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Doctoral Degrees (Clinical Medicine)

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    An exploration of the learning environment and career intentions: a mixed methods study of paediatric interns at KwaZulu-Natal.
    (2018) Naidoo, Kimesh Loganathan.; Van Wyk, Jacqueline Marina.
    Background: Globally, there is increased pressure on health professions education to be responsive to inequities in health care. These imperatives are clearly evident in KwaZulu-Natal (KZN) with its high disease burden. Poor doctor to patient ratios here are exacerbated by migration of medical practitioners to urban areas, private practice and developed countries. South Africa’s two–year internship aims at producing primary health care clinicians for the public health system. Gaps in knowledge of internship and intern career intentions, in resource challenged contexts, have translated to the failure by both higher education authorities and national health departments to include the internship period in strategies, to ensure that the inequities in health care are addressed. Aim: This explorative study used a mixed methodology approach to explore the factors that influence perceptions of the learning environment (LE) during internship and their influence on career intentions. Methods: The study used a social constructivist worldview drawing on a sequential explanatory mixed methods design to understand the construct of the LE and its influence on career intentions. Both quantitative and qualitative methods that included surveys using a locally validated version of the Postgraduate Hospital Educational Environment Measure (PHEEM) and focus group discussions were generated. This study was conducted among interns in Paediatrics at four hospital complexes in KwaZulu-Natal in 2015. The Communities of Practice theory and the Social Cognitive Career Theory were drawn on and supplemented by the theory of alienation and engagement to develop a conceptual framework that informed the analyses of the relationship between perceptions of the LE and career intentions. Results/Findings: Perceptions of the LE were found to be influenced by both external (disease burden, workload and resource constraints) and individual related contextual factors (supervisor -intern relationships, mentorship, feedback and demography). These factors acted as alienating influences that curtailed access and restricted participation within communities of practice in internship. A narrow view of the role and scope of interns was reflected in significant differences between interns and their supervisor’s perceptions of the LE and gaps in assessment practices of SA interns compared with international best practices. Poor perceptions of the LE drove interns away from SA’s public health system and from caring for children. There were strong aspirations to specialise and weaker aspirations to enter primary health care amongst the sampled interns. Conclusion: Contextual factors in a resource limited LE impacted on identity and career self-efficacy formation of SA interns who failed to see a future role for themselves in primary health care and child health within the public health system. Expanding on the framework of communities of practice a new model of understanding, of how the interplay of contextual factors in resource challenged contexts affects internship learning and career interest formation, was developed. This new knowledge of context on learning and career interest provides the framework to understand the discordance between national health needs and career aspirations of interns in resource challenged environments. This new understanding provides the theoretical underpinning for changes in policy, practice, curricula content and future research to improve access and create an expansive participatory framework for SA interns. These proposed changes in the SA learning environment has the potential to ensure a sustainable public health system and redress the inequity seen in distorted doctor patient ratios in areas of need.
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    Adequate analgesia in caring for paediatric burns patients in a peri-urban setting in KZN.
    (2020) Wall, Shelley Lynn.; Clarke, Damian Luiz.; Allorto, Nikki Leigh.
    This PhD thesis centres on achieving adequate analgesia in caring for paediatric burn-injured patients in KwaZulu-Natal, South Africa. The burden of burn injuries in sub-Saharan Africa is huge. A large number of children in the under-five age group sustain burns in the region annually. Pain is virtually synonymous with burn injuries. All children with burns experience pain, regardless of the cause, size or depth of the burn. This PhD study aimed to improve the care offered to paediatric burns patients by addressing obstacles to adequate analgesia in paediatric burns patients; and to offer a practical, easy to use, locally applicable analgesia protocol which can be used at district, regional and tertiary hospitals alike. The objectives were to identify deficits in the knowledge of doctors in terms of prescribing procedural analgesia for children with burns; to evaluate the use of an alternative analgesic agent, Methoxyflurane, for pain management during dressing changes in an outpatient department; to compare the analgesic requirements of children presenting with acute versus chronic burns; to evaluate the use of an alternative analgesic agent, Methoxyflurane, for pain management during dressing changes for patients admitted to the burns ward; to evaluate obstacles to adequate analgesia in paediatric burns patients; and to develop an analgesia protocol applicable to KwaZulu-Natal and other low-middle-income countries (LMIC), through the consensus of experts in the field. The development of this protocol was conducted in three phases. The first phase involved assessing obstacles to adequate analgesia in paediatric burns patients. The second phase involved assessing Methoxyflurane as an alternative analgesia option in both the inpatient and the outpatient setting; and the final phase involved the addition of Methoxyflurane to our analgesia protocols and reaching an expert consensus that the elements included in the analgesia protocol were applicable to KwaZulu-Natal and other low-middle-income settings. The analgesia protocol for paediatric burns patients has been developed with the local setting and resources as a primary consideration. It was specifically designed to be easy to use, safe in novice hands and locally applicable. In order to ensure that theoretical findings from the study are translated into practices that benefit all burn-injured children, this research should be combined with advocacy efforts.
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    Epidemiology of chronic kidney disease in KwaZulu-Natal: evaluation of risk factors, complications and diagnostic methods.
    (2017) Madala, Nomandla Daphne.; Assounga, Alain Guy Honore.
    Chronic kidney disease (CKD) is associated with increased morbidity and mortality as well as costly renal replacement therapy. The aim was to determine risk factors and complications that contribute to morbidity as well as a suitable diagnostic detection method for CKD. Methods Observational studies were done at 2 hospitals. To assess risk factors, 283 patients were included at the Durban site, and sub-studies undertaken within this sample for CKD complications, while 302 patients were studied at the Empangeni outreach site. To evaluate predictive performance of estimated glomerular filtration rate (eGFR), data from 148 patients were analysed. A further 76 patients were recruited, to develop an African equation. Cockcroft Gault, Modified Diet in Renal Disease and CKD Epidemiology Collaboration eGFR equations were compared with technicium-99-mdiethylenetriaminepentaacetic acid (99mTc-DTPA)-GFR as the gold standard. Body composition was assessed by anthropometry and dual energy X-ray absorptiometry. Data were analysed with STATA. Results The commonest CKD risk factors were hypertension (75%), diabetes (29%) and human immunodeficiency virus (HIV) infection (24%), with HIV commoner at the outreach site (28.5% vs 19.8%). Over 80% of females and ∼60% males were overweight/obese overall; however, clinical cardiovascular disease was commoner in Durban (28% vs 5%). Complications were observed in early CKD; prevalence increased as eGFR declined from ≥90 ml/min/1.73m2 to <30 ml/min/1.73m2: hyperuricaemia increased from 17% to 74%, metabolic acidosis (11.6% to 72.7%), anaemia (2.9% to 69.7%), hyperphosphataemia (10.1% to 48.5%), all p<0.001, respectively, and hypocalcaemia from 1.5% to 18.2% (p=0.003). Lower GFR levels were also associated with lower serum albumin levels, and lower whole body as well as regional lean mass and fat mass in males. A further observation at GFR <30 ml/min/1.73m2 was that eGFR underestimated 99mTc-DTPA-GFR in African patients. Prediction of 99mTc DTPA-GFR was also poor at GFR levels ≥60 ml/min/1.73m2, with eGFR overestimating 99mTc-DTPA-GFR. An eGFR equation developed in African patients resulted in significantly better GFR prediction and showed the lowest bias, highest precision as well as accuracy. Conclusion Efforts are needed to enable non-nephrologists to manage CKD risk factors and complications. Prediction of GFR may be substantially improved by using an equation developed in Africans.
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    The use of feedback and feed-forward action plans on the development of clinical skills in undergraduate medical students.
    (2019) Abraham, Reina Mary.; Singaram, Veena S.
    Background: Deliberate practice is a concentrated learning strategy aimed at achieving a defined goal and feedback enables skills and behaviours to be corrected or reinforced for improved patient care. Clinical skills are initially taught during the pre-clinical years in a clinical skills laboratory using simulated patients and manikins before applying them on real patients. There is a need to increase medical students’ engagement, orientation, acceptance and assimilation of feedback to enhance their clinical competence. To move feedback forward and to encourage a change from a unidirectional teacher-learner dialogue to a co-constructed dialogue, feedback strategies or ‘feed-forward action plan interventions’ need further investigation. Aim: To explore the medical students’ receptivity to feedback, their engagement with feedback interventions and the role of deliberate practice in tutor and peer clinical skills logbook formative assessment feedback. Methods: This mixed methods study comprised of both quantitative and qualitative aspects. Five semi-structured focus groups were conducted with twenty-five purposively selected third year medical students. In the first study, data was thematically analysed through a psychological framework, underpinned by four psychological processes: Awareness, Cognizance, Agency and Volition, to understand learner behaviour to feedback reception, interpretation and uptake. In the second study, high and low academic performing students’ experiences of self and peer feedback was explored. In the quantitative part of the study we adapted and developed a feedback scoring system based on the deliberate practice framework to assess the quality of the feed forward strategy implemented in the 2nd and 3rd year medical students tutor and peer logbooks to identify deliberate practice components i.e. task, performance gap and action plan. The sample consisted of 1025 feedback responses. Results: This study found that awareness, understanding, agency and volition revealed facilitators and barriers to feedback receptivity. Feedback aligning with the personal goals of the learner, the reliability of the teacher in delivering feedback and establishing relationships strengthened reception. The depth and timing of feedback utilization varied among students as their self-regulatory focus on the feedback process dominated their active use of feedback. Students with lower performance believed they lacked adequate skills to engage with self and peer feedback interventions. Higher-level students reported that receiving peer input helped them take responsibility for tracking and assessing their learning, suggesting that students require numerous self-evaluation opportunities to improve their judgment over time. Teacher feedback on interventions testing clinical cognition had a positive impact on feedback engagement and self-regulating learning. Analysis of the 2nd and 3rd year written feedback revealed all three deliberate practice components with a higher peer than tutor frequency in both classes respectively. Decreased student achievement was associated with increase in tutor gap xii and action feedback scores and vice versa in peer scores. The overall quality of feedback provided by tutors and peers was moderate and less specific (average score < or =2). Conclusion: Using the deliberate practice framework improved the feed-forward quality of feedback as comments contained elements facilitating deliberate practice. Providing constructive feed-forward feedback linked to tasks learning objectives and assessment outcomes has the potential to promote self-regulation by stimulating self-awareness and self-directed monitoring through reflection-in-action. The less competent learners received and used feedback differently and the above effects were either immediate or undeveloped. To motivate immediate feedback engagement due to their self-regulatory focus of postponing feedback use closer to exams, this study recommends the novelty of integrating the logbook sessions with a feedback design that makes learners actors in the feedback process after receiving feedback. Newer feedback initiatives that target a feedback intervention for learners to scaffold feedback by reflecting and formulating self-generated performance improvement goals based on what they did well and areas that need improvement would serve as a source of coaching to facilitate feedback interpretation and utilisation to feed forward. Goal setting supports learners’ active engagement with feedback by stimulating them to read and understand the feedback, identify areas that require development, develop learning goals and then convert these goals into action by adjusting their behaviour. Equipping learners to engage with peer feedback processes through the feed forward intervention enables development of shared responsibility and self-directed learners with greater agency over assessment and feedback process. Responsibility sharing has the potential to ensure sustainability of the educator’s effective feedback practices reducing the emotional burden on both students and educators. This study emphasises the importance of a clinical skills feedback culture as a faculty development programme to strategically direct student learning by reinforcing desirable behaviour change towards professional identity and professionalism. Further, a novel approach based on psychological processes to understand the barriers and facilitators of feedback receptivity is proposed. Using a theoretical framework based on deliberate practice and feedback intervention theories, this study expands our understanding of factors influencing the situational and learners’ self-regulatory use of feedback. In addition, a conceptual framework and a feedback-scoring tool are proposed to pave the way for moving feedback forward and to highlight the importance of feedback-feed-forward action plans. Key words: Clinical Logbook; Feedback; Evaluation; Deliberate practice; Feed-forward; Feedback literacy; Feedback culture; Clinical skills, Formative Assessment.
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    Snakebite in KwaZulu-Natal: the burden of disease and prediction of risk of adverse outcomes.
    (2016) Wood, Darryl Ross.; Hift, Richard Jefcoate.
    BACKGROUND The total number of snakebites per annum in KwaZulu-Natal (KZN) is unknown. Yet it is believed that the burden that snakebites place on hospitals in areas with a high incidence of snakebite is significant. There are no official snakebite guidelines in South Africa or KwaZulu-Natal. The result is non-uniform management practices and in many cases inappropriate prescribing of antivenom, which may potentially be harmful given a high rate of allergic reactions to antivenom. In order to standardise practice along evidence-based lines, it is important to identify factors predictive of a poor outcome so that treatment can be appropriately targeted at those individuals. AIMS 1. To determine a figure for the annual incidence of snakebite, identify regional variations in incidence and estimate the burden of snakebite on public hospitals in the north-eastern province of KwaZulu-Natal, an area in which snakebite is endemic. 2. To report a five-year prospective experience with snakebite in a highly endemic area of South Africa and to identify factors predictive of severity. 3. To develop and validate a severity scoring system to facilitate the management of snakebite in South Africa by allowing early identification of patients at increased risk of a severe course, and thereby develop an improved algorithm for the management of snakebite. 4. To determine the site of expansion accounting for the swelling in patients bitten by a cytotoxic snake species, in particular to distinguish between muscle compartment swelling and superficial swelling, and to determine the clinical utility of bedside ultrasonic examination as a potential tool for identifying patients with possible compartment syndrome. METHODS The work is reported as four sub-studies, using a selection of methodologies appropriate to each, which are fully described in Chapters 2-7. In order to determine incidence of snakebite, we applied a novel method whereby incidence was extrapolated from antivenom supply data provided by the central provincial pharmacy depot, with the appropriate conversion factor being determined from a stratified a sample of 6 hospitals. We analysed prospectively captured data on all patients admitted to Ngwelezane Hospi Emergency Department from September 2008 to December 2013 with a diagnosis of snakebite. Using the need for an active treatment intervention (ATI), which we defined as antivenom administration or surgical intervention as a proxy for severity, we analysed our data for factors present on admission which were predictive of severity. In a subsequent study, we developed a severity score on a cohort of patients, which was then validated in a separate and subsequent cohort of patients. We developed a methodology for the assessment of depth of bite in patients bitten on a limb whereby the ratio of the thickness of the deep muscle compartment and the subcutaneous compartment of the bitten limb, measured by bedside ultrasound, were expressed proportionally, and compared with the ratio on the unaffected limb. This information was then used to identify the major site of swelling. RESULTS Incidence We estimated that 11% (95% CI: 8-14%) of snakebite presentations to hospital resulted in the administration of antivenom. By extrapolation, the overall incidence for KZN was 16/100 000. There was wide geographic variation, with the highest incidence, at 82/100 000 in the subtropical north east of the province. The estimated annual cost of snakebite in KZN was between USD 1 135 782 and USD 2 877 314. Analysis of a case series and prediction of severity 879 cases were analysed. Envenomation was identified in over two thirds of admissions. Cytotoxic snakebites accounted for 98% of envenomations. Only 4 cases of haemotoxic bleeding and 5 cases of neurotoxicity were admitted. Although we demonstrated a significant correlation between severity and prolonged INR, reduced platelet count, haemoglobin, reduced or elevated leucocyte count and elevated serum urea. However, their use as predictors of severity was limited by poor sensitivity and specificity. Clinical factors correlating with severity were the paediatric age group and a delayed presentation to hospital. In the prospective study, 146 of 879 snakebite admissions in the development cohort and 40 of 100 in the validation cohort reached the primary end point of an ATI. Six predictors of risk for ATI were identified from the development cohort: age <14 years, delay to admission >7 hours, white cell count > 10x109 cells/l, platelet count<92 x109/l, haemoglobin <7.1 g/dl, INR >1.2. Each risk predictor was assigned a score of 1; ROC curve analysis returned a value of more than 4 out of 6 as the optimal cut-off for prediction of an ATI (AUC 0.804; 95% CI 0.758-0.84). Testing of the score on the validation cohort produced a sensitivity of 22.5% and a specificity of 96.6%. The PPV and NPV were 81.8% and 65.2% respectively. Ultrasonic determination of the site of swelling in cytotoxic envenomation The majority of bites were in the upper limb (27/42). Tissue expansion was noted in both the sub-cutaneous and muscle compartments of the envenomed limbs. The site of swelling was predominantly in the subcutaneous tissues, while swelling in muscle compartment was limited (the mean expansion coefficient for subcutaneous tissues was 2.0 (CI: 1.7-2.3) versus 1.06 (CI: 1.0-1.1) respectively). The difference between the groups was significant (P<001). One case, confirmed as compartment syndrome, showed marked swelling in the muscle group and stood out as a clear outlier in terms of the expansion coefficient. CONCLUSIONS The burden of snakebite is substantial, and is felt unequally across the province. Furthermore, we propose that our method may be used to estimate the incidence of other diseases treated with a standard regimen and for which incidence figures are otherwise unknown. Two-thirds of patients who present to hospital with snakebite in north-eastern South Africa will have symptoms of envenomation, with the overwhelming majority manifesting cytotoxicity. Bites by neurotoxic and haemotoxic species are rare. We have identified a number of factors which may potentially be of value in predicting severity, but which are on their own of insufficient accuracy to be reliable. Basic ultrasound techniques may be used to identify the site and degree of tissue swelling from cytotoxic envenomation. It is a non-invasive, painless procedure that can assist the clinician to assess the injured limb and may also be of benefit to monitor the progression of swelling. Our scoring system, which we propose to name the Zululand Snakebite Severity Score (ZSSS), is a useful adjunct to clinical assessment in managing snakebite. A patient with a positive result has an 80% probability of progressing to the point where an ATI is indicated. Its value is greatest in those patients who fall in the mild to moderate clinical category. This score now requires validation on a wider scale across South Africa, to determine its accuracy in areas other than those in which it was tested.
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    Acute pancreatitis in a high HIV prevalence environment: analysis of prevalence, demographics, prognosticators and outcomes.
    (2019) Anderson, Frank.; Thomson, Sandie Rutherford.
    Background It is unclear what is the true prevalence of HIV related acute pancreatitis and whether diagnostic and prognostic markers used in patients without HIV infection are as effective in HIV related pancreatitis and if morbidity is worse in HIV infected patients. Methods Using a prospective, descriptive design, HIV prevalence was compared in trauma and acute pancreatitis patients. Serum amylase was used to diagnose acute pancreatitis. Prognostication was by CRP, BISAP, Glasgow and APACHE II scores at 24 hours. Sensitivity, specificity and AUC were compared in predicting a severe outcome in acute pancreatitis. Complications and mortality were compared in 238 HIV+ve and HIV-ve patients admitted to 2 regional hospitals in Durban between August 2013 and October 2015. One hundred and eighty one patients were admitted with trauma. Results Between August 2013 and October 2015, 238 patients were admitted with acute pancreatitis and 181 with trauma. HIV infection was higher in patients with acute pancreatitis (38% vs 16%) (p=0.001) and they were also older (40 vs 33 years) (p=0.001). Fifty three percent of HIV +ve patients were female and 65% of the HIV-ve patients were male in the pancreatitis cohort and 59% of the trauma and pancreatitis patients were on Highly Active Antiretroviral Therapy. The prevalence of gallstone (27% vs 30%), alcohol (41% vs 52%), dyslipidaemia (0% vs 3%) and idiopathic (6% vs 14%) aetiologies were similar in HIV+ve and HIV-ve patients and a drug related aetiology (24% vs 0%) (p<0.001) was more prevalent in HIV related acute pancreatitis. CRP was more effective in predicting severe disease in HIV-ve patients (AUC= 0.75) and patients with CD4 counts of ≥ 200 cells/mm3 (AUC=0.73) and not HIV+ve patients (AUC= 0.59) or patients with counts below 200 cells/mm3 (AUC= 0.46). The BISAP system had similar efficacy with AUC of 0,71 and 0.74 in HIV-ve and HIV+ve patients respectively, was poor in CD4 count < 200 cells/mm3 (AUC=0.68) and good in CD4 count> 200 cells/mm3 (AUC=0.9). The Glasgow score was of similar efficacy in HIV-ve (AUC = 0.72) and HIV+ve patients (AUC=0.78) and better in patients with CD4 count < 200 cells/mm3 (AUC=0.83) and CD4 count ≥ 200 cells/mm3 (AUC=0.81). The APACHE II had uniform efficacy in both HIV-ve and HIV+ve patients (AUC >0.8) and both CD4 count ranges (AUC > 0.80). Septic complications occurred in 10(8%) of HIV-ve patients and 4(4%) HIV+ve patients. There was no difference in morbidity (25% vs 33%) and mortality (6% vs 6%). Conclusions HIV infections is more prevalent in acute pancreatitis than in a hospital trauma cohort which represented the general population. The APACHE II system was the most accurate in predicting morbidity and CRP least accurate. The outcomes were similar in HIV+ve and HIV-ve patients but the statistical assumptions in calculating the sample size, given the low frequency of morbidity and mortality observed in this study may have resulted in an alpha error.
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    Radiologic evaluation of breast disorders related to tuberculosis amongst women in Durban, KwaZulu-Natal, South Africa.
    (2016) Ramaema, Dibuseng Paulina.; Somers, Sat.; Hift, Richard Jefcoate.
    Women in KwaZulu-Natal Province, South Africa, are at high risk of developing breast tuberculosis (BTB) due to the increased incidence of HIV. However, there is a general lack of knowledge regarding the various diseases that can affect the breast. This is compounded by lack of the national breast screening program. As a result, many patients with breast cancer (BCA) and BTB are initially misdiagnosed by clinicians. It was evident from the study that much still has to be done in educating the public and healthcare workers about breast diseases. This project endeavoured to compare the effectiveness of various radiological technologies to identify breast problems. The study consisted of three phases all based at Ethekwini Municipality tertiary referral hospitals. The first phase aimed to determine the prevalence of the BTB using retrospective data over a period of 13 years. The same data further provided information of the clinical and radiological manifestations of BTB. This study concluded that while BTB is not common, it shares the clinical and radiology features with BCA, and is difficult to diagnose with current pathology methods. The second phase was done prospectively by recruiting patients who were newly diagnosed with BTB. The aim was to evaluate the use of modern imaging techniques to further describe the radiology patterns of BTB and to determine the radiological parameters that may be used in disease monitoring. The results provided insight into disease extent, and showed that it is usually more severe than perceived with current diagnostic methods. The third phase was performed using retrospective image analysis of patients who had BCA and BTB by using modern radiology techniques. The purpose was to identify the salient features that can differentiate BTB from the BCA. Several radiology parameters were identified as possible biomarkers for differentiation between the two conditions. The knowledge of their respective features would aid in the timeous diagnosis of both conditions, particularly in cases where the pathology results are inconclusive for various reasons. Overall the study highlights the lack of evidence based information on BTB. Recommendations and conclusions are provided in the last chapter.
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    The effect of HIV infection on the management of end-stage renal failure among patients undergoing continuous ambulatory peritoneal dialysis.
    (2017) Ndlovu, Kwazi Celani Zwakele.; Assounga, Alain Guy Honore.
    Continuous ambulatory peritoneal dialysis (CAPD) is cost effective, easy to learn, and requires no complex equipment, thus, is well-suited as a home dialysis modality in areas with distant or limited dialysis facilities. We aimed to evaluate the effects of HIV infection on CAPD outcomes in dialysis-requiring end-stage renal disease (ESRD) patients. The first report (Chapter 2) evaluated the effects of HIV-infection on primary end points of mortality and catheter failure, and primary morbidity outcomes of first peritonitis and hospital admissions at one year. HIV infection was not shown to adversely influence catheter failure rates or patency; however, uncontrolled HIV infection was associated with increased relative risk of mortality, first peritonitis, and hospital admissions. The second report (Chapter 3) evaluated the effects of HIV infection on all peritonitis episodes, including relapses and subsequent episodes at 18 months. HIV infection was associated with increased risk for overall peritonitis and peritonitis relapse. Although peritonitis was also associated with adverse catheter failure outcomes, HIV infection was not shown to result in significantly increased catheter failure rates at 18 months. The third report (Chapter 4) evaluated the effects of HIV infection on nasal carriage of Staphylococcus aureus, staphylococcal peritonitis, and catheter infection rates. HIV infection was shown to be a risk factor for methicillin-resistant S. aureus nasal colonisation, and that it can increase the risks of coagulase-negative staphylococcal peritonitis and S. aureus catheter infections in association with S. aureus nasal carriage. The fourth report (Chapter 5) evaluated shedding of HIV-1 particles into CAPD effluents. HIV particles were shown to be shed in detectable amounts into CAPD effluents even in patients with suppressed plasma viral load, raising concerns of a localised sanctuary site and potential infectivity of HIV-positive CAPD patients on a full complement of antiretroviral therapy. The thesis contributes to our understanding of the morbidity and mortality associated with uncontrolled HIV infection in ESRD patients on CAPD, the shedding of HIV-1 particles into CAPD effluents, and the resistance profiles of S. aureus colonisers and the organism patterns that are likely to cause infection, which may assist in guiding appropriate antibiotic therapy and prophylaxis.
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    Effects and mechanisms of interleukin-10 promoter polymorphisms on HIV-1 susceptibility and pathogenesis.
    (2012) Naicker, Dshanta Dyanedi.; Ndung'u, Peter Thumbi.
    HIV infection has risen to pandemic proportions. Interleukin-10 (IL-10), a potent antiinflammatory cytokine has been shown to enhance the establishment and persistence of chronic viral infections through inactivation of effector antiviral immune responses and it may also directly influence HIV-1 replication in cells of diverse lineages. IL-10 promoter polymorphisms have been shown to affect HIV-1 susceptibility and pathogenesis. However, the underlying mechanisms are poorly understood. We investigated the relationship between IL-10 promoter variants, plasma IL-10 levels, and markers of disease outcome in chronically HIV-1-infected individuals. To investigate the mechanistic role of IL-10 and its genetic variants on HIV pathogenesis, we studied markers of activation on B cells, CD4+ and CD8+ T cells, and assessed effects on CD4+ T cell proliferation with and without blockade of the IL- 10 pathway. We used Taqman genotyping assays to genotype three IL-10 promoter single nucleotide polymorphisms (SNPs) in our study cohort. Baseline plasma IL-10 levels were measured using Luminex technology for 112 individuals. Viral load, CD4+ T cell counts and cytotoxic T lymphocyte (CTL) immune responses were measured at baseline. The rate of CD4+ T cell decrease was calculated in 300 individuals with a median follow-up of 25 months. CD38, CD95, Ki67, IgG and PD-1, markers of activation or exhaustion were measured on B cells, and CD38, CD95, Ki67, HLA-DR and PD-1 were measured on CD4+ and CD8+ T cells in a subset of 63 individuals. CD4+ T cell proliferation was measured using Carboxyfluorescein succinimidyl ester (CFSE) assays, following IL-10 receptor blockade in a subset of 31 individuals. The IL-10 -1082G, -592A and -3575 variants were observed at frequencies of 0.3, 0.34 and 0.23 respectively, in our study cohort. Plasma IL-10 levels were significantly higher in the - 1082GG group than in the combined AA/AG group (p=0.0006). There was a significant association between the 592AA genotype and a greater breadth of CTL responses compared to the CC and CA (p= 0.002 and 0.004 respectively). The -592AA genotype associated significantly with an attenuated loss of CD4 cells (p= 0.0496), with -592AA having the least change in CD4 cells per year. The median expression of HLA-DR, a marker of T cell activation was significantly higher in the-1082AA group for CD8 cells (p= 0.047), and the - 592AA group for CD4 T cells (p= 0.01). The median expression of IgG on the surface of B cells was significantly higher in the -1082GG genotype and the -592CC genotype (p=0.0183 and 0.0659 respectively). Overall, IL-10 variants correlated with IL-10 expression and CD4 decline during chronic HIV-1 infection. IL-10 promoter variants may influence the rate of HIV-1 disease progression by regulating IL-10 levels, which in-turn, may affect the breadth of CTL responses. Furthermore, the increased expression of HLA-DR and PD-1 on CD8+ and CD4+ T cells, indicates that lower IL-10 levels are associated with increased immune activation and immune exhaustion. The increased expression of IgG on B cells, suggests that in a setting of lower IL-10, there is possibly a bias towards a Th2 immune response. These data suggest a significant role for IL-10 genetic variants and IL-10 in HIV pathogenesis. Further studies to determine whether and how the IL-10 pathway may be manipulated for therapeutic or vaccine strategies for HIV are warranted.
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    The influence of helminths on immune responses to HIV.
    (2009) Mkhize-Kwitshana, Zilungile Lynette.; Walzl, Gerhard.; Taylor, Myra.
    In South Africa, co-infection with HIV and intestinal parasites is a major challenge in disadvantaged communities who live in densely populated under-serviced urban informal settlements. This pilot cross sectional study evaluates the immunological effects of co-infection with Ascaris lumbricoides and Trichuris trichura on the immune response to HIV. The work was a substudy of a prospective double blind, placebo-controlled investigation to test whether regular deworming changes the immune profile of HIV positive individuals with concurrent helminth infection. The substudy has a cross sectional design and presents pilot data that defines immune profiles of HIV-1 positive individuals with and without gastrointestinal helminth (Ascaris lumbricoides and Trichuris trichura) infection. The hypothesis was that concurrent helminth infection adversely affects immune responses against HIV. It was conducted in an area of high helminth endemnicity and limited infrastructural resources. Individuals with known HIV infection were recruited from an HIV Support Group and HIV negative individuals residing in the same area (for demographic matching) were used for comparison. The substudy was to provide pilot data for future larger scale and possible interventional studies. The current work is limited by the cross sectional design, moderate sample size and practical challenges. The profile of lymphocyte phenotypes, viral loads, eosinophils, activation markers, expression of the nuclear proliferation antigen-Ki67 and activation regulator antigen CTLA-4 were analysed using flow cytometry in HIV positive and negative subgroups with or without helminth infection. The type-1, type-2 and inflammatory cytokines were analysed using multiplex cytokine array technology. These were correlated with immune responses to HIV. Non parametric statistics were used to describe differences in the variables between the subgroups. A major finding of the study was the result of the supplementary use of the serological marker, Ascaris lumbricoides-specific IgE in addition to the presence (or absence) of helminth eggs in stools to classify intestinal helminth infection status. Two significant outcomes of this measure were the enhancement of diagnosis of current or recent helminth infection and, more importantly, the distinction of different phenotypes of individuals who displayed different immunological responses to co-infection with HIV and helminths. The different helminth infection phenotypes are defined by stool egg positivity (egg⁺) or negativity (egg⁻) with either high or low Ascaris-specific IgE (IgEhi or IgElo) respectively. The four subgroups, egg⁺IgEhi, egg⁺IgElo, egg⁻IgEhi and egg⁻IgElo showed different interactions with regards to immune response to HIV. It should be noted that no Trichuris specific IgE tests are commercially available but that there is significant antigenic cross-reactivity with Ascaris antigen. The presence of helminth stool eggs and high Ascaris IgE (egg⁺IgEhi) was associated with the following characteristics: reduction in numbers of all lymphocyte populations, frequent eosinophilia, highly activated immune profiles, antigen specific proliferative hyporesponsiveness, impaired type 1 cytokine responses in unstimulated and antigen stimulated cells and increased TNFα levels. In HIV infected individuals, the egg⁺IgEhi helminth infection status was associated with lower but not significant CD4⁺ counts and higher viral loads. A strong negative correlation was observed between viral loads, CD4⁺ and CD8⁺ cells in this subgroup. Subgroups with high IgE (egg⁺IgEhi and egg⁻IgEhi) had elevated Th2 markers with lower CD4⁺ counts and higher viral loads in the HIV⁺ group. The inverse correlation between viral load and CD4⁺ counts found in all the HIV⁺ participants was strongest in these two subgroups. Individuals with parasite eggs in stool and low Ascaris IgE (egg⁺/IgElo) presented a modified Th2 profile. This subgroup had high absolute numbers of all lymphocyte subsets in both HIV⁻ and HIV⁺ groups with higher CD4⁺ counts in the HIV⁻ and lower viral load in the HIV⁺ groups as well as higher interferon gamma, lower IL-4 and higher IL-10. In conclusion, the results suggest that helminth infections may be associated with deleterious effects on the immune responses to HIV in certain groups of susceptible individuals. The underlying reasons for the different stool egg/Ascaris IgE combinations in settings with high exposure to helminthes is currently not clear but genetic predisposition and environmental factors could play a role. Future studies of helminth- HIV co-infection have to ensure adequate definition of helminth infection status by the use of both stool examination and measurement of helminth-specific IgE as the infection phenotype is associated with differential effects on HIV associated immune responses. This may also apply to co-infection with other pathogens, including tuberculosis. The long-term effect of helminth co-infection in HIV positive people was not assessed in this study but requires further studies.
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    Human lymphocyte antigens.
    (1992) Hammond, Michael Graham.
    This thesis embodies much of my work done over the past 25 years. The impetus for these studies was the need to provide the best tissue typing available for organ transplantation and to overcome the problems of defining HLA antigens in different ethnic groups. These goals were achieved by extensive international collaboration and participation in the International Histocompatibility Workshops. The discovery that the HLA antigens are associated with many diseases led to an epidemic of investigations in which over 500 diseases have been studied. In retrospect, it is not surprising that auto-immune diseases such as diabetes and rheumatoid arthritis showed such marked associations with HLA antigens. The studies in Part II of this thesis were aimed at finding out if the HLA associations reported in Caucasian populations were also present in the Black and Indian populations. These research interests led to my being invited by the National Science Council of the Republic of China in Taiwan to be a Visiting Professor at the National Taiwan University in Taipei for the 1989 academic year. I investigated the association between HLA and naso-pharyngeal carcinoma in Chinese during that year. I wish to express my appreciation to Dr Peter Brain who inspired the early investigations and continued to encourage and support my research. I am grateful to all my co-authors and the many colleagues, clinicians and laboratory staff who have contributed to the various research programmes. Studies of the relationship of the HLA system to cancer, diabetes, arthritis and other diseases have been supported in part by grants from the National Cancer Association and the Medical Research Council of South Africa.
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    Skin disorders in primary health care in KwaZulu-Natal : testing for solutions after assessment of burden of disease, and evaluation of resources.
    (2007) Aboobaker, Jamila B.; Abdool Karim, Salim Safurdeen.; Taylor, Myra.; Coovadia, Hoosen Mahomed.
    No abstract available.
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    Cardiovascular evaluation of hypertensive disorders of pregnancy by echocardiography.
    (2004) Desai, Dushyant K.; Moodley, Jagidesa.; Naidoo, Datshana Prakesh.
    Background: Preliminary observations suggest that aberrations in maternal central hemodynamics and uterine artery Doppler velocimetry reflect the severity of hypertensive disorders of pregnancy. In addition, the precise changes of cardiac output in normal pregnancy, particularly in the third trimester, have remained controversial. Aims and Objective: To measure concomitantly Doppler echocardiographic maternal central hemodynamics and uterine artery Doppler velocimetry and evaluate their association with adverse feto-neonatal outcome in hypertensive pregnant women. To evaluate cardiac output longitudinally in the latter half of pregnancy in normal healthy women. Design and Setting: Prospective study conducted at the Obstetric Unit, King Edward VIII Hospital, Durban, South Africa. Study sample: forty (40) pregnant hypertensives without any prior therapy and a further group of pre-eclamptic women (n=22) treated with stat dose sodium gardinal and alpha-methyldopa were studied. Results: i) A trend to a higher cardiac output was seen in the hypertensives compared to the normotensives. Hypertensive women were of larger stature; there was no difference in cardiac index. Fetal birthweight correlated poorly with cardiac index in pre-eclamptic women (r =0.21). A better correlation was seen with uterine artery resistance index (r = - 0.65) and systemic vascular resistance index (r = -0.49). Critical values for cardiac index and systemic vascular resistance index to predict poor adverse feto-neonatal outcome with good predictive values were not identified. ii) Pre-eclamptics treated with stat dose of sodium gardinal and/or methyldopa prior to echocardiography had a significantly lower systemic vascular resistance index and uterine artery resistance index compared to the untreated group. The lower systemic vascular resistance index in this treated cohort occurred from a combination of non-significant lower blood pressure and higher cardiac index. iii) Compared to normotensive women, untreated pre-eclamptics had a significantly lower heart rate (p< 0.001), a higher stroke index (p=0.018) and no difference in resultant cardiac index (p=0.452). iv) In gestational apoteinuric hypertensives presenting after 34 weeks gestation, maternal hemodynamics and uterine artery resistance index did not help define a higher risk group. v) In chronic hypertensives pregnancies, left ventricular hypertrophy correlated with severity of blood pressure. Higher risk chronic hypertensives were better selected by proteinuria than maternal central hemodynamics or uterine artery resistance index. vi) In normal pregnancy, maternal cardiac output peaked in early to mid third trimester and was maintained till term. Significant correlations were observed among maternal cardiac output, maternal body surface area and fetal birth weight. Discussion: i) This study shows that cardiac index and systemic vascular resistance index measured in the latter part of the second and third trimesters in hypertensive pregnant women were not associated with adverse fetal outcome. Large variations in cardiac index values were observed that restricted detection of satisfactory critical values for cardiac index and systemic vascular resistance index to predict adverse outcome. ii) An improved correlation of uterine artery resistance index with maternal hemodynamics and fetal birthweight in pre-eclampsia supports the hypothesis that poor placentation does not allow for a normal increase in uterine blood flow. iii) The poor correlation between uterine artery resistance index and maternal central hemodynamics, does not support the hypothesis that elevated cardiac output in hypertensive pregnancies (hyperdynamic disease model) occurs as a compensatory response to maintain adequate perfusion in a utero-placental bed with high resistance that did not decrease.