Background: Over 50% of HIV-infected children in South Africa have developmental delays. Early identification of affected children will lead to early intervention and favourable long-term outcome. Screening for developmental delay is not yet routine by many primary healthcare providers due to lack of locally available, rapid and sensitive screening tool s in busy Paediatric HIV clinics. A new screening tool was developed at the Red Cross War Memorial Children's Hospital (RCWMCH) for detecting moderate to severe global developmental delay among very young HIV infected children. The diagnostic accuracy and usefulness of the new tool was evaluated in this study. Objective: to validate the new RCWMCH developmental screening too l among HIV - infected South African children. Method: Forty-seven HIV-infected children in the age category 9-36 months attending the Infectious Disease Clinic (IDC) of the RCWMCH were screened using the new tool. Full developmental assessments of same children were performed using the Bayley Scale of Infant Development (BSID - III). Developmental Delay (global) was defined as composite scores 2 standard deviations below the mean in two or more developmental domains. Results: The sensitivity of the RCWMCH tool was 78.5%, specificity 54.6%, positive predictive value was 42.6%, and negative predictive value was 85. 7 %. Discussion: The RCWMCH screening tool was found to have sensitivity within the acceptable levels recommended for developmental screening tools. Its high negative predictive value will reduce unnecessary referrals for full developmental assessments in asymptomatic infants and toddlers. It is therefore recommended for screening for developmental delay among HIV-infected children from the age of 9 months to 3 years.

Background Since 2010, adult studies and clinical concerns about stavudine (d4T) toxicity had led to the phasing out of d4T from many antiretroviral treatment (ART) guidelines globally with substitution by abacavir. Recent studies, within Southern Africa, however have shown poorer virological suppression with abacavir (ABC) compared to d4T at their respective centres. Methods A retrospective study of HIV-positive children, who had been initiated on ART from 2005 to 2017, was conducted at an ART unit at New Somerset hospital, Western Cape, South Africa. Data was extracted from clinical notes and electronic medical records and virological suppression reviewed in those started on ABC and d4T based regimes. Results A total of 672 children were included in the study with a median age of 8.9 months (interquartile range (IQR) 4.1- 24.1 months) in the d4T based group and 11 months (IQR 3.5 - 29.9 months) in the ABC group. 64 of the 437 patients in the d4T containing group were transferred out, 15 reported to have died, and 49 were lost to follow up within the first 6months on treatment. Of the 181 ABC containing regimen group, 1 was transferred out to another care facility, 1 reported death within 6months of treatment and 2 children were lost to follow up. There was a noted increased risk of being virologically unsuppressed at 6months while taking ABC containing regimen compared to a d4T containing regimen. . The relative risk of being virologically unsuppressed at 6 months while taking abacavir/lopinavir (LPV/r) was 1.39 (95% confidence interval 1.03 to 1.88, p=0.04) compared to stavudine/LPV/r. The relative risk of being virologically unsuppressed at 6 months while taking abacavir/efavirenz (EFV) was 1.82 (95% confidence interval 0.98 to 3.37, p=0.054) compared to stavudine/EFV. Conclusion Our analysis again raises concerns about virological suppression in the abacavir era of paediatric ART, compared to the previous stavudine era, particularly in combination with LPV/r in the younger, more vulnerable children. Whether this is because of intrinsic properties of the different medications or is a marker of the evolving complexity of the South African ART rollout, may never be resolved. However, this is of concern as abacavir and LPV/r appear to be entrenched as first-line paediatric ART in a setting where attrition is high, many children are lost to follow up and virologic surveillance is not always optimal. Clinicians need to optimize retention strategies, especially of young infants, to ensure that children are retained in care, have viral load testing timeously, so that those virologically unsuppressed can be detected and treated early and appropriately.

Includes bibliographical references / Rheumatic Heart Disease (RHD) is a leading cause of heart disease in children and young adults in the developing world, with significant associated morbidity and mortality. Early secondary prophylaxis may retard the deleterious progression from its antecedent, acute rheumatic fever to permanent heart valve damage, and thus several echocardiographic screening programmes to detect asymptomatic RHD and institute early prophylaxis have been conducted. While effective interventions are available for ameliorating the effects of RHD, research on their use in different settings is scant. Key questions remain regarding the natural history of asymptomatic RHD and the optimal method for early detection. In addition, there is a lack of contemporary estimates of mortality and morbidity among the symptomatic population in the developing world. The primary purpose of the thesis was to determine the outcomes of asymptomatic and symptomatic RHD. More specifically, I sought to quantify the incidence, prevalence and outcomes of RHD in South Africa over the past two decades, determine the natural history of asymptomatic RHD and validate a focused protocol for screening in schoolchildren from Cape Town. In addition, I determined the baseline characteristics, prevalent sequelae and gaps in evidence-based implementation in children and adults from14 developing countries. Finally, I investigated the independent predictors for mortality and morbidity of RHD over a two-year period in patients from Cape Town, South Africa. My thesis has five key findings. Firstly, a systematic review of the literature showed that the incidence and prevalence of RHD over the past two decades in South Africa remains high, although there is evidence of falling cause-specific mortality at a population level. Secondly, asymptomatic RHD has a variable natural history that ranges from regression to a normal state, to persistence of disease, and progression to symptomatic RHD. Thirdly, a focused hand-held echocardiography protocol shows promising levels of sensitivity and specificity for detecting subclinical RHD. Fourthly, the baseline data from the global rheumatic heart disease registry demonstrates significant gaps in the implementation of medical and surgical interventions of proven effectiveness in low- and middle-income countries. Finally, the annual mortality rate for children and adults with RHD in Cape Town over a two-year period is 4.1%with cardiovascular events occurring at a rate of 0.18 events per patient per year. The findings encapsulated in this thesis have important implications for policy, practice and research related to the management of asymptomatic and symptomatic RHD in the world.

Aims and Objectives: To compare three risk assessment scales with respect to predictive validity Background: In paediatrics there are several competing scales and at least ten published paediatric pressure ulcer risk assessment scales have been identified. However there are few studies exploring the validity of such scales, and none identified that compares paediatric risk assessment scales. Design: Cross sectional study Methods: Three risk assessment scales, Braden Q, Garvin and Glamorgan, were compared. The total scores and sub-scores were tested to determine if children with pressure ulcers were significantly different from those with no pressure ulcer. Logistic regression was conducted to determine if the probability of developing a pressure ulcer was a better predictor of development of pressure ulcer compared with the total score of each scale. Receiver operating characteristic curves were computed and the area under the curve used to compare the performance of the risk assessment scales. Results: Data from 236 children were collected. 71 were from children in eleven hospitals who were asked to provide data on children with pressure ulcers (although seventeen did not have a pressure ulcer) of whom five were deep (grade 4). A sample of 165 were from one hospital, of which seven had a pressure ulcer, none grade four. The Glamorgan risk assessment scale had a higher predictive ability than either the Braden Q or Garvin. The mobility sub-score of each of the risk assessment scales was the most predictive in each case. Conclusions: The Glamorgan scale is the most valid of the three paediatric risk assessment scales studied in this population. Mobility alone may be as effective as employing the more complex risk assessment scale. Relevance to clinical practice: If a paediatric risk assessment scale is employed to predict risk, then unless it is valid, it may identify children who are not at risk and waste resources, or fail to identify children at risk possibly resulting in adverse health outcomes.

Sialic acid (SA) is a known major virulence factor of Haemophilus influenza (Hi). This study aims to analyse the functions of some candidate sialometabolism genes, and to further our current understanding on the Hi sialometabolism gene regulation. Two candidate sialometabolism genes (HI0227 and HI0148) and their adjacent ORFs (HI0228, HI0148.1 and HI0149) were studied. HI0148.1 and HI0149 are transcribed as a single gene in screened NTHi strains, and we refer to the combined ORF as NTHI0236 (the designation in strain 86-028NP). Across Hi strains screened, the sequences of HI0227, HI0148 and NTHI0236 are conserved. However, the sequence of HI0228 is heterogeneous. Mutants that lack the functions of HI0227, HI0228, HI0148 and NTHI0236 were compared to their respective wild type parent strains for ability to grow on SA (in aerobic and microaerophilic conditions), their ability to sialylate LPS and their ability to resist complement mediated killing. The mutants did not exhibit major differences in the tested aspects of sialometabolism compared to their respective wild type strains. Changes observed in some of the mutants in serum bactericidal assays and LPS profiles were due to the effect of phase variable genes. The sialometabolism functions of HI0227, HI0148, and NTHI0236 remain obscure, and we postulate that HI0228 is a pseudogene. Investigation of Hi sialometabolism gene regulation was conducted using mutants that lack different steps of the Neu5Ac catabolism pathway and the Neu5Ac activation pathway. The expression of nanE and siaP, respectively representing the Neu5Ac catabolism and transport operons, were assessed using RT-PCR and qPCR. We investigated a temporal/concentration effect of Neu5Ac on the expression of sialometabolism operons, which highlights the importance of studying the Hi sialometabolism gene regulation as a dynamic process. We further demonstrated that GlcN-6P, a Neu5Ac intermediate from the catabolism pathway, is likely the SIS sugar that interacts with SiaR, the repressor protein of the Hi sialometabolism operons. We postulate that upon binding of GlcN-6P to SiaR, the SiaR-mediated repression on the Hi sialometabolism operons is relieved, resulting in the induction of the expression of Neu5Ac catabolism and transport genes.

This thesis investigated the possible use of transdermal iontophoresis in paediatric care, as an alternative strategy to the oral and intravenous routes. More specifically, the potential for non-invasive delivery of ranitidine, midazolam, and phenobarbital; and the clinical sampling of iohexol through the skin were examined. The feasibility for monitoring kidney function was assessed in vitro and in vivo using the glomerular filtration rate (GFR) marker, iohexol. Sampling of iohexol in vitro was sensitive to the changes in its subdermal concentration, and pharmacokinetic parameters estimated from skin sampling agreed well with reference subdermal values. Similar observations were confirmed in vivo in a pilot study performed in four children undergoing routine iohexol GFR test. Iontophoresis was well tolerated in all subjects and the marker was successfully extracted through the skin. In 3 of 4 subjects, the elimination rate constant estimated from skin sampling data agreed well with blood sampling results. This study demonstrated the potential of transdermal iontophoresis as a non-invasive sampling approach which could significantly improve the quality-of-life of children. Drug delivery by transdermal iontophoresis was examined in vitro for three commonly used paediatric medicaments: ranitidine, midazolam, and phenobarbital. Experiments used both intact and compromised pig skin to model the less resistant skin of premature babies. Iontophoretic delivery across intact skin was superior than passive delivery and optimised conditions were achieved by use of maximal molar fraction of the drug, higher current intensity, and appropriate vehicle pH. Pluronic® F-127 gels were suitable drug matrices for the iontophoretic delivery of ranitidine. Midazolam and phenobarbital transdermal delivery through partially compromised skin barriers was controlled by iontophoresis. Across highly compromised skin, however, passive diffusion increased drastically and iontophoretic control was lost. Overall, it was possible to deliver therapeutically meaningful fluxes of all three drugs with acceptable patch application area.

The purpose of this study was to determine the indicators of customer satisfaction and service success of a newly established paediatric outreach nursing service. Referring agents and care recipients were both consumers of the paediatric outreach nursing service. Both groups of consumers were surveyed to determine their satisfaction with the service delivery. Two satisfaction survey tools were developed to measure customer satisfaction. The tools were piloted and refined prior to distributing them. Both tools had a series of closed-ended questions and 3 open-ended questions. Eight service indicators were developed. These were designed to test the effectiveness of the service provided. The service indicators were piloted over two periods of three months and then modified based on the findings of the pilot period. The Paediatric Outreach Service (POS) is a positive service model for health care delivery. The survey results indicated that stakeholders were generally satisfied with the service delivery. When measured against service indicators that were developed for POS, the service performance was above average, with some opportunity to improve practice. Underpinned by a family-centered framework, POS has the capacity to empower children and their families in the planning and implementation of a management plan for the child’s illness. Such empowerment may lead families to practice better healthcare, develop better health-seeking practices and ultimately lead to healthier children. The results from this study has implications for nursing practice. The data obtained from this study may be useful to service providers considering commencing a paediatric outreach nursing service. Data may also be useful for existing service providers to use in order to review the aspects that consumers value against the service they currently provide. Keywords ambulatory care; paediatrics; home-nursing; community; evaluation; satisfaction; success; indicators

Repeated cannulation of children during the course of treatment is distressing for the child, their family and to their nurses. Some paediatric units endeavour to minimise recannulation by employing strategies to reduce complications such as phlebitis and thrombosis formation. One strategy is to infuse low dose heparin and hydrocortisone (HEPHC). However, its effectiveness in prolonging cannula survival is inconclusive. There is also concern about the potential risks of administering these preparations to children. A randomised, controlled, blinded trial was conducted that examined the effectiveness of continuous infusion of low dose HEPHC in a group of children requiring long term intravenous antibiotics in a general paediatric unit. Comparisons of cannula complications and cannulae survival times were made in children receiving either continuous infusions of clear fluids or low dose HEPHC. The results demonstrated that there was no statistically significant difference (Logrank statistic=l.l, p=0.3) in cannula survival times between the two groups. It was also found that the bacterial and fungal colonisation of cannula for these children was extremely low. Based on these findings it is recommended that routine administration of low dose HEPHC to extend cannula survival time be discontinued. The findings also support current practice of removing cannula in children only when a complication occurs on completion of treatment.

The purpose of this study was to evaluate the clinical relevance of access targets for elective dental general anaesthesia (GA) by assessing incremental changes in dental disease burden over wait times at SickKids. A retrospective review of dental records were completed for 378 children who were prioritized by their dental and medical status. A scale was developed to measure cumulative dental disease burden over time. Statistically significant correlations were identified between cumulative disease burden and wait times for priority IV (p = 0.004), the entire sample (p < 0.003), DOSDCADCA (p = 0.005), comorbid (p = 0.036), healthy (p = 0.0002), female (p = 0.014) and male (p = 0.008) groups. The mean cumulative disease burden was not different between matched healthy and cormorbid groups (p = 0.38). A trend of increasing dental disease burden for children with longer wait times for dental GA was found but not clinically significant.

The purpose of this study was to evaluate the clinical relevance of access targets for elective dental general anaesthesia (GA) by assessing incremental changes in dental disease burden over wait times at SickKids. A retrospective review of dental records were completed for 378 children who were prioritized by their dental and medical status. A scale was developed to measure cumulative dental disease burden over time. Statistically significant correlations were identified between cumulative disease burden and wait times for priority IV (p = 0.004), the entire sample (p < 0.003), DOSDCADCA (p = 0.005), comorbid (p = 0.036), healthy (p = 0.0002), female (p = 0.014) and male (p = 0.008) groups. The mean cumulative disease burden was not different between matched healthy and cormorbid groups (p = 0.38). A trend of increasing dental disease burden for children with longer wait times for dental GA was found but not clinically significant.