Doctoral Degrees (Medicine)

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    Genotypic and phenotypic analysis of Neisseria gonorrhoeae for the identification of resistance to various antibiotics in pregnant women attending antenatal care at the King Edward VIII Hospital in Durban, KwaZulu-Natal, South Africa.
    (2021) Oree, Glynis.; Abbai, Nathlee Samantha.; Ramsuran, Veron.
    Introduction: Worldwide antimicrobial resistance (AMR) is making the clinical management of sexually transmitted infections (STIs) increasingly challenging with a particular emphasis on the emergence of antibiotic resistant strains of Neisseria gonorrhoeae (N. gonorrhoeae). In the current study, the detection and emerging patterns of drug resistant clinical isolates of N. gonorrhoeae to previous and current antibiotics to treat cervicitis pathogens as per syndromic management guidelines was investigated. Methodology: This cross-sectional study was conducted at King Edward VIII Hospital and included 307 antenatal attendees. Two endocervical swabs were collected from each enrolled woman. Each enrolled women also provided data on socio-demographic, behavioural and clinical factors. The first swab was placed in Amies Charcoal media immediately after collection. This swab was used to confirm the identification of N. gonorrhoeae clinical isolates using culture based assays. Culture confirmed isolates were grown in Mueller Hinton Broth and were each adjusted to have a bacterial suspension turbidity of a 0.5 McFarland Standard. These isolates were then subjected to antibiotic susceptibility testing to ceftriaxone, tetracycline, spectinomycin, azithromycin, ciprofloxacin, penicillin G and cefixime using the Etest™ method. The second swab was processed for molecular based assays. Extracted DNA from the second swab was subjected to the TaqMan quantitative Polymerase Chain Reaction (qPCR) assay, an in-house 16S ribosomal RNA (rRNA) PCR and PCR detection of the opacity (opa) gene. DNA extracted from the endocervical swabs and cultured isolates were used for the detection of specific targets (genes/plasmids/mutations) associated with resistance to penicillin, tetracycline, ciprofloxacin, spectinomycin, cefixime, azithromycin and ceftriaxone. All statistical analysis performed in this study was conducted in RS Studio. Results: The prevalence of N. gonorrhoeae was 7.8% (24/307) when detected by the TaqMan qPCR assay and 1.9% (6/307) by culture. When compared to culture, PCR for the opa gene and PCR for the 16S rRNA, the TaqMan qPCR assay was a more superior assay demonstrating a diagnostic accuracy of 94.5%. Susceptibility testing of the six isolates obtained after culturing showed resistant phenotypes for penicillin G (12 - 64 mg/L), tetracycline (1.9 - 32 mg/L) and ciprofloxacin (1.16 - 3 mg/L). Isolates displayed either dual or triple resistance to these 3 antibiotics. However, all isolates showed susceptibility to spectinomycin (>64mg/L), azithromycin (1mg/L), ceftriaxone (>0.125 mg/L) and cefixime (>0.125 mg/L). This study also detected the resistance determinants associated with penicillin, tetracycline, ciprofloxacin, spectinomycin, cefixime, ceftriaxone and azithromycin from the molecular level using the primary endocervical swab sample. Gene mutations and plasmids associated with resistance to tetracycline (tetM gene carried on a plasmid), penicillin G (penicillinase producing plasmid) and ciprofloxacin (Ser-91 mutation) were detected confirming the results obtained with the susceptibility assays. Resistance mutations associated with the remaining antibiotics were not detected. There was a 100% correlation of cultured isolates and endocervical swabs for detecting the specific AMR determinants conferring resistance to tetracycline, penicillin G, and ciprofloxacin. Conclusion: The TaqMan qPCR assay has the ability to serve as a future diagnostic assay for the detection of N. gonorrhoeae. Despite the lack of resistance to spectinomycin, cephalosporins and azithromycin in our study population, continuous surveillance for emerging patterns of resistance to these antibiotics is still required since they form part of the current South African treatment guidelines. The detection of resistance determinants from the molecular level without the need for culture may prove to be more feasible for future epidemiological investigations focused on tracking antimicrobial susceptibility or resistance patterns in N. gonorrhoeae.
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    Trauma care in Sub-Saharan Africa: challenges and opportunities in Botswana and Tanzania for implementing Afrocentric systems.
    (2021) Mwandri, Michael Bartholomew.; Hardcastle, Timothy Craig.
    Summary available in PDF.
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    An investigation into the mode of action of pyrazinamide on mycobacterium tuberculosis.
    (1999) Dwarka, Rahana Mohan.; Sturm, Adriaan Willem.
    Abstract available in PDF.
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    The Clinico-pathological manifestations of schistosomiasis in the African and the Indian in Durban.
    (1964) Bhagwandeen, Surridhine Brumdutt.; Elsdon-Dew, R.
    Abstract available in PDF.
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    Aspects of gastrointestinal tuberculosis at King Edward VIII Hospital.
    (1987) Pettengell, Keith Edward.; Mayet, Fatima G. H.
    Abstract available in PDF.
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    Increase in live infected cell number with drug and generation of a quasispecies are consequences of multiply HIV infected cells.
    (2018) Jackson, Laurelle.; Sigal, Alexander.
    HIV may form reservoirs in anatomical compartments and evolve a quasispecies in order to survive under selective pressures such as antiretroviral drugs. Lymph nodes and lymphoid tissue - critical sites for reservoir formation - are environments conducive to cell-to-cell spread, an efficient mode of HIV transmission. Cell-to-cell spread can lead to multiple infections per cell which in turn profoundly changes how the virus responds to selective pressure. In this thesis, my goal was to understand the consequences of multiple infections per cell on how the infection responds to and evolves in the face of inhibitors. The specific aims were to: (1) model and experimentally examine the effect of attenuating cell-to-cell spread by using antiretrovirals (ARVs) on infected cell viability; (2) test whether a stable quasispecies can be formed and maintained by complementation– a process where virions derived from different HIV genotypes infecting the same cell share components; (3) test the feasibility of new single-cell RNA-Seq methodology that can be applied to quantify the frequency of multiply infected cells in vivo. These studies showed that: (1) partially attenuating infection involving multiple virions per cell with drug resulted in an increase in the number of live infected cells in both cell line and lymph nodes at suboptimal drug strengths. The increase in live infected cells was a result of fewer HIV DNA copies per cell, relative to no drug; (2) under the selective pressure of efavirenz (EFV), when drug-resistant and drug sensitive HIV co-infect the same cell during drug resistant evolution, complementation takes place, driving the formation and maintenance of a quasispecies; (3) Novel single-cell RNA-Seq approaches are feasible to quantify the number of cells that are multiply infected in vivo. Inhibiting mechanisms such as cell-to-cell spread may therefore reduce infection in the face of ARVs and limit viral diversity and hence the ability of HIV to evolve resistance.
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    The epidemiology and impact of pretreatment HIV drug resistance in adults in South Africa.
    (2018) Chimukangara, Benjamin.; De Oliveira, Tulio De Paiva Nazareth Andrade.; Naidoo, Kogieleum.; Samuel, Reshmi.
    HIV drug resistance (HIVDR) present prior to initiating or re-initiating antiretroviral therapy (ART), is known as pretreatment drug resistance (PDR). Conventionally, PDR is detected by Sanger sequencing. Drug resistant minority variants (DRMVs) that are not reliably detected by Sanger sequencing can be detected by next generation sequencing. The aims of this research were to assess levels of PDR in HIV hyper-endemic areas (with high HIV incidence and prevalence) in KwaZulu-Natal (KZN) province, trends of PDR in South Africa, and the impact of DRMVs on ART. To assess PDR in adults from KZN hyper-endemic areas, 1845 sequences were analyzed from two population-based HIV surveillance studies; a longitudinal HIV surveillance programme in northern KZN (2013-2014), and the HIV Incidence Provincial Surveillance System (HIPSS) in central KZN (2014-2015). Overall, 182/1845 (10.0%) had NNRTI-PDR mutations, and when analyzed by study year, NNRTI-PDR was 10.2% (CI:7.5-12.9) for the HIPSS study in 2014. To assess PDR trends in South Africa, 6880 HIV-1 sequences were collated from 38 datasets of ART-naïve adults (2000-2016). Increasing levels of PDR were observed, most marked from 2010. Crude pooled prevalence of NNRTI-PDR reached 10% in 2014, with a 1.18-fold (CI:1.13- 1.23) annual increase (p<0.001), consistent with findings from the HIPSS data. This provided the first evidence of high-level NNRTI-PDR in KZN and South Africa, supporting the transition to dolutegravir in standard first-line ART, as recommended by the World Health Organization when NNRTI-PDR reaches ≥10%. A case-control (2:1) study in HIV/TB co-infected adult patients was done to assess the impact of DRMVs at different thresholds. Cases were patients that initiated ART and had viral loads ≥1000 copies/mL after ≥6 months on ART, and controls were those that initiated ART and achieved virologic suppression through 24 months. Pre-ART NNRTI-resistance was associated with ART failure. NGS improved detection of HIVDR at lower thresholds, but reduced the specificity of identifying patients at risk of virologic failure, with the specificity reducing from 97% (CI:92-99) at 20% threshold, to 79% (CI:71-86) at 2% threshold. In all, the findings presented in this thesis provide a broad message about the need to improve quality in HIV prevention and treatment services.
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    A standardised approach to the treatment and management of significant acinetobacter species infection at academic complex hospitals in KwaZulu-Natal.
    (2017) Swe Swe-Han, Khine.; Mlisana, Koleka Patience.; Baba, Kamaldeen.; Pillay, Manormoney.
    Introduction: Carbapenem-resistant Acinetobacter species (Acinetobacter spp.) are increasingly recognised as important pathogens, whose resistance patterns present a high-risk global challenge. However, there is limited scientific data and a lack of a standardised approach to help the clinician select optimal therapy in local setting. This study aimed to provide a standardised approach for the management of significant Acinetobacter spp. infection based on phenotypic and genotypic characterisation of local isolates, as well as clinical characteristics and outcomes of patients at academic complex hospitals in KwaZulu-Natal. Objectives: The significance of Acinetobacter spp. infections and the most effective drug combinations for optimal therapy were determined. Acinetobacter spp. isolates were phenotypically and genotypically characterised. This was followed by the development of a standard management guideline for local use, based on the data obtained in the different objectives. Methods: The research consisted of a retrospective and prospective observational and experimental laboratory component. The laboratory component included synergy testing of colistin, susceptibility to antimicrobial agents in use at local hospitals, polymerase chain reaction and sequencing for analysis of the resistant genes related to carbapenem, colistin and amikacin. Phenotypic, genotypic, and clinical characterisation were utilised to develop a standardised management approach of significant Acinetobacter spp. infection. Results: Acinetobacter spp. was identified as a significant cause of sepsis and mortality among patients in a surgical intensive care unit (ICU). Cases of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Acinetobacter spp. increased over seven years, together with the emergence of pandrug-resistant (PDR) isolates. The results of synergy testing of colistin combinations with amikacin, carbapemens (imipemen, meropenem), ciprofloxacin, tazocin, linezolid, rifampicin and vancomycin against Acinetobacter spp. was highly diverse and speciesdependent. Characterisation of Acinetobacter spp. isolates showed that oxacillinase β-lactamase (OXA-23)-producing MDR isolates correlated with their antibiogram. Pulsed field gel electrophoresis (PFGE) showed horizontal transfer between seven clusters, each containing two patients each, totalling 14 patients. However, the PFGE typing revealed a diverse collection of MDR Acinetobacter spp. clones, and that isolates from not more than two patients were related. This suggests, therefore, that no outbreak had occurred based on the PFGE typing interpretation. Further genetic investigation revealed that the aphA6 gene were associated with amikacin resistance and IpxA gene may be associated with colistin resistance in our local setting. Conclusion: The results highlighted the importance of antibiotic stewardship in the treatment of Acinetobacter spp. infection. Individual-specific antibiograms are recommended as the best 2 approach for treatment in KwaZulu-Natal (KZN) and synergy testing should be performed for individualised direct therapy. The clinical and microbiological indicators of significant infection are crucial when establishing the decision to treat. The study provided a valuable standardised approach, including a flow chart of criteria for sepsis and colonisation; a standardised algorithm for the management; and synergy test at academic complex hospitals, Medical Microbiology laboratory, National Health Laboratory Service (NHLS) in KZN.
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    Culturally competent patient-provider communication with Zulu patients diagnosed with osteosarcoma.
    (2016) Brown, Ottilia.; Aldous, Colleen Michelle.
    Background: Communicating the diagnosis and prognosis of cancer is widely documented as a challenging task. Furthermore, ensuring that patients understand their treatment options is considered good practice; however literature in this regard tends to be limited. Performing these tasks in cross-cultural clinical settings complicates patient-provider communication. This study focused on Zulu patients diagnosed with osteosarcoma and was conducted at a tertiary (training) hospital in the province of KwaZulu-Natal (KZN), South Africa. The primary motivation for undertaking this research stemmed from observations in clinical practice that Zulu cultural beliefs and practices play a significant role in the management of osteosarcoma and hence culturally competent communication was an essential requirement at this site. In addition, patients typically present at the study site with locally advanced or metastatic disease. The late presentation of patients and further delays stemming from patients’ preferences to fulfil cultural practices results in treatment limitations and very poor prognosis. Healthcare providers in this setting are therefore expected to simultaneously inform patients of the diagnosis of osteosarcoma, the significant limitations with regard to treatment options, and prognostic considerations in a culturally sensitive manner that engenders cooperation in the patient while allowing them the opportunity to fulfil their cultural obligations. Aim and Objectives: This study aimed to develop an evidence-based practice guideline with recommendations for engaging in culturally competent communication with adult Zulu patients regarding the diagnosis, treatment and prognosis of osteosarcoma. Four objectives were devised in order to meet the aim of the study. Objective 1: Conduct an integrative literature review to gather evidence from previous research. Objective 2: Gather evidence from healthcare providers about the approach taken when they discuss osteosarcoma, its treatment and prognosis with Zulu patients as well as the cultural aspects considered during these discussions. Objective 3: Gather evidence from Zulu patients by exploring their understanding of the osteosarcoma diagnosis, its treatment and prognosis, and their experience of patient-provider communication throughout the illness experience was conducted. Patients’ cultural descriptions related to the management of osteosarcoma were also elicited. Objective 4: Develop an evidence-based practice guideline for culturally competent patient-provider communication with osteosarcoma patients based on the evidence collected in Objectives 1, 2 and 3. Methods: Objective 1: Whittemore and Knafl’s approach to conducting an integrative literature review was used. A number of databases were systematically searched and a manual search was also conducted. Specific inclusion and exclusion criteria were set and documents were critically appraised independently by two reviewers. Thirty-five documents were included following these processes. Data extraction and synthesis followed and were also independently verified. Objective 2: We used an exploratory descriptive contextual study design and conducted focus group interviews with professional nurses, allied health professionals, and orthopaedic physicians. Three focus groups with a total of twenty-three participants were conducted. Focus group interviews were audiotaped and transcribed verbatim. We thematically analysed the interview transcripts using Guba’s Model of Trustworthiness to ensure rigour. Objective 3: We used a qualitative case study approach with in-depth interviews that were conducted in isiZulu, audiotaped and transcribed verbatim. The transcripts were translated into English and back translated. Transcripts were then analysed thematically. Data were verified using Guba’s model of trustworthiness. Objective 4: The AGREE II (Appraisal of Guidelines, Research and Evaluation) appraisal instrument was used as a guide for developing the evidence-based practice guideline. The AGREE II is a 23 item tool comprising six domains, five of which were considered in developing the guideline. Results: The integrative literature review provided directives on how to deliver culturally competent communication to cancer patients. The review also highlighted the grave need for scientifically rigorous research in the field of culturally competent communication in the management of cancer. Our research with the healthcare providers produced a number of strategies for communicating with Zulu patients about the diagnosis, treatment and prognosis of osteosarcoma. These strategies also addressed cultural considerations and provided detailed information on the cultural factors that have to be taken into account when managing Zulu patients diagnosed with osteosarcoma. Challenges encountered with regard to discussing diagnosis, treatment and prognosis also emerged. In addition to revealing strategies and challenges that are confirmed in the literature, this study also unearthed unique strategies and challenges peculiar to this cross-cultural clinical setting. Despite the uniqueness of some of these strategies, they could be useful in other cross-cultural clinical settings where patients belong to collectivistic cultures, and observe traditions and other practices that are significantly different to Western medical approaches. Our findings also emphasised the importance of training healthcare providers on communication of sensitive information in cross-cultural clinical settings. Our research with Zulu patients diagnosed with osteosarcoma revealed that these patients had extensive understanding of the diagnosis of osteosarcoma, diagnostic procedures, the treatment options applicable to treating osteosarcoma and the side-effects of chemotherapy. These findings also revealed patients’ varied perceptions of and emotional responses to diagnosis and treatment and exposed difference in healthcare provider and patient perceptions of amputation. A significant contribution of the patient study is embedded in Zulu patients’ descriptions of their cultural and health beliefs and practices. Specific rituals that are performed to ensure successful outcome of medical procedures, to cleanse patients from bad luck and to address the issue of witchcraft were outlined. Consultation with a reputable traditional healer was flagged as an important cultural practice. However, patients varied in their adherence to traditional belief systems, participation in rituals and the extent to which they deferred decision-making to the familyreinforcing the importance of not stereotyping based on pre-existing knowledge of a cultural group. The evidence-based practice guideline was developed based on the findings from the integrative literature review and the studies conducted with the healthcare providers and the Zulu patients. These three sources of evidence facilitated the development of a guideline that presents generic requirements and recommendations for culturally competent communication, and denotes specific strategies for communicating diagnosis, treatment, and prognosis to Zulu patients diagnosed with osteosarcoma. The evidence-based practice guideline also explicates areas that require further research and refinement. Conclusions: The obvious contribution of this research is represented in the evidence-based practice guideline. However, each of the objectives makes a significant contribution to knowledge and practice. This study breaks ground and alerts to the magnitude of research that is required in cross-cultural clinical settings, especially in the South African context as literature in this context with regard to culturally competent communication is very limited. The need for training our healthcare providers in communication of sensitive information in cross-cultural clinical settings strongly emerged from the data. Policy directives that support culturally competent patient-provider communication at a healthcare systems level could significantly contribute to addressing resource constraints and creating clinical environments that are conducive to culturally competent communication.
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    An investigation into the renewed need for the care and prevention of congenital disorders in South Africa.
    (2017) Malherbe, Helen.; Aldous, Colleen Michelle.
    Abstract available in PDF file.
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    The prevalence of bacterial vaginosis in KwaZulu-Natal and its association with the vaginal immune response and shedding of HIV and HSV-2.
    (2017) Naido, Kavitha.; Sturm, Adriaan Willem.
    Introduction: South Africa has a high burden of sexually transmitted infections (STIs) and HIV. The role of Gardnerella vaginalis in the development of BV has been disputed after the recovery of G. vaginalis from healthy patients and the discovery of new bacteria using molecular identification. Infection with HSV has been associated with increased vaginal HIV RNA copies and bacterial vaginosis has been implicated as a risk factor for the transmission of HIV. Methodology: Consenting patients of > 18 years were recruited from two different primary health clinics. Microscopy was used to diagnose BV and serology for HIV, HSV-2 and syphilis testing. Chlamydia trachomatis and Neisseria gonorrhoeae were detected by BD Probetec, and conventional PCR was used for the diagnosis of Trichomonas vaginalis and recognised ulcer pathogens. Quantitative bacteriology and HIV viral loads were done using the Applied biosystems ABI 7500 Real Time instrument. Immune cells from vaginal tampon specimens were analysed using flow cytometry. Results: In both clinics, of the discharge pathogens T. vaginalis had the highest prevalence. The prevalence of both T. vaginalis and N. gonorrhoeae was significantly higher in Boomstreet clinic (p<0.05). The Umlazi D clinic had significantly more patients with BV (p<0.0001) and HSV-2 (p<0.05). Of the patients with ulcers, HSV-2 was detected in a one third of the specimens in each of the clinics. One patient was diagnosed with lymphogranuloma venereum (LGV). The Nugent score group 0-3 was dominated by Lactobacillus spp. while the Nugent score group 7-10 was dominated by Gardnerella vaginalis. The group with Nugent score 7-10 was shown to have significantly higher levels of immune cells that are proposed HIV targets. Lactobacillus spp. was associated with the group that was HIV antibody negative and Prevotella spp. with the HIV antibody positive group (p < 0.05). Prevotella spp. was not associated with shedding of HIV. The number of bacterial copies of G. vaginalis was significantly higher in patients shedding HIV (p < 0.05). In those shedding HSV-2 the number of copies of G. vaginalis was also higher but this did not reach statistical significance. Conclusion: The trend in STI prevalence was similar to that described previously. We report circulating LGV and there is a possible increase in gonorrhoeae which needs to be confirmed. The potential pathogenic role of G. vaginalis in BV as well as the increased risk of HIV transmission is emphasized.
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    “Sowing the seeds” the use of feedback in postgraduate medical education : a key factor in developing and enhancing clinical competence.
    (2016) Bagwandeen, Chauntelle Ingrid.; Singaram, Veena S.
    Background: The importance of feedback in enhancing clinical competency in the postgraduate medical education arena is well documented. Many definitions of, and models and frameworks for delivering feedback exist. Trainee specialists must learn how to use the feedback that they receive to hone their knowledge, skills and professional performance. Clinical supervisors must be equally effective in delivering the best feedback possible in all spheres of the training platform so as to impact positively on performance. However, while many studies have explored how feedback is given and received in postgraduate medical education, these studies have been conducted in homogenous settings. Aim: This study set out to examine how contextual and demographic factors affect the provision of feedback in a clinical training environment with heterogeneous demographics. This study aimed to investigate the perceptions of the registrars, consultants and Clinical Training Heads regarding the quality and factors that influence the process of giving and receiving feedback, so as to make recommendations for improvement and to develop policy guidelines for the enhancement of postgraduate clinical speciality training in diverse clinical training environments. Methods: A mixed methods approach was adopted for this study. Qualitative and quantitative analysis was done regarding the perceptions of the quality of the current delivery of feedback across six disciplines at a teaching hospital. Consultants and registrars consented to complete a questionnaire consisting of open- and close-ended questions to determine the quality, quantity, type and timing of feedback. Responses were coded on a five-point Likert Scale and combined to give an overall positive or negative response. The relationship between demographic factors such as age, race, gender, home language and discipline of study were also evaluated, with responses to open-ended questions used to extend and enrich the quantitative data. Descriptive statistics were used to analyse the data. Differences between groups were calculated using Pearson’s Chi Square test for independent variables, with a p–value of < 0.05 regarded as being statistically significant. Semi-structured interviews were conducted with the Clinical Training Heads to explore their feedback regarding the feedback received about feedback from the consultants and registrars. The Walt and Gilson (1994) triangular framework for policy analysis was used to explore the perceptions of current practice of the Clinical Training Heads of six major disciplines. A thematic analysis was conducted of their perceptions of how feedback was currently given and received by consultants and registers, with a view to developing policy guidelines to improve the practise of giving and receiving feedback. Results: The results revealed a disparity in the perceptions of consultants and registrars regarding current practise. Although consultants believed that they provided adequate feedback, registrars disagreed, citing an overall dissatisfaction with the process. Registrars believed that consultants lacked training in how to give feedback , and that important elements such as prior provision of the standards to be obtained, as well as feedback being based on directly observed performance were missing. Consultants concurred that they lacked capacity in how to give adequate feedback, but felt that heavy workloads, fear of negative reactions and the apathy of registrars as well as their failure to act on feedback when given, hampered the process. Male consultants and registrars both reported better experiences of giving and receiving feedback overall. Registrars who were English second language speakers had statistically significantly more favourable outcomes with feedback compared to English first language speakers. The Clinical Training Heads reported that lack of appropriate institutional support and an overall guiding framework, combined with multiple administrative bodies of registrars as well as language barriers, were challenges to be overcome. They identified areas for future improvement, including standardisation of the process, more effective use of logbooks and better monitoring and evaluation. Conclusion: Registrars and consultants agreed that feedback was essential to ensuring that clinical competencies were achieved. However, ongoing in-service education and training of consultants and registrars was necessary to ensure that consultants were fully capacitated to provide constant, high quality feedback and that registrars were able to recognise feedback when it was given. Feedback needs to be an integral part of the culture of the university teaching and learning ethos. To this end, policy guidelines incorporating elements of identified ‘Best Practices’ on how to give feedback were developed and recommended for implementation under the auspices of an overarching Postgraduate Committee for Teaching and Learning.
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    Metabolic complications of antiretroviral therapy (ART) in a South African black population..
    (2014) Magula, Nombulelo Princess.; Lalloo, Umesh Gangaram.; Motala, Ayesha Ahmed.
    Aims To determine the prevalence and incidence of lipodystrophy (fat distribution [lipoatrophy and lipohypertrophy] and metabolic complications [insulin resistance-dysglycaemia and dyslipidemia]) in HIV-1 infected adult subjects of second generation Zulu descent at baseline and during 24 months of follow-up on antiretroviral therapy (ART). Methods The total study group included three groups: HIV infected ART naive patients eligible for ART (HIV-ART, n=150), age, gender and ethnically matched HIV infected not eligible for ART (HIV-no ART, n=88) and HIV negative (control, n=88) subjects. All participants had demographic, anthropometric, biochemical and radiological assessments at baseline; in addition, the HIV-ART group had follow-up assessments for 24 months on ART (tenofovir, lamivudine and nevirapine or efavirenz). Fat distribution was assessed using FRAM questionnaires, computerized tomography (CT) scans and dual energy absorptiometry X-ray (DXA). Disorders of glycaemia (diabetes mellitus (DM), impaired glucose tolerance and impaired fasting glucose) were defined using WHO criteria. Total, LDL, HDL cholesterol and triglycerides were measured for each group; CD4 cell count and HIV RNA for group 2 and 3, at baseline, 3, 6, 12, 18 and 24 months. Poisson approximations estimated incidence of disorders of glycaemia. Results At baseline, when compared with the control group, the mean BMI (kg/m2) was significantly lower in the HIV-ART and HIV-no ART subjects (26.4 vs. 28.6 vs. 29.1; p =0.01). Prevalence of lipoatrophy as measured by participant and physician examination questionnaires was similar in the three groups. Visceral and subcutaneous fat area by CT scan were similar between the groups but limb and trunk fat mass by DXA scan was significantly lower in the HIV-ART compared to control subjects. In the HIV-ART group, at the 24 month follow-up, there was a significant mean reduction in HIV RNA (p<0.0001) and increase in CD4 cell count (p<0.0001). The mean BMI increased to 29.4 kg/m2 and no lipoatrophy developed; DXA scan showed a 33.6% increase in trunk fat mass (mean difference 4.2 kg, p <0.0001) and 30.8% increase in total fat mass (mean difference 9.4 kg, p < 0.0001); visceral (p 0.005) and subcutaneous (p 0.0002) fat area also increased. At baseline, the prevalence of DM was 0% in HIV-ART and HIV-no ART and 4.9% in control subjects (p 0.005); the prevalence of “any dysglycaemia” was 3.7% in HIV-ART and HIV-no ART compared to 8.6% in control subjects. When compared with group 1, mean values in group 3 were lower for the following serum lipids: total cholesterol (p<0.0001), LDL (p=0.0007) and HDL (p<0.0001). There was no difference in mean total triglycerides in the three groups (p=0.3). During follow-up, in the HIV-ART group, using glucose-based WHO criteria, the incidence of diabetes mellitus was 2.3 per 100 person year follow-up (PYFU) and of “any dysglycaemia” 7.6 per 100 PYFU. The only independent predictor of DM was visceral: subcutaneous fat ratio measured by CT scan (HR 2.95 [95% CI 1.25-6.98], p 0.01). Significant predictors for development of “any dysglycaemia” included systolic blood pressure (HR 1.04 [95%CI 1.02-1.07], p=0.0006), serum albumin (HR 0.85 [95% CI 0.76-0.94], p=0.002), CD4 cell count (HR 0.988 [95%CI 0.978-0.997], p=0.01) and efavirenz (HR 6.27 [95%CI 1.65-23.80], p=0.01) Serum total (p<0.0001), LDL (p<0.0001) and HDL-cholesterol (p<0.0001) increased significantly during follow-up. Conclusion: In this cohort of South Africans with HIV-1 infection, at baseline (prior to ART) there was no significant fat redistribution or lipoatrophy and an absent to low prevalence of dysglycaemia. In the follow-up study, ART use was not associated with lipoatrophy although there was significant increase in BMI and in limb and trunk fat mass by DXA scan. ART was associated with increased incidence of dysglycaemia. These findings underscore the importance of clinical monitoring on ART. The association of efavirenz with dysglycaemia warrants further evaluation.
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    Characterization of CD4+ and CD8+ T cell responses in HIV-1 C-Clade infection.
    (2011) Ramduth, Dhanwanthie.; Kiepiela, Photini.; Ndung'u, Peter Thumbi.; Walker, Bruce D.
    HIV-1 specific CD4+ T cell activity in clade C infected subjects has not been studied. CD4+ T cells play a vital role in controlling infectious diseases and there is a need to augment our knowledge of HIV immunology to aid vaccine design. We therefore embarked on a study to characterize HIV-1 specific CD4+ T cell activity in both adults and infants; assess the relationship between CD4+ and CD8+ immune responses; and the relationship between CD4+ T cell activity and markers of disease progression (viral loads and CD4 counts). Our study revealed that the magnitude of CD8+ T cell responses correlated significantly with CD4+ T cell responses, but that the percentage of CD8+ T cells directed against HIV-1 was always greater than that of CD4+ T cells. Gag was the frequently targeted HIV-1 protein by CD4+ T cells and had the highest density of epitopes targeted by CD4+ T cells. Patients with either a dominant CD4 or CD8 T cell response against Gag had significantly lower viral loads than patients in whom non-Gag proteins were the main target (p< 0.0001 for CD4 activity and p= 0.007 for CD8 responses). Single IFN- producing CD4+ T cells were present in significantly higher numbers than cells producing both IFN- and IL-2 simultaneously (p=0.009). Gag also dominated the CD4+ T cell response in acutely infected infants with IFN- production detected more frequently than IL-2 or TNF- . Longitudinal analysis of infants receiving early ARV treatment and then ceasing after 12 months revealed that early treatment conferred no protection against increasing viremia and disease progression. CD4+ T cell responses were detected sporadically in untreated infants indicating a dysfunctional immune response in the face of constant exposure to high levels of viremia. Taken together, the data reveal that a vaccine inducing Gag specific CD4+ T cell responses has the potential to confer some degree of protection, but other immunological parameters need to be investigated especially in infants.
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    The effect of self-generated hypoxia on the expression of target genes coding for electron transport related products in mycobacterium tuberculosis.
    (2010) Ramchandra, Prathna Harrikaran.; Sturm, Adriaan Willem.
    The work presented here aims at identifying whether the genes identified in the genome of Mycobacterium tuberculosis that code for products involved in anaerobic metabolism are active or inactivated genes. The study consists of three distinct parts. In part one, serial dilutions of sputum of patients with pulmonary tuberculosis (PTB) were grown on agar surface and in high columns of un-agitated broth. The highest dilution from which mycobacteria was grown was for all patients significantly higher in the broth cultures than on the plates suggesting the presence of anaerobically metabolizing mycobacteria in the lungs of patients with PTB. Part two of the study identified gene expression by measuring the concentration of transcripts for 5 genes involved in aerobic or anaerobic pathways. This was done over a period of 15 weeks using un-agitated broth cultures (the Wayne method). Undulating patterns of gene expression were found with the genes coding for anaerobic metabolic pathway components expressed at higher levels than those coding for aerobic pathway components while the cultures grew older. Part three aimed at measuring transcription products of the same set of genes directly in sputum specimens. Although quantitation at bacterial cell level in the sputum could not be achieved, expression of all genes was established with on average larger quantities of transcripts of genes coding for the anaerobic pathway components.
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    Respiratory health survey in an Indian South African community : distribution and determinants of symptoms, diseases and lung function.
    (1992) Lalloo, Umesh Gangaram.; Seedat, Yakoob K.; Becklake, Margaret.
    A cross-sectional epidemiologic survey of the respiratory health status was conducted in the adult (15 years and older) Indian South African population resident in Lenasia, Johannesburg to study the distribution and determinants of respiratory symptoms, disease and lung function level. A slightly modified self-administered version of a standardised respiratory health questionnaire and a wedge spirometer was used. There were a high proportion of current smokers among men. Although women smoked less than men in other communities they nevertheless smoked on average more heavily than other Indian South African women. Indian men and women who smoked had a high prevalence of respiratory symptoms. The women also demonstrated an increased susceptibility to the effects of cigarette smoking when compared with women in other communities. Indians in this study had spirometric lung function levels that were lower than that recorded in recent studies in Blacks and Whites in South Africa. Respiratory symptoms, disease and lung function level were examined in a multiple logistic regression model which contained all the potential determinants recorded in the present study. Voluntary tobacco smoking, recent chest illnesses and any kind of heart trouble was associated with a significant risk for having most of the respiratory symptoms and diseases in men and women. In addition exposure to dust in the work environment, little or no exercise,>Std. 8 education a history of any kind of chest trouble and respiratory trouble before the age of 16 years was associated with an increased risk for having respiratory symptoms in men in this model. An increased risk for respiratory symptoms was demonstrated in women only with age. Age and standing height were the most important determinants of lung function level in men and women in the regression model. Dust exposure in the work environment was associated with a significantly lower lung function level in men. Alcohol consumption and a history of whooping cough was also independently associated with a lower lung function level in men but were of borderline significance. In women involuntary /passive tobacco smoke exposure and respiratory trouble before the age of 16 years were associated with a lower lung function level. Women who spent most of their lives in a rural area and those who had a university education had a higher lung function level. The deleterious effects of smoking on lung function were minimal in this study possibly because lung function was performed only in subjects in the 18-45 year age category. A "healthy smoker" effect was demonstrated in men. Men who ever smoked and were without cardiorespiratory symptoms had significantly higher lung function levels compared to men who never smoked and were without symptoms.
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    Impaired glucose tolerance (IGT) : a study in South African Indians in Durban.
    (1990) Motala, Ayesha Ahmed.
    No abstract available.