A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Paediatrics and Child Health 29 May 2017 / Introduction Sepsis, and in particular, severe sepsis, remains a major cause of death in children worldwide. One of the areas where the burden of sepsis is keenly felt is in the paediatric intensive care unit (PICU) setting, contributing significantly to childhood mortality. Fungal organisms have emerged as a major organism contributing to nosocomial sepsis in PICU. No local data regarding nosocomial fungal sepsis in the non-neonatal, PICU population exists regarding this matter. This study describes the characteristics of patients with nosocomial fungal sepsis in the PICU at South Africa’s largest hospital Chris Hani Baragwanath Academic Hospital (CHBAH). Methods This study was a retrospective review of patient records. All patients aged 0-16 years admitted to the PICU at Chris Hani Baragwanath Academic Hospital (CHBAH) from January 2008 through December 2011 were assessed. A total of seventeen patients who developed nosocomial fungal sepsis were included in this study. Results The incidence of candidaemia was reported to be 3.2 per 100 cases. The major age group affected by nosocomial fungal sepsis was the under one age group. The most common diagnoses on admission were lower respiratory tract infection (LRTI) followed by haematology-oncology and acute gastroenteritis cases. ICU factors found to commonly co-­‐exist with proven nosocomial fungal sepsis were presence of a central venous catheter (100%), mechanical ventilation (82%), arterial line (70%), and systemic corticosteroid use (47%). The penicillin class was the most common antimicrobial that patients were found to be on at the time of nosocomial sepsis. The most common fungal organism as a cause for nosocomial sepsis was C. parapsilosis rather than C. albicans. Furthermore, the majority of this study’s isolates were susceptible to voriconazole rather the current empiric antifungal of choice, namely fluconazole. Conclusion The presence of central venous catheters, arterial lines, mechanical ventilation and systemic corticosteroid use is common in paediatric patients with nosocomial fungal sepsis. However, this study was unable to determine statistically significant factors associated with fungal sepsis in a tertiary PICU due to the surprisingly small number of cases (n=35) detected over a four-year period. This perhaps represents the most striking finding of the study together with a concerning pattern of fluconazole resistance (14%) among isolated organisms. / MT2017

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Thesis (M.Soc.Sc.) - University of KwaZulu-Natal, Pietermaritzburg, 2009. / Full text also available online. Scroll down for electronic link.

In 1973, Winnie and co-workers stated that no technique could truly be called simple, safe and consistent until the anatomy has been closely examined. This is evident when looking at the literature where many anatomically based studies regarding regional techniques in adults have resulted in the improvement of known techniques, as well as the creation of safer and more efficient methods. Anaesthesiologists performing these procedures should have a clear understanding of the anatomy, the influence of age and size, and the potential complications and hazards of each procedure to achieve good results and avoid morbidity. A thorough knowledge of the anatomy of paediatric patients is also essential for successful nerve blocks, which cannot be substituted by probing the patient with a needle attached to a nerve stimulator. The anatomy described in adults is also not always applicable to children, as anatomical landmarks in children vary with growth. Bony landmarks are poorly developed in infants prior to weight bearing, and muscular and tendinous landmarks, commonly used in adults, tend to lack definition in young children. The aim of this research was therefore to study a sample of neonatal cadavers, as well as magnetic resonance images in order to describe the relevant anatomy associated with essential regional nerve blocks, commonly performed by anaesthesiologists in South African hospitals. This research has brought to light the differences between neonatal and adult anatomy, which is relevant since the majority of paediatric regional anaesthetic techniques were developed from studies originally conducted on adult patients. Current techniques were also analysed and where necessary new improvements, using easily identifiable and constant bony landmarks, are described for the safe and successful performance of these regional nerve blocks in paediatric patients. In conclusion a sound knowledge and understanding of anatomy is important for the success of any nerve blocks. This study showed that extrapolation of anatomical findings from adult studies and simply downscaling these findings in order to apply them to infants and children is inappropriate and could lead to failed blocks or severe complications. It would therefore be more beneficial to use the data obtained from dissection of neonatal cadavers. / Thesis (PhD)--University of Pretoria, 2010. / Anatomy / unrestricted

Purpose: There is very little documented evidence regarding the training of paediatric surgeons in South Africa since its inception as a formal speciality in 2007. This study aims to assess South African paediatric surgical trainees' perspectives regarding their training. Methods: A prospective study was conducted via an emailed electronic survey. The sample population included all current paediatric surgical trainees in South Africa. The questionnaire covered the trainees' demographics, exposure to different aspects of paediatric surgery, extent of after-hours clinical service, self - reported surgical competency and consultant supervision. Results: Forty one (95%) out of 43 trainees responded to the survey with 29 (71%) being female. Reported training deficits included lack of exposure to burn care in 12 trainees (30%), no urology exposure in 8 (20%), no paediatric trauma or minimally invasive surgery exposure in 6 (15%). Eighteen trainees (44%) reportedly worked more than 65 hours per week with clinical responsibilities being the biggest hindrance to attending academic teaching. Trainees were more comfortable performing open procedures compared to laparoscopic but most respondents felt adequately supervised. Conclusion: There exists a significant heterogeneity amongst the different training institutions with protected academic time and exposure to burns, urology and minimally invasive surgery remaining major obstacles in training.

MSc (Med) Emergency Medicine, Faculty of Health Sciences, University of the Witwatersrand / Adequate exposure to paediatric pre-hospital emergency cases for students undertaking clinical learning is a key component of preparation for independent practise. Both clinical reasoning and psychomotor skills require practise in a realistic environment in order to best equip the qualifying practitioner for demands of the real world of pre-hospital emergency care. The aim of this study was to retrospectively describe the exposure of pre-hospital emergency care students in the University of Johannesburg‟s National Diploma in Emergency Medical Care programme to emergencies involving paediatric patients in the Greater Johannesburg Metropolitan area over a continuous eight year period, between 1 January 2001 and 31 December 2008. Patient care records contained in an electronic clinical learning management information system entered over the eight-year study period were analysed in order to characterise the exposure of students to paediatric emergency cases in general, and clinical skills performed during this exposure. Results showed that, with the exception of infants and children seen by first year students, median exposure to paediatric emergency cases for students in all academic years was below 50%. Exposure to emergencies involving younger patients was generally lower than that for older patients, however the acuity of patients increased with decreasing age. Exposure to most clinical skills also decreased with decreasing patient age. Opportunities for students to practise critical or invasive skills were relatively rare. Suggestions for the improvement of student exposure to paediatric emergency cases and clinical skills include a period of internship and greater utilisation of hospital-based clinical skills exposure and practice.

An evolution in methods of identifying the causal mutations and candidate genes for Mendelian disorders has occurred recently. Though several studies have reported the causative mutations in non syndromic tooth agenesis, there are only two reports on autosomal recessive nonsyndromic tooth agenesis in consanguineous families. Since the consanguinity rate is high in tribal population of Saudi and Pakistan, this study identified consanguineous families in these populations to investigate the molecular basis of tooth agenesis. This study aimed to study the phenotype of familial tooth agenesis in Saudi and Pakistani families of consanguineous marriage, and to identify the causative mutations. A further aim was to investigate the influence of the agenesis gene on tooth size in one large Saudi family. Sixteen families with non-syndromic tooth agenesis, were clinically characterised for the pattern of inheritance, tooth agenesis severity and type of teeth affected. Genetic analysis including homozygosity mapping and exome sequencing was performed in eight families. Hand measurements of Saudi family tooth dimensions were made on dental study models. The most affected tooth type in studied families were the lower second premolar and upper lateral incisors. The homozygosity mapping approach failed to identify the regions of the diseased mutations in these families. The exome sequencing data revealed a heterozygous novel frameshift mutation in exon 2 of the MSX1 gene, c.750_751insACCGGCTGCC (p.A250fs) in one Saudi family and a homozygous novel mutation in exon 8 of the SMOC2 gene, c.681T>A (p.C227X), in the Pakistani family. It was found that there was a significant (p <.0.05) trend of reduction in the crown sizes both in the tooth agenesis group and their family members with no tooth agenesis compared to the control group. It is concluded that homozygosity mapping was not sensitive to identify the elusive tooth agenesis gene and whole exome sequencing technique is needed in future studies. The tooth measurement study indicates and confirms that crown size is closely related to tooth agensis.

Enteric fever continues to affect people living in endemic settings substantially causing at least 20 million cases of febrile illnesses every year with 1% mortality. Over the last decade there has been considerable debate surrounding the burden and disease profile of enteric fever in the paediatric population. This is partially due to the similarity of the clinical features of paediatric enteric fever to most other febrile illness seen in endemic settings. The treatment of enteric fever is proving to be a challenge with the emergence of antimicrobial resistant strains, particularly the 4.3.1 genotype (H58 haplotype), which is spreading rapidly. Multi-drug resistant (MDR) enteric fever, defined as infection with typhoidal Salmonellae that exhibit a combined resistance to ampicillin, cotrimoxazole and chloramphenicol emerged in the 1990s and was mediated primarily via the 4.3.1 genotype population through the horizontal acquisition of antimicrobial resistance determinants. Subsequently, fluoroquinolones became the drug of choice and the treatment of enteric fever following which fluoroquinolone resistance emerged, again through the 4.3.1 genotype. However, these antimicrobial trends may not be uniform across endemic regions and an understanding of these differing patterns as well the temporal changes in these trends are important in planning treatment strategies. In the short and medium term work needs to be focused on achieving the greatest benefits from the prudent use of the recently WHO pre-qualified Vi-TT conjugate vaccine candidate. Whilst the long term vision towards eradicating enteric fever needs to focus on better understanding the underlying the biology of this disease through the use of contemporary technologies while simultaneously improving infrastructure for the provision of clean water, adequate sanitation and hygiene. This thesis aims to age-characterise the disease burden of typhoid fever in endemic regions of South and South-East Asia as well as the African continent. Following this, the molecular epidemiology of enteric fever in two endemic settings in the Indian subcontinent is delineated with a keen focus on the 4.3.1 genotype (H58) population as well the phenotypic patterns and molecular determinants of antimicrobial resistance. This thesis finally systematically reviews the global trends of antimicrobial resistance of S. Typhi isolates over time both from a phenotypic and molecular perspective. The key results from this thesis include; the age stratification of disease occurrence in endemic regions which showed a substantial proportion occurs in the youngest age group in both Africa and Asia, the uniform dominance of 4.3.1 genotypes conferring a high degree of fluoroquinolone resistance contrary to earlier suggestions of younger children being more susceptible to a broader range of infecting genotypes, the dissimilarities between the antimicrobial resistance carrying capabilities of lineage I and lineage II strains of the 4.3.1 genotype as well as novel AMR gene arrangements and finally the temporal trends of AMR in S. Typhi which were different between Asia an Africa. The high prevalence of lineage I strains in Africa and South-East Asia in contrast to the high prevalence of lineage II strains in the Indian subcontinent reflect the antimicrobial selection pressures as well the evolutionary characteristics of circulating pathogen populations in these regions. The implications of the data reported in this thesis have implications for treatment and prevention strategies. For the first time in history an opportunity has risen to effectively vaccinate the youngest age group (0-4 years) from typhoid through the Vi-TT conjugate vaccine. As highlighted in this thesis the youngest age group (0-4 years) have a high disease occurrence in endemic areas as seen in a meta-analysis as well as through data from two endemic sites collated and reported in this thesis. The older age groups also suffer greatly from this disease calling for a broad based vaccine strategy. The implications for treatment of enteric fever are however more relevant in the immediate term which suggest that in endemic regions in Asia, fluoroquinolones have little role to play in treatment protocols while fluoroquinolones are still relevant in the African setting. In Asia, reverting back to former first-line antimicrobials might be an option but the possibility of re-emergence of widespread resistance to these currently sensitive antimicrobials is very high exemplifying the ability of S. Typhi to adapt to changing antimicrobial pressures.

Salivary proteins such as statherin (STN) are known to be involved in enamel de/remineralisation, the inhibition of crystal growth, and spontaneous precipitation of calcium phosphate salts. The active N-terminal of STN (STN21) is involved in binding with Ca2+ and in reducing HA demineralisation. In addition, salivary Histatin-1 (HTN) inhibits crystal growth of calcium phosphate salts but does not inhibit their spontaneous precipitation. These salivary peptides do not occur as individual molecules in saliva, they are part of a complex salivary system. The aims were to investigate the effect of salivary STN, HTN and their 21 N-terminal peptides (STN21, and HTN21) individually and when in combination on the demineralisation rates of HA and enamel using scanning microradiography. In addition, to understand their effect on HA and enamel demineralisation, peptide adsorption onto HA and enamel was measured spectrophotometrically. Also, peptide aggregation, surface charge and, conformation in solution were investigated. The adsorption and demineralisation reduction of non-human STN was also investigated. STN, HTN and STN21 individually showed similar adsorption and demineralisation reduction efficacy in HA but not in enamel. HTN21 showed the lowest demineralisation reduction of all peptides. STN21 when in combination with either HTN, or HTN21, showed the greatest demineralisation reduction of all peptides. The increase in peptides demineralisation reduction efficacy when in combination suggests co-operative efficacy, which is further increased with the removal of the C-terminal. All individual peptides were found to adopt an α-helical conformation at the N-terminal, which is important in peptide adsorption onto HA surfaces. When in combination conformational changes led to peptide interaction and caused an increase in their net negative charges. In conclusion, it was found that the degree to which demineralisation is reduced by peptides is correlated with the amount of peptide adsorbed.

The establishment of trust in the nurse-parent relationship is espoused to be fundamental in achieving partnership-in-care within paediatric nursing. Paediatric nursing has progressed since the 1960's and in the 1990's, the major breakthrough was the emergence of the partnership model. Hence, it would be ideal to investigate the elements facilitating the foundation of trust in the formation of a nurse-parent relationship. The purpose of this study is to identify the concept of formation of trust in the relationship between parents whose children suffer from chronic asthma and the paediatric nurses responsible for their care in a paediatric medical setting. The study also determined and explored the characteristics of a trustworthy nurse, and identified those factors which facilitated or impeded the development of trust between the paediatric nurse and the parent within the culture of the paediatric medical setting. Parents of hospitalised children were sought for data collection. Data was collected using field observations and semi-structured interviews. Participant observation and all ethnographic field notes were used to describe culture in relation to the concept of trust in the nurse-parent relationship. The findings indicated that elements vital to the development of trust between parents and paediatric nurses were pre-existing trust, knowledge of asthma, communication, building a relationship and confidentiality. Based on these findings, a model of trust and partnership was developed. The implications of the findings have been significantly related to keeping parents informed of their child's condition, the continuity in nursing care and paediatric nurses to introduce themselves at the beginning of each change of shift.