Paediatrics (RCH) - Theses
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ItemNo Preview AvailableAutism Spectrum Disorder (ASD) and Anaesthesia( 2019)This thesis addresses the question of what is the best evidence-based management for children with ASD (autism spectrum disorder) coming under anaesthetic care in the hospital setting. The increasing prevalence of ASD (1) has meant that most anaesthetists need to become proficient in understanding and managing children with ASD. Children with ASD have higher hospital contact than their neurotypical peers.(2) Behavioural problems, sensory sensitivities, language deficit, and inflexibility with change contribute to the difficulties experienced by children with ASD in the hospital setting. (3)Hospitals may be inherently challenging to children with ASD: being inflexible places, with the sound of crying children, with invasive monitoring techniques and bright lights.(4) One unpleasant anaesthetic experience can lead to heightened anxiety and future refusal to attend hospital. In order to find the context for best anaesthetic care, we have reviewed the existing literature about ASD and its management in chapter one. The first part of chapter two is a review of anxiety and premedication in general terms. The evidence for current best practices in managing children with ASD in the perioperative period is outlined in the second part of chapter two. To further understand the family and staff perspective of optimal care, we conducted a qualitative study of 29 individuals including 15 parents of children with ASD who had had a recent anaesthetic and 14 staff members that had looked after them in different capacities at two hospitals in Melbourne, Australia in chapter three. Chapter four contains discussion and conclusion. It includes discussion about the discontinued preparation/premedication trial (CLOMID). The flaws in the design and obstacles in its execution are examined. Our data showed important organisational, educational and resource matters. Problems such as prolong waiting for an operation date, lack of training of staff including anaesthetists and nurses, lack of availability of simple equipment and private spaces in the recovery rooms- were to be addressed. Good communication, clear explanation, and friendly attitudes as well as flexibility and individualised care of patients were considered useful. The supplementary material includes a protocol for a preparation /premedication study that has not been concluded as well as two social stories that I have designed.
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ItemInvestigating the biology of paediatric T cell acute lymphoblastic leukaemia to facilitate more effective individualised therapy( 2019)Acute lymphoblastic leukaemia (ALL) takes up the highest percentage of paediatric cancer. The treatment requires intensive chemotherapy for two to three years, as well as haematopoietic stem cell transplantation for poor-prognosis cases. Compared to B cell lineage ALL (B-ALL), T cell lineage ALL (T-ALL) has a lower 5-year event free rate, higher rate of relapse, and a worse outcome for relapsed cases. Individualised therapy, targeting at oncogenic changes in each patient, can make treatment more effective and less harmful. This requires understanding of the oncogenic biology of each individual leukaemia. We have attempted to develop a T-ALL model based on hiPSC-derived T cells, which will be in human origin, maintain normal genetic pattern, mimic in vivo T cell development, and can be massively produced for high throughput lab work. This model may make up for the shortcomings of conventional leukaemia cell lines and mouse models. This project investigates the biology of T-ALL by focusing on two novel fusion genes – TCF7-CSF1R and ETV6-CRX – identified by RNA sequencing of paediatric T-ALL patient samples. We have shown that TCF7-CSF1R is sufficient to immortalise mIL-3 dependent Ba/F3 cells. The ETV6-CRX fusion gene is anticipated to block differentiation. Establishing consistent expression of this fusion will require further optimization. The feasibility of setting up a hiPSC-derived T-ALL model was also assessed, with respect to protein expression in human T-ALL/lymphoma cell lines, hiPSC differentiation efficiency, hiPSC-derived T cell lentiviral infection rate, and cytokine withdrawal during differentiation. This project provides potential directions for improvement of methods for exogenous gene expression, such as the usage of CRISPR-Cas9 based techniques to introduce gene modifications for fusion genes such as ETV6-CRX that are difficult to express, particularly in hiPSC-derived T cells that have a low viral infection level. The T cell differentiation protocols also need to be optimised to make the T cell production easier and efficient. Detailed functional assay during T cell differentiation needs to be conducted in the future. In this thesis, Chapter 1 presents the background of this project; a literature review introducing human haematopoietic system, in vivo thymocyte development, paediatric TALL, novel oncogenic fusion-related genes, and in vitro T cell generation; the aims and hypothesis. Chapter 2 introduces the methods and materials used in this project. Chapter 3 presents the identification, cloning, and expression of novel fusion genes. Chapter 4 investigates the ability of these novel fusion genes to support cell survival and proliferation in conventional Ba/F3 cell line. Chapter 5 assesses the feasibility of setting up the hiPSC-derived T-ALL model. Chapter 6 makes a discussion on the results and concludes the whole project.
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ItemCirculating microRNAs in Rett syndrome( 2019)Rett Syndrome (RTT) is a severe neurological disorder with diagnostic challenges and undetermined patholophysiology. Small regulatory RNAs known as miRNAs are essential in a multiple biological processes, including brain development. Using next generation sequencing in a mouse model of RTT, I identified circulating, plasma miRNAs that are differentially expressed in RTT mice. Many of these miRNAs were previously shown to have neurological functions or be involved in RTT. The biomarker potential of these miRNAs was further explored using quantitative PCR.