Background: The effectiveness of World Health Organization (WHO) guidelines for pneumonia case management in sub-Saharan Africa has been contested. This thesis aims to determine the clinical effectiveness of these guidelines among children admitted to Kenyan hospitals in a period after the introduction of the pneumococcal and Haemophilus influenzae type B (Hib) conjugate vaccines. The studies focus on the treatment of children with chest indrawing pneumonia, who were previously regarded to be at high-risk requiring inpatient treatment but were reclassified as lowrisk (non-severe) in the WHO guidelines updated in 2013. Methods: This thesis consists of: (i) A systematic review linked to a national guidelinedevelopment exercise appraising the evidence for the WHO pneumonia guidelines, (ii) a prospective observational study evaluating adherence to, and effectiveness of the pneumonia guidelines in the national referral hospital in Kenya, (iii) a multi-centre pragmatic randomised controlled trial (RCT) comparing amoxicillin versus benzyl penicillin for chest indrawing pneumonia (iv) a cohort study comparing treatment effects among children enrolled in the antibiotic RCT with a similar group who received routine care, and (v) a multi-centre retrospective cohort study of children hospitalised with pneumonia describing factors associated with mortality, focusing on characteristics that increase risk of death among children who would, under current guidance, be assigned a non-severe classification. Results: Although evidence from clinical trials supported the adoption of oral amoxicillin for severe pneumonia over benzyl penicillin (the standard treatment) for chest indrawing pneumonia, a Kenyan guideline development panel raised concerns of generalizability citing the limited data from sub-Saharan African populations in whom mortality was argued to be high. This concern was explored using prospectively collected observational data from 385 children. Treatment failure and mortality were infrequent (< 2%) for chest indrawing pneumonia where strict definitions requiring documented evidence of clinical deterioration were applied. In comparison, high rates of treatment failure (21.4%) and mortality (10.5%) were observed for severe pneumonia (formerly very severe pneumonia). Using propensity scores to model treatment effects comparing guideline recommended regimens with more costly, broad-spectrum alternatives, similar risks of treatment failure were observed in both groups. Amoxicillin was compared with benzyl penicillin in a pragmatic clinical trial of 527 children that also revealed low and comparable risks of treatment failure (8%) and mortality (< 1%) for the two treatments. Consistent results were observed in an observational cohort of children hospitalised at the same health facilities over the period the trial was conducted. However, analyses of data from > 16000 children suggested that the presence of commonly-occurring clinical signs may be associated with increased risk among children with non-severe pneumonia. Specifically, very low weight-for-age Z score (WAZ) or pallor in children with non-severe pneumonia were shown to be associated with absolute risks of mortality as high as those for severe pneumonia. Conclusions: Findings from locally-conducted observational studies and a clinical trial indicate low risks of treatment failure and mortality among children with chest indrawing pneumonia following treatment with benzyl penicillin monotherapy or amoxicillin. In contrast, mortality for severe pneumonia was greater than 10 percent. These results are consistent with the updated WHO recommendations and have more recently informed the revision of the national policy for pneumonia case management in Kenya. However, these guidelines may apply to sub-populations of children with non-severe pneumonia and either very low WAZ or pallor. This evidence is expected to contribute to ongoing debates on the adoption of WHO guidance for pneumonia case management in similar settings across sub-Saharan Africa where coverage of the Hib and pneumococcal conjugate vaccines is high.

Children with the congenital heart defect TOF require surgical repair. Their myocardium is exposed to chronic hypoxia due to insufficiently oxygenated blood shunted from the right to the left side of the heart through the VSD, resulting in cyanosis. Such corrective surgery often requires the use of CPB. During these procedures the aortic clamp is applied to allow access to the heart for the surgical correction creating an ischemic environment. When the clamp is removed and blood flow returned, the heart is reperfused. This exposes the myocardium to IR injury. Super-high oxygen (O2) levels are often used in the bypass circuit after the cross-clamp is released. This means during reperfusion the myocardium is exposed to high levels of O2. This is thought to be harmful, especially to children with cyanosis pre-operatively. A growing body of evidence suggests that these high levels of O2 may be damaging to the infant myocardium but the mechanisms are not that well understood. The first aim of this project was to investigate the molecular changes that occur within the infant myocardium in the context of congenital heart disease by comparing myocardium from the cyanotic patient group (TOF patients) and acyanotic patient group (patients with sub-aortic stenosis or truncus arteriosus i.e. disorders requiring myocardial resection but where the myocardium is acyanotic) during the ischemic phase. This was performed to reflect as near to pre-operative gene expression levels as possible. This thesis focused on the expression of inflammatory mediators (TLRs) and stress proteins (HSPs). It was found that TLR4 (p=0.0303), TLR2 (p=0.0177) and HSP27 (0.0303) mRNA expression were significantly higher in the myocardium from the cyanotic patient group compared to the acyanotic patient group. This could indicate a consequence of the hypoxic environment within such myocardium. HSPs are stress proteins, which are induced upon cellular stress. The Aplein receptor (APJ) is upregulated in the heart during ischemia and IR injury and thought to be cardio- protective. Additional work was performed that investigated the protein expression of HSP27 and APJ during the ischemic phase in cyanotic and non-cyanotic TOF myocardium. This expression was compared with various measurements of cardiac function. HSP27 protein expression was significantly elevated in cyanotic myocardium pre-operatively. It was also associated with improved right ventricle function and systemic perfusion. This supports a cardio-protective effect of HSP27 in cyanotic TOF. APJ was found to be associated with 2 improved systemic perfusion when both cyanotic and non-cyanotic patient data were combined. In order to determine if stress genes (HSPs) were inducible in the infant myocardium, they were exposed to classic heavy metal inducers sodium arsenite and cadmium chloride. Of the six HSPs investigated, all were shown to be present within the ischemic myocardium. Myocardial HSP32 (p=0.0156), HSP72 (p=0.0156) and HSP90 (p=0.0156) mRNA expression were significantly increased by exposure to heavy metals. Therefore, HSPs were shown to be inducible in infant myocardium. This was a good experimental control for the re-oxygenation experiment. The expressions of the same genes were also examined in vitro during an attempt to mimic re-oxygenation of the ischemic myocardium when the aortic-clamp is removed. Tissue was removed during the ischemic phase from both cyanotic and acyanotic patients and exposed to differential O2 levels. It was found exposure to 20% and 60% O2 for 4 hours induced mRNA expression of HSP32 (p=0.0391 and p=0.0078 respectively) and HSP72 (p=0.0078 and p=0.0078 respectively). This could indicate cellular stress during re- oxygenation of infant myocardium during surgical correction. No difference was indicated between the cyanotic and acyanotic patient group. The work of this thesis was focused on myocardial mRNA/ protein expression. Whether there is an alteration in circulating inflammatory mediators was not the focus of the present study but the results within this thesis highlighted the need for future studies to look at the effect of circulating factors on myocardial inflammation. This project is novel because it allowed a better understanding of the molecular mechanisms at work within infant myocardium and how they are influenced by re- oxygenation injury. It also examined how they are affected by cyanosis. It has highlighted the best ways in which such investigations could be extended. It has contributed important molecular data to the area of research and could potentially help lead to an improvement in myocardial protection during cardiac surgery with CPB.

The aim of the systematic literature review was to gain an in-depth understanding of how parents of children with an autism spectrum diagnosis experience stigma and in what ways they might manage this. Electronic databases and reference lists of published articles were systematically searched and six qualitative articles were selected for inclusion in the review. Findings from the studies formed the data for a thematic synthesis. Four interconnected themes were identified which capture parents experience of stigma: parent blame/responsibility; hidden disability; diagnosis/label and social isolation/avoidance. A further four themes were identified to highlight ways in which parents may manage this: diagnosis as a weapon; celebrating; increased resilience over time and planning and avoidance. The review suggests that negotiating public spaces may continue to be a challenge for some parents who experience both felt and enacted stigma. The aim of the study was to explore how parents share an autism spectrum diagnosis with their child and the processes which may be involved in this. Literature regarding parental experiences of autism assessment and diagnosis indicate that this is a highly emotive time for both parent and child and highlights multiple factors which may impact on the sharing process. There is also an indication in the literature that there is often a delay between the autism diagnosis being confirmed and this being shared with the child. In the absence of autism specific research, literature pertaining to diagnosis disclosure in developmental disabilities and in paediatric chronic illness is examined, outlining a range of emotional and social factors which may shape parental decisions of whether to share their child’s diagnosis with them. The researcher adopted a critical realist position and employed a qualitative approach to explore this under-researched area. A total of 10 parents were recruited to the study and participated in a semi-structured interview. Transcribed interviews were analysed using thematic analysis. A secondary thematic analysis was undertaken to produce a leaflet reflecting the accounts shared by the group of parents in the study. It is hoped that this may be useful to other parents who are contemplating sharing an autism spectrum diagnosis with their child and the professionals who support them. Three inter-connected themes were identified, each with further sub-themes: (1) Sharing is a process: naming autism, exploring and meaning-making and acceptance and integration; (2) Parental motivation to share: providing an explanation and protection and (3) Parental management of sharing: parental preparedness, perceived child preparedness and approach and strategies. Sharing is a process and its related sub-themes are discussed in the journal paper, whilst the remaining themes and sub-themes are presented in the extended paper. The findings illustrate that sharing an autism diagnosis with one’s child is a complex and dynamic process involving the balancing of many parent, child and social factors. Commonalities with previous literature are discussed alongside some alternative insights gained. The thesis concludes with personal reflections of aspects of the research process including the nature of autism as a diagnosis and the potential ethical issues raised when considering whether this is shared with children or not.

Six electronic databases were searched and 153 studies which identified the number or the rate of paediatric medication errors were identified; mainly from the US. These studies were compared to identify factors responsible for the great variations seen in reported error rates (Chapter 2). The most important factors were the use of different denominators, different definitions of medication errors, and the use of different methods of data collection. To explore further the reasons for the wide ranges of error rate identified in Chapter 2, the studies that used the same denominators, methods, and error types were compared, yet showed a difference between the highest and lowest error rate of more than 50% (Chapter 3). Factors identified for the variation in error rates included differences in setting, drugs studied, participants, study design details and countries involved. To try to clarify the relationship between the method of data collection and results obtained (Chapter 3), the rates of specific types of medication errors reported by studies using different methods but the same denominator were compared. Conclusions were difficult to draw due to the heterogeneity of the current literature. Prescription errors are probably best studied using chart review and administration errors by direct observation. The relationship between the clarity of definitions and results was investigated in Chapter 3, in terms of how clearly the studies had defined errors and the degree to which the definition(s) used matched each study’s aim. Studies were too heterogeneous and unfortunately could not adequately be compared. Chapter 3 also explores the interventional tools reported. Of all studies, 59 used interventional tools and assessed their benefit. These included dosing supporting tools, electronic prescribing, education, health and safety strategies, clinical pharmacist services and pre-printed forms among others. Most studies reported that their interventions effectively reduced or prevented medication errors, despite in some cases not measuring errors before and after interventions and even in some studies where error rates increased. Chapter 3 also explores the UK studies. Very few studies occurred in the same setting and used both the same methodology and denominators to identify the rate of the same types of medication errors. It was difficult to draw firm conclusions but prescribing and administration errors seem to happen more often in paediatric units in general hospitals than in specialist children’s hospitals. Most studies were of prescribing errors with other types of error rarely studied in the UK. Four studies identified the time of day most associated with errors; three the time of day and days of the week most associated with errors; and one the days of the week most associated with errors (Chapter 3). However, given the diversity of definitions of times of day, shifts, and weekdays, it was impossible to draw conclusions regarding the temporal aspect of medication errors from these studies. A second systematic review was conducted to explore the current literature that examines the role of paediatric clinical pharmacists in reducing the rate of medication errors (Chapter 4). Twenty-five studies published until the end of July 2013 were identified that reported pharmacists’ activities in reducing or preventing medication errors. The most commonly intercepted types of errors were wrong dose, wrong drug and wrong route of administration. The most common types of pharmacists’ contributions were reactive information giving in response to other healthcare professionals’ queries, education of healthcare professionals and cost saving. Based on knowledge gained from the second systematic review, an observational study of the role of paediatric clinical pharmacists was conducted in two NHS Trusts in the UK (Chapter 5). By shadowing pharmacists, they were observed during their day-to-day work and their contributions to health care were documented, as well as the errors that they identified and addressed. Having ultimately shadowed 14 pharmacists over the course of 197 ward visits, clinical pharmacists were found to play an important role in improving the health care services provided to paediatric patients and are effective in averting different types of medication errors. Pharmacists intercepted errors in 8.4% of all prescriptions and the overall contribution rate of all prescriptions was 54.8%. The most common types of errors intercepted by pharmacists were omission errors (27.9%), wrong dose (24%) and illegible prescribing (19.2%). The most common types of contributions were annotating prescriptions with information (e.g. administration instructions) (19.2% of all prescriptions), drug history check (97% of all new patients) and allergy status checked (100% of all new patients). The acceptance rate of pharmacists’ recommendations by doctors was very high (99.5%).

Parents of children with autism spectrum disorder (ASD) experience numerous challenges caring for their children. Research shows that those parents, and specifically mothers, suffer from high levels of stress and poorer well-being compared to parents of children with other disabilities. Developing and evaluating interventions to help enhance their well-being and their interaction with their children is recommended (NICE, 2013). Parenting interventions have been shown to be efficacious for parents of children with ASD , yet practical barriers may have an impact on their widespread uptake (McConachie & Diggle, 2007). Self-help parenting interventions with minimal therapists’ support, which have the potential to overcome barriers to adherence, have been used with parents of children with other neurodevelopmental disorders. However, there is limited evidence evaluating these interventions and their effectiveness for parents of children with ASD. Moreover, most parenting interventions for parents of children with ASD focus on developing the parents’ abilities to enhance specific skills in their children, while only few include psychoeducation components addressing knowledge about ASD and parental well-being. The main aims of this thesis were to understand the impact of having a child with ASD on parental functioning both internationally and for Saudi Arabian mothers and to then develop and evaluate both quantitatively and qualitatively the effectiveness of a brief psychoeducation intervention for mothers of children with ASD in the Kingdom of Saudi Arabia (KSA). Chapter One provides an introduction to ASD including its current definition, diagnosis, co-morbidities, risk factors, and treatment options. In addition, it discusses the theoretical models related to parenting children with ASD, and autism within the context of KSA including gaps in current research there. Chapter Two (study one), presents a systematic review investigating the impact of having children with ASD on parental life. Autism was found to impact areas including response to ASD, parental well-being, relationships, positive perception, financial problems, and future worries. Differences in findings between mothers and fathers were identified. Chapter Three (study two) explores the unmet needs of Saudi mothers of children with ASD in KSA through a pilot qualitative study that used semi-structured interviews. Mothers expressed a range of issues and needs including feelings of lack of sufficient information about ASD, the need for parental training, shortage of quality ASD services, lack of fathers’ assistance, and stigma associated with having children with ASD. Moreover, mothers insisted that barriers such as lack of transportation add to their burden. Chapter Four (study three) presents a meta-analysis evaluating the effectiveness of parenting interventions on parental functioning of parents of children with ASD. Analyses revealed that parenting interventions are effective in enhancing parental well-being (stress, depression, and anxiety), parenting practices, and in increasing parents’ sense of competence SOC. Chapter Six (study four) delivers the findings from a small-scale randomised controlled trial (RCT) investigating the effectiveness of a self-help psychoeducation intervention with minimal therapists’ support, delivered via WhatsApp for mothers of children with ASD in KSA. The intervention was successful in reducing maternal reports of stress, depression, ASD symptoms, and child behaviour problems. Change of clinical significance was minimal and limited to maternal depression. Chapter Seven (study five) describes a qualitative study that evaluates the acceptability and views of mothers who participated in the trial in Chapter Six. Mothers had positive views of the intervention and many of them were actively engaged in the intervention and discussed new parenting skills and behaviours that they had acquired. Finally, Chapter Eight provides a general and overall discussion of the thesis findings, including a summary of the findings of all the studies within the thesis. In addition, methodological strengths and considerations, clinical implications, and direction for future research are discussed. Collectively, the studies within this thesis provided evidence for the effectiveness of self-help psychoeducation parenting intervention with minimal therapist support and delivered via a virtual medium for mothers of children with ASD in KSA indicating that such interventions may have a place in future routine care.

Research report submitted in partial fulfilment of the requirements for the degree of Master of Medicine in Paediatrics. Johannesburg, 2015. / Urinary tract infections (UTIs) are an important cause of morbidity in children in developing countries and increasing antimicrobial resistance is reported in many countries. This retrospective study describes the performance of urine dipsticks, the aetiology and the antimicrobial susceptibility of paediatric UTIs at Rahima Moosa Mother and Child Hospital, Johannesburg. METHODS: We conducted a retrospective study of results from patients investigated for UTI over a four year period between January 2009 and December 2012 in the Department of Paediatrics & Child Health at Rahima Moosa Mother and Child Hospital. RESULTS: Escherichia coli was the commonest isolated uropathogen. Dipsticks sensitivity to identify UTI was 40% for leucocyte esterase and 34% for nitrites. The specificity was 94.6% for leucocyte esterase and 96% for nitrites. Malnutrition was associated with greater risk of having a UTI, with odds ratio of 2.06 (95% Confidence interval 1.4-2.9). In addition malnourished children tended to present with more resistant uropathogens. Resistance to sulphamethoxasole/trimethoprim and cephalexin has been progressively increasing between 2009 and 2012. From 64% to 79% for sulphamethoxasole/trimethoprim and from 24% to 63% for cephalexin. CONCLUSION: Positive urine dipsticks results allow immediate patient treatment but negative results need to be interpreted within the clinical context due to a high rate of false negatives. Malnourished children are significantly predisposed to urinary tract infections and tend to have more resistant uropathogens. Resistance to cephalexin is rising and studies to assess patient outcomes are needed to determine whether cephalexin still has a role in the treatment of paediatric UTI.

Introduction: Objectives were to describe time intervals between presentation to a tertiary care center, diagnosis and treatment in pediatric acute lymphoblastic leukemia (ALL) and Hodgkin disease (HD), and measure their impact on overall survival (OS) and event-free survival (EFS). Methods: Children in POGONIS (Pediatric Oncology group of Ontario Networked Information System) with ALL or HD from 1997-2007 were eligible. Time intervals were dichotomized at clinically defined cut-points. OS and EFS were examined with univariate and multivariable Cox proportional hazards (CPH) models. Results: In ALL, in multivariable analysis, those with treatment > 3 days after diagnosis had inferior OS (adjHR=2.49; 95%CI 1.4-4.43;p=0.002), and inferior EFS (adjHR=1.73; 95%CI 1.01-2.96;p=0.047). In HD, in multivariable analysis, those with treatment > 7 days after diagnosis had superior EFS (adjHR=0.37; 95%CI 0.18-0.77;p=0.008). Conclusions: Time to treatment is associated with survival in ALL and HD. Future research will further delineate the relationship between time to treatment and outcome.

Introduction: Objectives were to describe time intervals between presentation to a tertiary care center, diagnosis and treatment in pediatric acute lymphoblastic leukemia (ALL) and Hodgkin disease (HD), and measure their impact on overall survival (OS) and event-free survival (EFS). Methods: Children in POGONIS (Pediatric Oncology group of Ontario Networked Information System) with ALL or HD from 1997-2007 were eligible. Time intervals were dichotomized at clinically defined cut-points. OS and EFS were examined with univariate and multivariable Cox proportional hazards (CPH) models. Results: In ALL, in multivariable analysis, those with treatment > 3 days after diagnosis had inferior OS (adjHR=2.49; 95%CI 1.4-4.43;p=0.002), and inferior EFS (adjHR=1.73; 95%CI 1.01-2.96;p=0.047). In HD, in multivariable analysis, those with treatment > 7 days after diagnosis had superior EFS (adjHR=0.37; 95%CI 0.18-0.77;p=0.008). Conclusions: Time to treatment is associated with survival in ALL and HD. Future research will further delineate the relationship between time to treatment and outcome.

The thesis work entails a bench-to-bedside translational research approach to the development of pediatric fixed dose combination of zidovudine/lamivudine/nevirapine (60/30/50mg) orally disintegrating tablets. A simple and cost-effective, direct compression method was used. Preformulation studies that included analytical and bio-analytical assay development, excipient selection and characterization of drug-excipient interaction for initial formulation were conducted. Response surface methodology was utilized to optimize the formulation in terms of disintegration time and crushing strength. Stable ODT tablet was developed with desired friability (&lt; 1%), reasonable crushing strength, disintegration time (&lt; 30sec) and other quality attributes such as potency and dissolution. An open label randomized two-way cross-over bioequivalence of the product (with approved IRBs), conducted in 24 healthy adult volunteers, indicated the product to be bioequivalent with the innovators. 90% C.I of the point estimates of PK parameters evaluated were in the range of 80-125% as specified by FDA. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmaceutics / MS; / Thesis;

Thesis (MDSc)--University of Queensland, 2002. / Includes bibliographical references.