Background Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A proportion is presumed to be genetic, but this aetiology is buried under the burden of infections and perinatal insults, in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs), are most severely affected by this diagnostic gap, as the rate of actionable findings is highest in DEE-associated genes. This research study investigated the genetic architecture of epilepsy in South African (SA) children clinically diagnosed with DEE, highlighting the clinical utility of informative genetic findings and relevance to precision medicine for DEEs in a resource-constrained setting. Methods A group of 234 genetically naïve SA children with drug-resistant epilepsy and a diagnosis or suspicion of DEE, were recruited between 2016 and 2019. All probands were genetically tested using a DEE gene panel of 71 genes. Of the panel-negative probands, 78 were tested with chromosomal microarray and 20 proband/parent trios underwent exome sequencing. Statistical comparison of electroclinical features in children with and without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. Results Pathogenic/likely pathogenic (P/LP) variants were identified in 41/234(17.5%) * probands. Of these, 29/234(12.4%) * were sequence variants in epilepsy-associated genes and 12/234(5.1%) * were genomic copy number variants (CNVs). Sixteen variants of uncertain significance (VUS) were detected in 12 patients. Of the 41 children with P/LP variants, 26/234(11%) had variants supporting precision therapy. Multivariate regression modelling highlighted neonatal or infantile-onset seizures with movement abnormalities and attention difficulties as predictive of a positive genetic finding. This, coupled with an emphasis on precision medicine outcomes, was used to propose the pragmatic “Think-Genetics” decision tree for early recognition of a possible genetic aetiology, pragmatic testing, and multidisciplinary consultation. Conclusion The findings presented here emphasise the relevance of an early genetic diagnosis in DEEs and highlight the importance of access to genetic testing. The “Think-Genetics” strategy was designed for early recognition, appropriate interim management, and genetic testing for DEEs in resource constrained settings. The outcomes of this study emphasise the pressing need for augmentation of the local genetic laboratory services, to incorporate gene panels and exome sequencing. *These percentages were rounded off to whole numbers in the published articles included in this thesis (i.e., rounded off to 18%, 12% and 5%, respectively).

Advancements in the medical field with regard to the development of new techniques, reassessment and analyses of the old and unsatisfactory techniques and the expansion and improvement of acceptable techniques have led to an increase in the use of regional anaesthetic nerve blocks in paediatric patients. However, several regional anaesthetic procedures are currently not being performed by anaesthetists due to the high number of complications and difficulties experienced. Some medical practitioners are under the impression that they lack the knowledge and confidence to perform these regional nerve blocks, especially on neonatal and infant patients. In order to assist these doctors in refining their anatomical knowledge and increasing their confidence in performing these nerve blocks, the procedures which are experienced as problematic need to be identified and evaluated. The aim of this study was therefore: (1) to establish the most efficient method of blocking the maxillary nerve within the pterygopalatine fossa; (2) to investigate which head and neck regional nerve blocks are performed most frequently on paediatric patients and identify problem procedures that are performed by practicing anaesthesiologist in South Africa; (3) to develop a clinical anatomy information base for the selected procedures. Three methods / techniques for maxillary nerve blocks were simulated and compared on 24 dry paediatric skulls and 30 dissected paediatric cadavers. The depth and angles at which the needle travels to block the maxillary nerve in the pterygopalatine fossa, after existing the skull through the foramen rotundum, was measured and compared. The method using the supra-zygomatic approach (method B), from the frontozygomatic angle towards the pterygopalatine fossa, exhibited no statistical significance (p > 0.05) when comparing the measurements in the skulls and cadavers. Method A, a supra-zygomatic approach from the midpoint on the lateral border of the orbit, as well as method C, an infra-zygomatic approach with an entry at the site of a vertical line extending along the lateral orbit wall, showed statistical significance when comparing measurements in the skulls and cadavers. It can therefore be concluded that method B produces the most consistent data and should be tested in a clinical setting. Seventeen commonly performed paediatric regional nerve blocks were identified. A detailed questionnaire was completed by 111 respondents, either electronically or from others attending either the Pain Interventions and Regional Anaesthesia Conference or the South African Society of Anaesthesiologists Conference. Difficulties in performing the regional anaesthetic nerve blocks, and complications encountered, were the main areas of focus, when selecting the four problem procedures. The problem procedures selected are the following: supra-orbital and supra-trochlear nerve blocks, infra-orbital nerve block (Extra-oral approach), superior laryngeal and recurrent laryngeal nerve blocks. A detailed anatomical information base was developed through an extensive literature review. This will aid in educating and facilitating doctors in performing paediatric regional nerve blocks, thereby enabling them to successfully practice medicine. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Anatomy / unrestricted

Introduction: Nausea and vomiting are the most common and distressing side effects of chemotherapy because they negatively impact on quality of life and treatment compliance. Adequate control of nausea and vomiting in children receiving chemotherapy is imperative. Currently, the first-line drug for the prophylaxis and treatment of chemotherapy-induced nausea and vomiting (CINV) in paediatric patients is the serotonin (5HT3) receptor antagonist, ondansetron, administered intravenously. However, the parenteral route of administration of this drug is now being questioned as it is inconvenient for children and there is pressure to switch to an available oral formulation. The aim of this study was to evaluate the ease of administration, efficacy and cost-effectiveness of intravenous (IV) and oral tablet (OT) formulations of ondansetron in paediatric cancer patients receiving moderately emetogenic chemotherapy at the Steve Biko Academic Hospital in Pretoria, Gauteng (South Africa).Methods: It was an open-label, parallel, randomized trial. Thirty (30) patients scheduled to receive moderately emetogenic chemotherapy were recruited from the paediatric oncology department of the hospital. These patients were randomized to receive the same dose of either IV or OT ondansetron for the prophylaxis of CINV for one chemotherapy cycle. The efficacy of the agents was determined using a visual analogue scale (VAS) completed by the paediatric patients, which was compared to a one page questionnaire completed by the parents of the patients. Both questionnaires were completed at the end of chemotherapy (treatment period) as well as after a week without chemotherapy treatment (follow-up period). The patients’ plasma concentrations of ondansetron at four different time points were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). The ondansetron plasma concentrations obtained in the IV group were compared to those obtained in the OT group. The cost-effectiveness calculations included the direct costs of antiemetic prophylaxis and treatment, the use of any rescue medication and the length of hospital stay. Results: The VAS revealed that patients who were given antiemetic prophylaxis with OT ondansetron experienced less acute and delayed nausea than the patients in the IV ondansetron group; however, these differences were not statistically significant (p=0.538). Vomiting was similar in the two groups (p=1). There was a statistically significant difference between the patients and their parents in the perception of acute nausea (p=0.018), with parents overstating the level of acute nausea felt by their children. The plasma concentrations of ondansetron in patients on the IV formulation were higher than the ones in patients on the OT formulation at all the time points investigated. At 30 minutes post-dosing the mean plasma concentration of ondansetron in the IV group was significantly higher than in the OT group (p=0.0015), but the differences in plasma concentrations between the two groups from 2 hours were fairly comparable. The cost of antiemetic prophylaxis for IV ondansetron was significantly higher than the cost of antiemetic prophylaxis using the equivalent OT dose (p=0.0351). Conclusion: For the prevention of CINV, OT ondansetron, a 5HT3 receptor antagonist, proved to be an easy to use and cost-effective alternative to IV ondansetron in paediatric cancer patients receiving moderately emetogenic chemotherapy treatment. / Dissertation (MSc)--University of Pretoria / Pharmacology / unrestricted

Enteroviruses are associated with various diseases accompanied by rare but severe complications. In recent years, outbreaks of enterovirus D68 and enterovirus A71 associated with severe respiratory infections and neurological complications have been reported worldwide. Since information on molecular epidemiology in respiratory samples is still limited, the genetic diversity of enteroviruses was retrospectively analysed over a 4-year period (2013–2016) in respiratory samples from paediatric patients. Partial viral major capsid protein gene (VP1) sequences were determined for genotyping. Enteroviruses were detected in 255 (6.1%) of 4187 specimens. Phylogenetic analyses of 233 (91.4%) strains revealed 25 different genotypes distributed to Enterovirus A (39.1%), Enterovirus B (34.3%), and Enterovirus D (26.6%). The most frequently detected genotypes were enterovirus D68 (26.6%), coxsackievirus A6 (15.9%), and enterovirus A71 (7.3%). Enterovirus D68 detections were associated with lower respiratory tract infections and increased oxygen demand. Meningitis/encephalitis and other neurological symptoms were related to enterovirus A71, while coxsackievirus A6 was associated with upper respiratory diseases. Prematurity turned out as a potential risk factor for increased oxygen demand during enterovirus infections. The detailed analysis of epidemiological and clinical data contributes to the non-polio enterovirus surveillance in Europe and showed high and rapidly changing genetic diversity of circulating enteroviruses, including different enterovirus D68 variants.

Submitted in partial compliance with the requirements for the Master’s Degree in Technology: Chiropractic, Durban University of technology, Durban, South Africa, 2016. / INTRODUCTION: The utilization of complementary and alternative medicine (CAM) in the treatment of paediatric patients is increasing, especially the utilization of chiropractic treatment for children. However controversy exists regarding the reasons why parents may or may not choose to utilize chiropractic treatment for children. Parents are the gatekeepers to care as they consent to all treatment that is given to their children. Parents that have a lack of knowledge and understanding regarding chiropractic, as well as a negative perception regarding chiropractic treatment for children may be reluctant to choose chiropractic treatment as a treatment option. Both positive and negative opinions regarding chiropractic treatment have been identified in other populations in South Africa which emphasizes the need to explore the way parents feel about chiropractic treatment for children. A lack of knowledge and understanding of CAM has been identified as a reason for underutilization. Insight into the status of knowledge, understanding and perception of parents regarding chiropractic treatment for paediatric patients in the Durban Metropolitan Area equips the profession to better understand how parents view chiropractic treatment for children. AIMS AND OBJECTIVES: The main aim of this research was to explore and describe the knowledge, understanding and perception of parents regarding chiropractic treatment for paediatric patients. The outcomes of such a study can provide useful information which can serve as a baseline from which education and chiropractic treatment awareness can be built, as well as dispelling any misconceptions and myths regarding chiropractic treatment for children. RESEARCH DESIGN: An explorative, descriptive, qualitative research design was followed in this research. This research design was chosen in order to evaluate the knowledge, understanding and perception of parents regarding the utilization of chiropractic treatment for paediatric patients, within the Durban Metropolitan area. RESEARCH METHODOLOGY: Semi-structured interviews were conducted with participants of the Durban Metropolitan Area in order to determine the current knowledge, understanding and perception of parents regarding chiropractic treatment for paediatric patients within this area. Interviews were conducted with the participants until saturation was met, after which an additional five interviews were conducted. A total of 13 interviews were analyzed. The data was transcribed and coded by the researcher as well as a co-coder. NVivo software was utilized for the coding process. RESULTS: It was found that the participants had a lack of knowledge and understanding regarding chiropractic treatment for children. The participants felt that this lack of knowledge and understanding of chiropractic treatment for children left them unsure, resulting in the non-use of this form of treatment for their children. The participants were however not opposed to the utilization of chiropractic treatment for children; they felt fear and concern regarding chiropractic treatment as they felt they were uneducated regarding the outcome of the treatment, what the treatment would involve and the reasons why chiropractic treatment should be utilized for children. The participants mentioned that if they had increased knowledge and understanding they would feel more comfortable in utilizing chiropractic treatment for their children. The participants felt that they did not have the resources to learn more about chiropractic treatment and they showed interest in learning more about chiropractic treatment for children. Recommendations were made for further research and for the chiropractic profession regarding increasing the knowledge and understanding of parents regarding chiropractic treatment. / M

AIM The objective of this study is to determine factors that may contribute to hospital admissions in a cohort of medically insured South African patients in the era of HAART. METHODS This was a retrospective cohort of all HIV-positive adult and paediatric patients enrolled on a medical aid disease management programme in South Africa over a period of three years. Patient-specific demographic and clinical information were obtained from the medical aid records. Survival analysis was used to analyse time to first admission looking at admissions occurring after enrolment to the programme, during the study period of between 01 January 2006 and 31 December 2008. Only the right censored cases were included in the analyses. Descriptive analyses were conducted on the key prognostic factors. Variables that were significant in the univariate were considered in the multivariate Cox proportional hazards model. RESULTS A total of 8440 patients were included in the analysis. Half of these patients had at least one admission during the observation periods with 43.28% having had 2 or more admissions. The average admission rate was 2 admissions per patient over the 36 month observation period. Young children, adolescents and the very old (> 60 years) were significantly more likely to be admitted than the middle age groups, HR = 1.30 [95%CI 1.21 -1.40] p<0.01, 1.24 [95%CI 1.10 – 1.41] and 1.13 [95% CI 1.10 – 1.27] p<0.01 respectively. Low CD4 cell counts of < 200 cells/ µL were significantly associated with a higher likelihood of hospitalizations with hazard ratios even greater for CD4 cell counts of less than 100 cells/ µL, HR= 1.34 [95%CI 1.29 – 1.39], p<0.01. Cases were more likely to be admitted by a clinical haematologist or gynaecologist than by other specialist categories.HR =1.58 [95%CI 1.29 –1.94] and 1.17[95%CI 1.08 – 1.27] respectively with p<0.01. CONCLUSION Factors that are associated with hospital admissions in this private sector, medically insured population are a younger and older age, low CD4 cell counts and admission by a clinical haematologist and gynaecologist. These results suggest that disease management strategies should be intensified for the younger and older age groups. All HIV-positive patients should be closely monitored for CD4 deterioration so that treatment is initiated timeously. Routine haematological investigations should be recommended for all HIV-positive patients in order to pick up and treat haematological conditions before they result in a hospital admission. Evidence based guidelines, outlining the place of caesarian section deliveries in the HIV population, should be developed for use by gynaecologists specifically in the private sector. Copyright / Dissertation (MSc)--University of Pretoria, 2011. / Clinical Epidemiology / unrestricted