Paediatrics (RCH) - Theses

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    Neurological risk factors in infants having noncardiac surgery and their relationship to growth and neurodevelopmental outcome
    Moran, Margaret ( 2017)
    INTRODUCTION: With advancements and improvements in surgical techniques, neonatal and antenatal care over the last sixty years, the mortality following neonatal non-cardiac surgery (NCS) has fallen to less than five percent. Consequently, the focus has now shifted to morbidity and long-term outcomes with increasing concern that these children are at risk of neurodevelopmental (ND) impairment. Other high risk neonatal groups, including those born prematurely and those who require early cardiac surgery, are known to have increased risk of ND impairment and frequently have abnormalities detected on brain imaging in the newborn period. The neurobiological substrates for ND impairment following NCS are unclear and likely to be multi-factorial but may include brain injury. The effect of neonatal NCS on brain structure, growth and development has not been described. AIMS: The aim of the study was to investigate neurological risk factors, in particular brain injury, in infants requiring neonatal NCS, and their impact on growth and ND outcomes over the first two years of life. METHODS: Infants undergoing major NCS in the first two weeks of life at The Royal Children’s Hospital, Melbourne for a diagnosis of oesophageal atresia (OA), congenital diaphragmatic hernia (CDH) or abdominal wall defect (AWD), were enrolled in this case-controlled prospective study. Infants were excluded if they were born before 32 weeks’ gestation or if they had a known genetic anomaly associated with ND impairment. Magnetic resonance imaging (MRI) of the brain was performed, time and clinical status allowing, pre-operatively and repeated prior to hospital discharge along with an assessment of neurobehaviour using Prechtl’s general movements. Surviving infants were followed up at six, 12 and 24 months when growth and neurodevelopment were assessed using the Alberta Infant Motor Scale (AIMS) and/or the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III). Thirty-nine infants were matched for gestation at birth, gestation at time of post-operative MRI and gender with controls. Control infants were recruited from a neighbouring perinatal hospital as part of another research trial. RESULTS: Over 27 months, 54 infants were recruited with slight male preponderance of 61%. The mean (standard deviation [SD]) gestation at birth was 37.9 (2.3) weeks with a mean birth weight of 2.93 (0.67) kilos. Twenty-one of the participants had AWD, 17 had OA and 16 had CDH. Surgery was performed at a median (interquartile range [IQR]) age of 24 (10 – 53) hours with a mean (SD) duration of 133 (56) minutes. Four infants died prior to 24 month follow-up (mortality rate 7%), with three of the four dying before hospital discharge. Infants requiring neonatal NCS had poor growth in the first six months, in particular prior to hospital discharge. There was evidence of catch-up growth for weight and height by 24 months. However, head growth remained poor, in particular for those children with CDH. Compared to control infants, there was poor head growth in the first month of life in infants following NCS. At 24 months of age, infants who had NCS were lighter and tended to be shorter than matched controls. Pre-operative MR imaging of the brain, obtained in a small number of participants (n=7), revealed delay in brain maturation in six of the seven participants. Post-operative imaging, obtained in 51 participants, also revealed high rates of delay in brain maturation (47%), with delay in cortical folding more common than delay in myelination. Abnormalities on MR imaging were detected in 51% of cases with white matter signal abnormalities (WMSA) and ventricular dilatation seen most frequently at 18% and 27% respectively. WMSA were associated with delay in brain maturation and with intracranial haemorrhage. Compared to matched controls, infants undergoing NCS had smaller biparietal diameters, smaller transcerebellar diameters and larger ventricles. Infants requiring NCS were more likely to have delay in cortical folding [odds ratio (OR) 5.92 (95% confidence interval (CI) 1.91, 19.47), p < 0.001] and WMSA [OR 9.81 (95%CI 1.18, 446.25) p = 0.01]. Following NCS, infants had significantly lower scores than test norms on AIMS assessment at six and 12 months (p = 0.003 and < 0.001 respectively). BSID-III assessment was performed at mean (SD) age of 12.4 (0.8) months in 48 survivors and at a mean (SD) age of 27.0 (2.4) months in 45 survivors. Language and motor composite scores were lower than test norms at both 12 and 24 months, with p < 0.001 and 0.04 for language at 12 and 24 months, and p < 0.001 and 0.01 for motor, at 12 and 24 months. Participants were performing in the low average range, with mean (SD) scores of 91.5 (15.2) and 94.2 (14.4) at 12 and 24 months for language and 90.4 (11.4) and 94.4 (13.6) for motor. Mild developmental impairment at 24 months was found in one third of the group with composite scores greater than 1 SD below the mean in at least one domain, with 9% having delay in all three domains. ND impairment at 12 months was predictive of ND impairment at 24 months. Compared to matched controls, infants requiring neonatal surgery had lower composite scores for cognition, language and motor at 24 months. Similar to previous reports, the control group performed significantly better across all domains than test norms. Perinatal and peri-operative risk factors associated with ND impairment at 24 months were compromise at birth with an Agpar score of less than seven at one minute, markers of illness severity, feeding dysfunction and failure to thrive, in particular poor weight gain in the first six months. Markers of illness severity including a rising base excess in the first 24 hours post-operatively, longer duration of mechanical ventilation and hospital stay. Increasing left lateral ventricular size was the only MRI parameter that remained significant for ND impairment on multivariate analysis. Gestational age at birth had little impact on ND outcome at 24 months, for infants requiring NCS born at 32 weeks’ or more of gestation. CONCLUSIONS: Infants requiring early NCS are at increased risk of ND impairment at 24 months. Post-operative MR brain imaging revealed high rates of brain immaturity and abnormalities, including white matter signal abnormalities and ventricular dilatation. A clear-cut link between early brain injury and maturational delay and subsequent ND impairment was not found. Increasing illness severity, feeding dysfunction and failure to thrive are associated with ND impairment at 24 months.
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    Environment versus genetics in the development of health-related problems in childhood obesity
    Kao, Kung-Ting ( 2017)
    Introduction: Childhood obesity is a major health concern affecting a quarter of all Australian youth. Obese youth are at risk of multi-systemic obesity-related comorbidities (ORC), such as Prediabetes and Type 2 Diabetes Mellitus (T2DM), Hypertension, Hyperlipidaemia, Non-alcoholic fatty liver disease (NAFLD), Polycystic ovarian syndrome (PCOS), Obstructive sleep apnoea (OSA), mental health and orthopaedic issues. However, within the obese population, the severity of obesity is a poor predictor of these comorbidities. As such, current guidelines advise screening obese youth for all comorbidities, which is both time consuming and costly. ORC, as with obesity itself, are complex polygenic disorders involving interaction between genetic and environmental risk factors. Furthermore, many of these interactions are likely mediated by epigenetic variation, linking environmental exposures with genetic predisposition. Therefore, clarification of the role of environmental exposures, genetic risk factors and epigenetic profile in obese youth may provide valuable insight into determining which obese youth are at risk of developing ORC. The aim of this study was to characterise and investigate the associations between environmental, genetic and epigenetic factors with obesity-related comorbidities in obese youth. This information obtained will allow clinicians to better predict and profile the comorbidity burden in obese youth for targeting interventions to those most likely to benefit. Materials and Methods: The Childhood Overweight BioRepository of Australia collected comprehensive clinical and anthropometric data, as well as blood samples for genetic, metabolic and hormonal profile testing from patients (age 1 to 18 years) attending the Weight Management Clinic at the Royal Children’s Hospital, Melbourne. Anthropometric measures included standard measurements of weight, height and waist circumference (converted into BMI z-score (BMI-Z) and waist-height ratio for analyses) as well as total percentage body fat (%FM) and percentage truncal body fat (%truncal) using bioimpedance. Dietary intake was assessed using the Australian Child and Adolescent Eating Survey and physical activity was measured objectively using accelerometry. Genetic typing and epigenetic profiling of single nucleotide polymorphisms (SNP) and measures of DNA methylation were performed using the SEQUENOM MassARRAY platform. Results: 349 participants were included in the study. Both metabolic and non-metabolic ORC are common in obese youth. The most commonly used measure of adiposity, BMI-Z, was the anthropometric marker least associated with ORC, while important ORCs such as T2DM and hyperlipidaemia were not significantly associated with any of the anthropometric measures. The presence of two or more significantly elevated anthropometric markers was associated with the presence of a higher number of ORCs. Almost all obese youth reported poor vegetable intake and high sedentary behaviour (TV-watching and total media) time. Although initial analyses observed associations between sedentary behaviour (TV-watching and total media use time) with prediabetes and hyperlipidaemia, unhealthy food options with mental health issues, and high fruit intake with NAFLD, these associations lost significance after correction for multiple testing by false discovery procedure (FDR). However, low vitamin D levels were significantly associated with hypertension, independent of adiposity and season. The Fat Mass and Obesity (FTO) gene has the largest influence on adiposity amongst obesity-risk genes to date and has been associated with ORCs. In our cohort, the FTO risk allele was associated with poorer longitudinal weight outcomes in pre-pubertal children, but not pubertal adolescents. The FTO SNP however was not associated with any ORCs. We also examined the association between the top 22 T2DM risk SNPs identified from previous studies and Prediabetes or T2DM status. The SLC30A8 rs13266634 SNP appeared to be protective of prediabetes/T2DM status in unadjusted analysis but lost significant on FDR testing. The addition of T2DM SNPs profile to TV-watching time improved the predictive model for Prediabetes/T2DM status. We were not able to replicate the previously reported association of FTO CpG hypomethylation with prediabetes/T2DM in obese children and adolescents. However FTO hypomethylation was seen in obese youth with NAFLD, independent of age, sex and total body adiposity. FTO methylation was independent of FTO expression, which was not associated with any ORC. Conclusion: Anthropometry is not associated with comorbidities in childhood obesity. Environmental factors do not appear to be associated with comorbidities. Low vitamin D level is associated with hypertension. Genetic factors impact on weight gain but not comorbidities, and epigenetic factors may contribute to NAFLD. Combining these environmental and genetic elements with established clinical risk factors in the assessment of each individual ORC may assist in enhancing current clinical models of care for obese children and adolescents.
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    Improving pain and distress management of children in the emergency department
    Babl, Franz Eduard ( 2015)
    This thesis represents a compilation of peer-reviewed papers addressing the care for children in pain or undergoing painful or distressing procedures in the emergency department. After an introductory chapter, papers related to one of several themes are briefly introduced and placed in context with each other. The papers, and their compilation in this thesis, aim to provide guidance for paediatricians and emergency physicians caring for children on how to prepare for and reduce procedural and non-procedural pain and distress. Many aspects of this work, including certain research findings, evolving approaches to pain and sedation management and evidence-based teaching materials, are being used by, or have been implemented in, the Emergency Department at Royal Children’s Hospital and other emergency departments across Victoria, Australia, as well as interstate and overseas.
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    Structural and functional evaluation of gas-trapping in infants with cystic fibrosis
    Ebdon, Anne-Marie ( 2014)
    Air-trapping is frequently identified in infants with cystic fibrosis (CF) on chest CT scans. Aim was to examine the association between the measured functional residual capacity (FRC) using infant lung function under sedation, and air-trapping scores obtained from chest CT images, acquired under general anaesthesia. Thirty-eight lung function tests were analysed from CF infants aged 3-24 months. Twenty CT scans were performed on the infants. No statistical significance was found between the lung function and CT results when simple linear regression was applied. In conclusion, no associations were found between measured FRC and air-trapping CT scores in infants with CF.
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    Abnormalities in linear growth and the growth hormone-insulin like growth factor axis in children with chronic inflammatory disease
    Wong, Sze Choong ( 2015)
    Impaired linear growth is commonly encountered in children with chronic inflammatory conditions such as juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD), especially those with Crohn's disease (CD). Sub-optimal nutrition, prolonged use of glucocorticoid (GC) and chronic inflammation mediated by pro-inflammatory cytokines all play a role in contributing to the underlying aetiology of growth retardation by their effects on the secretion and sensitivity of systemic factors and directly at the level of target organs. In a group of children with JIA at acute relapse requiring intra-articular glucocorticoid injections, systemic IGF1 and IGFBP3 were noted to be normal but ALS was disproportionately low. Interleukin (IL5) and IL15 were noted to be associated with height in these children. In children with IBD and growth retardation who underwent evaluation of the GH axis with insulin tolerance test, my study demonstrated for the first time that a spectrum of abnormalities in secretion and sensitivity of GH and IGF1 may exist. Exposing fetal metatarsals to serum and synovial fluid of children with JIA at relapse show variable deficits in local bone growth not reversed by addition of blocking antibodies to TNFα, IL1β and IL6 did not reverse bone growth. In the first randomized controlled trial of rhGH at 0.067 mg/kg/day in children with IBD and growth retardation, my study showed that height velocity in the treated group improved by 140% over a 6 months period compared with only 17.4% in the control group. Similar to rhGH trials in other groups of children with chronic disease, reduction in insulin sensitivity was noted with no evidence of abnormalities in glucose homeostasis. Finally, systemic IGF1 increased in the rhGH treated group but remained within 2 standard deviation during the treatment period.
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    Assessment of pulmonary function in childhood neuromuscular weakness
    Gauld, Leanne Maree ( 2004)
    Children with neuromuscular weakness may have severe or progressive weakness that results in pulmonary restriction. Weakness can also result in spinal deformity that worsens the pulmonary restriction. Corrective spinal surgery carries significant respiratory risk. Accurate respiratory assessment is important for pre-operative risk assessment. Aims: 1) to evaluate the current clinical practice of pulmonary function testing and their role in respiratory assessment in children with neuromuscular weakness undergoing corrective spinal surgery and 2) to develop a precise method of predicting pulmonary function tests in children with neuromuscular weakness.
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    Clinical management strategies for disorders of gonadal function from infancy to late
    ZACHARIN, MARGARET ( 2013)
    This body of work defines problems of altered sex hormone function from birth to the end of adolescence and demonstrates the ability of interventions to optimize outcomes. The breadth and prevalence of sex hormone alterations in these conditions is outlined and a range of rational and beneficial treatment options to optimize outcomes, reduce risks and increase understanding across the medical and family spectrum is provided. Evidence is given for a clear plan for identification and management, for paediatricians working in resource constrained environments. The document describes normal processes of development, growth and puberty, indicates aberrations due to structural or functional changes, either primary or secondary to acquired health disorders and complications of treatment omission or failure and provides information based on my publications in the area, as to management considerations and strategies at different ages and for different conditions together with implications for health outcomes in the face of adequate treatment or otherwise. New concepts and new treatments are discussed, with particular reference to offering improved outcomes whilst bearing in mind ethical principles underlining management.
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    Inhalation pneumonitis in children with severe cerebral palsy
    BAIKIE, GORDON ( 1999)
    Aspiration occurs frequently in children with severe cerebral palsy. Our study demonstrated at least one positive test for aspiration in 68% of children. The salivagram was positive in 56%, the barium video-fluoroscopy in 39%, and the milk scan in only 6%. The study demonstrates poor agreement between radiological tests of aspiration. This suggests that the tests measure different aspects of swallowing, that the intermittent nature of aspiration results in poor agreement, or that the tests are poor measures of aspiration. Positive radiological tests of aspiration are associated with a history from parents that the child has asthma and with poorer motor skills. A history of cough or wheeze, of cough with feed, of regurgitation and of recent asthma are associated with positive tests. Poorer overall adaptive ability, smaller head circumference centile, higher resting respiratory rate and abnormal measures of gastro-oesophageal reflux are associated with positive tests of aspiration. Chronic respiratory acidosis occurred in some children. Our study of this abnormality was hampered by the problem of defining normal values, and the appropriate reference range for our methodology. Using the Arbus nomogram definition of chronic respiratory acidosis we found an association between chronic respiratory acidosis and larger angle of scoliosis, poorer clearance of aspiration from the lung on salivagram, poorer clearance of acid from the oesophagus on pH probe, a history of pneumonia, and better weight for height Z score. Gastro-oesophageal reflux is associated with aspiration as mentioned. Both younger age and decreasing levels of ability are associated with greater frequency of gastro-oesophageal reflux. A history of asthma, regurgitation, a parental impression that the child aspirates but not a history of vomiting, were more frequent in children with gastro-oesophageal reflux. Altered voice following liquid feeding was associated with gastro-oesophageal reflux. We found less gastro-oesophageal reflux amongst children with more severe scoliosis, though this may have been the result of inadequate probe placement. There is poor agreement between the pH probe and milk scan in the diagnosis of gastro-oesophageal reflux.
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    The quality of life of young women with a menstrual problem and families attending a hospital-based gynaecological clinic in Melbourne, Australia
    Abdul Ghani, Nur Azurah ( 2010)
    BACKGROUND: Menstrual disorders are very common among young women and have been shown to have negative effect on physical and psychosocial health. Despite high prevalence of menstrual dysfunction in young women, only small percentage seeks medical help. Very few papers have examined health related quality of life (HRQL) in younger population with menstrual problem. AIMS: The aim of the study was to assess young women’s and their parents’ perception on the impact of menstrual problem on the young women’s quality of life and identified factors that have impact on it. It was also aimed to describe the quality of life of parents of young women with menstrual problems and factors influencing their quality of life (QoL). METHOD: This was a descriptive, cross-sectional study conducted in Royal Children’s Hospital, Melbourne between 1st October 2008 till 30th June 2010. Research tools used for young women were PedsQL 4.0 generic module (Teen-report) and Parent Bonding Instrument whereas tools for parents include PedsQL 4.0 generic module (Parent-report), SF12v2 and Kessler Psychological Distress Scale. RESULTS: A hundred and eighty four young women and parents completed self-administered questionnaires. The most common menstrual problems seen in our gynaecological clinic were dysmenorrhoea (38.6%), followed by heavy menstrual bleeding (33.6%), oligomenorrhoea (19.6%) and amenorrhoea (8.2%). The mean overall score was 70.48+16.44 with 42.5% having a score below one standard deviation from the norms. Young women with dysmenorrhoea had the poorest score in physical function whereas those with amenorrhoea had the lowest score in psychosocial function. Higher body mass index, smoking, alcohol drinking, sexual activity, parental anxiety and parental overprotection were associated with poorerscore. Overall, parents rated lower QoL scores than young women themselves in all four domains (physical, emotional, social and school). Parent-child agreements were moderate to good with best agreement in school functioning. Parents’ of young women with menstrual problems reported lower QoL scores than the norm in all domains with worse scores in ‘role emotional’ and ‘mental health’ domain. Parental anxiety and medical illnesses were associated with poorer parental QoL. CONCLUSION: Although menstrual problems are not life threatening, they can pose a significant impact not only on the quality of life of these young women but also their parents. Identification of these impacts might lead to recognition of potential services or education to improve this. Understanding the characteristics that predict QoL may help clinician identify patients who are risk for poor QoL.