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(2020)ThesisThis thesis examines the clinical translation of two novel therapeutic drugs in rare paediatric neurological disease via expanded access programs (EAP). Patients with rare diseases commonly encounter barriers to care and lack of disease-modifying treatments. EAPs help address this need by providing access to therapeutic drugs before commercial availability, however, there is usually limited knowledge regarding the safety and full impact of the drug. Two drugs were recently made available via an EAP for children in New South Wales: cannabidiol for paediatric drug-resistant epilepsy (DRE) and nusinersen for spinal muscular atrophy (SMA). In a time when there was no evidence regarding the use of cannabidiol in paediatric DRE, an EAP was established due to unprecedented patient demand. Our study analysed the safety, adverse effects and preliminary efficacy of cannabidiol in patients with DRE. Cannabidiol was well tolerated, with sedation commonly reported (37.5%). Elevated transaminases were seen in 5% and demonstrated the necessity of medical monitoring. Although many patients reported improved overall health, indirect measures of seizure control did not show improvement, thus signifying the need for larger, randomised-controlled trials. In children with SMA type 1 (SMA1) treated with nusinersen, respiratory, bulbar and nutritional outcomes were analysed, as previous studies had demonstrated increased survival and motor function but had not assessed the broader impact on the burden of disease. Our study demonstrated substantial ongoing comorbidities due to respiratory and bulbar weakness, with the need for ongoing nocturnal noninvasive ventilation, gastrostomy feeding and recurrent acute hospitalisations. Greater burden of disease was seen more in patients with two SMN2 copies. Most children showed improvement in motor outcome assessments, a stark change in the natural history of SMA. These findings show the impact of nusinersen in modifying the phenotype of children with SMA1, yet ongoing significant morbidities and requirement for multidisciplinary supportive medical care. In conclusion, these studies provide additional real-world clinical data on the implementation and extent of efficacy of two novel drugs for rare neurological diseases. EAPs serves to address an unmet clinical need and facilitate the translation of research into practice to advance future health practice and research in rare diseases.
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(2020)ThesisDNA cytosine methylation is an important epigenetic modification that plays a key role in gene expression. DNA methylation has been shown to be involved in numerous processes, including X-chromosome inactivation in mammals, retrotransposon silencing, genomic imprinting, carcinogenesis and the regulation of tissue specific gene expression during development. Gene expression is tightly regulated via DNA methylation (5mC) and the aberrant expression of meiotic genes in mitotic cells via CpG promoter hypomethylation has been proposed to cause cancer. Cancer/Testis Antigens (CTAs) are a group of genes that encode tumour specific antigens and are expressed in the testis, certain cancers but not in normal post-natal somatic tissues. CpG island methylation and histone modifications appear to play a role in the epigenetic regulation of CTA expression, however, very little is known about their functions in vivo. A widely studied but poorly understood question to date is the mechanisms behind aberrant CTA reactivation in cancer. Given that 5mC mediated gene repression has been found to exist in vertebrate genomes and CTAs have also been identified to be a subset of highly evolutionarily conserved genes, it is critical to understand the role of 5mC mediated CTA silencing in vertebrates. By gaining a deeper understanding into the mechanisms behind this highly conserved pattern of gene repression on a specific subset of genes, we would be able to identify methods to prevent aberrant gene expression. In this study, I analysed publicly available whole genome bisulfite sequencing (WGBS), RNA-seq and chromatin immuno-precipitation followed by massively parallel sequencing (ChIP-seq) data of developing embryonic and adult somatic tissue of 3 vertebrate species to elucidate the evolutionary epigenetic regulation of CTAs in vertebrate genomes. Integrative WGBS, RNA-seq and ChIP-seq analysis revealed that CTAs are evolutionarily conserved in zebrafish, mice and humans and mechanisms of their epigenetic regulation are also conserved. I observed that histone modifications could potentially serve as an indicator of the methylation status of CTA gene promoters and that the expression of CTAs was inversely related to gene promoter 5mC levels. I demonstrate that CTAs when over-expressed cause embryonic lethality in zebrafish and the same genes are aberrantly hypomethylated at their CpG islands in a subset of human cancers. Overall, my work shows that CTAs are epigenetically regulated in an evolutionarily conserved manner and possibly via a conserved transcription factor, ETS1, that is expressed both in embryonic and cancerous tissue.
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(2020)ThesisThe "ophthalmohelioses" represent a conglomeration of ocular surface and adnexa disease strongly influenced by increased ultraviolet light B exposure. Despite overlapping pathogenesis pathways, the severity of these differs across the different spectrums. Ocular surface squamous neoplasia (OSSN), pterygium and conjunctival melanocytic lesions represent the three most impacting subtypes of such "ophthalmohelioses" affecting the ocular surface. OSSN represents a broad class of squamous dysplastic lesions ranging from benign papillomas till invasive squamous cell carcinomas. Melanocytic tumours such as primary acquired melanosis have a great propensity to become malignant, especially if cells are atypical. Finally, pterygium is a benign growth commonly treated with surgical excision, but patients often face an endless remitting-relapsing cycle of pterygium recurrence and repeat surgery. If untreated, patients sight limitation secondary to visual axis invasion. The early detection of OSSN, pterygium and melanocytic lesions is non-existent and often disease requires to be excised and subsequently microscopically analysed before a formal conclusion is made. For pterygium, the identification of Fuchs' Flecks at the head of pterygium may serve as satellite cells ahead of the main pterygium body. Handedness may serve a role in the eye in which pterygium is worse or develops. From a therapeutic point of view, these three "ophthalmohelioses" tend to recur consistently despite optimized treatments. This therapeutic dilemma presents themes of concern, including vision disruption, secondary to repeat surgeries given the relapsing-remitting characteristic of all three disease entities. Topical eye drops such as interferon alfa-2b combined with retinoic acid serve as a potential solution which offer superior tumour-free follow-up and rapid tumour resolution of OSSN or primary acquired melanosis lesions. The viral influence of human papilloma virus upon OSSN may be mitigated with the application of topical cidofovir. Additionally, specialized pterygium surgery may be an effective alternative to otherwise other subtypes of pterygium excision, others often being anatomically more destructive. At essence, a focus of novel therapeutic options that target pathways within "ophthalmoheliosis" pathogenesis is being presented within this thesis which may hopefully improve and expand ophthalmologist's arsenal against disease spectrums very relevant to the Australian populace.
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(2020)ThesisWhole genome sequencing (WGS) is a powerful tool for diagnosis of Mendelian disorders. This study is aimed at evaluating the utility of WGS for molecular diagnosis of a multiethnic Intellectual Disability(ID) cohort. Individuals were recruited through the Clinical Genetics department of a tertiary hospital in New South Wales, Australia, over three years. All patients had varying degrees of syndromic or non-syndromic ID; some had neurological syndromes. WGS was undertaken using singleton, duo or trio approach after assessment of clinical features, family history and screening genetic investigations. Next Generation Sequencing (NGS) technology was utilised for sequencing and analysing genomic data at Genome.One, a NATA accredited WGS laboratory in Australia. Analysis included sequence variation and copy number limited to exonic and flanking splice site regions of known Mendelian disease-causing genes. Families where no diagnosis was made on initial analysis, were reanalysed two years later. A total of 46 probands from 43 families underwent WGS. There were 8/43 (18%) consanguineous families. A final diagnosis was made in 22/43 (51%) families. A variant providing a partial explanation of the phenotype was found in 3/43(6.9%) families. Actionable incidental findings were reported in 3/43 families. No copy number variants were identified. The RAS-MAPK pathway and microtubule related proteins emerged as predominant causative pathways within this phenotypically diverse cohort. Reanalysis revealed candidate variants in 6/14 families reanalysed representing a potential increased yield of 14%. In summary, application of WGS for investigation of an unselected ID cohort demonstrated a significant diagnostic yield. A clinical and genomic data review two years after the initial analysis was an achievable and worthwhile exercise, increasing the diagnostic yield to 65%.
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(2020)ThesisBackground: Women in the forensic mental health system (FMHS), have been poorly researched. Historically research has been difficult due to low numbers of women in secure care, making obtaining robust data regarding the demographic characteristics and experiences of these women difficult. Women in custodial settings have higher rates of mental illness and psychological distress. The studies available regarding women in FMHS show that they present with complex health needs and multiple diagnoses. Methods: The female forensic population of NSW in high secure or custodial settings during a 12-month period from February 2016 (17) were approached for participation in the Forensic Mental Health Patient Survey (FMHPS). Women who were considered unable to participate (due to illness and/or risk posed) were not interviewed but data was instead obtained from a review of their clinical records. This resulted in data being obtained from 14 women. Results were compared with a community sample of women from the second National Survey of High Impact Psychosis (SHIP) conducted in sites across Australia in 2010. A detailed description of the sociodemographic, clinical and forensic characteristics of the samples was established and, where possible, formal comparisons between the two samples were undertaken using regression analyses. Results: FMHPS women were more socially disadvantaged than the SHIP group. The odds of not suffering literacy problems were 6.6 times higher in the SHIP sample and the FMHPS women were significantly more likely to have experienced trauma (odds of assault 19 times higher). FMHPS women were more likely to have experienced various forms of restrictive practices during their care, previously used illicit substances and developed tolerance to substances. As with other criminal justice populations, women of Aboriginal and/or Torres Strait Islander background were over-represented in the FMHPS sample. Social isolation and loneliness were also notable in the FMHPS group. Conclusions: Women within forensic services are a significantly disadvantaged group. They present with complex psychological and social issues, often impacted by re-traumatisation through their treatment. Whilst the numbers of women in FMHS are low, they warrant further research to ensure that their needs are being adequately and appropriately met.
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(2020)ThesisIntroduction: Australia has the second largest immigrant population in the world. Health literacy is a crucial factor in enabling patients to manage their own health and wellbeing and improving their health outcomes, particularly in the context of an increasingly complex health care system. Individuals with lower health literacy can experience inferior health outcomes and higher mortality rates, higher health-related costs, and higher use of health services; and they are less likely to undergo cancer screening and have low levels of healthcare knowledge. Aims: This project aimed to explore health literacy profiles of two immigrant Australian populations affected by cancer - Arabic and Vietnamese - and their Anglo-Australian counterparts, using the validated Health Literacy Questionnaire (HLQ). The project aimed to identify potential correlates of poorer health literacy between the groups and identity implications of these relationships on future research and within a clinical setting. Methods: Patients were eligible to participate if: a) aged 18+ years; b) diagnosed with cancer in the last five years; c) identified English, Arabic or Vietnamese as their primary language; d) were born outside of Australia (for immigrant groups) or in a predominantly English-speaking country for the Anglo-Australian group; and e) were cognitively able to provide informed consent. Levels of health literacy were evaluated using a cross-sectional self-report questionnaire provided to consenting patients in their preferred language. Multiple regression analysis was utilised in order to identify differences between Anglo-Australian and immigrant populations while controlling for pre-determined variables (correlates). Results: Results indicate that the immigrant and Anglo-Australian patients display very similar health literacy and eHealth literacy profiles with the exception of their ‘ability to find good health information’. In addition to this, self-efficacy, as displayed through the ability to ‘understand and participate in care’, and education, displayed statistically significant relationships on several domains of health literacy, irrespective of immigrant status. ‘Understanding and participating in care’ was also the only domain to show a significant relationship with eHealth literacy, also irrespective of immigrant status. Implications: The health system needs to be better enabled to meet the information needs of immigrant cancer patients. It is recommended that health care professional training be undertaken so that clinicians and other health care professionals can develop and maintain a meaningful working relationship with their patients, regardless of their health literacy levels. Moreover, research into the types of information and availability of services within the healthcare setting should be undertaken to improve the health system and enable it to create a more informed and involved health consumer, who is empowered to actively participate in their own health and wellbeing, irrespective of their health literacy levels.