIONs) coated with trans-10,cis-12 conjugated linoleic acid (10E, 12Z) and functionalized with either a vascular endothelial growth factor receptor (VEGFR) binding or a matrix metalloproteinase 2 (MMP-2) binding peptide, for specific delivery of PTX to VEGFR and MMP-2 expressing NSCLC tumors. A preceding nanosystem without the peptides (CLA-coated PTX-SPIONs) was originally fabricated as proof of concept for the application of 10E, 12Z CLA as a surface coating and drug partitioning biomolecule. CLA-coated PTX-SPIONs exhibited a spherical shape, with an average particle size and zeta potential of 96.5 ± 0.6 nm and −27.3 ± 1.9 mV, respectively. The nanosystem had a drug loading efficiency of 98.5% and demonstrated a sustained site-specific in vitro release of PTX over 24 h (i.e., 94% at pH 6.8 mimicking the tumor microenvironment). Enhanced anti-proliferative activity was also observed with the CLA-coated PTX-SPIONs against a lung adenocarcinoma (A549) cell line after 72 h, with a recorded cell viability of 17.1%. Thereafter, the fabricated nanosystem was optimised for direct tumor-targeting by functionalization with HRH or CTT peptides, to give CLA-coated PTX-SPIONs@HRH and CLA-coated PTX-SPIONs@CTT. A new design methodology was established for the tandem surface functionalization of CLA-coated PTX-SPIONs with the antiangiogenic peptides, via coupling reactions. A series of robust nanotechnological techniques were employed for pertinent physicochemical characterization, in vitro evaluation of drug release, anti-proliferative activity, and quantification of VEGF-A and MMP-2 levels. Meanwhile, in vivo testing was carried out on a lung tumor xenograft mouse model. Both nanosystems exhibited a marked cellular uptake and internalization by A549 cells, and CLA-coated PTX-SPIONs@HRH significantly reduced secretion levels of VEGF-A in human dermal microvascular endothelial cells (HMEC-1) from 46.9 pg/mL to 35.6 pg/mL, meanwhile CLA-coated PTX-SPIONs@CTT significantly inhibited MMP-2 secretion by almost 70% , indicating specific anti-MMP-2 activity. A 76.6% and 69.7 % tumor regression was observed in a lung tumor xenograft mouse model treated with CLA-coated PTX SPIONS@HRH and CLA-coated PTX-SPIONs@CTT, respectively, demonstrating tumor targetability and angiogenesis inhibition. Lastly, the pharmacokinetics (PK) evaluation revealed that both nanosystems prolonged the half-life of PTX and circulation time in vivo. In essence, potent antiangiogenic tumor-targeted PTX delivery nanosystems were successfully fabricated, and the obtained results suggest potential application of CLA-coated PTX SPIONs@HRH and CLA-coated PTX-SPIONs@CTT for effective management of NSCLC.

4. Electronic Theses and Dissertations (ETDs) - Faculties submissions

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