Electronic Theses and Dissertations (PhDs)

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Potential protein biomarker discovery for gallbladder cancer in a South African cohort
(2024) Baichan, Pavan
Gallbladder cancer (GBC) has a poor prognosis with the prevalence of GBC varying according to geographical location. The prevalence of GBC in South Africa is poorly tracked, and the molecular mechanisms associated with GBC in African patients are inadequately understood. This study aimed to determine dysregulated proteins in tissue and blood plasma in South African GBC patients to identify potential molecular mechanisms of disease progression and plausible biomarkers. Following ethical approval, tissue from 27 GBC, 13 gallstone disease (GD), and five normal tissues were obtained. Blood plasma was collected from 54 GBC and 73 benign biliary pathology (BBP) patients who consented to the study. A bottom-up proteomics approach was undertaken, using PAC and HILIC digestion methods, and SWATHMS for quantitative proteomic profiling. Hierarchical cluster analysis, PCA analysis, and Spearman’s rank correlation analysis were performed. Furthermore, pathway and network analyses were conducted. There were 62, 194, and 105 dysregulated proteins in the GBC/Normal, GBC/GD, and GD/Normal group comparisons, respectively, and 33 dysregulated proteins in the GBC/BBP plasma comparison. The dysregulated proteins in GBC patients enriched pathways involved in smooth muscle contraction, metabolism, extracellular matrix organisation and interactions, innate immunity, and platelet and neutrophil degranulation. Further analysis showed that S100A8 and S100A9 were downregulated in GBC plasma patients with GD history compared to those with no GD history. Additionally, APOE and ITIH3 were elevated in non-metastatic staging GBC patients. Seven proteins were found to be commonly dysregulated in GBC/GD and GBC/BBP comparisons and another two proteins were commonly dysregulated in the GBC/Normal, GBC/GD, and GBC/BBP comparisons, termed “Commonly dysregulated proteins (CDPs)”. Quality control assessment of the MS2 fragment ion chromatograms of the CDPs indicated strong signal-to-noise ratios and correct fragment-to-precursor matching. The CDPs could distinguish between GBC and controls and the Spearman’s rank correlation test showed significant correlations between the expression of the CDPs. The identified dysregulated proteins aid in further understanding the molecular mechanisms associated with GBC in patients with African ancestry. The alteration of specific proteins in tissue and plasma samples suggests their potential use as biomarkers for GBC patients in this sample cohort.
Integrated biological and behavioural assessment of human immunodeficiency virus and sexually transmitted infections among tertiary student men who have sex with men in Nairobi, Kenya: project bespoke
(2024) Mwaniki, Samuel Waweru
Aims: The aims of this study were to: assess the appropriateness and acceptability of using respondent-driven sampling (RDS) as a strategy for recruiting tertiary student MSM (TSMSM) in a HIV/STIs bio-behavioural survey, estimate HIV/STIs prevalence and associated risk factors among TSMSM, explore experiences of TSMSM with access and use of health services, and assess healthcare providers’ (HCPs’) attitudes and perspectives towards care for TSMSM. Methods: The study was done in Nairobi, Kenya. During the first phase in September and October 2020, formative in-depth qualitative interviews were held with key personnel working in MSMfriendly health facilities (n=3), and TSMSM peer leaders (n=13), to assess the appropriateness and acceptability of using RDS to recruit TSMSM in a bio-behavioural survey. Subsequently, during the second phase in February and March 2021, six TSMSM selected from the 13 in the first phase, started off the RDS recruitment of another 242 TSMSM who participated in a cross-sectional biobehavioural survey to estimate HIV/STIs prevalence and associated risk factors. The survey was digitally self-administered on REDCap® platform. Participants received serological testing for HIV and Treponema pallidum, and pooled molecular testing for Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, and Trichomonas vaginalis using urethral, anorectal and oropharyngeal samples. The third phase in September 2021 involved qualitative work to assess health access and delivery for TSMSM. In-depth interviews were held with TSMSM (n=22) purposely selected from the TSMSM (n=248) who participated in the biobehavioural survey. The interviews explored experiences of TSMSM with access and use of health services. During the same month, HCPs (n=36) took part in six focus group discussions to assess their attitudes and perspectives towards care for TSMSM. Qualitative data was analysed 2 thematically using NVivo v.11 (first phase) and v.12 (third phase), and quantitative data was analysed using Stata v.15 and RDS-Analyst v0.72 (second phase). Results: Formative qualitative work demonstrated that RDS was both appropriate and acceptable for recruiting TSMSM in the bio-behavioural survey. The median age of TSMSM who participated in the bio-behavioural survey was 21 years (interquartile range 20-22 years). RDS-adjusted prevalence of HIV, at least one of the five STIs, chlamydia, gonorrhea, Mycoplasma genitalium infection, trichomoniasis and latent syphilis were: 3.6%, 58.8%, 51.0%, 11.3%, 6.0%, 1.5% and 0.7%, respectively. Higher risk of HIV infection was independently associated with studying in private tertiary institutions, preferring a sex partner of any age, last sex partner being >25 years, meeting the last sex partner online and prevalent gonorrhea infection. Inconsistent condom use, and the last sex partner being a regular partner were independently associated with testing positive for at least one of the five STIs. From the qualitative work in the last phase, TSMSM vocalized experiences of prejudice, stigma and discrimination in public and institution-based health facilities, but felt they were equitably handled in community pharmacies, private and MSM-friendly health facilities. A majority of HCPs articulated positive attitudes towards care for TSMSM, while a minority expressed discomfort and displayed attitudes that likely reflected on their lived biases as it related to offering care and services to TSMSM. Conclusion: The demonstrated high HIV prevalence among TSMSM in Nairobi reflects the urgent need for tailored structural, biomedical and behavioural prevention interventions for this young key population. Structural interventions are required to address the environmental, social and economic factors that influence individual risk and protective behaviours in relation to HIV infection. Biomedical interventions such as pre-exposure prophylaxis are necessary to reduce the chances of transmission of HIV. The observed high prevalence of curable STIs calls for interventions to improve prevention, as well as prompt detection and treatment of these STIs. This is important because untreated STIs biologically potentiate the transmission and acquisition of HIV, and cause considerable morbidity on their own. Furthermore, there is a need for interventions that foster inclusive attitudes among, and improve the knowledge/skills of HCPs in tertiary institution-based health facilities, so as to make services more culturally competent, equitable and accessible for TSMSM.
Support programme for healthcare professionals involved in adverse events in public hospitals in Gauteng
(2024) Nkosi, Elizabeth Malefu
Background: Adverse events in the healthcare services result not only in administrative and financial costs to the healthcare institution, but also in personal costs to the patients and their families, who are often angry, disappointed, and sad. In the current litigious healthcare climate, relatives, supported by legal advisors, often seek redress as a way of managing their distress. Thus, patients are not the only victims of adverse events. The healthcare professionals that are directly involved often shoulder the blame, sometimes fairly, and sometimes unfairly, while they too need psychological support. A culture of blame in institutions can lead to healthcare professionals involved in an adverse event being marginalised, feeling personally responsible for the event and that they have failed the patient, and they are left to suffer in silence. While anecdotal evidence exists that such stress may lead to negative coping mechanisms, the researcher has not identified any research study conducted in public hospitals in Gauteng, South Africa that identifies and describes the influence that the involvement in an adverse event has on healthcare professionals. Such evidence is required to develop a support programme that could assist healthcare professionals who have been directly involved in adverse events, to minimise the concomitant stress, and to enable these professionals to continue to provide quality care after such an event. Aim: The purpose of this study was to develop, describe, and evaluate the implementation of a support programme for healthcare professionals involved in adverse events in public hospitals. Methodology: A sequential, multimethod research design was used. The study was conducted in five phases. Phase 1 consisted of a scoping review of the international literature that focused on the experiences of the nurses and doctors. The question asked in the scoping review was: What is known from existing literature about the support programmes for healthcare professionals involved in adverse events in clinical settings, and are they effective? Phase 2 involved storytelling that explored the impact of adverse events on involved healthcare professionals. Smith and Liehr’s (2005) methodology was used, that is, healthcare professionals who were directly involved in or affected by one or more adverse events in the public hospitals in Gauteng narrated their experiences. Phase 3 used semi-structured interviews with the managers to explore how best to support health professionals involved in adverse events. Phase 4 involved developing a support programme according to the Wits Trauma Model developed by Eagle, Friedman and Shumkler, from the Psychology Department of the University of the Witwatersrand, in 1993 (Eagle, 2000). Phase 5 focused on confirming and validating the programme to support healthcare professionals involved in adverse events in public hospitals. This phase was subdivided into two sections: Phase 5.1 comprised the Delphi group; and Phase 5.2 comprised the Focus group. In the first round involving the Delphi group, technical data was collected from the experts who validated the programme by means of the survey that was distributed on Research Electronic Data Capture. Concerns arising out of the first round with the Delphi group and that required attention were addressed during the Focus group discussion. Results: Hospitals were not aware of the magnitude of second victimhood and hence the delay in reviewing the structures in place to provide support to those involved. Just (fair) culture principles were not adhered to as there were no guidelines for their implementation, hence the second victims were left traumatised and in isolation following their involvement in adverse events, and they experienced blaming by management instead of being provided with much needed support. Limitations: The limitations to the study include the small sample size during the data collection phases, due to the Coronavirus disease of 2019 pandemic. Due to the restrictions that were implemented it was not possible to contact all the staff as they had been relocated to other healthcare facilities, were absent, or had resigned. Those who were snowballed were no longer at the facilities where they were originally identified, and therefore the researcher was unable to capture their experiences. Objectivity was not maintained as the documents for the Delphi group were hand-delivered, participants were able to identify the researcher, and hence the social desirability concern. The face-to-face encounters made adherence to anonymity impossible. The model components were not practical in terms of the developed programme. Round two of the Delphi group could not be scheduled, thus challenging the study model. Conclusion: The impact of adverse events on healthcare professionals remains an underestimated health concern. Experiences are magnified by unsupportive work environments, and are evident in increased hostility, blaming, fear of punishment, and reputational harm. The second victims require support to enable them to recover and learn from their involvement. The programme was developed, which included the summarised structure and the detailed process for implementation by hospital management on how to manage the adverse events in public hospitals in Gauteng.
Predicting in-hospital mortality in heart failure patients using machine learning
(2024) Mpanya, Dineo
The age of onset and causes of heart failure differ between high-income and low-and-middle-income countries (LMIC). Heart failure patients in LMIC also experience a higher mortality rate. Innovative ways that can risk stratify heart failure patients in this region are needed. The aim of this study was to demonstrate the utility of machine learning in predicting all-cause mortality in heart failure patients hospitalised in a tertiary academic centre. Six supervised machine learning algorithms were trained to predict in-hospital all-cause mortality using data from 500 consecutive heart failure patients with a left ventricular ejection fraction (LVEF) less than 50%. The mean age was 55.2 ± 16.8 years. There were 271 (54.2%) males, and the mean LVEF was 29 ± 9.2%. The median duration of hospitalisation was 7 days (interquartile range: 4–11), and it did not differ between patients discharged alive and those who died. After a prediction window of 4 years (interquartile range: 2–6), 84 (16.8%) patients died before discharge from the hospital. The area under the receiver operating characteristic curve was 0.82, 0.78, 0.77, 0.76, 0.75, and 0.62 for random forest, logistic regression, support vector machines (SVM), extreme gradient boosting, multilayer perceptron (MLP), and decision trees, and the accuracy during the test phase was 88, 87, 86, 82, 78, and 76% for random forest, MLP, SVM, extreme gradient boosting, decision trees, and logistic regression. The support vector machines were the best performing algorithm, and furosemide, beta-blockers, spironolactone, early diastolic murmur, and a parasternal heave had a positive coefficient with the target feature, whereas coronary artery disease, potassium, oedema grade, ischaemic cardiomyopathy, and right bundle branch block on electrocardiogram had negative coefficients. Despite a small sample size, supervised machine learning algorithms successfully predicted all-cause mortality with modest accuracy. The SVM model will be externally validated using data from multiple cardiology centres in South Africa before developing a uniquely African risk prediction tool that can potentially transform heart failure management
Adverse childhood experiences and social and health outcomes in later life
(2024) Naicker, Sara N.
Background: Well-established literature points to early life experiences and childhood adversities setting the foundation for health and development and influencing life trajectories. Nurturing, responsive caregiving in a safe and stable environment is associated with healthy, productive lives throughout adulthood. On the other hand, adverse experiences in childhood are associated with poor health and wellbeing, risky behaviour and reduced human capital. How this adversity is measured and the context in which it is measured may provide insight into the relationship between adversity and outcomes over and above what has been found in high income countries. Aim: The overall aim of this study is to examine adverse childhood experiences (ACEs) in a South African birth cohort. Specific objectives of the study include: a) developing prospective and retrospective profiles of ACEs in the sample, b) establishing levels of agreement between these two profiles of ACEs, c) estimating the prevalence and clustering of ACEs in this population-based urban sample, d) examining the associations between exposure to ACEs and a range of physical and mental health and social outcomes, and e) understanding the role that recent stress plays in the relationship between exposure to ACEs and poor outcomes. Methods: This study uses a secondary analysis design using data from the longitudinal Birth to Thirty cohort. The cohort began in 1990 with the enrolment of 3,273 pregnant mothers and has followed the children born to these women for more than thirty years. The 10-item ACE Index developed by the CDC-Kaiser’s ACEs Study was expanded to include five additional ACEs common in the South African context – chronic unemployment, violence in the community, household death, parent death, and separation from parents. Prospective profiles of ACEs were collated from data collected over the first 18 years of the child’s life, initially reported by primary caregivers until age 11, then self-reported from ages 11 to 18. Retrospective profiles of ACEs were collected in young adulthood when the participants were 22 years old, along with an index of recent stressors. A series of human capital outcomes – those encompassing physical and mental health and psychosocial adjustment, were assessed at age 28. ACEs in the sample were conceptualized in three ways ‒ as single adversities, such as physical or sexual abuse, cumulative adversity in the form of the ACE score, and clusters of adversity determined by their patterning. Cohen’s kappa statistics and concordance rates were generated to establish the levels of agreement and consistency between prospective and retrospective reports of ACEs (timing) and between reports given by caregivers and children at age 11 (source). Descriptive statistics and latent class analysis were used to estimate the prevalence of ACEs and to explore the patterning of ACEs among participants. Logistic regression analysis explored associations between all three conceptualizations of ACEs and outcomes, disaggregated by sex. Mediation and moderation analyses were conducted to examine the influence of recent stress on mental health outcomes. Findings: Comparisons between prospective and retrospective reports of ACEs show that there is relatively low-to-moderate agreement between timing and sources of reports of ACEs. Agreement varies depending on the adversity in question – with greater levels for objective Naicker, S.N. 2023. Adverse Childhood Experiences and Social and Health Outcomes in Later Life experiences such as parental death and lower levels for subjective experiences such as chronic unemployment. Differences in agreement were partly due to prospective and retrospective reports identifying largely different groups of people; those who only report high exposure prospectively, those who only report high exposure retrospectively and those that overlap. Using either prospective or retrospective reports, the prevalence of ACEs in this sample were high, although there were significant decreases in prevalence from prospective reporting to retrospective reporting. ACEs tended to co-occur, and where one ACE was reported, the likelihood of others increased. Clusters of ACEs split distinctively into high-low:dysfunction abuse categories; with one group likely to have low exposure, another with high generalized exposure to all ACEs, a third with moderate exposure characterized by household dysfunction and a fourth with moderate exposure driven by emotional abuse and/or neglect. All three conceptualizations of ACEs were significantly associated with poorer outcomes. Single ACEs such as physical, sexual and emotional abuse, and exposure to intimate partner violence, were independently and strongly associated with poorer outcomes in adulthood. Increased exposure to ACEs, or cumulative adversity, was also linked to poorer outcomes in a graded manner, with the likelihood of experiencing poor outcomes increasing along with exposure. The clusters with high levels of exposure to ACEs and moderate levels of exposure driven by emotional abuse were most at risk for poor outcomes. There were significant differences in exposure to ACEs, outcomes and the associations between the two by sex. Associations also differed for prospective and retrospective reporting with the strength of association varying depending on the outcome in question. Recent stressors were found to play a confounding role in the relationship between ACEs exposure and poor outcomes. Although recent stressors had a different impact on those who reported high ACEs exposure prospectively versus those who reported high ACEs exposure retrospectively. The influence of recent stressors on the mental health of those who reported high exposure to ACEs prospectively supported a sensitization model. In contrast, the role of recent stressors on the mental health of those who reported high exposure to ACEs retrospectively supported a stress inoculation model. This suggests two potential pathways for risk. Conclusion: In combination and accumulation, it is demonstrated here that adverse experiences in childhood have an impact on health and wellbeing in adulthood. Specific individual ACEs can be teased out for their independent effect on outcomes, but the additive effects of multiple adversities lead to almost exponential increases in the risk for a myriad of negative physical and mental health and social outcomes. These findings provide important links from South Africa’s context of high levels of violence in all forms and multiple hardships that families with large burdens of care endure, with little support, to many of the human capital outcomes on which productive, healthy and happy lives depend. Born at the dawn of democracy, with anticipation for opportunity, many of the children in this cohort were raised in contexts of adversity that may have been experienced as normative in those settings. Regardless of whether these experiences leave enough of a mark to be recalled later in life, the strain of cumulative adversity has had persistent and serious effects on their mental health, their ability to finish school, find a job and stay out of trouble.
Long-term outcomes of HIV infected, and uninfected children aged 1-59 months following inpatient management of severe acute malnutrition
(2024) Bwakura-Dangarembizi, Mutsawashe
Children with complicated severe acute malnutrition (SAM) are at a high risk for mortality and morbidity in the time after hospital discharge, and those with HIV are particularly vulnerable. What is not known is whether this higher risk for poor outcomes in children with HIV has improved in the era of treating all who are infected. The thesis' main aim was to characterize the 52-week outcomes of children aged 1 to 59 months who were hospitalized for complicated SAM and to identify the characteristics present at hospital discharge that were most predictive of these outcomes. The thesis utilised the HOPE SAM study, an observational cohort established in Zimbabwe and Zambia that enrolled children hospitalised for complicated SAM and followed them up for one year after discharge from hospital. The study outcomes were death, morbidity, nutritional recovery and body composition assessed using skinfold thickness and bioelectrical impedance analysis. There were 3 main findings from the thesis; nearly 1 in 10 children treated for SAM died and the risk of dying continued throughout the one year following discharge. Children living with HIV had an almost 4-fold higher mortality compared to those without HIV regardless of whether they were receiving antiretroviral therapy or not; wasted children and those with ongoing SAM had a 2-fold higher mortality compared to those who had oedema on admission; and cerebral palsy was associated with a nearly 6-fold higher mortality risk. Similar risk factors, with the exception of HIV infection and addition of stunting were associated with impaired anthropometric recovery and increased hospital readmission. In this cohort, the time to hospital readmission was correlated with low peripheral fat mass and low lean mass. Overall, this thesis emphasizes the vulnerability of children treated for SAM even after they are released from the hospital and identifies high-risk populations that require focused interventions to enhance outcomes

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