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(2021)ThesisIn Australia, non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest-growing cancers. NAFLD related HCC (NAFLD-HCC) is associated with poor prognosis and is a leading cause of cancer-related death. The work in this thesis provides insight to host determinants of this disease in New South Wales, with a particular focus on metabolic comorbidities and their impact on survival. Moreover, we provide evidence for interactions between the gut microbiome and its metabolites in orchestrating aberrant peripheral and intrahepatic immune responses associated with poor outcomes. We make several key observations: 1) NAFLD-HCC is a distinct clinical entity, whereby the accumulation of metabolic risk factors and presence of type II diabetes are independent negative predictors of survival 2) Divergence in gut microbiome composition and function occurs in NAFLD-HCC, distinct from NAFLD-cirrhosis, and appear to direct the peripheral immune response toward an immunosuppressive phenotype ex vivo that is associated with poor outcomes and 3) In longitudinal animal studies, gut dysbiosis occurs early in the trajectory of liver injury, and occurs in parallel to immunosuppressed peripheral and intrahepatic immune responses that develop as HCC ensues. This data provides evidence for the identification of patients with NAFLD-HCC who are at risk of poor outcome and serves as a platform for the development of gut-based interventions, which, when timed early, may offset the burden of this deadly disease.
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(2021)ThesisWhile MYCN-amplified neuroblastoma has been the focus of neuroblastoma research in the past three decades, most human neuroblastomas do not harbour MYCN oncogene amplification, and their tumorigenic factors are unknown, highlighting the importance of identifying other oncogenic factors. Long noncoding RNAs (lncRNAs) play important roles in cancer oncogenesis. Here, I have shown the lncRNA PRKCQ-AS1 is upregulated by super-enhancers upstream of the PRKCQ-AS1 gene that drive its over-expression only in MYCN non-amplified neuroblastoma cell lines through the well-known super-enhancer components CDK7 and BRD4. Targeting CDK7 with THZ1 or targeting BRD4 with AZD5153 significantly downregulate the expression of the lncRNA PRKCQ-AS1, but not its neighbouring protein-coding gene PRKCQ or the well-documented super-enhancer[1]associated c-Myc oncogene. I have shown that PRKCQ-AS1 was a cytoplasmic lncRNA and bound to the RNA binding protein (RBP) MSI2 in MYCN non-amplified neuroblastoma and that their binding could be blocked by the MSI2 RBP inhibitor Ro 08–2750. I have also shown that MSI2 bound to two fragments of PRKCQ-AS1 RNA spanning about 300bp towards to the 5’ end of PRKCQ[1]AS1. Additionally, RNA immunoprecipitation and subsequent sequencing identified the oncogene BMX as the downstream target most significantly modulated by the PRKCQ-AS1 RNA and MSI2 protein interaction, which in turn activated the MEK/ERK signalling pathway. Functional studies revealed that PRKCQ-AS1 promoted MYCN-non-amplified neuroblastoma cell proliferation in vitro and tumour progression in vivo. The PRKCQ-AS1- binding protein MSI2 and their target BMX also promoted MYCN-non-amplified neuroblastoma cell proliferation. In human neuroblastoma tissues, there was a strong correlation between the expression of PRKCQ-AS1 and MSI2 and the expression of BMX, and high PRKCQ-AS1, MSI2 and BMX expression in human neuroblastoma tissues correlated with poor clinical outcome in patients. Additionally, high levels of both PRKCQ[1]AS1 and MSI2 expression were strong prognostic factors for poor patient outcome independent of the current standard markers including age at diagnosis, disease stage and MYCN gene amplification. My study therefore identified PRKCQ-AS1 and its binding protein MSI2 as factors important for MYCN-non-amplified neuroblastoma cell proliferation and tumorigenesis and the interaction between PRKCQ-AS1 and MSI2 as a valid target for the treatment of MYCN-non-amplified neuroblastoma.
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(2021)ThesisPrimary liver cancer is characterised by poor prognosis, growing disease burden and propensity to develop on a background of chronic liver injury. Delivery of oncogene expression plasmids by hydrodynamic tail vein injection (HTVI) is an emergent method of modelling liver cancer, but does not reproduce chronic injury and fibrosis typical in human liver cancer. Injury and fibrosis contribute to the pathogenesis of liver cancer, although this is not well characterised in plasmid-HTVI liver cancer models. Two previously published plasmid-HTVI models (SB/AKT/c-Met, SB/AKT/NRas) were combined with the hepatotoxin thioacetamide (TAA) to induce liver injury. Consistent with previous characterisation, SB/AKT/c-Met developed steatosis with hepatocellular tumours, while SB/AKT/NRas developed steatosis with both hepatocellular and cholangiocellular tumours. TAA did not increase tumour burden but altered the phenotype of surrounding tissue. TAA reduced plasmid-induced steatosis and increased inflammatory cells and fibrosis with different morphology to TAA alone. In order to find novel gene expression and pathways associated with the cancer-injury combination, liver tissue was subject to whole transcriptome sequencing. Metabolism, inflammation, cell cycling and proliferative signalling pathways were among those that differed by either cancer or injury alone. The cancer-injury combinations had gene expression profiles distinct from cancer or injury alone, with a few differentially expressed genes not explained by either cancer or injury alone. In cancer-injury combinations, some pathways were synergistically upregulated but in many cases cancer and injury were antagonistic. Lipid and xenobiotic metabolism were novel pathways uniquely activated in the cancer-injury combinations. Selected genes were validated by conventional gene expression assays and immunohistochemistry. By characterising a plasmid-HTVI model with concomitant liver injury and fibrosis, it was found that liver injury did not accelerate or increase tumorigenesis but altered the phenotype and transcriptomic profile of the cancer models. In some cases, injury and oncogenes antagonised each other with respect to cancer-associated processes such as fibrosis and steatosis. Novel genes and pathways associated with the cancer-injury combination give insight into how chronic injury interacts with liver cancer in humans.
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(2022)ThesisEosinophilic chronic rhinosinusitis (eCRS) or type 2 dominant chronic rhinosinusitis (CRS) is a complex inflammatory disease mediated by type-2 cytokines, including interleukin (IL)-5. Management of this condition is often difficult, requiring multimodal approaches with local and systemic medications as well as surgical therapy. Biologic therapies, including mepolizumab (a monoclonal antibody targeting IL-5), have been successfully used in eosinophilic asthma and are emerging as a new treatment in CRS and eCRS, however there is limited data in this field. This thesis focuses on biomarkers and biologics in CRS. Firstly, identifying and assessing clinical biomarkers that are available to the guide management in patients with CRS and eCRS. Secondly, a prospective open-label single-arm single-centre study of the effectiveness of mepolizumab in patients with eCRS was performed. In this study, biomarkers as well as clinical, functional, and patient reported outcomes are assessed to determine the utility of mepolizumab as biologic treatment for eCRS.
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(2021)ThesisAim: To determine the role of topical Caffeine, a Xanthine derivative in slowing myopia either as a single-drug or in combination with Atropine. Methods: A systematic review and meta-analysis for Atropine in myopia control was followed by a short-term dispensing trial to select a single Atropine concentration to use in combination with Caffeine. In a prospective, randomized, dispensing trial, children with myopia were assigned to daily use of either Caffeine-2%, Atropine-0.02% with Caffeine-2% or Atropine-0.02%. A parallel non-randomised group of spectacle lens wearers were controls. The six-month change in spherical equivalent, axial length, pupillary diameter, and accommodative amplitude were compared between groups. Finally, a validation trial monitored pupillary and accommodative amplitude changes over 24 hours with various concentrations of Atropine and Caffeine, either single or combined. Comparison between groups were performed using repeated measures Analysis of Variance with significance set at 5%. Post-hoc multiple comparisons conducted using Bonferroni correction. Results: Meta-analysis confirmed dose-dependent efficacy and side effects for all concentrations of Atropine excepting 0.01%. Similarly, short-term trial demonstrated no pupillary diameter/accommodative change with Atropine-0.01% in approximately 30% of eyes. Atropine-0.02% was selected to be used in combination with Caffeine and at six months, change in spherical equivalent/axial length was -0.20±0.34D/0.08±0.11mm, -0.20±0.30D/0.11±0.11mm, -0.39±0.38D/0.19±0.15mm and -0.33±0.29D/0.18±0.11mm with Atropine-0.02%, Atropine-0.02% with Caffeine-2%, Caffeine-2%, and single vision spectacles respectively. The pupillary diameter increase/reduction in accommodative amplitude was 1.20±0.85mm/-3.14±4.08D, 0.76±0.58mm/-2.84±4.35D, -0.07±0.47mm/-0.78±3.43D and -0.10±0.32mm/-0.22±3.81D respectively. Temporal observations of pupil diameter indicated, a) no significant variation with Caffeine, b) Post instillation to 60 minutes – Caffeine-2% combined with 0.05% and 0.1%-Atropine resulted in significantly fewer eyes reaching higher pupillary diameter compared to monotherapy with 0.05% and 0.1%-Atropine. There were no significant changes for accommodative amplitude. Conclusion: Caffeine-2% did not slow myopia when used either individually or in combination with Atropine. However, Caffeine in combination with Atropine significantly minimised the increase in pupillary diameter that occurs with use of Atropine.
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(2021)ThesisConcern about falling is a common and serious health concern for older people. However, older people's participation in proven interventions for reducing concern about falling remains low. Health literacy could be influential to older people’s long-term participation in health programs for concern about falling. This thesis aimed to understand the relationship between health literacy and concern about falling in community-living older people. Six studies were conducted: (i) proposed a multicomponent theoretical model on health literacy and concern about falling; (ii) conducted a systematic review and meta-analysis exploring the relationship between health literacy and physical activity; (iii) developed and validated the Falls Health Literacy Scale (FHLS), a health literacy instrument specific to falls; (iv) developed cut-points for the 30-item and 10-item Iconographical Falls Efficacy Scales (IconFES) and evaluated their construct and predictive validity to falls and reduced physical activity; (v) assessed the effectiveness of a six-week online cognitive behavioural therapy (CBT) program for reducing concern about falling; (vi) explored how health literacy affects adherence to a home-based exercise program. The main findings were: (i) health literacy is closely related to many determinants of concern about falling and greater efforts are needed to clarify the impact of health literacy on intervention adherence and decision-making of older people with concern about falling; (ii) older people with inadequate health literacy are less likely to engage in physical activity on ≥5 days per week than those with adequate health literacy; (iii) the FHLS is sensitive to levels of fall-related health literacy, with good validity in an older population; (iv) the developed IconFES cut-points were sensitive to variables associated with concern about falling and predicted fall incidence and physical activity restriction after one year; (v) online CBT is a feasible treatment method for older people, and a targeted program with a well-integrated psychoeducation module on concern about falling seems warranted to boost the therapeutic effects; (vi) education, history of falls, anxiety and neuroticism moderate the relationship between health literacy and adherence of older people to a home-based exercise program. The thesis findings elucidate key aspects of the relationship between health literacy and concern about falling in older people.
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(2021)ThesisBackground: Cervical spine degenerative conditions effect up to two-thirds of the population and are the most common cause of acquired disability in patients over the age of 50. These disorders commonly present with axial pain, myelopathy, radiculopathy or a combination of these symptoms. Surgical intervention is generally indicated in with failure of conservative management or with evidence of cord compression or myelopathy. Anterior cervical discectomy and fusion (ACDF) is an effective option. It is not well established what factors contribute to dysphagia and recurrent laryngeal nerve palsy complications following ACDF surgery. Objective: 1. To determine the rates of dysphagia and recurrent laryngeal nerve complications following ACDF reported in the literature and potential associated factors. 2. To determine rates of dysphagia and recurrent laryngeal nerve injuries in a large Australian series of ACDF by a single surgeon. Methods: For the systematic reviews, electronic searches were performed using electronic databases. Relevant studies reporting the rate of dysphagia or recurrent laryngeal nerve injury as an endpoint for patients undergoing ACDF for degenerative disease, myelopathy, cervical canal stenosis or ossification of the posterior longitudinal ligament were identified according to prior inclusion and exclusion criteria. Statistical analysis was performed using odds ratio (OR) as the effective size. I2 was used to explore heterogeneity. For the retrospective chart review, consecutive patients undergoing ACDF from 2015 to 2019 for cervical radiculopathy and/or myelopathy were included. Univariate logistic regression analysis was performed to identify risk factors of RLN palsy, swallowing problems and adjacent-level ossification disease (ALOD). Results and conclusions: We found that based on pooled analysis that there was a higher rate of dysphagia for multiple-level ACDF (6.6%) compared with single-level ACDF (4%). The pooled incidence of recurrent laryngeal nerve palsy from the literature was 1.2%, with no difference between multiple- and single-level ACDF. These rates were similar to analysis of our retrospective series, with 1.8% patients having recurrent laryngeal nerve palsy and 4.0% with clinical dysphagia. We confirm based on our series that multi-level operation was associated with higher rate of RLN palsy, but this was not affected by other factors including age, gender, and the use of plate, internal fixation or number of screws.
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(2021)ThesisHuman papillomavirus (HPV) is one of Australia’s most common sexually transmissible infections and the primary cause of most cases of cervical cancer. HPV also causes other cancers, including penile, anal and oropharyngeal, and around 90% of all cases of genital warts. HPV-related cancers and genital warts are associated with a considerable health and economic burden. Australia became the first country in the world to implement a national school-based HPV vaccination program. Relatively high HPV vaccination coverage has been achieved in Australia, reaching just over 80% overall in 2017, yet this is still 10% lower than global recommendations by 2030, and considerably lower than targets of 95% for childhood immunisations. In Australia, analyses of HPV vaccination data to date have showed lower coverage in areas with lower socioeconomic status and in some geographical areas, but no studies have investigated variation in coverage across schools, which is where HPV vaccines are delivered. Adolescents should have equal access to the HPV vaccine course, irrespective of which school they attend. My thesis aimed to quantify the variation in HPV vaccination initiation across schools in three jurisdictions, and to understand school characteristics associated with lower coverage, particularly in schools where HPV initiation coverage was lower than for the dtpa vaccine (dtpa vaccine is co-administered and co-consented with HPV vaccine, so lower coverage for HPV would indicate HPV vaccine-specific hesitancy). My thesis also aimed to explore strategies to address the gaps identified. I undertook four interlinked studies using mixed quantitative and qualitative methods. The first study, a population-based ecological analysis of school-level data, identified that 23% of schools in the three jurisdictions in 2016/ 2017 school year had HPV initiation coverage at least 5% lower than for dTpa vaccine. This outcome was associated with schools with a higher proportion of adolescents from areas with higher socioeconomic advantage and from English-speaking backgrounds, and with smaller schools. The second study focused on using a school-level attributable risk measurement (taking the strength of the association and prevalence of school factors into account). This study found small schools, special education schools, schools with lower attendance and schools with higher enrolments of Aboriginal and Torres Strait Islander (Indigenous) students were most strongly associated with lower vaccination initiation coverage (<75%). Although special education schools had a lower school-level attributable risk measurement (as there was a small number of such schools), they had a much higher odds ratio than other school-level factors. My third study, a systematic review and meta-analysis, investigated the effectiveness of vaccine decision aids in decreasing decisional conflict regarding immunisations and increasing vaccination uptake with an inclusion period up to July 2019. The review found that decision aids slightly increased vaccination uptake and moderately increased intention to vaccinate, as well as a reduction in decisional conflict. However, there were no studies on HPV vaccination decision aids that met the inclusion criteria for the systematic review. The fourth study was an evaluation of a pilot intervention to determine the impact, acceptability and sustainability of an enhanced HPV vaccination catch-up program for Indigenous students who were missing at least one dose, which took place in term 3 and 4 in 2019. The study involved analysis of vaccination data, calculation of costs of the program and in-depth interviews conducted in term 1 2020, with immunisation providers delivering vaccinations in low HPV vaccination coverage schools. The evaluation demonstrated that the pilot intervention was considered beneficial with additional doses administered to Indigenous adolescents at a moderate extra cost; however, the process of following up with parents was very time consuming. Despite follow-up, some students did not attend the scheduled vaccine clinics, suggesting the need for additional strategies (e.g., out-of-school programs, more flexible vaccination clinics) to reach them. My research has identified the need for qualitative research to understand the reasons for low vaccination coverage in specific school settings, and the reasons for potential HPV vaccine-specific hesitancy. There is also a need to develop HPV vaccination-specific decision aids and evaluate their impact. Finally, future interventions should consider targeting students outside the school-based program. Overall, my thesis has highlighted the importance of collecting and analysing school-level data. It provides important insights that are needed to address the current gaps in the HPV vaccination program and to achieve equity in HPV vaccination coverage.
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(2021)ThesisInternationally, mandatory Continuing Medical Education (CME) linked to re-registration has improved physicians’ competencies and been implemented widely in developed countries but there has been mixed success in developing countries due to problems in three broad areas: educational design, educational delivery, and CME governance. The aim of this research was to analyse the status of CME in South East Asia Region (SEAR) and Eastern Mediterranean Region (EMR) with reference to WHO guidelines and to develop recommendations on best practice for developing countries. A scoping review of CME current practices for all 33 countries in SEAR and EMR regions showed evidence of CME provision in most countries, with 14 implementing mandatory CME linked to re-registration. All 14 countries have statutory bodies regulating CME. An in-depth review of five of these 14 countries showed that all specify a wide scope and range of educational activities and workplace learning as accredited CME and accredit a wide range of local providers with variation in assessing physicians' learning needs. Three have designated CME sub-committees introducing the CME programme with a structured phase-in period, while one is implementing regionally on a state-by-state basis. All five countries regulate against commercial entities providing accredited CME events. In order to explore in detail the CME situation in one country that has struggled to implement mandatory CME, in-depth interviews with medical education stakeholders in Pakistan identified the presence of a number of accredited institutions providing structured activities and credits to physicians. The previous attempt to implement mandatory CME faltered due to inadequate rural coverage, limited accredited providers, rapid implementation and lack of infrastructure. The implementation strategies proposed included a preparatory phase-in period, involving the national licensing body for CME regulation, and accrediting a wide range of providers. Findings from these reviews and interviews were compiled into 31 recommendations. These were put to a panel of regional experts in an online meeting using nominal group technique to develop a consensus on best practice for implementing CME for developing nations. The panel discussion identified eight of the 31 recommendations as most relevant for developing countries seeking to implement mandatory CME.