Electronic Theses and Dissertations (PhDs)

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    A study of the physiology of pepsinogen in the human with special reference to its disturbance in diseases of the upper gastro-intestinal tract
    (University of the Witwatersrand, Johannesburg, 1953) Hirschowitz, Basil Isaac; Jones, F. Avery
    This study was originally undertaken to determine the clinical value of estimating pepsinogen in the urine in cases of peptic ulcer because recent publications had shown that uropepsin (urinary pepsinogen) excretion in ulcers differed from normal controls. Briefly, the state of knowledge of pepsinogen when this study was undertaken was as follows: pepsinogen was discovered by Langley in 1881 and eventually isolated in 1958 by Herriot who described its physico-chemical properties. It was known to be formed in the stomach wall and mainly secreted into the stomach where it was irreversibly changed into pepsin in the presence or hydrochloric acid. None was reabsorbed and this pepsin was destroyed in the alkaline small intestine. Some pepsinogen diffused directly into the blood stream from the peptic cells and as far as could be ascertained was lost, till it appeared in the urine - a fact discovered by Brucke in 1861. Its transport to and the mechanism of its excretion by the kidney were the subject of hypothetical discussion only. In disease urinary pepsinogen had been studied for some time and the final conclusions were that it was increased in ulcers, especially duodenal ulcers and decreased or absent in pernicious anaemia. It was apparent early in this study that investigation of urinary pepsinogen alone would be of little value in advancing the knowledge of the normal and abnormal physiology of pepsinogen in the human. The investigation was then extended to study the pathological disturbances of urinary pepsinogen more closely, and if possible to determine what happened to pepsinogen between the stomach and the urine. This latter project became possible after the development of a technique not previously described for determining blood pepsinogen and it was found that pepsinogen diffuses from the peptic cells into the blood, and circulate as free pepsinogen in the plasma. From the plasma it is freely diffused through the body and filtered through the glomerular membrane and then reabsorbed in the tubules of the kidney to the extent of 65 - 95%. This new concept of pepsinogen excretion by the kidney calls for a re-orientation of the conclusions previously held of the significance of the urinary pepsinogen in disease, In this report, an attempt is made to present the whole cycle of pepsinogen metabolsim from its formation in the stomach to its appearance in the urine, with-normal and abnormal variations, as a unified concept. While in places comments or conclusions may appear dogmatic, it is realized that this study has produced more questions than answers. It is hoped, however, that a small contribution will have been effected by this work towards a better understanding of the direction of further advances in the knowledge of the aetiology and pathological behaviour of peptic ulcers.
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    The Use of Social Media Platforms in Implementing Quality Improvement Initiatives for Quality Assurance of Paediatric Chest Radiographs in Radiological Departments of Varying Radiographer Expertise
    (University of the Witwatersrand, Johannesburg, 2024) Hlabangana, Linda Tebogo; Andronikou , Savvas
    Introduction Chest radiographs are the most widely performed diagnostic imaging test in children. Good quality radiographs assist in making the correct diagnosis. In resource limited settings, such as in Africa, there are several limiting factors that affect the quality of the radiograph which go beyond the availability of equipment and human resources, including geopolitical and socioeconomic challenges. Novel innovations are required to overcome these challenges by leveraging off technology and the widespread distribution of smart phones. Aim The aim of the study was to evaluate the improvement in the quality of chest radiographs performed in children after initiating quality improvement interventions at three radiology departments. The interventions used the Internet, Facebook® and Twitter®) to remotely communicate with the radiographers. Methods A longitudinal, descriptive study was performed at three radiological centres in South Africa. They study had a retrospective phase (before intervention), and a prospective phase. Over a period of six months, communication on quality factors of chest radiographs and how to improve quality were sent out using Facebook and Twitter. Thereafter, radiographs were collected and the quality assessed. Results A total of 966 radiographs were included in the study. The most common errors overall were “scapula in the way” (38.7%), “rotation” (34.7%) and “poor collimation” (22.2%). The errors “parts cut off” (1.3%) and “wrong/no left/right marker” (1.7%) were the least common. Rahima Moosa Mother and Child Hospital demonstrated non-significant improvement in the quality of radiographs over the duration of the study. The other two centres demonstrated no significant or sustained improvement in the quality of chest radiographs performed. The research did not demonstrate a significant benefit from the intervention. There was vi low engagement with the social media platforms. A total of six radiographers followed the Twitter handle and the Facebook page had 37 friends/followers, eight of these were radiographers participating in the study. Conclusions Although social media have demonstrated impactful use in education and communication, the usage by radiographers in South Africa to improve the quality of chest radiographs is limited. . There was no significant benefit demonstrated from the use of Facebook and Twitter as educational and information tools. Further research using low-data consumption social media apps to create locally relevant and sustainable solutions for quality assurance and quality improvement in radiography are required.
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    The Feasibility of Introducing a Harmonised Treatment Regimen, Comparing Affordable Blood Tests and PET-CT Scans, to Improve Two-Year Survival Rates in Children, Adolescents and Young Adults with Hodgkin Lymphoma in South Africa
    (University of the Witwatersrand, Johannesburg, 2024) Geel, Jennifer Ann; Ballot , Daynia; Metzger, Monika
    Paediatric classical Hodgkin lymphoma (cHL) is highly curable using chemotherapy and radiotherapy. Prior to this study, no collaborative, prospective cHL studies had been performed in South Africa. The retrospective assessment informed the creation of the prospective harmonised guideline. We aimed to determine a baseline survival rate and prognostic factors; explore reasons for mortality in HIV-positive patients, assess the feasibility of introducing a harmonised treatment guideline, prospectively assess survival and analyse the prediction of chemosensitivity at interim assessment. In the retrospective analysis, multiple potential prognostic factors were analysed and survival rates calculated with Kaplan-Meier curves and Cox regression analysis. An initial survey was conducted of the clinical researchers before the launch of the prospective study, followed by a mid-study assessment. Two-year overall survival was calculated by Kaplan-Meier curves and computer-learning models were utilised to compare chemosensitivity based on interim PET-CT assessment with changes in haematological and non-specific markers of disease activity. The retrospective analysis accrued 294 patients, of whom 29 were HIV-positive. The 5-year overall survival was 84% in HIV-negative and 49% in HIV-positive patients. Advanced stage, HIV infection and treatment with regimens other than doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) were associated with lower survival rates. In HIV-positive patients, an AIDS-defining CD4 count and hypoalbuminaemia were associated with poorer prognosis. The pre-study assessment indicated that the majority of centres fulfilled all criteria to participate in the study. The mid-study assessment identified barriers to participation and methods to mitigate these challenges. Analysis of 132 prospectively accrued patients (19 HIV-positive, 113 HIV-negative) treated on a risk-stratified, response-adjusted treatment regimen resulted in higher survival rates of 93% in HIV-negative and 89% in HIV-positive patients. Changes in low-cost, widely available blood tests correctly predicted chemosensitivity, identifying patients who may not require radiotherapy. In conclusion, higher survival rates for paediatric cHL were documented following the introduction of a harmonised management guideline in South Africa. In settings that do not have access to PET-CT, changes in affordable blood tests may be used to substitute for xvi radiological interim assessment, although a format suitable for individual patients is yet to be developed for the clinical setting. This research marks the inaugural collaborative effort where patients from every South African paediatric oncology unit and the majority of private paediatric oncology practices, were afforded the opportunity to participate in a prospective study aimed at enhancing survival rates.
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    Developing an Intervention to Improve Informed Decision-Making for Oncology Patients in South Africa
    (University of the Witwatersrand, Johannesburg, 2024) Blanchard, Charmaine Louise; Norris, Shane
    Introduction Patients making cancer treatment decisions face several challenges including grappling with difficult terminology and deliberating different options based on the information provided and their own values while experiencing high levels of stress. Informed cancer decision making by South African patients in the public healthcare sector, is further complicated by the constrained resources in the oncology clinics limiting the time available for consultations with the oncologists. Language and socio-cultural barriers impact on the patient’s ability to make fully informed treatment decisions, which are legally and ethically required. While decision aids (DAs) exist in high income countries (HICs) to assist patients to make informed cancer treatment decisions, there are no studies reporting the development of cancer treatment DAs in South Africa. Aim The aim of this thesis was to develop a decision support intervention (DESI) to improve cancer patient informed treatment decision making. Methods This thesis applied the Intervention Mapping (IM) framework to the development of the DESI. The three objectives of the thesis related to the first step of the IM process namely a needs assessment to develop the logic model of the problem. The first objective was to assess the effectiveness of decision aids (DAs) in addressing vulnerable patient-reported decision needs by conducting a mixed methods systematic review to understand the synergies and gaps between the DAs and the patients’ needs. For the second objective a quantitative study was undertaken to measure the South African patient’s health literacy (HL), factors associated with HL, their decision control preferences (DCPs), and to assess their decision needs. The study enrolled 124 patients diagnosed with cancer at three tertiary level oncology clinics in South Africa (two in Gauteng and one in KwaZulu Natal). For the third objective a qualitative study was undertaken to understand the patient experiences of making cancer treatment decisions and the oncology staff perceptions of the decision- making process. In-depth interviews with 30 patients and eight focus groups with oncology staff were conducted at the same clinical sites as the quantitative study. The results of the XVII three studies were triangulated to provide a logic model of the problem which informed the next steps of the IM process, resulting in an evidence-based theory driven intervention program. Results The systematic review identified significant gaps between the DAs and the vulnerable patients’ decision support needs, particularly relating to communication in the consultation and providing counselling and coaching support for decision-making. The 124 South African patients at the study sites in Gauteng and KwaZulu Natal had mostly marginal (69%) to limited (11%) health literacy, positively associated with their level of education (OR 2.2, 95% CI 0.58 – 8.55 for high school and OR 14.6 95% CI 2.2 – 96.61 for tertiary education) and socio-economic status (OR 4.1, 95% CI 1.03 - 15.98, for the wealthiest tertile). The patients reported high information needs (71%) despite reporting understanding a lot of what the doctors explained (77%) and feeling comfortable a lot, asking questions (82%) in the consultation. Most patients (82%) preferred an active decision-making role. The qualitative study findings confirmed the high levels of information needs, but most patients did not ask questions in the consultation and often played a passive role in decision-making. Language and cultural differences between the patients and the oncologists were identified by oncology staff as major barriers to informed decision-making, and support from the patients’ families, the oncology nurses and the palliative care teams addressed some of the patients’ decision needs. Following the logical, iterative process of the IM framework a locally relevant decision support intervention program was developed. Conclusion Patients have high levels of cancer and treatment information needs and wish to be active participants in their treatment decision making yet often lack the self-efficacy to engage in treatment deliberation with their oncologists. Language and cultural discordance between the patient and oncologist compounded by the time pressures of the clinic, are barriers to effective patient-centred communication in the consultation. It is vital that adequate training is provided to oncologists to improve culturally sensitive patient-centred communication when supporting cancer patients to make informed treatment decisions.
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    From the onset: Impact of Nutrition and Lifestyle during the Preconception period in Urban South African Young Adults
    (University of the Witwatersrand, Johannesburg, 2023-03) Mukoma, Gudani Goodman; Norris, Shane A.
    Background: In South Africa, 22% of adolescents are overweight or obese, the onset of tobacco smoking is shown to peak between the ages of 15 and 22, 1 in 3 adolescents watch more than 3 hours of television per day, and nearly half of all adults are insufficiently active. Physical inactivity, poor diet, risky alcohol use, illicit drug use are among the behavioural risk factors associated with obesity and mental health problems, all of which have morbidity and mortality implications for adult health. Risks in later life include premature death, long-term disability, childbirth complications, gestational diabetes, diabetes and cardiovascular diseases. However, there is data paucity showing the personal, social, and environmental factors that are determinants of health, especially diet, physical activity (PA), obesity, and associated NCDs in South African adolescents and young adults. Aim: To investigate the individual, household, and environmental factors that influence adolescents' dietary and physical activity habits and to identify ways in which these factors can be leveraged for interventions to better ensure the health of future generations, especially during the crucial preconception years. Methods: This thesis was purposely designed to use a sequential mixed-methods approach that integrates quantitative (Chapter 3 paper 1: cross-sectional and Chapter 6 paper 4: longitudinal) and qualitative (Chapter 4 paper 2: longitudinal and Chapter 5 paper 3: cross-sectional) analyses in order to meet the four specific objectives of my research. The methods selected for this series of investigations were primarily influenced by the substantive research questions that arose, as opposed to methodological and epistemological concerns alone. I utilized three pre-existing data sources, including the "Birth-to-Twenty Cohort," the "Determinants of Type 2 Diabetes Mellitus (T2D)" study, and the "Soweto household enumeration survey." I have gathered new prospective data that is quantitatively and qualitatively longitudinal and cross-sectional. Results: The findings of this thesis in the context of Soweto show that the relationship between dietary patterns and nutritional status (BMI) is independent of socioeconomic status (SES). Adolescents and young adults face a variety of intersecting barriers resulting from personal preferences and their living conditions, which influence their dietary and physical activity habits while occurring at the time; this is important to consider when designing interventions to promote healthy behaviour change. Unexpected stressors, such as the outbreak of the COVID-19 pandemic, contributed to exacerbating adolescents' and young adults' poor health conditions, and as a result, the prevalence of poor nutrition intake, a lack of physical activity, and mental health issues increased. Although the nutrient patterns of adolescents and adults were comparable over time, their associations with BMI were not. The associations with BMI of the "plant-driven nutrient pattern," "fat-driven nutrient pattern," and "animal-driven nutrient pattern" revealed sex differences. Conclusion: Adolescent diet and lifestyle continue to be important research areas in the intent to enhance preconception health and reducing maternal and infant mortality.
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    Nutrition of ageing black South African women and correlates with anthropometry and cardiometabolic outcomes
    (University of the Witwatersrand, Johannesburg, 2023-09) Kankwende, Caroline Belinda Tsitsi; Gradidge, Philippe; Norris, Shane; Chikowore, Tinashe
    Background: Obesity is most prevalent among black women who reside in urban areas in South Africa yet the nutrient patterns of this cohort of women has never been investigated, nor have correlates of body composition indices such as adiposity and body mass index (BMI). These body composition indices are important to analyse as they have been shown to be positively associated with hypertension which is prevalent in this cohort of women. Aim: There were three main goals: 1) To determine the baseline nutrient patterns of middle-aged black South African women residing in Soweto and correlates to body composition indices 2) To evaluate the longitudinal association of nutrient patterns with adiposity in a cohort of middle-aged black South African women over a period of 5.5- years 3) To elucidate the longitudinal associations of nutrient patterns and blood pressure and to explore whether this is an indirect effect mediated by body mass index (BMI) using structural equation modelling Methods: A longitudinal study of children and their families, originally called the Birth to Twenty Plus (Bt20+) cohort and now referred to as the Middle-aged Soweto Cohort (MASC), was used to as the original dataset for this thesis. This study also drew on another embedded study, the Study of Women Entering and in Endocrine Transition (SWEET) study of older women transitioning through menopause. Data on (i) dietary information; (ii) body composition and anthropometry measurements; (iii) blood pressure; (iv) lifestyle behaviours (physical activity, tobacco use, and alcohol use); (v) psychosocial factors; (vi) socioeconomic status; and (vii) educational status were used. A total of 498 Women aged between 40 and 60 years old were included in the study. Principle component analysis (PCA) was applied on the dietary data both at baseline and at 5- years follow-up. This was conducted to extract nutrient patterns from 25 nutrients derived from the food frequency questionnaire (FFQ) and the resulting nutrient patterns are detailed in results chapter 3 (nutrient patterns derived from the baseline FFQ) and results chapter 4 (comparison between both baseline and follow-up nutrient patterns from the FFQ). Simple and complex body composition were recorded for each participant with complex body measurements taken using (DXA). Chapter 3 details the results of the 3 baseline nutrient patterns and correlates with body composition parameters. Using generalized estimating equations, associations between both baseline and 5- years follow-up nutrient patterns and adiposity were evaluated. The results are discussed in results chapter 4. Lastly, the results chapter 5 examined associations between both baseline and follow-up nutrient patterns and blood pressure were examined and furthermore, investigated whether BMI mediates the relationship between repeated measures of nutrient patterns and blood pressure. Results: The majority of the research participants (88%) were classified as individuals having obese status defined by their BMI. The fat mass index (FMI), lean mass index (LMI), gynoid fat, hip and waist circumference, and visceral and subcutaneous adipose tissue (VAT and SAT respectively) measurements were all substantially larger in the group with predominantly individuals having overweight and obese classification compared to woman in the lean group (p <0.001). Protein consumption was greater in the group with individuals having overweight/obese classification, while fat and carbohydrate consumption were matched. At baseline, the "Plant driven nutrient pattern," characterized by higher factor loadings of plant protein, starch, and B vitamins, explained 25% of the total nutritional variance; the "Animal protein driven nutrient pattern," characterized by animal protein and saturated fat, explained 23% of the variance; and the third pattern was the "Vitamin C, sugar and potassium driven nutrient pattern," which had higher factor loadings of vitamin C, sugar and potassium. At baseline, increased consumption of the animal protein driven nutrient pattern resulted in a 1.19 kg/m2 (p = 0.002) increase in BMI, 10.17 cm2 for VAT, 24.43 cm2 for SAT, 0.01 (p = 0.009) increase for VAT/SAT ratio, 0.69 kg/m2 (p = 0.005) increase for FMI, and 0.48 kg/m2 (p = 0.002) increase for LMI. Furthermore at baseline, statistically significant associations were found for the animal protein driven nutrient pattern with all body composition indicators. Subcutaneous adipose tissue increased in the presence of a plant-driven nutrition pattern (p = 0.045). At 5-year follow-up, although the value of the factor loadings of the individual nutrients changed between baseline and follow-up, the nutrients with the highest loadings for each principal component (PC) did not change therefore the overall nutrient patterns remained the same. Only DXA-derived measurements of fat mass, FMI, VAT, and gynoid fat mass (FM) increased with time, while lean mass considerably reduced. Repeated measures of the animal protein driven nutrient pattern was associated with significant increases in FMI, LMI and VAT and repeated measures of the vitamin C, sugar, and potassium driven nutrient pattern was significantly associated with an increase in FMI and LMI. For the purposes of this study, repeated measures of animal-driven nutrient patterns were shown to be significantly related with repeated measures of systolic blood pressure (SBP) only. When structural equation modelling (SEM) was applied, only significant relationships were observed between age and SBP. This relationship was not mediated by BMI but may involve other factors that were not included in this analysis. Conclusions: This thesis explored the nutrient patterns linked to obesity and cardiometabolic complications, namely blood pressure, in a cohort of black middle-aged African females. It has been previously demonstrated that this cohort has been has a high prevalence of obesity. According to literature reviews, programs focusing on nutritional and behavioural changes could aid African women in their fight against the obesity and hypertension epidemic that we are facing today. The animal-driven nutrient pattern was found to be substantially associated with increases in body fat in this cohort at baseline. At 5-year follow-up, the nutrient patterns remained the same and repeated measurements of the vitamin C, sugar, and potassium-driven nutrient pattern were associated with significant increases in FMI and LMI and the animal-driven nutrient pattern remained significantly associated with LMI, FMI and VAT, a measure of visceral obesity which is a major risk factor for cardiometabolic conditions. This is problematic in a population that consists predominantly of individuals that are classified as having an obese and overweight status. As a result of a higher BMI, a greater likelihood of developing cardiometabolic multimorbidity exists which is defined as the co-occurrence of two or three cardiometabolic conditions. This may result in reduced quality of life and an increased burden on the already overstretched healthcare system in South Africa. Furthermore, this study found that only the animal protein driven nutrient pattern had a significant relationship with SBP which was significant. When SEM was applied, BMI did not mediate the relationship between blood pressure and any of the nutrient patterns. No other noteworthy direct relationships between blood pressure and the other nutrient patterns were found. Researchers can apply the findings of this study to improve nutritional policies and guidelines aimed at combating not just obesity, but high blood pressure among black women in Sub-Saharan Africa. It is necessary to conduct further extensive research to verify these findings.
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    Role of novel biomarkers in predicting chronic kidney disease progression among black patients attending a tertiary hospital in Johannesburg, South Africa
    (University of the Witwatersrand, Johannesburg, 2023) Meremo, Alfred Jackson; Naicker, Saraladevi; Duarte, Raquel; Paget, Graham; Dickens, Caroline
    Background: Chronic kidney disease (CKD) is a leading health issue and its magnitude has been increasing globally; where the developing countries are the most affected and they are the least equipped to deal with its associated consequences. Chronic kidney disease can rapidly and quietly progress to late CKD stages in impoverished environments. Early recognition of patients who are likely to develop end-stage kidney disease (ESKD) is important. Methodology: A prospective longitudinal study was conducted on CKD patients of black ethnicity attending at the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) renal outpatient clinic in South Africa, as from September 2019 to March 2022. Patients provided blood and urine samples for investigations in the laboratory at study enrolment (0) and at the 24 months follow up. The concentrations of the transforming growth factor isoforms [(TGF)-β1, TGF-β2 and TGF-β3) were determined in serum and urine at baseline using the Human TGF-β duoset ELISA. Data were descriptively and inferentially processed by the REDcap and analyzed using STATA version 17 and multivariable logistic regression analysis was applied to find out the predictors of CKD progression. Results: A total of 312 patients were recruited into the study; the median age was 58 (IQR 46 -67) years and 162 (51.9 %) were male. Hypertension was present in majority (96.7 %) of the patients. Diabetes mellitus was present in 38.7 % of patients and 38.1 % of the study patients had both hypertension and diabetes mellitus. A total of 297 (95.2%) patients completed the study. Death was reported in 5 (1.6%) patients and 10 (3.2%) of patients were lost to follow up. The prevalence of CKD progression was 49.5%, 33% had CKD remission and 17.5% had CKD regression while the prevalence of CKD progression by change in uPCR > 30% was 51.9%. Almost half (47.8 %) had a sustained decline in eGFR of > 4 ml/min/1.73 m2 /year or more, 35.0% of the patients moved to a more severe stage of CKD and 19.9% had more than 30% 6 decline in eGFR in two years. For patients with CKD progression, 54.9% patients were men and at baseline, their median age was 59 (46 - 67) years, urine protein creatinine ratio (uPCR) increased at 0.039 (0.015-0.085) g/mmol, eGFR was 37 (32 -51) mL/min/1.73 m2; the median serum TGF-β1 was 21210 (15915 – 25745) ng/L and the median urine TGF-β3 was 17.5 (5.4 –76.2) ng/L. For those who had CKD progression, hypertension was present in the majority (95.2%) of the patients. Diabetes mellitus was present in 59 (40.1%) patients and 58 (39.5%) patients had both hypertension and diabetes mellitus; 48.3% had severely increased proteinuria, 45.6% patients had anaemia, 34.0% had hyperuricemia and 17.7% had hypocalcaemia at baseline. For those patients with CKD progression vs those without CKD progression, the baseline median serum TGF-β1 was 21210 (15915 – 25745) ng/L vs 24200 (17570 – 29560) ng/L, the baseline median urine TGF-β3 was 17.5 (5.4 – 76.2) ng/L vs 2.8 (1.8 – 15.3) ng/L; however, baseline serum and urine TGF-β isoforms did not predict progression of CKD on univariate and multivariable analyses. Regarding use of medications among patients with CKD progression, calcium channel blockers (amlodipine) were used by majority (85.2 %) of the patients. Diuretics were used by 63.4% of the patients and 31.7 % of the patients were using insulin. Variables associated with CKD progression after multivariable logistic regression analysis were moderately elevated proteinuria (OR 2.1, 95% CI (1.1 – 3.9), P= 0.019), severely elevated proteinuria (OR 6.1, 95 % CI (3.2 – 11.6), P = 0.001), hyponatraemia (OR 4.5, 95% CI 1.8 - 23.6, P= 0.042), hypocalcaemia (OR 3.8, 95 % CI 1.0 - 14.8, P = 0.047), anaemia (OR 2.1, 95% CI 1.0 - 4.3, P= 0.048), elevated HbA1c (OR 1.8, 95 % CI 1.2 - 2.8, P = 0.007), diabetes mellitus (OR 1.8, 95 % CI 1.9 - 3.6, P = 0.047), current smoking (OR 2.8, 95 % CI 1.9 - 8.6, P = 0.049), medications which were calcium channel blockers (OR 2.07, 95 % CI 1.04 – 4.12, P = 0.038), diuretics (OR 2.35, 95 % CI 1.37 – 4.00, P = 0.002), insulin (OR 1.96, 95 % CI 1.01 – 3.84, P = 0.048) and baseline serum calcium levels (OR 0.06, 95 % CI 0.01 -0.64, P = 0.019). An increase in uPCR > 30% at two years identified most patients with CKD progression; clinicians and nephrologists should utilize change in uPCR > 30% at two years to identify those patients with CKD who are likely to progress more rapidly, who require closer surveillance and monitoring with emphasis on slowing or stopping progression of the CKD. Conclusion: Our study has demonstrated a higher prevalence of CKD progression in a prospective longitudinal study among black patients than that reported in previous studies. CKD progression was associated with current smoking, hyponatremia, hypocalcemia, anaemia, elevated HbA1c, diabetes mellitus, and proteinuria. While patients with CKD progression had lower baseline concentrations of serum TGF-β1 and increased baseline urinary TGF-β3 concentrations, baseline serum and urine TGF-β isoforms did not predict progression of CKD. The roles of the various serum and urine TGF-β isoforms in CKD progression at baseline are still unclear and highlight the importance of further studies to determine their isoform specific effects.
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    Predicting in-hospital mortality in heart failure patients using machine learning
    (University of the Witwatersrand, Johannesburg, 2023-05) Mpanya, Dineo; Ntsinjana, Hopewell
    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 through precision medicine.
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    Identification of (Novel) Immune Targets with Potential Roles in the Progression of Pancreatic Ductal Adenocarcinoma (PDAC)
    (University of the Witwatersrand, Johannesburg, 2024) Nsingwane, Zanele; Nweke, Ekene
    Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a growing incidence and mortality despite novel therapeutic strategies. Its aggressiveness and difficulty to treat suggest the need for a better understanding of associated molecular mechanisms which could be targeted for treatment. The complement signalling pathway may play diverse roles in PDAC by eliciting an immune response, inducing inflammatory responses, and may elevate pathways linked to chemoresistance. However, their role in the progression of PDAC is not fully understood. This study aimed to identify potential immune response-related targets in a group of patients. Methods: In this study, 30 tissue samples (tumours and corresponding normal tissues) were obtained from 15 PDAC patients, 34 plasma samples were obtained from 25 PDAC patients, 6 patients with chronic pancreatitis, and 3 healthy control participants. Targeted pathway-specific PCR analysis was conducted to determine the gene expression profiles of immune-response-related genes. The circulating levels of complement proteins C3 and C5 were further investigated. Pharmacological inhibition of the complement pathway in MIA PaCa-2 pancreatic cancer cell lines was performed and the effect on cells was assessed by cell proliferation, cell migration, and cell cycle assays. Finally, SWATH-mass spectrometry was performed to identify potential molecular mechanisms during inhibition. Results: The results identified C3 to be overly expressed in early PDAC compared to later stages in plasma (p=0.047). Pharmacological inhibition of the complement pathway led to increased cell growth (p<0.0001), proliferation (p=0.001) and migration (p=0.002) in vitro. Proteomic analysis implicated several proteins such as the mitochondrial and histone proteins, that could play a role in inducing this phenotype. Conclusion: Both Complement C3 and C5 are elevated in PDAC samples compared to healthy ones. Furthermore, the inhibition of the complement pathway was shown in vitro to result in a more aggressive phenotype by stimulating cellular growth, proliferation, and migration, indicating the involvement of complement C3 and C5 in tumour progression. This study helps to further delineate the role of the complement pathway in PDAC progression.
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    An in-silico analysis of the glycosylation inhibitors Brefeldin A and Tunicamycin C in colorectal cancer; characterization of novel targets
    (University of the Witwatersrand, Johannesburg, 2024) Naidoo, Vivash
    Colorectal cancer (CRC), a prevalent malignancy in South Africa, is significantly influenced by posttranslational modifications such as glycosylation. This study investigates the complex interactions between genes, signalling pathways, and cellular processes involved in CRC progression and glycosylation. The glycosylation inhibitors, Tunicamycin and Brefeldin A, are known to hinder colon cancer cell proliferation, migration, and invasion, making them potential therapeutic agents. We used Swiss Target Prediction Software to identify target proteins for both compounds and revealed that Protein Kinase C Alpha (PRKCA), Peroxisome Proliferator- Activated Receptor Gamma (PPARG), and Mitogen-Activated Protein Kinase 1 (MAP2K1) are specific for Brefeldin A, and TK1 and PRKCA for Tunicamycin, respectively. These proteins were selected based on their potential role in the glycosylation process and their role in CRC-related pathways. Further, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis disclosed significantly enriched pathways, including Epstein-Barr virus infection, cellular senescence, and cancer pathways. The 3D-crystallographic structures of PrKC1 (PDB ID 6ar4), TK1 (PDB ID 1w4r), PrCK1 (PDB ID: 6ar4) and MAPK (PDB ID: 3eqc) were retrieved from RCSB Protein Data Bank. The compounds BSP and EGCG were downloaded from PubChem. All non-relevant co-crystallized molecules, including ions, crystallographic water, and others, were removed. Missing residues in the proteins were filled in using the MODELLER algorithm on the UCSF Chimera Graphic User Interface. Molecular docking of Tunicamycin C and Brefeldin A was performed with UCSF Chimera, and the docked conformations were visualised in Maestro and Chimera. The complexes with the top docking scores were selected and prepared for molecular dynamics simulation studies to offer structural and dynamic perspectives on the inhibitory potential of the compounds against the target proteins. The Origin Lab software tool was used to post- analyze the docking conformations. Molecular Dynamics simulation was conducted using Graphics Processing Units version of the Particle Mesh Ewald Molecular Dynamics engine in the AMBER18 suite. Our investigation into the dynamic events leading to the proximal binding of Tunicamycin at the pockets of TK1 and PrKC1 suggested that the binding of Tunicamycin induced a conformational perturbation of the 3D structures of these proteins, resulting in a structural deviation that inhibited their activity. Tunicamycin's time-based dynamics indicated a stable pattern, leading to optimal interaction and maximal stabilization in the hydrophobic pockets of TK1 and PrKC1. Binding energy calculations showed a high-affinity interaction of Tunicamycin with these proteins. Similarly, the structural investigation revealed that the binding of Brefeldin A to Mitogen- Activated Protein Kinase (MAPK) and Protein Kinase C (PrKC1) inhibited their activity. A detailed analysis of active site residues revealed crucial residues that contributed to the binding stabilization of Brefeldin A. It was noted that the Brefeldin A/MAPK complex produced a binding energy of -22.18±4.50Kcal/mol while the Brefeldin A/PrCK1 complex produced a binding energy of -23.90±5.36Kcal/mol. These findings provide crucial insights into designing novel inhibitors of TK1 and PrKC1, potentially blocking glycosylation progression in cancer treatment. This study underscores the potential for exploiting glycosylation inhibition as a therapeutic strategy against CRC, opening avenues to mitigate cancer progression