Medicine (RMH) - Theses
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ItemOptimisation of Medical Therapies in Inflammatory Bowel Disease( 2022)Treatment expectations and outcomes for patients with IBD have greatly improved in recent decades due to the increased availability of highly effective medical therapies and the emergence of better strategies for using these agents. Concurrently, improvements in the personalisation of individual treatment decisions have occurred via the incorporation of numerous precision medicine tools into clinical practice. The optimisation of thiopurine immunomodulators has been enhanced via the use of pharmacogenomics and therapeutic drug monitoring. The use of concomitant allopurinol in thiopurine hypermethylators or patients with intolerance to thiopurine monotherapy has increased the efficacy and persistence of thiopurine therapy, although the exact mechanism of the favourable metabolic interaction remains to be confirmed. Despite an increased number of small molecule and biologic treatment options now available thiopurines will remain important medical therapies for IBD patients for the foreseeable future, hence their optimisation remains important. Anti-TNF agents have revolutionised the management of patients with luminal and fistulising disease, but their optimal dose and optimisation strategy remains to be determined. Reactive TDM in patients with secondary loss of response to anti-TNFs is now standard of care, although supportive data are stronger for infliximab than adalimumab. Proactive TDM of anti-TNFs, although intuitively appealing, is not supported by results from prospective studies, although recent results from studies involving multiple IMIDs are encouraging. Perhaps the proof of efficacy of proactive TDM will finally emerge from further refinement of dashboard-driven precision dosing pharmacokinetic models. Increased practicability of TDM should come from more widespread update of rapid testing, including remote sampling and monitoring. The modern-day potential to de-escalate medical therapies in IBD reflects the ability to first achieve prolonged objective remission in a substantial proportion of patients with current therapies. Data informing de-escalation treatment decisions have only emerged from recent studies, usually involving the cessation of either immunomodulators or anti-TNFs from patients receiving combination therapy. Although relapse rates are higher with anti-TNF withdrawal, the high anti-TNF re-treatment success rates demonstrated from recent well-designed studies suggest that biologic de-escalation, with its associated cost and safety benefits, may be considered in appropriate patients. To date the personalisation of IBD treatment decisions has been guided by outcomes research from epidemiological and clinical cohort studies and the results of clinical trials. More recently genome wide association studies and whole genome sequencing have increased the genotypic individualisation of patients, although the translation of this knowledge to clinical practice has been slow. Precision medicine tools have also expanded to include microbiome-based characterisation of disease phenotypes and predictors of treatment response, although the impact of this knowledge in clinical practice is only currently emerging. Future precision-medicine advances will incorporate the development of multiomics signatures of IBD into systems biology platforms that can be analysed and validated across multiple cohorts. This knowledge should help further personalise treatment decisions, and ultimately may be informative for the future prediction, and even prevention, of IBD.
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ItemNo Preview AvailableExpanding our understanding of the clinico-epidemiology, cellular biology and pathogenesis of human prion diseases( 2021)This thesis primarily constitutes a compendium of published manuscripts encapsulating a substantial volume of work relating to prion diseases, undertaken from 1999 to 2020 through the Australian National Creutzfeldt-Jakob Disease Registry based at the University of Melbourne, frequently in collaboration with pre-eminent domestic and international scholars in the field of prion diseases. The thesis is divided into two principal parts. The first comprises 78 peer-reviewed papers submitted in full, representing a diverse array of acclaimed, often landmark or pivotal, studies published in prestigious general medical and specialist journals where I have been either senior and corresponding author, primary author or leader of the Australian contribution in major multi-national projects. This body of work is divided into seven sections spanning: normal prion protein cellular biology; prion pathogenesis; human prion disease epidemiological studies; human prion disease bio-marker studies; clinical aspects of human prion disease; prion disease treatment studies; and studies of human prion-like diseases. A short review at the start of the thesis and a preamble before each of these sections dealing with my principal publications are offered to place these published studies in the context of extant clinical and scientific literature. The second part of the thesis is submitted for completeness, comprising four sub-sections encompassing 61 publications and reports, listed by title and publication details, dealing with human prion disease for which I was a significant contributor.
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ItemSuccessful elements of an improved model of care for refugees and immigrants in regional Australia( 2020)Abstract/Overview Australia has benefited from a long history of migration, including accepting refugees and asylum seekers (referred to as refugees within this discussion) from a wide range of countries experiencing conflict and hardship. Multiple health care challenges exist for refugees, including language difficulties, low health literacy, poor mental health and exposure to infectious diseases that may be unfamiliar to Australian health care practitioners. This is exacerbated by the growing numbers of immigrants and refugees settling in regional areas, where there are poorer health outcomes and provision of quality health care is more difficult. The published papers included in this thesis outline a number of the challenges in the provision of high-quality health care to refugees who settle in regional Australia, and some solutions that have been successfully utilised to improve health care provision to this population. The demonstrated solutions used for refugee populations are also valid for other immigrants and locally born Australians living in regional areas. The literature review provides the context and rationale for each of these papers with more specific references included within each paper. The literature review provides an overview of the topic and outlines the importance of the papers in addressing issues previously poorly understood or not considered. Paper one investigates the challenges of identifying appropriate screening for newly arrived immigrants and focuses on the cost effectiveness of screening new arrivals for H pylori. Modelling outlines the situations where a screening program could be considered and highlights the uncertainties that exist within the assumptions used for this modelling. Expanding on specific infectious disease challenges in immigrant populations, paper two examines the genotypes of hepatitis B that are encountered in immigrants from Burma and paper three describes genotypes amongst African immigrants. Papers two and three address the clinical relevance of genotype and country of birth in the management of hepatitis B. The subsequent three papers examine the provision of health care to refugees and immigrants via telehealth. Paper four outlines the development of a tertiary hospital based Infectious Diseases telehealth program. Paper five measures and compares the effectiveness of healthcare delivered to regional areas via telehealth, with a focus on care for individuals with hepatitis C virus. Paper six then describes the extension of the use of telehealth to include the provision of interpreters. The discussion outlines the conclusions that have been drawn from these papers, and then suggests further improvements for the care of refugees and immigrants who settle in regional areas. Reducing the gap in health care outcomes between those who live in large urban centres and those who live in regional areas is relevant to the whole population. Drawing on these findings, recommendations are outlined to reduce this gap.
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ItemLiver-bone relationships: integrative pathophysiology, diagnostic, prognostic, preventive and therapeutic considerations( 2019)Over the last 10 years we examined complex multidirectional interactions between the digestive system and osteoporotic fractures focusing on pathophysiological and clinical issues of liver-bone relationships. These included: vitamin D, vitamin K and parathyroid hormone in chronic liver and pancreatic diseases (2 papers: [1, 2]); associations between liver function, bone-mineral biomarkers, indices of iron metabolism and adipokines (leptin, adiponectin, resistin) in orthogeriatric patients (3 papers: [3-5]); diagnostic and prognostic indicators of osteoporosis, fractures, and in- hospital outcomes (5 papers: [6-10]). A shortened overview of our main findings is presented.
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ItemNovel methods of symptom measurement in Parkinson's disease( 2019)Parkinsons Disease is a common neurodegenerative disorder characterized by bradykinesia, rigidity, gait impairment and rest tremor. Non-motor features including anosmia, Rapid eye movement sleep behavior disorder, autonomic dysfunction, neuropsychiatric manifestations and cognitive changes are increasing recognized. The course of Parkinsons Disease is a progressive one and symptoms can fluctuate hour to hour. As such, symptom measurement plays a vital role by generating quantifiable targets to facilitate monitoring of disease progression and treatment response. In the absence of a reliable biomarker, symptom measurement is the cornerstone upon which diagnosis and clinical decisions are made and prognosis is gauged. Conventional methods of subjective symptom reporting and validated objective clinical rating scales, to more contemporary approaches of technology-based quantitative measurement methods all have their unique strengths and shortcomings. While motor symptoms have more measurable physical properties, the best targets and the optimal method and platform to use remain unclear. Measurement of non-motor symptoms proves to be more challenging and remains a glaring gap in this field. A more measurable non-motor problem is cognitive impairment, which can be present even in the early stages of Parkinsons Disease. Cognitive assessment has both diagnostic and prognostic implications. However, it is uncertain which tests are most useful and more modern computerized approaches have not been extensively or rigorously studied. This compilation focuses on novel approaches and methods of measurement of motor and cognitive symptoms in Parkinsons Disease. Short and simple screening tests were developed. Specifically, motor symptoms were assessed and measured using smartphone technology and a self-reporting questionnaire. Following a critical statistical appraisal of the literature on cognitive assessment in parkinsonian disorders, a smartphone based cognitive test was developed to assess executive dysfunction. The aims of this compilation are: To establish the feasibility of using smartphone technology to measure motor deficits and cognition in patients with Parkinsons Disease by validation of a purpose built application; To examine the pros and cons of objective motor assessment versus subjective symptom reporting by comparing the validated smartphone application and a self-reporting questionnaire using the clinical example of a motor phenomenon known as sleep benefit and To interpret existing literature on the role of cognitive assessment in the diagnosis of Parkinsons Disease and other parkinsonian disorders using an innovative statistical approach.