Medicine (RMH) - Theses
Permanent URI for this collection
Search Results
1 - 6 of 6
-
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.
-
ItemUsing mathematical modelling to challenge accepted methods and paradigms of tuberculosis control and transmission( 2018)Tuberculosis (TB) represents a major public health issue at the global level. Despite the availability of vaccines and treatments, TB still kills around 1.6 million persons each year due to a combination of unresolved challenges. Firstly, around 40% of diseased individuals are never identified and can therefore not be provided with adequate care. A second substantial challenge is the extremely high prevalence of latent tuberculosis infection (LTBI), which serves as a large reservoir of future disease that is difficult to control. Furthermore, the emergence of drug-resistant TB (DR-TB) has hampered the progress made by TB control in the last decades and required novel strategies to be adopted. Optimal approaches to address these challenges are hampered by substantial knowledge gaps. The lack of a comprehensive epidemiological understanding of TB has also resulted in today’s TB control relying heavily on strong assumptions or preconceived opinions, which are not necessarily supported by evidence. In this thesis, I used mathematical modelling to challenge several of these accepted paradigms. First, this thesis presents a simple model incorporating epidemiological and programmatic characteristics used to quantify the respective contributions of the different pathways leading to DR-TB at re-treatment around the world. This exercise identified failure to detect DR-TB at first presentation as the leading source of DR-TB at re-treatment. This challenges the accepted paradigm that DR-TB results mainly from poor treatment adherence during treatment of drug-susceptible patients. Important geographical heterogeneity was also observed in the results, and so a web-based interface was built to allow the model to be applied immediately to any epidemiological setting. Next, this thesis presents a novel exploration of the relationship between TB incidence and the effectiveness of preventive treatment (PT). Although it is widely accepted that using PT would be less efficient in high-burden settings, the exploration suggests that PT would yield optimal efficiency where TB incidence is as high as 700 new cases/100,000/year. To improve TB modelling methods, this thesis next presents an evaluation of the existing approaches used to simulate the transition from LTBI to active disease. This was done by comparing the reactivation dynamics produced by different model structures to those empirically observed in contacts of infectious TB patients. This exercise demonstrated that two latency compartments are needed to replicate the TB reactivation dynamics in a compartmental model. It further highlighted that the usual cut-off of two or five years used to distinguish late from early latency should be revised to a much shorter duration. Finally, a novel modelling approach combining country-specific social mixing data with time-variant programmatic parameters within a TB agent-based model is presented in this thesis. The newly built tool was used to detail the profile of Mycobacterium tuberculosis (M.tb) transmission and TB burden in the five highest TB burden countries (India, Indonesia, China, the Philippines and Pakistan). Findings include the unexpectedly high contribution of adolescents and young adults to M.tb transmission. This study also provides estimates of the age-specific size of the latent infection pool, along with the age-specific risk that this infection reservoir represents in terms of future disease.
-
ItemFalling down the cascade: the gaps in care delivery for people living with chronic hepatitis B in Australia( 2017)In Australia, an estimated 239,000 people were living with chronic hepatitis B (CHB) in 2016. Most of the affected community were born overseas and acquired their infection early in life, in countries with high and intermediate prevalence of hepatitis B. The mortality attributable to CHB is from both liver cancer (hepatocellular carcinoma) and cirrhosis. Hepatocellular carcinoma has poor five-year survival, increasing incidence globally, and was projected to become the sixth most common cause of cancer death in Australia in 2016. The first “Global Hepatitis Health Sector Strategy” was signed in 2016 by all the member states of the World Health Assembly including Australia, with the aim of eliminating viral hepatitis, including hepatitis B, as a public health concern by 2030. The five studies presented in this thesis use the cascade of care framework to approach different aspects of the health system response to chronic hepatitis B in Australia. The studies have used different data sources and methodologies to measure the cascade and explore factors associated with the delivery of care. The first study presents an analysis of national data from 2012. It proposed, for the first time, a cascade of care for chronic hepatitis B in Australia that included a novel “enrolled in care” indicator. The second study presents findings from a multicentre retrospective study of adherence to antiviral therapy for chronic hepatitis B from 2010-2013. The study measured the proportion of people adherent to treatment in tertiary settings and analysed the demographic and health system factors associated with poor adherence. The third study analysed the association of a pharmacy-based adherence measure (the medication possession ratio) with viral outcomes using a time-to-event analysis for favourable and unfavourable viral outcomes. The fourth study presents findings from a retrospective analysis of primary care data in a community health centre that received external support from a tertiary service to improve the delivery of guideline-based care for chronic hepatitis B, including surveillance for hepatocellular carcinoma. This study evaluated four and a half years of data focusing on hepatocellular carcinoma surveillance participation and adherence. The fifth study presents findings from a qualitative study: semi-structured interviews of African-Australians living with chronic hepatitis B. This study explored participants’ understanding of health risks associated with hepatitis B, including their perceptions of their risk of developing hepatocellular carcinoma. Findings from this thesis have shown that few people living with chronic hepatitis B in Australia were enrolled in care. It provided the first multicentre estimates of the adherence of people on antiviral therapy for chronic hepatitis B in our health system (using medication possession ratio as the measure of adherence) and that factors associated with poor adherence were younger age and poor continuity of clinician. In a further study, the association between medication possession ratio and unfavourable viral outcomes was demonstrated for the first time. This analysis found that there was no true cut-off point or threshold to define adherence and the risk of poor outcomes. Rather, there was an increasing hazard ratio for unfavourable events with decreasing medication possession ratio. The findings also include results from a study that demonstrated hepatocellular carcinoma surveillance in a tertiary-supported general practice – with both participation and adherence to six-monthly scans with supported recall and reminder systems – is hard to achieve. Finally, the fifth study presented as part of this thesis found that African-Australians living with chronic hepatitis B perceived and experienced significant risks to social and emotional wellbeing from the shock of diagnosis, fear of infectiousness, and discrimination from telling others about their illness, as well as physical or liver-related problems. The results from this thesis have informed the development of the current Australian cascade of care for chronic hepatitis B and provided insights into the challenges of delivering health services to people living with chronic hepatitis B. These findings have led to recommendations for further development of the cascade at a national and regional level, and the need for further research and evaluation of the health system response to chronic hepatitis B. The work presented demonstrates that Australia has failed to meet the targets of the 2014-2017 National Strategy and needs to rapidly improve essential elements of the cascade, including increasing the proportion diagnosed and enrolled in care, to reach the targets of elimination of chronic hepatitis B as a public health concern by 2030.
-
ItemMathematical modelling for programmatic responses to tuberculosis in the Asia-Pacific( 2016)Despite being a treatable disease, tuberculosis (TB) has not yet been controlled globally, and the burden in Australia’s region remains huge, with two Asia-Pacific countries, India and China, constituting one third of cases worldwide. Moreover, several highly endemic regional hotspots exist and multidrug-resistant TB (MDR-TB) threatens to derail control efforts. The epidemic in the Asia-Pacific region differs markedly from other parts of the world, as transmission is not primarily driven by HIV-coinfection as it is in sub-Saharan Africa, nor by transmission in conjugate settings (such as prisons and hospitals) as in the former Soviet states. Mathematical modelling can help to understand the reasons for our failure to achieve control and to better direct programmatic resources. This thesis first presents the construction of a dynamic ten-compartment model to simulate TB transmission in highly endemic regions of the Asia-Pacific and describes its general characteristics. Findings include the importance of reinfection during late latency, the contribution of community transmission to MDR-TB burden, the importance of properly addressing MDR-TB despite a possible fitness cost and the need to model partially protective vaccines. Next, strategies for TB control were modelled in Western Province, Papua New Guinea, a region characterised by high burden, high proportions of MDR-TB and poor-quality programmatic data. After calibrating to local conditions, the model was used to simulate five programmatic responses to TB and Bayesian inference was employed to explore the uncertainty range around plausible outcomes. The model was then used as the basis for participation in an international collaboration to consider whether the post-2015 Sustainable Development Goals (SDGs) for TB are achievable with current tools. Eleven leading global modelling groups were invited to participate in the multi-modelling exercise to simulate six “ambitious but feasible” interventions for India, China and South Africa. The previously developed model was elaborated to incorporate smear-negative and extrapulmonary TB, initial default and misdiagnosis of MDR-TB, and was then calibrated to each country to capture local TB dynamics before applying interventions. Key conclusions include the small impacts of improved care quality and molecular diagnostics but greater improvements resulting from expansion of access to care, and that active case finding may significantly reduce disease burden. As most targets were not met under the modelled scenarios, future technological advances, such as new treatments and vaccines, are likely to be required to achieve the ambitious rates of decline envisaged in the post-2015 agenda. To improve understanding of TB dynamics, this thesis explores the latent period between infection and active disease. Using Victorian TB Program data, individuals recently infected with M. tuberculosis were linked to subsequently notified active cases, and the resulting dataset was used to perform a survival analysis on the outcome of progression to active disease. I then imputed censorship to account for effective loss to follow-up through death, migration out of the surveillance region and preventive treatment. Results show the five-year risk of disease is 11-18%, several-fold higher than commonly accepted estimates. These revised estimates have important implications for programmatic responses, individual patients and structuring and parameterising compartmental models.
-
ItemIndigenous Australians have a distinctive gut microbial profile compared to Caucasian controls and patients with inflammatory bowel disease( 2015)The aetiology of inflammatory bowel disease (IBD) is yet unknown but it is thought to occur in a genetically predisposed individual following an environmental trigger. The incidence of IBD has risen rapidly in industrialised nations but remains low in developing countries. In Canada, the incidence of IBD is high in their urban population but extremely low in their Indigenous populations. This has led to the “hygiene hypothesis”, which postulates that a reduced exposure to antigens due to urbanisation may lead to an increase in immune mediated diseases such as IBD. Many studies have shown that patients with active IBD have changes in gut microbiota or “dysbiosis”. My first hypothesis was that IBD is rare in Indigenous Australians (IA). I confirmed this by setting up an IBD database at the Royal Darwin Hospital in the Northern Territory (NT) and by interrogating the hospital records from 2007-2014. The NT has a large Indigenous population with a third of its population being Indigenous. The IBD database revealed that the prevalence of IBD in Indigenous Australians in the NT is 5/100,000 compared to 186/100,000 in the non- Indigenous population. My second hypothesis was that IA have a distinct gut microbial profile that may account for their low incidence of IBD. I utilised 16S amplicon based techniques to study gut microbial profiles in IA, Caucasian controls and IBD patients. Whilst it is difficult to prove causality, I demonstrated that gut microbial profiles of IA are highly abundant in Prevotella sp and lactic acid producing bacteria, and are different from Caucasian controls and IBD patients. The gut microbiota of IA are also enriched in enzymes that are involved in propionate production, a food source for colonocytes. My third hypothesis was that the gut mucosa of IA would have a higher expression of anti-inflammatory cytokines. I showed, through quantitative real-time PCR, that there was a trend in increased expression of Thymic Stromal Lymphopoeitin (TSLP) in IA. TSLP is a cytokine that is involved in preventing helminthic infections and has been shown in mouse models to confer some protection to IBD. Patients with IBD showed a typical pro-inflammatory cytokine expression pattern. My results demonstrate that IA, who have a low incidence of IBD, have a distinctive gut microbial profile and a trend in increase of the cytokine TSLP. This may be directly related to their traditional lifestyle. Testing their gut microbial profiles in mouse models of colitis may reveal if their gut microbiota are truly protective against IBD.
-
ItemHIV in Victoria's African communities: reducing risks and improving care( 2013)The acquired immunodeficiency syndrome caused by the human immunodeficiency virus is an important issue for Australia’s African communities. As in other industrialised countries, African immigrants are over-represented in Australia’s HIV epidemic, diagnosed late and endure social isolation after diagnosis, but focused responses, applied without understanding local HIV epidemiology and social context, risk intensifying stigma against African communities and African Australian people living with HIV in Australia. This study explored the social epidemiology and clinical features of HIV in Victoria’s African communities, collecting data from national and Victorian HIV surveillance databases, a clinical case series of African-born HIV patients and a qualitative inquiry with several African communities. Diverse geographical, biological, psychosocial and structural factors influenced exposure, diagnosis, clinical features and experience of living with HIV. Most exposure occurred in Africa, prior to migration, through heterosexual sex. Some occurred after migration, in Australia and abroad, through heterosexual sex and sex between men. Low self-perceived risk and lack of awareness of HIV in Australia contributed to exposure and delayed diagnosis. HIV was understood as a deadly, highly contagious “African” disease, posing little threat in Australia, being one of several intersecting challenges to the wellbeing and cohesion of African communities during resettlement. Understanding of HIV was based largely on experience in Africa and the process of HIV screening during immigration. HIV-related stigma, based on risk stereotypes of sexual immorality and fear of contagion and death, was the major barrier to social support and information. Key clinical issues for African-born PLHIV included high prevalence of TB and viral hepatitis. HIV treatment uptake was high and response was good. HIV exposure via sex between men led to HIV-1 subtype B infection; those with heterosexual or other exposure carried various non-B subtypes. African communities actively participated in the study leading to greater engagement in Victorian and national HIV responses. Study results provided insights into HIV epidemiology and clinical features in Victoria’s African communities and informed a conceptual framework that should further the understanding of HIV epidemiology in mobile and marginalised populations.