Paediatrics (RCH) - Theses
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ItemCardiovascular associations of HIV infection in children( 2015)Vertically-acquired HIV infection is a devastating disease in childhood that may affect any organ, including the cardiovascular system. With increased survival of HIV infected children due to antiretroviral (ART) treatment availability, chronic cardiovascular problems become a confronting challenge, not only because HIV infection may cause cardiac problems readily manifesting in childhood but also because it potentially increases future cardiovascular disease risk in adulthood. This thesis explores various possible cardiovascular effects of HIV infection in children, particularly the differential effects of ART-naïve compared to ART-exposed HIV infection on left ventricular (LV) remodelling, pulmonary hypertension, and arterial elasticity. We conducted a cross-sectional study enrolling 56 ART-naïve, 59 ART-exposed HIV infected, and 51 healthy children in Jakarta, Indonesia and performed cardiac/vascular ultrasound, and blood tests for biomarkers. There were marked differences in the cardiovascular parameters between the two groups. We found that ART-naïve HIV infection was associated with LV dilation while the ART-exposed seemed to cause concentric hypertrophic remodelling. ART-exposed HIV infected children who showed evidence of higher pulmonary artery pressure than healthy children, whereas the ART-naïve children had reduced right ventricular function. For arterial elasticity, the ART-naïve had higher strain and lower elastic modulus, but thicker intima-media thickness, whereas the ART-exposed had similar vascular properties as healthy children. In conclusion, HIV infection in children have significant impacts on childhood cardiovascular system with particular differential effects between ART-naïve and ART exposed HIV infection. Routine cardiovascular surveillance is needed for children with HIV infection.
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ItemScoliosis in children with cerebral palsy: a population based study( 2015)Introduction Scoliosis is the most common spinal deformity in children with cerebral palsy. Previous published studies have been based on institutionalised patients and not on a total population of individuals with cerebral palsy. Methods This study was based on both prospective and retrospective cross-section analysis of 292 children identified from the Victorian Cerebral Palsy Register. These children were spread across GMFCS levels I–V. The children were assessed during their transition clinic appointment prior to exit from the Royal Children’s Hospital. The research looked at three main sections: clinical review for scoliosis, radiographic assessment of scoliosis, and CHQ and CPCHILD questionnaires survey. Cobb angles were measured by two experienced observers. Results If a Cobb angle of more than 10° was used, then 40% of patients were classified with scoliosis. By changing the definition of scoliosis in cerebral palsy to a Cobb angle greater than 40°, the prevalence of “clinically important scoliosis” was 12.7%. The majority of the severe curves occurred in children at GMFCS levels IV and V. As the GMFCS level increased, the mean Cobb angle increased. The mean score for the questionnaires decreased as the GMFCS level increased. Conclusion The CP scoliosis and the scores for the questionnaire were closely related to the GMFCS levels. The prevalence of CP scoliosis is overestimated in other studies. Our study shows the prevalence of CP scoliosis is 12.7% using a Cobb angle of more than 40°. Non-ambulant children are at high risk of developing scoliosis and formal spine surveillance should be considered.
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ItemDefining the phenotype of a cohort of children with non-syndromic Pierre Robin Sequence( 2015)Background Pierre Robin Sequence (PRS) is a common craniofacial anomaly comprising of micrognathia, cleft palate, glossoptosis and upper airway obstruction. It is a condition which affects 1 in 6000 neonates, often resulting in airway and feeding difficulties. Although it is a well-known condition, many aspects about the diagnosis, aetiology and management of Pierre Robin Sequence are contentious or unknown. Specifically, the exact phenotypic spectrum of this condition has been poorly studied. The major aim of this Master of Surgery is to provide an accurate phenotypic characterisation of a large cohort of non-syndromic Pierre Robin Sequence patients. A retrospective review of diagnosis and management of this cohort was also performed, along with a preliminary investigation into the possible genetic aetiology of a subset of patients. Methods A cohort of 141 non-syndromic PRS patients managed at the Royal Children’s Hospital in Melbourne from 1985 to 2012 was identified by cross-referencing two clinical databases. A detailed review of each patient’s medical file was performed and patients were categorised into either “Isolated PRS” or “PRS-Plus” groups. A subset of patients with a family history of cleft and/or a musculoskeletal anomaly were selected for targeted DNA sequencing of the non-coding elements of SOX9 (chromosome 17), a potential candidate gene for non-syndromic PRS. Results Our cohort comprised 83 Isolated PRS patients and 58 PRS-Plus patients. In the PRS-Plus group, the most common malformations beyond the craniofacial region involved were the musculoskeletal and ocular systems, with choanal stenosis/atresia being the single most common coexisting condition. PRS-Plus patients were found to have worse outcomes at birth as well as during the neonatal period, with a higher proportion being born small-for-gestational-age, have failure to thrive and require surgical intervention for airway and feeding. No significant genetic mutations were identified in the non-coding elements of SOX9 in the subset of patients who had DNA sequencing. A single nucleotide substitution was identified in the GATA1 transcription factor binding site, however the functional significance of this variant is yet to be determined. Summary Pierre Robin Sequence is a phenotypically diverse condition which contains a wide spectrum of features far beyond what was initially described. The results of this study supports the existence of a “PRS Spectrum” ranging from the mildest isolated PRS patients to the more complex syndromic PRS patients. Patients with additional anomalies outside of the craniofacial system had poorer outcomes at birth and during the neonatal period. Further studies are required to determine whether these differences can be explained by underlying biological causes such as genetic mutations, or whether this is a result of inadequate initial management.
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ItemSurgical strategies for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries and pulmonary atresia with intact ventricular septum at the Royal Children's Hospital, Melbourne, Australia( 2013)Congenital heart disease affects approximately six to eight babies in every thousand live births. In Australia over two thousand babies are born with congenital heart disease each year, with about half requiring either surgery or catheter intervention. The other half has minor abnormalities that have little to no functional impact and rarely require intervention. Historically most patients with complex congenital heart disease died in childhood. However, the past three to four decades has seen considerable advances in the fields of cardiac surgery, cardiology, cardiac imaging and intensive care, to the extent where most congenital cardiac lesions are now considered repairable with minimal morbidity. There remain, however, specific cardiac lesions that have yet to achieve this level of safe correction. Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals, and pulmonary atresia with intact ventricular septum are two such lesions. Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals is a rare and complex lesion. There is considerable variability in the anatomy, morphology and geometry of the native pulmonary vessels and the collateral arteries. The ultimate goal of therapy is a biventricular repair with closure of intracardiac defects and establishment of right ventricle to pulmonary artery blood flow. Throughout the world, surgeons have tried many different techniques to achieve this goal. The Cardiac Surgery Unit at the Royal Children’s Hospital in Melbourne achieved excellent early success in the treatment of this malformation in the 1980s – 1990s. However, long-term follow-up has revealed limitations in the surgical strategy applied during that era. Whilst complete repair was achievable in 67% of patients, survival to thirty years of age was only 58% and after complete repair only 51% of patients were alive twelve years later. A new approach – “repair without unifocalisation” was devised and is explained in this thesis. The first twenty patients who then underwent this surgical technique are examined. Early survival is excellent with no deaths to date. Complete repair was achieved in 60% of patients, 30% are awaiting complete repair, and 10% of patients are deemed unlikely to achieve complete repair and my need to be assessed for heart/lung transplantation when their symptoms progress. Pulmonary Atresia with intact ventricular septum is another lesion in which it has been difficult to achieve low morbidity and mortality. In this malformation there is complete obstruction between the right ventricle and the pulmonary arteries, and newborn babies are typically dependent on ductal blood flow for pulmonary perfusion. With a lack of a ventricular septal defect there is no outflow from the right ventricle and this results in variable degrees of right ventricular and tricuspid valve hypoplasia, and sometimes extensive right ventricular hypertrophy with coronary artery anomalies. Surgical strategies aimed at achieving a biventricular repair with reconnection of the right ventricle to the pulmonary artery have always been the ideal, as this most closely reflects the natural physiological state. However, poor results emphasized by a 5-year survival of only 49%, have encouraged surgeons to explore different strategies in the treatment of this malformation. In this modern era it is quite clear that a single surgical strategy to this malformation is inappropriate. If a univentricular palliation pathway is used exclusively then many patients fail to attain a biventricular repair and the long-term benefit this provides. If a biventricular strategy is applied exclusively then early mortality increases to unacceptable levels. An approach utilising both biventricular and univentricular repairs appears to provide the best balance between decreasing early mortality and providing the best long-term prognosis. Unfortunately there are limited criteria to decide which patients should be directed towards a univentricular or biventricular repair. Using data from patients operated on over a period of sixteen years at the Royal Children’s Hospital I have tried to identify preoperative variables that may guide this decision making process. Multivariate analysis revealed two significant risk factors for mortality. These were the presence of right ventricle to coronary artery connections and a tricuspid valve size Z score of less than negative two. Surgical results revealed an 80% ten-year survival rate. Using a simple three tiered right ventricle size categorization one can stratify those with the smallest right ventricles to univentricular palliation and those with near normal right ventricles to biventricular repair. Those patients with moderate sized right ventricles can be directed towards biventricular repair except if they also possess the significant risk factors for mortality. This approach is hoped to improve survival.
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ItemTelomerase and its role in calcitriol-induced cell death in human colon adenocarcinoma HT29 cells( 2013)Since its discovery in 1984, the role of telomerase in maintaining cellular longevity has been well-studied, raising hopes for cancer therapeutics that selectively target the telomerase pathway. Similarly, various investigations have looked into the impacts of Calcitriol (Vitamin D) in cancer cell death on different cancer cell lines. The role of Calcitriol in mediating telomerase in relation to cancer cell death, however, has not yet been clearly established. To this end, this work is focused on examining the potential role of telomerase in mediating Calcitriol-treated cancer cells. We found that even though Calcitriol alone is sufficient in inducing cell death in colon cancer (HT29) and breast cancer (MCF7) cell lines, it is inadequate in terms of inhibiting telomerase expression or activity levels in colon (HT29), breast (PMC42, MD231) and prostate (PC3) cancer cell lines. Inhibition of telomerase expression and activity was only evident with the combinatorial treatment of Calcitriol along with Retinoic Acid (Vitamin A). Furthermore, we were able to observe in Calcitriol-treated HT29 cells intracellular vacuoles consistent with a catabolic process of autophagocytosis as reported elsewhere in literature. Another interesting observation was that while telomerase activity levels in HT29 cells treated with both Calcitriol and Retinoic Acid were reduced maximally at 48 hours (consistent with Calcitriol having a half-life of about 20 hours in vivo), these activity levels appear to “rebound” beyond the baseline levels of untreated cells at 72 and 96 hours although cell death were maximum at these stages. This strongly suggests that an alternative pathway may be involved. We postulate that this increased in telomerase activity may be attributed to the level of cellular stress imposed as a consequence of Calcitriol treatment rather than Calcitriol itself acting through telomerase to cause cancer cell death. However, further work is needed to characterize this phenomenon. Collectively, we conclude that while Calcitriol alone is sufficient in inducing cell death in cancer cell lines, this outcome is likely mediated via programmed cell death pathway rather than a telomerase-mediated pathway.
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ItemFamily function and congenital heart disease( 2013)Introduction: Congenital heart disease (CHD) is one of the most common birth defects, and the most complex defects often require cardiac surgery in early infancy. Cardiac surgery typically requires intensive care unit admission. The ongoing effect on the family from having a baby with CHD that requires surgery in early infancy has been incompletely defined. Aim: To describe family function and the burden of having an infant with operated CHD, in the families of two year-olds who underwent surgery for CHD in early infancy. Method: The primary caregivers (n = 99) of young infants (less than 8 weeks of age) that required cardiac surgery in Melbourne, Australia and Auckland, New Zealand completed a series of psychosocial questionnaires assessing family function, family burden, significant life stress, and coping style when their child with CHD was 2 years old. Initial surgery complexity (RACHS-1), need for reoperation, maternal education, timing of diagnosis, and intensive care length of stay was also collected. Results: Healthy family function was found in the majority (79%), Unhealthy family function related to significant life stress (p < 0.02) and avoidance coping style (p < 0.02). Unhealthy family function did not relate to complexity of surgery, diagnostic class, need for reoperation, intensive care length of stay, or maternal education. There was a greater family burden for those with more complex lesions (single ventricle physiology with initial palliation) compared to less complex lesions (biventricular physiology requiring corrective surgery) (p < .02). Conclusion: The majority of families of two year-olds with operated CHD had healthy family function. Unhealthy family function was not related to surgical complexity, reoperation, or diagnostic class, but was related to significant life stress and coping style. Families that indicated a higher level of maternal education were more likely to utilise an adaptive style of coping. However those with a lower level of maternal education were more likely to utilise a less adaptive style of coping. Maternal education per se did not influence family function or family burden however coping style did. Family burden was greater for those that required reoperation and had a greater surgical complexity and significant life stress.
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ItemQuality of life assessment in children requiring oral anticoagulant therapy( 2011)The absence of robust evidence regarding the management and clinical outcomes of anticoagulant therapy in children challenges interpretation of the risks and benefits of long-term anticoagulation therapy for children. Decisions about treatment increase in complexity in light of the potential burden of treatment on children and families. Quality of life (QoL) is a recognised and validated measure of the burden of treatments for children; yet, there is a lack of data about the impact of long-term warfarin therapy on QoL for children and families. This thesis describes the first study to evaluate the impact of a home international normalised ratio (INR) self-testing (home ST) program on the QoL of children and their families. The aim of the study was to determine if participation in a home ST program improves QoL for children requiring long-term warfarin therapy and their families. Parents of children requiring long-term warfarin therapy and children aged eight to 18 years participated in the QoL study. Three validated QoL questionnaires, the Pediatric Quality of life Inventory Generic Core Scale™, the Pediatric Quality of Life Family Impact Module™ and the KIDCLOT Pediatric Anticoagulation Quality of Life © inventory were employed to measure QoL. Questionnaires were completed before commencing home ST and six to 12 months later. Participants answered four open-ended questions when completing the questionnaires for the second time. Fifty-six families entered the home ST program during the study period. The children were aged between 2 and 17 years. Fifty-five parents and 35 children completed QoL questionnaires. Results of INRs tested at home were collected. The percentage of time the children’s INRs were in their target therapeutic range was 71.3%, which is comparable to many published paediatric studies of home ST. Parents reported statistically significant improvements in QoL for themselves, their family and their child, across all questionnaires following the commencement of home ST (mean difference in score p ≤ 0.003 on all questionnaires). The children’s scores of their own QoL also improved; however, this improvement was not significant. Parents’ report of their children’s QoL was significantly lower than the children’s report of QoL on all questionnaires at both time points. As well as being the first validated baseline QoL data in an Australian population of children requiring oral anticoagulant therapy, this study reports QoL for the largest cohort of children requiring warfarin therapy worldwide. The employment of both quantitative and qualitative methods to assess QoL enhanced understanding about the impact of home ST on QoL. This study has demonstrated that home ST in a population of children requiring long-term warfarin therapy is safe, efficacious and improves the QoL of children and parents. This study confirms home ST successfully reduced the burden of therapy and maintained excellent clinical outcomes. The results of this study not only identify the impact of warfarin therapy upon QoL in children, but offer an alternative evaluation strategy to sensitively measure the impact of interventions in this population. Accurate QoL assessments ensure children’s and families’ values are integrated with the current evidence for best clinical practice.