Masters Degrees (Paediatrics and Child Health)

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    Outcomes of elective surgical patients admitted to a tertiary Paediatric Intensive Care Unit.
    (2021) Ntombela, Zamaswazi Princess.; Masekela, Refiloe.; Hlophe, Sbekezelo Thembelihle.
    Background: A paediatric intensive care unit (PICU) is a unit for critically ill medical and surgical children. It is imperative that the spectrum and outcome of elective surgical patients is reviewed to help develop admission criteria for elective surgical patients to assist in prudent resource allocation. Objectives: To describe the clinical characteristics, diagnosis, complications, and outcome of elective surgical admissions, to the PICU. Methods: A retrospective chart review of all elective paediatric surgical patients admitted between 01 January 2018 to 31 December 2019 at Grey’s Hospital PICU, a tertiary hospital. All elective surgical patients admitted at Grey’s PICU were included in the study. Data was analyzed using the statistical analysis involved both descriptive and inferential statistics. The descriptive statistics included frequency tables for categorical variables and number summaries for continuous variables. To determine the factors associated length of stay, general linear model was fitted using the Gamma family distribution since the length of stay was skewed. All the tests were benchmarked at α = 0.05 level of significance. Ethical approval to access patient records was obtained from the Biomedical Research Ethics Committee of University of KZN (BREC/00001304/2020), Greys Hospital and Department of health. Results: There were 320 elective surgical bed requests for PICU of which 279 (87.2%) were accepted but only 234 were admitted to PICU, the rest did not require PICU post theatre. Forty one (12.8%) were not accepted due to unavailability of resources. The median age for this study population was 2 years (0 - 16 years). Gender distribution 50.0% were male, 35.0% female and 15.0% unknown. The majority, 80.9% were HIV negative with normal nutritional status (75.9%). Elective surgical admissions constituted 30.0% (234/ 798) of total PICU all admissions. The average waiting period was 4.0 days with an average length of stay of 2 days. With regards to indications for surgery, the majority were for airway problems 91 (28.0%) and 45 (14.2%) for feeding difficulties. 158 (49.7%) had no reported comorbidity. The most common comorbidity was cerebral palsy 5 (11.0%) followed by right heart failure 19 (6.0%). With regards to outcomes, 98.7% were discharged with no complications and 3 (1.3 %) died. Conclusion: Elective surgical admissions constituted a third of all PICU admissions with the majority having upper airways abnormalities, with a good outcome. Majority of bed requests were met. Mortality was low and length of stay was shorter amongst the elective surgical cases. Children under the age or one year requiring surgery need prioritization for access to post operative PICU care.
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    Evaluation of an exclusive breastfeeding promotion programme in an informal settlement in Durban.
    (2002) Bentley, Jane.; Coutsoudis, Anna.
    Abstract available in PDF.
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    Validation of bioimpedance against isotope methods for the determination of body composition in HIV infected South African children.
    (2010) Sewnath, Alesha.; Chhagan, Meera Kurson.; Adhikari, Miriam.
    Abstract available in PDF.
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    The role of parenteral phenobarbitone in the treatment of neonatal hyperbilirubinaemia.
    (1993) Adam, Omar Farouk.; Adhikari, Miriam.
    Abstract available in PDF.
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    Assessing reported adherence to antiretroviral therapy using the method of verbal recall in children from Kwa-Zulu Natal, South Africa.
    (2017) Ebrahim, Hassina.; Bobat, Raziya Ahmed.
    Sub-Saharan Africa has the highest number of children living with HIV. HIV is one of the major causes of under-five mortality in Africa. Antiretroviral therapy in the paediatric population has improved mortality, led to a better quality of life, as well as overall health and well-being of children. Adherence is a critical factor in determining treatment outcomes and success. Non-adherence to therapy increases risk of treatment failure, delays immunological recovery and increases opportunistic infections. In the paediatric population, there is a paucity of studies assessing adherence rates, particularly in resource limited settings. Adherence behaviour is found to be more complex in children. A number of factors affect adherence in children. These include socio-economic factors, medication factors as well as healthcare provider dynamics. The purpose of this secondary analysis of a prospective study was to describe adherence in a cohort of children attending a regional hospital in Kwa-Zulu Natal, South Africa, from September 2006 until October 2009. This study also examined factors associated with adherence such as age of the child, gender, as well as the role of the primary caregiver. Since there is no “gold standard” for assessing adherence to antiretroviral therapy, this area of research needs to be explored further. Secondly, assessing factors associated with adherence will assist in looking at ways to improve treatment outcome. In the main study, prospective patients who were treatment naïve and met criteria to commence antiretroviral therapy were identified in outpatients and clinics. Baseline and follow-up questionnaires were used to capture information including adherence details over the preceding week as well as since the last visit to hospital. Adherence was assessed using the method of verbal recall. Missed doses and the reasons for these were recorded and analysed. Additional factors possibly associated with adherence were also recorded and analysed further. This study reported an overall adherence rate of 94 per cent, similar to rates reported in other studies. Adherence rates over the past week as well as since the patient’s last visit were similar. There was a substantial degree of agreement between verbal recall for the preceding week as well as since the last visit (kappa statistic 0.64, p < 0.005). It was found that children older than five years were more likely to be adherent than those under five years (OR 0.871, 95 % CI 0.22-3.376) and males were twice as likely to adhere as females (OR=2.05, 95% CI 0.49 -8.59). The impact of this study is that it will provide information on adherence in children in Kwa-Zulu Natal, South Africa. This could encourage other such studies to be undertaken to improve adherence rates and hence treatment success. By examining factors associated with adherence as well as identifying possible barriers, we may improve treatment success in children. Adherence to antiretroviral therapy is important, especially in the paediatric population as it is shown to increase survival, improve immunity, as well as help prevent the development of opportunistic infections. Sub-optimal adherence is associated with treatment failure and drug resistance. The use of verbal recall as a measure of adherence is useful in a resource limited setting.
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    Comparison of virological responses of children commenced on an abacavir versus stavudine based antiretroviral regimen at King Edward VIII Hospital : Durban.
    (2016) Montgomery, Stephane.; Archary, Moherndran.
    Background: UNAIDS estimated that in 2014 just over 160 000 children in South Africa were receiving HAART, accounting for 20% of the global HAART cohort. Finding the appropriate HAART regimen that is safe, well tolerated and efficacious is of extreme importance in ensuring continued and ongoing success of the Paediatric HAART program. In 2010 the World Health Organisation, due to concerns of short and long term stavudine toxicity changed the recommendation regarding first-line HAART regimen from a stavudine based regimen. In South Africa, an abacavir based regimen was chosen as the preferred background regimen. However questions have been raised as to whether this change has replaced the safety concerns associated with stavudine with a less efficacious regimen. Method: A Retrospective chart review was conducted to evaluate the virological responses at 6 and 12 months in a cohort of children initiated on an abacavir based regimen at King Edward VIII hospital between January 2012 – December 2012. Data of 94 children under the age of 12 years who were initiated on abacavir and lamivudine with either lopinavir/ritonavir or efavirenz regimen (abacavir cohort) were analysed using Fisher’s exact test and logistical regression to evaluate virological suppression at 12 months. The data was compared to a prior retrospective chart review conducted between 2004 – 2010 at King Edward VIII Hospital during which a stavudine and lamivudine with either Lopinavir/ritonavir or efavirenz (stavudine cohort) was the standard of care. Results: In both the abacavir cohort and stavudine cohort there was no difference in gender distribution and the mean age of initiation was 6years. In the abacavir cohort, 62,8% were initiated on ABC/3TC/EFV and 37,2% on ABC/3TC/KAL. 88,4% were initiated on D4T/3TC/EFV and 11,6% were initiated on D4T/3TC/KAL in the stavudine cohort. The virological suppression rate in the abacavir cohort was 80.7% compared to 85.2% in the stavudine cohort, which was not a significant difference (p= 0,38:). In the abacavir cohort there was no statistical significant difference in virological suppression between patients on efavirenz versus lopinavir/ritonavir (p= 0.427:). Conclusion: This study demonstrates that children treated with an abacavir based regimen have a good probability of virological suppression, and there was no statistical difference between patients initiating an abacavir-based regimen versus a stavudine based regimen. These findings are in keeping with data from several clinical trials and support the WHO recommendation of an abacavir-based regimen for infants and children initiating antiretroviral treatment.
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    The accuracy, sensitivity and specificity of rapid point-of-care testing for CD4+ T cell count enumeration and TB diagnosis.
    (2014) Skhosana, Mandisa.; Kiepiela, Photini.; Coutsoudis, Anna.
    Objectives: The PIMA CD4+ T cell count analyser has been favourably evaluated for use in point-of-care (POC) situations in Mozambique and Zimbabwe, has also been recommended by the World Health Organisation (WHO), however, there is limited information on its use in Primary Healthcare (PHC) settings in KwaZulu Natal (KZN) South Africa. The main aim of this study therefore assessed the accuracy, sensitivity and specificity of the Alere PIMA Point of Care (POC) analyser CD4+ T cell count enumeration compared to the South African National Health Laboratory Services (SA-NHLS) methodology, which uses Beckman Coulter with Panleucogating (PLG/CD4). The potential role of using the PIMA CD4 analyser as a predictor of antiretroviral therapy (ART) eligibility was also assessed. Material and Methods: The study took place at Lancers Road clinic, a busy primary health clinic (PHC) facility under the eThekwini Health Unit. An extra two millilitres of venous blood was drawn from the same blood draw as for the routine CD4 NHLS test (Beckman Coulter) into another EDTA tube for the comparison of the enumeration of CD4+ T cells using the PIMA analyser during January – July 2013. Results: A total of 268 patients were recruited for the PIMA analyser comparison with NHLS PLG/CD4 while a sub-set of 100 blood samples were also analysed on the FACS calibur. In the 100 samples the PIMA analyser results correlated better with the FACS calibur results (mean bias of 7.52, Bland Altman limits of agreement -111 to 126 and correlation of 0.970) than with the NHLS PLG/CD4 results (mean bias of -12.78, Bland Altman limits of agreement -226.041 to 200.481 and correlation of 0.90). In the 268 samples the overall mean difference between the PIMA analyser – NHLS PLG/CD4 was 17.5 cells/μl (95% CI 6.2 to 28.8). The percentage similarity (SIM) between the two (Mean ± SD) was 106 ± 15.5; indicative of acceptable agreement between the two tests. When categorised by the following CD4+ T cell counts of: ≤350 cells/μl; 351-500 cells/μl; ≤500 cells/μl and > 500 cells/μl , the mean difference of PIMA analysers – NHLS PLG/CD4 was 33 cells/μl (95% CI 23 to 42); 22 cells/μl (95% CI -3.5 to 47); 30 cells/μl (95%CI 21 to 39); and cells/μl (95% CI -78 to 6.1) respectively. Under the current South African guidelines of ≤350 cells/μl CD4+ T cells, the sensitivity of the PIMA analyser was 83.5% and specificity 92%. At this threshold of ≤ 350 cells/μl there were 35 (13%) misclassifications, of which 27 were false negatives. This implies that 27 patients would have been falsely deemed ineligible for ART according to the PIMA analyser. The mean difference between the PIMA analyser and NHLS PLG/CD4 in this group of 27 patients was 112 cells/μl. The positive predictive value was high at 95% such that 95% of the patients eligible for treatment according to PIMA analysers would have also been deemed eligible for treatment on the NHLS PLG/CD4 test. Using future South African treatment guidelines threshold of CD4+ T cell counts ≤500 cells/μl , a high sensitivity of 94% was observed at the sacrifice of lower specificity of 78%. According to the NHLS PLG/ CD4 test result, 164/268 (61%) of patients were eligible for ART (CD4+ T cell count ≤350 cells/μl) compared to 145/268 (54%) with the PIMA analyser POC CD4+ T cell test. Of those eligible for ART according to the ART register at Lancers Road PHC, 110/164 (only 67%) of these patients were initiated on ART. Of those who did not return for their results 35/268 (13%), twenty of 35 (57%) were eligible for ART according to the NHLS PLG/CD4 laboratory CD4 test result, all of whom were not initiated on ART. Conclusion: The overall agreement between the PIMA analyser POC and NHLS PLG/ CD4+ T cell count enumeration in adult HIV positive individuals was acceptable with clinically insignificant mean bias. Together with high positive predictive value, and sensitivity and acceptable specificity the PIMA analyser POC lends itself to an excellent facilitator of improved healthcare.
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    Innate immune mechanisms in limiting HIV-1 pathogenesis among South African adults and mother-infant pairs.
    (2012) Ndlovu, Bongiwe Goodness.; Carr, William Henry.
    This study was conducted to investigate the role of natural killer cell surface receptors, KIRs and their cognate HLA ligands in preventing HIV-1 acquisition and disease progression in HIV-1 exposed infants. Using DBS stored for 8 years from 21 pregnant South African women we evaluated 3 methods of gDNA extraction with and without whole genome amplification (WGA) to characterize immune-related genes: IL-10, KIR and HLA class I. However, IL-10 SNP typing was only for testing the quality of gDNA. QIAamp DNA mini kit yielded the highest gDNA quality (p<0.05; Wilcoxon Signed Rank Test) with sufficient yield for subsequent analyses. In contrast, WGA was not reliable for SSP-PCR analysis of KIR2DL1, KIR2DS1, KIR2DL5, and KIR2DL3 or high resolution HLA genotyping using a sequence-based approach. A cohort of 370 infants; 124 HIV-1 perinatally infected, 120 exposed uninfected and 126 unexposed healthy infants was used for KIR and HLA genotyping. After adjustment for viral load and multiple comparisons, the frequency of HLA-Cw*04:01 allele was likely to be associated with susceptibility to mother-to-child acquisition of HIV-1 in exposed infected (EI) infants (p=0.05; Logistic Regression analysis). HLA-A*23:01 was likely to be associated with decreased CD4 T lymphocyte count in HIV-1 infected infants (p=0.01; ANOVA), whereas HLA-B*81 tended to be associated with higher CD4 T lymphocyte count (p=0.04, ANOVA). We speculate that HLA-Cw*04:01 interacts with KIR2DL1 and inhibit NK cell responses which predispose the infants to HIV-1 infection. KIR2DS1 and KIR2DL5 were both associated with faster HIV-1 disease progression. Identified protective HLA-class I alleles could be used to present viral epitopes to either NK cells via KIRs or CTLs and enhance immune activation which may promote resistance to HIV-1 infection.
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    The association of early neonatal feeding on clinical outcomes and cytotoxic T lymphocyte (CTL) responses in HIV exposed low birth weight infants.
    (2011) Dassaye, Reshmi.; Coutsoudis, Anna.; Sunpath, Henry.
    BACKGROUND Sub-saharan Africa remains to date at the forefront of the HIV/AIDS epidemic. Despite breastfeeding being a significant mode of postnatal HIV transmission it remains the main nutritional source and pillar of child survival for the majority of infants born in Africa. It is therefore, not surprising that considerable research has centred on making breastfeeding safer in terms of HIV transmission. The flash heat treatment method (HTEBM) provides a unique opportunity to safely breastfeed infants but prevent mother-to-child transmission of HIV. Cytotoxic T lymphocyte (CTL) responses have been well documented in HIVinfected adults and children. However, there is a lack of literature on CTL responses in HIV exposed low birth weight infants. This pilot study attempted to examine the association of early neonatal feeding on the clinical outcomes and CTL responses in HIV exposed low birth weight infants. METHODS Seventy-seven patients that fulfilled inclusion and exclusion criteria were enrolled. The clinical outcomes of these patients were evaluated over a 9 month period. Fifty-five of these patients were also investigated for cytotoxic T lymphocyte (CTL) responses by means of the IFNγ ELISpot (megamatrix and confirmation) assays at the 6 weeks, 3, 6,and 9 months follow-up. RESULTS Two HIV-1 infected infants generated a CTL response at a single time point using the ELISPOT matrix screening assay. These responses could not be confirmed and were undetectable at any of the consecutive visits. At the time of detection of responses the infants were fed unheated breastmilk. HIV-1 exposed uninfected infants were unable to elicit a HIV-1-specific CTL response irrespective of feed. With regards to clinical outcomes, infants born o HIV infected mothers with a CD4 count < 500cells/μl were 2x more likely to acquire other infections at birth compared to those infants born to HIV infected mothers with a CD4 count >500cells/μl. Also, infants born to HIV infected mothers with advanced disease (CD4 count 0-200 cells/μl) had a lower birth weight compared to infants born to HIV-1 infected mothers with a CD4 count > 350 cells/μl. We also investigated the feasibility of the flash heat treatment method at birth. While inhospital, 38 HIV-1 infected women fed their infants HTEBM after receiving counseling and support from the nursing staff at the King Edward VIII hospital. The numbers decreased rapidly post hospital discharge, mainly due to mixed feeding. DISCUSSION In conclusion we have shown that it is feasible for HIV infected mothers to heat treat their expressed breastmilk during hospital admission. Furthermore, we were able to demonstrate in this small cohort of patients that the clinical outcomes and growth parameters of infants fed HTEBM were similar to that of infants fed either formula or unheated breastmilk. We were unable to demonstrate HIV-specific responses in the infected infants or the uninfected infants who had been exposed to heat inactivated virus in HTEBM. Our findings indicate that this pilot study was limited in its ability to detect CTL responses in HIV exposed low birth weight infants and further studies are warranted.
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    The role of HLA-C restricted CD8+T cell responses in the control of HIV replication.
    (2010) Mkhwanazi, Nompumelelo Prudence.; Ndung'u, Peter Thumbi.
    Certain HLA-B-restricted CD8+ T cell responses are associated with control of viremia whereas HLA-Cw* restricted responses, including Gag epitopes are associated with high viremia. To better understand the role of HLA-Cw* restricted epitopes in viral control, HLA-Cw* restricted epitopes were optimally defined. Seventy eight study subjects from a cohort of 451 chronically infected participants had HLA-Cw* restricted CD8+ T cells responses as quantified by intracellular cytokine staining assessing IFN-γ secretion. Fine mapping and HLA restriction of the optimally defined HLA-Cw* restricted epitopes were performed using ELISPOT assay. Functional avidity of responses was assessed by peptide dilution in an ELISPOT assay. Two novel HLA-Cw* restricted epitopes Cw*04- TF10 (in reverse transcriptase) and Cw*08-RM9 (in gp120) were optimally defined. A previously described epitope, Cw*07- KY11 (Nef) was the most frequently targeted epitope in this cohort (30/78) and has high functional avidity compared to other HLA-Cw restricted CD8+ T cell responses. The polyfunctionality of HLA-B*57/5801-restricted Gag-specific HIV-1 CD8+ T cell responses and HLA-Cw*07-KY11 restricted CD8+ T cell responses within the same study subject was determined. Polyfunctionality of CD8+ T cell responses to HLAB* 57/5801 and HLA-Cw*07 restricted epitopes were determined in nine study subjects assessing IFN-γ, TNF-α, IL-2, MIP-1β, and CD107a by multicolour flow cytometry. Additionally gag and nef genes were sequenced from plasma. HLA-B*57/5801-restricted IFN-γ-producing CD8+ T cell responses were of lower magnitude than HLA-Cw*07 responses (p=0.0012) for the nine subjects. The majority of responses were monofunctional (75%), irrespective of HLA restriction. HLA-B*57/5801 and HLACw* 07 restricted CD8+ T cells did not differ significantly in polyfunctionality (p=0.84). Possession of ≥3 functions correlated positively with CD4+ T cell counts (r=0.85; p=0.006). The percentages of monofunctional CD8+ T cells inversely correlated with CD4+ T cell counts (r=-0.79; p=0.05). There was no correlation between polyfunctionality and viral load and sequence variation within targeted epitopes did not impact polyfunctionality. These results suggest that polyfunctionality of HIV-1-specific CD8+ T cells is associated with disease progression independent of restricting HLA alleles, and that loss of these polyfunctional cells correlates with increased in the frequency of monofunctional virus-specific CD8+ T cells. In addition, sequence variation does not appear to significantly impact CD8+ T cell polyfunctionality in chronic HIV infection.
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    Transmission rates of HIV-1 and the mortality rate in high risk infants exposed to HIV, in the PMTCT programme, at the Neonatal Unit, of King Edward VIII Hospital , Durban, South Africa.
    (2012) Nair, Nadia.; Adhikari, Miriam.
    Introduction. Previous studies have established that infants born to mothers with advanced HIV disease and co-infections are smaller, premature and have rapidly progressive HIV disease and an early death. King Edward VIIIth Hospital, in Durban, admits many sick mothers and manages a large proportion of low birth weight and ill newborns. On discharge and follow-up, the mortality and morbidity of these infants are known to be high and are related to the prematurity. How much is related to being HIV exposed is still uncertain. Aim. To determine the perinatal transmission rate of HIV-1 and mortality at 12 months in HIV exposed infants that were admitted to and discharged from the Neonatal Unit, in Durban, South Africa. Methods. In this observational study, data from the outpatient charts of HIV exposed infants that required specialised neonatal care and subsequent follow up, between the period November 2007 and December 2009, were collected. Perinatal transmission rates and mortality of these infants were compared with maternal and infant risk factors. Results. Data on 463 HIV exposed, predominantly low birth weight infants are presented. The median maternal CD4 count was 309cells/mm3 with 16.8% of mothers commenced on HAART. Maternal co-infection with TB was found in 19.2% of the cohort. Early HIV transmission occurred in 11.5% of infants and was influenced by the type of ARV exposure (None, 20%; single dose NVP, 14.3%; dual therapy, 10.6%; maternal HAART, 8.5%). The dual therapy regimen for 7 days was more protective than that for 28 days (p=0.045). HIV infection was associated with higher risk of neonatal sepsis (RR 1.6; 95% CI, 1.1-2.3; p=0.015). The mortality for the cohort at 12 months was 10%. Maternal HAART was associated with a lower mortality: 2.95% vs.10.2% (RR 3.0; 95% CI, 0.4-20.5). There was a higher mortality rate in those that were low birth weight (RR 4.2; 95% CI, 1.02-18.8; p=0.037); those that were HIV infected (RR 4.8; 95% CI, 1.9-11.6; p=0.002) and those that were breastfeeding compared to formula feeding (RR 2.7; 95% CI, 1.1-6.8; p=0.038). Discussion. Rates of HIV transmission within the PMTCT programme were similar to that reported by the Department of Health. Early maternal ARVs for PMTCT prophylaxis, prevents HIV transmission. The coverage of maternal HAART was sub-optimal. Breastfeeding was associated with a higher HIV transmission rate and was most likely associated with non-exclusive breastfeeding during neonatal admission. Recommendations. Maternal HAART or ARV prophylaxis should be commenced early in the pregnancy for the best benefits. Meticulous attention should be paid to the feeding practices of high risk HIV exposed infants admitted for specialised neonatal care.
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    Optimum timing for vitamin A supplementation in children with diarrhoea.
    (2001) Elson, Karin Inga.; Coutsoudis, Anna.
    Vitamin A has well recognised benefits for the reduction in severity of diarrhoeal episodes but the impact of therapeutic doses given during diarrhoea on the biochemical and clinical outcomes is less clear. In this study these potential therapeutic benefits were investigated to establish the optimum time for vitamin A supplementation to improve vitamin A status. Establishing the optimum time for vitamin A supplementation during an infectious stage would improve cost effectiveness and clinical benefit. Young children (174) between the ages of 3 and 60 months with severe diarrhoea were randomised in a double - blinded placebo controlled trial into one of 2 groups. The 1 st group received 60 mg of retinol as retinyl palmitate on admission during the acute diarrhoeal stage. The 2nd group received the same dose of vitamin A once symptoms had resolved, usually between 3 - 7 days. At each of these two time points, children not receiving vitamin A were given an identical placebo dose. Baseline (day 0) and day 3 serum samples were collected for vitamin A, retinol binding protein (RBP) and other biochemical markers. At four and eight weeks after discharge both morbidity and weight gain were recorded. The modified dose response test (MRDR) was conducted at the eight - week follow - up to estimate vitamin A liver stores. Initially, most of the children presented with watery diarrhoea and dehydration and were clinically very ill. At day 3 plasma retinol concentrations improved in both groups viz. from 0.57umol/L to 0.97umol/L in the 1st group and from 0.49umol/L to 0.90umol/L in the 2nd group. Similar improvements were found in retinol binding protein viz. 21.28 mg/L to 31.06 mg/L in the 1st group and 17.05 mg/L to 24.80 mg/L in the 2nd group. At 8 weeks there was also no significant difference between the two groups either for serum retinol (0.69umol/L and 0.73umol/L respectively) nor for MRDR ratios (0.036 and 0.049 respectively). The MRDR results at 8 weeks indicated that these children did not have depleted vitamin A liver stores and that the low serum retinol levels seen at baseline were probably due to the acute phase response during an infectious episode. The results of these analyses showed no significant difference between the two treatment groups thus indicating that there was no benefit to giving vitamin A on recovery from an infectious episode instead of on admission, as is currently practised.
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    Investigation into optimal amikacin dosing in children.
    (1996) Forsyth, Nan Barbara.
    Aminoglycoside antibacterial agents, such as amikacin, continue to play an important role in the treatment of Gram-negative infections. However, although extremely effective, they are not without potential adverse events, the most important of which being nephro- and ototoxicity. Research into factors thought to influence both the efficacy and toxicity, has challenged the rationale upon which these agents have classically been dosed. Various studies in adult patients have found that a new approach to dosing (use of single daily administration) has equal or greater efficacy or safety compared to the standard multiple daily dosing of these agents. Similar studies comparing regimens in children are few, and as yet no comparative investigation has been performed using amikacin in children (as a separate and distinct group). Additionally, in evaluating the impact of altering dose regimens, it is imperative that the documented age-related aminoglycoside pharmacokinetic alterations, be taken into account. Amikacin pharmacokinetic parameters (determined using traditional methods) have been previously published for various (usually small) groups of children. However, population parameters are not currently available for South African children . This study therefore aimed to investigate optimal amikacin dosing in children by studying: a) the comparative efficacy and toxicity of two dosing regimens, and b) the population pharmacokinetic parameters derived using one of the alternative approaches capable of utilising routine, sparse serum drug concentration time data. This investigation was conducted in the paediatric surgical and burns wards of King Edward VIII Hospital , Durban. Study patients (0.6-12 years) received amikacin either once daily (15mg/kg) or twice daily (7.5 mg/kg) by slow intravenous bolus. Concomitant medication was given as prescribed. Regimen efficacy (favourable, unfavourable or indeterminate outcome) was assessed by patient temperatures, clinical improvement and white cell counts. Clinical nephrotoxicity was evaluated by changes in serum creatinine, and renal tubular damage (investigated in a small subgroup of patients) was indicated by detection of urinary low molecular weight proteins. Ototoxicity (cochleotoxicity) was assessed by pure tone audiometry. Pertinent demographic and treatment details (amikacin concentration time data) were recorded for the population pharmacokinetic analysis. The Nonlinear Mixed Effects Model (NONMEM) programme was used to derive appropriate models describing clearance (CL) and volume of distribution (V), as well as mean values of these pharmacokinetic parameters for this population. Fifty four patients were entered into the regimen assessment. Patients in the single daily regimen (n=27) had significantly greater (p<0.05) mean (SO) peak (±0.5 hour post-dose) serum amikacin levels (37.7 (6.9) mg/L) as well as cumulative dose (91.5 (26.5) mg/kg) and duration of therapy (5.7 (1 .5) days) when compared with those of the twice daily group (19.5 (3.7) mg/L, 70.1 (26.1) mg/kg and 4.6 (1 .6) days respectively). No statistically significant differences were found between the groups in terms of outcome (18/24 and 22/25 patients in the once and twice daily dosing groups had favourable outcomes; there were no unfavourable outcomes). Pure tone audiometry (evaluated post-therapy , in 20 patients from each dosing regimen) revealed no statistically significant differences between the number of patients in the two groups with possible drug-related ototoxicity. None of the patients assessed (including an additional 14 patients with burn injury) developed clinical nephrotoxicity. Urinalysis was performed in 17 amikacin treated patients (9 and 8 from the once and twice daily dosing regimens respectively) and 9 control subjects. Low molecular weight proteinuria was absent in all of the latter patients except one, in whom pre-existing renal disease was suspected. Tubular dysfunction ascribed to possible drug effect was detected in similar numbers of patients in the two treatment groups (3 and 2 patients in the once and twice daily dosing groups respectively). In the pharmacokinetic assessment (156 serum levels from 82 patients) using a one compartment model, the final models which best described the data were as follows : CL (Uhr) = 0.271 x age(yrs) + 2.46 x body surface areatrrr'), V (L) = 7.34 x body surface areatrn") Other fixed effects tested, which did not render the data more probable, included serum creatinine measurements at the start of treatment, gender, presence of burn injury and drug regimen. Interpatient variation was 15% and 18% for CL and V respectively, with intrapatient variation or residual error of 10%. The weight adjusted population parameter estimates (95% Confidence Interval) for this group were CL =0.180 (0.175 ,0.185) Uhr/kg and V =0.293 (0.286, 0.300) Ukg, which are within the range of values published previously for other children of similar ages. The findings of this investigation , consistent with those of other similar studies, indicate that daily amikacin administration (in combination with a B-lactam), to children with normal renal function, has similar efficacy to, and no greater toxicity than multiple daily dosing. However, the role, if any, of the significantly greater cumulative dose and duration of therapy in the daily dosing group is unknown. As uncertainty remains regarding the precise duration of certain post-exposure events (and hence, the ideal duration of the interdose interval), and with the rapid drug clearance in this group of patients , future in vitro and in vivo investigations may shed even further light on the optimal dosing approach in these patients.
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    HIV-1 specific T-Cell responses in chronic HIV infected children during continuous treatment and structured treatment interruptions (STI).
    (2010) Reddy, Shabashini.; Ndung'u, Peter Thumbi.
    BACKGROUND Sub-Saharan Africa has the highest number of HIV-infected individuals and limited treatment programs. The use of Highly Active Antiretroviral Therapy (HAART) has resulted in a considerable decrease in morbidity and mortality among HIV-infected individuals. Long-term use of HAART has several limitations relating to cost, drug toxicity and adherence. Structured Treatment Interruption (STI) has been proposed as a therapeutic approach which limits the exposure to continuous HAART, but retains the benefits thereof. The role of HIV-specific Tcell responses in the control of viraemia has not been well studied in children and it is not clear when these responses become detectable or whether they are associated with improved viral control. Furthermore, antiretroviral drug resistance is well documented in adults infected with HIV-1 clade B virus but comparable information is lacking for chronic paediatric clade C virus infection. This pilot study focused on a chronic HIV-infected paediatric cohort from Durban, South Africa, to assess the immunologic and virologic responses in perinatal HIVinfected children undergoing STI. METHODS Thirty chronic HIV-infected treatment naïve children were enrolled and randomised into either the treatment interruption or continuous treatment group. Longitudinal measurements of viral loads and CD4 percentages were done at scheduled intervals. Peripheral blood mononuclear cells (PBMCs) were screened for cytotoxic T-lymphocyte (CTL) gamma interferon (IFN-?) enzyme-linked immunospot (ELISpot) assay responses using 410 peptides which spanned the entire HIV-1 clade C proteome. Intracellular cytokine staining (ICS) was done to distinguish between IFN-? Gag-specific T-helper and cytotoxic T cell responses. Pre-HAART drug resistance mutations testing and HLA typing were done for all children. RESULTS There was a significant increase in the median CD4 percentage after HAART was introduced. Six children randomized to the STI arm did not undergo treatment interruption because their viral loads remained detectable at the time of scheduled interruption. Most HIV proteins were targeted in this paediatric cohort. Gag was the most frequently targeted HIV-1 protein (93.1%). In both treatment groups, there were broadening of T-cell responses, however, the magnitude of T-cell responses decreased over time on HAART. Drug-resistant mutations were detectable in 4/29 children before initiation of HAART. CONCLUSION In this pilot study, the HIV-1-specific CD8+ and CD4+ T-cell responses were detected before and during HAART. Although the treatment interruption period was short, there were no adverse outcomes in either the continuous or treatment interruption groups in terms of death or other clinical outcomes. This study suggests that it is important to continue to explore alternative treatment strategies in order to reduce cost and toxicity as well as to enhance adherence.
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    The effect of corticosteroid therapy on growth in Black South African children with nephrotic syndrome.
    (1986) Manikkam, Noel Edwin George.
    The most useful drugs in the management of nephrotic syndrome are the corticosteroids. These drugs are as well known for their adverse effects as they are for their therapeutic advantages. The two most common paediatric side effects are suppression of linear growth and posterior subcapsular cataracts. Both of these untoward effects are insiduous and therefore less easily perceived. Although many workers have studied the growth inhibiting effects of the corticosteroids in the various diseases e.g. asthma, very little work was done to investigate these effects in patients with nephrotic syndrome. Furthermore, the Renal Clinic, King Edward VIII Hospital, Durban continues to use a daily regime of prednisone instead of the alternate day regime which is widely recommended to minimise growth retardation. This study was therefore undertaken to investigate the growth inhibiting effects of repeated courses of daily, high-dose prednisone in African and Indian children with nephrotic syndrome. All children with nephrotic syndrome with relevant data in their records and with no other chronic illness were selected from the Renal Clinic. Of the 125 selected, 87 children had been treated with prednisone for an average of 35,9 weeks and 38 had been treated symptomatically. The heights of those that received prednisone were measured at an averace of 77 weeks after completion of therapy. The mean height standard deviation score (SDS) of the treatment and control groups of Indian children were -1,06 and -0,92 respectively, both being between the 10th and 25th percentile, whilst the mean height SDS of the treatment and control groups of African children were -1,82 (just below the 5th percentile) and -1,77 (between the 5th and 10th percentile) respectively. From the results, it is evident that repeated courses of daily prednisone therapy, even when it exceeds 36 weeks, does not inhibit growth in both African and Indian children. Although there was no significant difference between the races and sexes with respect to growth and corticosteroid therapy, this study does confirm earlier reports that most of the African children with nephrotic syndrome had obvious glomerular lesions whilst most of the Indians had minimal change nephrotic syndrome.
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    Aids for the early diagnosis of tuberculous meningitis (TBM)
    (1985) Ramkissoon, Arthi.; Coovadia, Hoosen Mahomed.
    Mortality and morbidity rates associated with tuberculous meningitis (TBM) are substantial. The average duration of the untreated disease from onset to death is about 17 days. The prognosis of TBM is known to correlate with the stage of the disease at the time of diagnosis and commencement of chemotherapy. Early diagnosis improves the chances of recovery without neurological sequelae. Early diagnosis is a problem because the presenting symptoms are non-specific and the onset of the disease is typically insidious. To date no single test is available that is totally reliable and specific for TBM. I have attempted to develop a reliable and easily applicable test for the diagnosis of TBM. In fulfilling this objective, the work undertaken may be divided into three major sections:- 1. Detection of soluble Mycobacterium tuberculosis antigens in the cerebrospinal fluid (CSF) of patients with TBM and in control groups by using Mycobacterium bovis BCG antigens. The technique used was that of inhibition enzyme-linked immunosorbent assay (ELISA). The principle of this technique is illustrated in Fig. 5. 2. Detection of soluble M. tuberculosis antigens in the CSF of tuberculous and control groups of patients by using antibodies raised against M.bovis BCG. The technique used was that of the double antibody sandwich ELISA. An outline of this ELISA is given in Fig. 6. 3. Correlation of chloride levels in the blood and CSF of patients with tuberculous and other forms of meningitis. It has been established that the SERUM/CSF ratio of bromide tends towards unity in patients with TBM because the permeability of the blood-brain barrier is impaired. Since both bromide and chloride are chemically similar (both being halides), it was thought that a similar pattern may exist for BLOOD/CSF chloride ratios; and this was investigated. The method used for the INHIBITION ELISA had to be standardized before the samples could be tested. This involved investigating the acceptability of various microtitre plates; determination of the optimal working dilutions for the coating solution and conjugate; and determination of optimal conditions for the various incubation periods, both in terms of time and temperature. A total of 70 specimens was tested. These consisted of 25 normal CSF controls; 25 pleural and ascitic fluid samples; 10 TBM samples, and 10 bacterial meningitis CSF samples. It was found that a distinction existed between the absorbance values obtained from positive TBM CSF samples (Mean 0,658 + 0,043) and that from normal CSF samples (Mean 1,089 + 0,224). The mean absorbance of the culture-positive bacterial CSF's also differed significantly from the other 2 groups (Tables VII; IX). Some overlap occurred amongst the absorbance values of bacterial culture positive CSF's (Range 0,975-0,879) and normal CSF's (Range 1,486-0,934). The mean absorbance value for bacterial positive CSF samples (0,920 _+ 0,029) differed significantly (p <0,01) from those of normal CSF (1,089 + 0,224) and TBM CSF's (0,658 + 0,043). The difference between the mean values obtained with tuberculous and non-tuberculous groups of pleural and ascitic fluid was also significant (p < 0,01). The method used for the DOUBLE ANTIBODY SANDWICH ELISA was that of Sada et al. (1983). Before the samples could be tested, the method had to be standardized and similar investigations to those for the INHIBITION ELISA were performed. In addition, antibodies raised against M.bovis BCG were conjugated to alkaline phosphatase since no commercial preparation was available. Unfortunately no distinction was recorded between negative and positive test specimens, even on repetition of the entire procedure. Measurement of chloride was done by a fully automated procedure using the BECKMAN ASTRA-8. A total of 149 samples were tested. Of these 10 were tuberculous, 34 were viral, and the remainder were bacterial meningitis. No pattern was established that could differentiate TBM from viral or bacterial meningitis. The results obtained are tabulated in Table III and illustrated in Figures 9, 10, and 11. In summarizing, the use of the INHIBITION ELISA technique for the accurate diagnosis of TBM seems promising. However, its validity in the clinical situation will have to be assessed further and with greater numbers of specimens before it can be adopted as a diagnostic procedure for TBM. OBJECTIVE. To determine 1. The ability and reliability of the INHIBITION ELISA1 technique to detect mycobacterial antigens in pleural, ascitic, and cerebrospinal fluids. 2. The accuracy and reproducibility of the double antibody sandwich ELISA in the detection of mycobacterial antigens in CSF of patients with tuberculous meningitis (TBM). 3. Whether a correlation exists between blood and CSF chloride levels in patients with tuberculous and other forms of meningitis.