Paediatrics (RCH) - Theses

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    Fiji integrated therapy – safety and efficacy of community control strategies for lymphatic filariasis and scabies in Fiji
    Hardy, Myra ( 2022)
    Neglected tropical diseases (NTDs) are a collection of 20 diseases recognised by the World Health Organization (WHO) as causing significant harm to the health, social engagement and economic potential of billions of people living in poverty, predominantly in the tropics. Both lymphatic filariasis (LF) and scabies are NTDs. One effective approach to reduce the burden of NTDs in endemic communities is annual mass drug administration (MDA). This strategy involves providing free medication to all community members regardless of infection status at the same time. Lymphatic filariasis (LF) is a caused by the nematode Wuchereria bancrofti, transmitted between humans by mosquitoes. Chronic complications of LF include irreversible lymphoedema and hydroceles. Lymphatic filariasis remains endemic in areas of Fiji, despite regular annual MDA using diethylcarbamazine and albendazole (DA) since 2000. Experts in the field hypothesised that adding ivermectin to DA would improve the efficacy of the MDA and help accelerate towards the goal of elimination of LF as a public health problem. Scabies is a pruritic rash caused by the microscopic mite Sarcoptes scabiei variety hominis. Secondary bacterial infections from Staphylococcus aureus and Streptococcus pyogenes are common and can lead to local skin infections, sepsis and auto-immune complications including glomerulonephritis and potentially rheumatic fever. Scabies is endemic in Fiji with an estimated national prevalence of scabies of 18%. Scabies can be successfully controlled with two-dose ivermectin-based MDA. Experts in the field have highlighted evaluation of one-dose ivermectin-based MDA as a priority, because if non-inferior to a two-dose schedule it would reduce barriers to implementation of scabies control efforts. The Fiji Integrated Therapy study was initiated to evaluate the impact of MDA with ivermectin, diethylcarbamazine and albendazole, known as IDA, on 2 remote islands within the Eastern Division of Fiji where LF and scabies are co-endemic. Data arising from this cluster randomised controlled study underpins this thesis. There are 3 main components: 1) safety of IDA; 2) efficacy of IDA for LF and 3) evaluation of community control strategies for scabies. The first part of the thesis evaluates the safety of IDA MDA compared to DA. Adverse events were monitored for the first 7 days after treatment. Six hundred (16.7%) participants experienced an adverse event with no difference between treatment groups. Most (93.2%) symptoms were graded as mild with no serious events attributable to treatment. Participants with microfilaremia were more likely to experience an adverse event (43.2% versus 15.7%). The second part of the thesis reports on the efficacy of IDA compared to DA for LF. Contrary to IDA efficacy studies in other countries with different transmission profiles, we found no difference between treatment groups for clearance of microfilaremia 12 months after treatment (DA 69.2% versus IDA 62.5%). There was no difference in community prevalence of LF at 12 months. The possible reasons for this unexpected finding are discussed. The third part of the thesis addresses the effectiveness of different community control strategies for scabies. One-dose ivermectin-based MDA was non-inferior to two-dose ivermectin-based MDA for reduction in community prevalence of scabies at 12 months. Screen and treat with permethrin for individuals with scabies and their household contacts was also non-inferior, however this approach would be labour intensive and expensive and unlikely to be feasible at scale. Overall, IDA MDA was well tolerated and effective in reducing the community prevalence of LF and scabies in endemic communities in Fiji. The lack of benefit by the addition of ivermectin on LF in Fiji needs further exploration in similar transmission settings to understand the possible reasons for this finding. The success of one-dose ivermectin-based MDA for the control of scabies needs further research to determine if it can be replicated in urban and non-island settings. The findings from this thesis have informed LF and scabies control policy within Fiji, the Pacific region, and globally.
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    The effect of α-actinin 3 deficiency on the regulation of skeletal muscle mass and response to androgens
    Roeszler, Kelly Nicole ( 2022)
    Loss of muscle mass and strength (muscle wasting) due to declining androgen levels is common and leads to a reduced quality of life. a-Actinin-3 (ACTN3) is a major structural component of skeletal muscle. A common polymorphism in ACTN3 gene (R577X) is strongly associated with sprint performance and muscle power in elite athletes. Homozygous inheritance of the 577X null allele results in a-actinin-3 deficiency and occurs in ~20% of the global population but does not cause disease. An Actn3 knockout (KO) mouse model of human a-actinin-3 deficiency demonstrates lower muscle mass and strength due to reductions in size of type 2B muscle fibres, however, the mechanism behind this remains elusive. Maintenance of muscle mass is the delicate balance of protein synthesis and degradation pathways, and the a-actinins are known to interact with various members of these pathways. a-Actinins can also directly interact with and influence androgen receptor (AR) signalling, which is activated by androgens to stimulate muscle growth. On this basis, we hypothesise that reduced muscle mass with a-actinin-3 deficiency is caused by alterations in pathways regulating this process. We further hypothesise that a-actinin-3 deficiency influences the skeletal muscle response to androgens. This thesis aims to examine the effect of a-actinin-3 deficiency and androgens on muscle mass regulation at baseline and under atrophic (wasting) and hypertrophic (growth) conditions. Understanding how ACTN3 genotype influences muscle mass may help identify individuals at increased risk of muscle wasting due to loss of androgens and determine their response to therapies that treat these conditions. We show at baseline that a-actinin-3 plays a key role in protein synthesis through the regulation of PI3K/Akt/mTOR, myostatin and Smad3 signalling and expression of genes associated with protein breakdown (atrogin-1 and MuRF1) in skeletal muscle. a-Actinin-3 deficiency down-regulates AR signalling in skeletal muscle (-68%) and reduces androgen-responsive gene expression (Smox and Odc1) but does not alter circulating testosterone levels. Under atrophic conditions, a-actinin-3 deficiency increases the muscle wasting response to androgen deprivation. In hypertrophic settings, a-actinin-3 deficient muscles are less responsive to androgens (dihydrotestosterone), particularly in females. a-Actinin-3 deficiency impairs androgenic response in key pathways involved in muscle growth/breakdown and metabolic signalling and suggests these play a vital role in the differential skeletal muscle response between Actn3 genotypes. a-Actinin-3 deficiency also significantly reduces the muscle hypertrophic response to follistatin, a potent inhibitor of myostatin. Given that androgens can directly modify myostatin expression in skeletal muscle and a-actinin-3 deficiency decreases both AR and myostatin signalling at baseline, our findings suggest that a-actinin-3 may be an essential adaptor linking/facilitating crosstalk between these two pathways in the regulation of muscle mass. Together, these findings indicate that a-actinin-3 deficiency plays a crucial role in regulating these pathways to maintain skeletal muscle mass. a-Actinin-3 deficiency has a profound effect on androgen signalling and may worsen the muscle wasting response to androgen deprivation and limit the potential for muscle growth with androgen and follistatin therapies. Future clinical trials should consider the impact of ACTN3 R577X genotype on therapies aimed at treating muscle wasting.
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    Early lifecourse body composition and adolescent cardiovascular function and structure: A community-based longitudinal cohort study
    Gillespie, Alanna Nicole ( 2021)
    http://hdl.handle.net/11343/321883 Background: Understanding if the timing, duration and severity of childhood body composition, from lean to obese, is associated differentially with adolescent cardiovascular phenotype will enable a better understanding of the timing and nature of adiposity-associated cardiovascular risk. Aims: To examine how adolescent cardiovascular function and structure are associated with (1a) individual or (1b) combined measures of adolescent body composition; (2) body mass index (BMI) trajectories between birth and 14 years; and (3) BMI, fat mass index (FMI), lean mass index (LMI) and waist-to-height ratio (WHtR) trajectories between 4 and 14 years. Methods: Design: Participants from the PEAS Kids Growth Study, a longitudinal community-based cohort in Melbourne, Australia, were measured on 16 occasions from birth (n=493) to 14-17 years (n=196 with cardiovascular data). Measures: Body composition: BMI/waist z-score, WHtR, FMI, LMI. Cardiovascular phenotypes: Systolic/diastolic blood pressure (S/DBP), augmentation index (AIx), pulse wave velocity (PWV), retinal arteriole-to-venule ratio (AVR), carotid intima media thickness (cIMT). Analysis: Aim 1-3: Adjusted linear regression models assessed associations between adolescent body composition/childhood trajectory and cardiovascular phenotype. Aims 2-3: Latent class analysis identified participants with similar childhood body composition trajectories. Results: 196 PEAS adolescents (75% of invited, 46% male) completed a direct assessment of cardiovascular phenotype. Aim 1: Each SD increase in adolescent BMI z-score was associated with higher SBP (2.5mmHg, CI: 0.9 to 4.0) and AIx (2.9%, CI 1.2 to 4.6). Higher waist z-score, FMI and LMI were also associated with higher SBP and AIx; but not DBP, PWV, AVR, or cIMT. Moderate variance was explained by each adjusted model (highest for BMI z score with SBP, R2=0.24). Aim 2: Three BMI trajectories were identified: low normal, high normal, and consistently overweight between birth and 14 years. Consistently overweight children had higher AIx (7.8%, CI 2.6 to 13.0, R2=0.13) but no other differences in cardiovascular phenotype compared the reference group. Aim 3: Three trajectory groups of BMI, WHtR, FMI and LMI (low, medium, and high) were identified between 4-14 years. Children following the high FMI trajectory had higher SBP (5.6mmHg, CI 1.1 to 10.1, R2=0.22) and DBP (3.9mmHg, CI 0.7 to 7.2, R2=0.08), compared to the reference group. Those in high BMI and WHtR trajectories had higher AIx and SBP (WHtR trajectory only); but vascular structure was similar for all, regardless of body composition trajectory. In contrast, LMI trajectories were not associated with any measure of function or structure. Discussion: Associations were evident between adolescent and 10-year trajectories of BMI, FMI, and WHtR with cardiovascular function. Interestingly, associations between LMI and cardiovascular function were only evident cross-sectionally in adolescence. Nonetheless, despite high BMI, FMI and WHtR for over a decade, and poorer cardiovascular function, following a high trajectory during childhood was not associated with worse vascular structure in mid-adolescence in this cohort. This may be due to the small number of very obese adolescents in this sample. Future studies measuring body composition and cardiovascular phenotype throughout childhood and into adulthood are necessary to understand how to minimise adiposity-associated lifecourse cardiovascular risk.
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    End-organ consequences of the Fontan circulation
    Wilson, Thomas Gregory ( 2022)
    The Fontan procedure is the last in a series of staged surgical procedures offered to children born with complex congenital heart disease in whom a two-ventricle repair is not feasible. Since its first description, the Fontan procedure has undergone a number of technical modifications which have further improved survival and reduced associated morbidity. Due to improved survival, the number of people living with a Fontan circulation is growing, and the average age is increasing. However, with more patients surviving into adulthood we are unfortunately seeing that many will develop complications. Ventricular dysfunction, circulatory failure, atrioventricular valve (AVV) regurgitation, cardiac arrhythmias, protein-losing enteropathy, plastic bronchitis and thromboembolic phenomena have all been increasingly recognized as potential complications after the Fontan operation. Hepatic fibrosis, cirrhosis and hepatocellular carcinoma have also been described, as well as renal dysfunction in the form of reduced glomerular filtration rate (GFR) and microalbuminuria. The aim of this thesis was to (i) characterize the prevalence and severity of hepatic and renal complications in patients with a Fontan circulation, (ii) identify potential risk factors that may contribute to the development of hepatic and renal complications after the Fontan procedure, and (iii) inform screening practices for end-organ complications in these patients. In this thesis I have demonstrated that: (i) the majority of patients with a Fontan circulation have non-invasive evidence of liver fibrosis by early adulthood, (ii) a smaller but significant proportion of patients will be diagnosed with liver cirrhosis by early adulthood, (iii) a minority of patients will develop hepatocellular carcinoma, which may occur in adolescence or early adulthood, (iv) history of cardiac arrhythmia or AVV failure is associated with an increased risk of advanced liver disease, (v) mild renal dysfunction is common in patients with a Fontan circulation, however, does not appear to negatively impact mid-term outcomes, (vi) creatinine based estimated GFR should be interpreted with caution in children with a Fontan circulation, and tends to over-estimate true or measured GFR in children and adults with a Fontan circulation, (vii) many of the patients who were found to have hepatic or renal dysfunction were identified on routine screening. This thesis has drawn attention to the significant proportion of patients with a Fontan circulation who will develop hepatic or renal dysfunction during long-term follow-up. These findings encourage us to consider the implications of end-organ dysfunction on the medical management of a population that is growing in numbers and age. This work emphasizes the importance of routine surveillance in identifying those with significant liver and kidney dysfunction after the Fontan procedure, and identifies a number of potentially modifiable risk factors for more advanced disease. In the absence of any proven pharmacological treatment for these complications, it is likely that optimisation of the Fontan circulation itself in combination with the avoidance of secondary end-organ insults will be the key to minimising the burden of hepatic and renal disease in this population.
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    Effectiveness of mass drug administration regimens for the control of scabies
    Lake, Susanna June ( 2022)
    Scabies is a neglected tropical disease (NTD) of the skin that causes approximately 455 million cases around the world each year. It is most prevalent in low resource, crowded, tropical environments. Scabies is caused by a parasitic mite that burrows into the skin and causes intense itch, which can lead to a break in the skin barrier. Secondary bacterial infection can lead to serious invasive and immune modulated disease. Mass drug administration (MDA) has been used in the control of a number of NTDs and there is evidence that it may be an effective control strategy for scabies in populations with a high prevalence. The first part of this thesis explores the impact of scabies on the community and on individuals, providing evidence for the need for public health control. The impact of scabies on the community was assessed in a survey in Western Province in Solomon Islands. A total of 5239 participants were enrolled across 20 villages. Scabies prevalence was 15% (95% CI 11.8 – 19.1) and impetigo prevalence 5.6% (95% 4.2 – 7.3). Dermatology quality of life interviews were conducted in one-third of participants to assess the impact of scabies on individuals. This study found that scabies has a small, but measurable, impact on quality of life in children and adults, and that the impact increased with the severity of the disease. The second part of this thesis investigates the public health control of scabies. A systematic review and meta-analysis was conducted to assess the impact of MDA on both scabies and impetigo. The meta-analysis included 9 studies and found that MDA with ivermectin or permethrin led to an overall relative reduction of 79% scabies prevalence and 66% impetigo prevalence. A variety of drug and dose regimens were used across the included studies and it was not clear if one regimen was more effective than others. The major study in this thesis is the Regimens of Ivermectin for Scabies Elimination (RISE) trial. RISE was a cluster-randomised non-inferiority study of one versus two doses of ivermectin-based MDA. There were 20 villages included in the study, with 10 villages randomised to each dose group. Participating villages were scattered across 7 different island groups and neighbouring villages did not take part in MDA. The study aim was to assess the prevalence of scabies in one and two dose villages 12 months after MDA, but due to the COVID-19 global pandemic this was delayed to 21 months. At 21 months after MDA there was no change in scabies prevalence in either the one or two dose groups. There was a reduction in the severity of scabies and the prevalence of impetigo in both groups. The results were unexpected. There was considerable movement of people in and out of the study villages between baseline and 21 months which may have contributed to the finding of static scabies prevalence in both groups. Despite the lack of effect seen in the RISE trial the systematic review and meta-analysis demonstrated that MDA can have a substantial impact on scabies prevalence. The RISE trial provided important information about implementation of MDA and the need for neighbouring villages to receive treatment. The question of whether one dose of ivermectin-based MDA is non-inferior to two doses needs further research.
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    Ivermectin-based mass drug administration for the serious bacterial complications of scabies
    Thean, Li Jun ( 2022)
    Scabies is a skin disease caused by the mite Sarcoptes scabiei var. hominis, which is especially prevalent in populations experiencing overcrowding and poverty. Recognised as a neglected tropical disease by the World Health Organization in 2017, scabies is characterised through skin lesions and intense itch. The host is made vulnerable to secondary bacterial infection through skin breaches, scratching and inhibition of the complement system via mite secretions. Bacterial infection predominantly caused by Staphylococcus aureus and/or Group A Streptococcus most commonly manifesting as impetigo can complicate scabies. Impetigo can progress to more complicated skin and soft tissue infection, invasive bacterial infection and post streptococcal sequelae which cause significant morbidity and mortality. Previous studies in the Pacific Islands, including in Fiji, demonstrated that ivermectin-based mass drug administration substantially reduces scabies prevalence by approximately 90%, and leads to a concomitant reduction in impetigo prevalence by 60% to 70%. The focus of this thesis was to determine if ivermectin-based mass drug administration also leads to a reduction in the more serious bacterial complications of scabies. The studies and intervention described in this thesis take place in Fiji’s Northern Division (population ~131,914 in 2017). Four studies are reported in the thesis. The first study investigated the burden of hospitalisations for skin and soft tissue infections using prospective surveillance at the referral hospital of the Northern Division, and found a very high population incidence of 647 admissions per 100,000 person-years (95% CI 571-660). The second study investigated the burden of invasive infections caused by S. aureus and group A Streptococcus, using prospective surveillance also at the referral hospital, and found a high incidence at 45.2 and 12.3 per 100,000 person-years, respectively. The third study investigated the incidence of primary healthcare presentations for scabies and skin and soft tissue infections using a prospective surveillance system established at all primary healthcare facilities in the Northern Division, and found that there were 13,736 presentations over 50 weeks, equivalent to a population incidence of 108 presentations per 1000 person-years. The final major study investigated the impact of ivermectin-based mass drug administration on the bacterial complications of scabies. Ivermectin-based mass drug administration was deployed across the whole of the Northern Division. Coverage of mass drug administration was high – with the first dose achieving 97% and the second dose 87% coverage. The primary outcome measure was the annual incidence of hospitalisations for skin and soft tissue infections, with the study finding that the incidence declined significantly by 17% in the year after mass drug administration (from 467 to 388 per 100,000, incidence rate ratio 0.83 95% confidence intervals 0.74% to 0.94%). This finding was supported by a reduction in the annual incidence of primary healthcare presentations by 21%, and by a reduction in scabies and impetigo prevalence by 29% and 60% respectively. There was no decrease in the incidence of invasive infections and post streptococcal sequelae. Overall, this thesis demonstrates that scabies control through mass drug administration can lead to a reduction in the incidence of bacterial skin and soft tissue infections, measured as a fall in healthcare utilisation and community prevalence. These results are encouraging and provide further evidence of the broader benefits of scabies control via mass drug administration. In settings where scabies is endemic and where resources are limited and health priorities compete, this thesis highlights the underestimated burden of scabies and strengthens the case for policy targeting control of this neglected tropical disease.
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    Utilising high resolution impedance manometry to diagnose and manage oesophageal dysfunction in children with oesophageal atresia
    Tan Tanny, Sharman Pei Yi ( 2022)
    Oesophageal atresia is the most common congenital oesophageal abnormality and requires life-saving surgery in the neonatal period. Despite successful surgery, most patients will have ongoing oesophageal dysmotility. Dysmotility in oesophageal atresia is a life-long risk. Dysmotility results in chronic swallowing dysfunction into adulthood – leading to poor food bolus transport, choking, and even death. We are currently unable to reliably predict which patients will develop dysmotility and require oesophageal dilatations. Therefore, clinical management is reactive, rather than proactive. This research seeks to understand the motility patterns in oesophageal atresia, as well as the dilatation burden and late mortality risk. This research utilises high resolution impedance manometry, which provides accurate and reliable measurements of oesophageal wall compliance, to develop an understanding of how compliance relates to food bolus transport. This will allow for objective characterisation of oesophageal contraction in patients with oesophageal atresia. Simultaneously, patient and carer quality of life will also be assessed. With the largest cohort of patients with oesophageal atresia undergoing high resolution impedance manometry internationally, this research demonstrates that the distinct motility patterns of these patients remain consistent over time. This informs patient management and parental counselling, as well as the development of a strategy for predicting and preventing morbidity and mortality in oesophageal atresia.
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    The use of genomic sequencing technologies to diagnose rare neurological disease
    Stutterd, Chloe Alice ( 2022)
    Background Neurological diseases with presumed genetic aetiology contribute a significant burden of disease in the population, particularly the severe diseases of childhood. Without a genetic diagnosis, families cannot access accurate genetic counselling, prenatal and preimplantation testing, prognostic information, or targeted therapeutics. Genomic sequencing technologies have enabled an unprecedented improvement in the diagnosis of these rare diseases. Aims and Methods The aim of this project is to investigate the use of genomic sequencing technologies to diagnose rare neurological disease. In part 1, a gene panel was applied to a cohort of 124 individuals with polymicrogyria to identify causative variants and determine the genetic mechanism. In part 2, duo exome sequencing was used to investigate the cause of two novel phenotypes affecting siblings in two unrelated families. In part 3, trio genome sequencing was used to investigate the genetic causes underlying a cohort of 26 patients from 22 families with unclassified disorders of white matter. In addition to identifying the genetic basis of these diseases, this project aimed to evaluate the use of three different genomic sequencing strategies, discover novel gene-disease associations and describe expanded gene-disease phenotypes. Results In part 1, 25 of 123 individuals with polymicrogyria were identified as having a causative variant. Five individuals with heterozygous variants in keeping with a dominant mechanism had an allele fraction less than 0.33, consistent with mosaicism. The highest diagnostic yield was achieved for patients with an abnormal head size, particularly macrocephaly, and those with the additional brain malformations seen in association with tubulinopathies. In part 2, both families investigated with duo exome sequencing received a diagnosis. One of the diagnoses characterised the neuropathology associated with recessive pathogenic variants in VAC14, and the other resulted in expansion of the clinical and radiological phenotype associated with recessive pathogenic variants in HMBS. In part 3, trio genome sequencing identified a cause in 15 of 22 families with unclassified white matter disease. The phenotypic spectrum associated with known genes was expanded in 11 cases, and for nine, the implicated gene had not previously been associated with white matter disease. Discussion: Advantages and limitations to the different genomic technologies were identified and dependent on the context of study. A gene panel was suitable for investigation of a singleton cohort with a high probability of somatic variants as high sequencing depth is achievable, exome sequencing applied to family studies with multiple affected individuals facilitated a narrowing of the search space for identification of shared variants, and trio genome sequencing was particularly advantageous for its recognition of de novo variants. Conclusions The results of this project have advanced the understanding of the genetic causes of polymicrogyria and white matter diseases and informed the approach to genetic testing for these rare and genetically heterogeneous diseases. Additionally, this research has led to ongoing projects that aim to improve care for patients and families affected by rare neurogenetic diseases.
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    Inter-arm blood pressure differences at rest and exercise: significance in children and potential mechanisms
    Clarke, Melanie ( 2021)
    High blood pressure (BP) is one of the leading risk factors for cardiovascular disease and is a key contributor to arterial stiffening, end organ damage, and cognitive decline. Importantly, high BP often begins in childhood, and if left untreated may track into adulthood. However, if diagnosed and treated, reducing high BP lowers the risk of disease. Clinical guidelines for best practice with regards to BP measurement have been established for both adults and children. Although not routinely followed in many settings, a common recommendation for both adult and paediatric populations is to measure BP in both arms. The measurement of bilateral BP holds clinical importance as an inter-arm blood pressure difference (IAD) of greater than or equal to 10 mmHg (IAD+) is associated with cardiovascular disease and premature morbidity and mortality in adults. Additionally, both the magnitude and prevalence of IAD+ has been shown to increase with exercise. While IAD has been investigated in adults, no studies exist on IAD in children despite the recommendation to measure bilateral BP in clinical guidelines. Further, the mechanisms which cause this difference remain unknown. Therefore, the primary purpose of this thesis was to examine IAD in children and adolescents under resting conditions, exercise conditions, and explore a potential mechanism which may result in IAD. Four investigations were performed that 1) quantified the magnitude of IAD and the frequency of IAD+, as well as determined inter-arm BP classification differences, under resting conditions in children and adolescents; 2) generated normative data for exercise BP response in children and adolescents undergoing treadmill exercise stress tests to enable objective assessment of exercise BP classification; 3) quantified the magnitude of IAD and frequency of IAD+ and inter-arm classification differences under exercise conditions in children and adolescents; 4) used a one-dimensional computational model to investigate inter-arm difference in arterial stiffness as a potential mechanism underlying IAD. The frequency of IAD+ in children and adolescents was similar to that of adults under both resting an exercise conditions. The average magnitude of IAD was 5 mmHg under resting conditions and 7 mmHg under exercise conditions.The inter-arm classification difference was ~20% under resting conditions. Normative data generated from treadmill exercise tests was used to determine that ~10% of children and adolescents have an exercising inter-arm classification difference. Lastly, the modelling study supported the hypothesis that inter-arm differences in regional arterial stiffness may contribute to IAD. Data presented in this thesis supports the recommendation to measure BP in both arms and provides a strong rationale for conducting this measurement in apparently healthy children. Measuring BP in both arms under both resting and exercise conditions may be important for detecting high BP in children and adolescents. Lastly, it was shown that mechanistic investigations with regards to IAD can be performed using 1D models and may be useful where in-vivo studies are not physiologically possible.
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    Exome sequencing in infants with congenital deafness, a model for genomic newborn screening
    Downie, Lilian Claire ( 2021)
    Background Genomic technology is emerging as a powerful diagnostic tool to provide precision management and personalised care. It also has potential to be used at a population level to provide predictive and tailored health information, including as part of newborn screening (NBS). NBS traditionally detects serious and treatable childhood conditions, including congenital hearing impairment. As the majority of childhood hearing impairment has an underlying genetic cause, genomics is the ideal technology to investigate this condition. Aims and Methods The aims of this research were to: a) characterise the genetic causes of congenital hearing impairment in the population; b) understand the impact genomic testing has on the pathway of care following this diagnosis; and c) examine the factors that may influence the uptake and success of a genomic NBS tool. The methods used to investigate these aims were: 1. Offering diagnostic genomic testing to a cohort of infants with hearing impairment and observing the effect of this investigation on their healthcare journey; 2. Determining the cost-effectiveness of this genomic testing pathway when compared with the standard of care; 3. Offering parents additional analysis of non-deafness genes and investigating what factors influence their choices around seeking predictive health information for their infant; 4. Undertaking a systematic literature review to understand the current status of the field of genomics as a potential tool for NBS. Results Genomic sequencing was performed on 106 infants diagnosed with congenital deafness through newborn screening. Fifty-nine infants (56%) had a genetic cause for their hearing impairment. The majority (n=38, 36%) had a diagnosis that indicated their hearing impairment was isolated, such that they did not need to undertake surveillance for other health conditions. Those who received a syndrome diagnosis (n=21, 20%) were able to access accurate prognostic information, support and tailored healthcare. Streamlining the care of this cohort according to their underlying diagnosis was cost-effective when compared to standard of care, where most infants do not have a cause for their hearing impairment identified. Genomic testing also had non-health related benefits for families, i.e., personal utility. Parents made varying choices regarding receiving predictive information from the testing. Seventy-two parents (68%) accepted the offer of additional information. These findings are consistent with those identified in our systematic review of the literature – that “one size does not fit all”. Conclusion Offering genomic sequencing to a cohort of infants with congenital hearing impairment served as an ideal model to investigate genomic NBS. It re-enforced the diagnostic power of the test for congenital hearing impairment, translating into a cost-effectiveness analysis and an application for a Medicare item number. More broadly, this research identified the key elements required for genomic NBS to be acceptable and successful at a population level. Areas for future work are to refine the scope of testing with a strategy for gene list composition, and to identify the optimum timing and consent process. Getting these elements right will enhance newborn screening by increasing its scope and sensitivity, not just for congenital hearing impairment, but for improving the health of many children and their families.