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(2018)ThesisThe CD8+ T cell responses play a pivotal role in controlling viral replication during HCV infection. HCV evades the immune system by rapid viral evolution affording escape from immune selection pressure including at MHC-I restricted epitopes. However, some CTL epitopes remain conserved well past the time of establishment of chronic infection, implying additional mechanisms immune failure exists. CD8+ T cells exhibiting an exhausted phenotype have been extensively reported during the chronic stage of illness for chronic viral infections, such as HCV and HIV. Additionally, impaired differentiation and trafficking of CD8+ T cells is known to be associated with immune escape and exhaustion of CTLs, but the timing and mechanisms and expression patterns of inhibitory receptors as wells as impairments in differentiation during primary HCV infection remains unclear. HCV-specific CD8+ T cell responses against the transmitted founder virus identified via ELISpot. Immune escape was observed in the NGS data set in ~33% of all ELISpot identified epitopes. The majority of HCV-specific CD8+ responses identified via IFN- ELSPOT in chronic progressors were also characterised by a dominant population of terminally differentiated effector memory cells (CCR7lowCD45ROhighKLRG1highCD127low), and elevated expression of co-inhibitory markers (PD-1 and 2B4) targeting both conserved as well as escaped HCV variants at the peak of immune response (as early as 70-90 days post infection). However, evidence of long-term central memory subpopulations with moderate IFN-γ production was identified in a subset of responses. There was an association of viral escape with the magnitude (IFN- production) of the response, suggesting ongoing evolution of CTLs in response to prolonged viral exposure. Analysis of T-bet expression revealed that T-bet expression on HCV-specific CD8+ T cell was not associated with clearance. Immuno-phenotyping of liver showed that, liver was enriched with T cells expressing the chemokine receptors CCR2, CCR5, CXCR3, and CXCR6. Additionally, the studies revealed preferential expression of CXCR3 on HCV-specific CD8+ T cells in both chronic and acute HCV infection suggesting a key role for CXCR3 in regulation of HCV-specific CD8+ T cell trafficking to the site of infection in the liver. Taken together the studies in this thesis provide both consistent findings with more limited studies in HCV and comparable contexts in HIV, and clear contrasts with previous reports in murine LCMV models. The findings offer novel insights into our understanding of the immunopathgenesis of primary HCV and into HCV vaccine design.
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(2022)ThesisTo achieve Universal Health Coverage and the United Nations’ Sustainable Development Goals’ by 2030, the World Health Organisation recommended the use of social enterprise, digital technology, and citizen engagement in the delivery of Integrated People-Centered Health Services (IPCHS). We aimed to develop and test a framework for using social enterprise, digital health, and citizen engagement to deliver IPCHS and achieve the WHO strategic vision for 21st-century primary care. We conducted a hermeneutic review of frameworks, models, and theories on social enterprise, digital health, citizen engagement, and IPCHS. This involved multiple iterative cycles of (i) searching and acquisition, followed by (ii) critical analysis and interpretation of literature to assemble arguments and evidence for conceptual relationships. This process identified a set of constructs that we synthesized into a conceptual framework to provide theoretical grounding for an empirical inquiry into how social enterprises use digital technology to engage citizens in co-creating IPCHS. We tested this preliminary framework with two community health alliances (CHAs) in South Western Sydney (SWS), namely the Wollondilly Health Alliance and the Fairfield City Health Alliance (FCHA). Each CHA comprised the local council of the local government area (LGA), the SWS Local Health District, and the SWS Primary Health Network who collaborated to address the health challenges faced by local communities. We developed comparative case studies using a combination of documentary analysis and semi-structured interviews with stakeholders from both CHAs. The reassignment of CHA staff to address the COVID-19 pandemic limited CHA operations and prevented many CHA stakeholders from participating in the case study, possibly introducing selection bias. Nonetheless, findings from the case studies yielded evidence for several of the conceptual relationships between social enterprise, digital health citizen engagement, and IPCHS identified in our initial framework; but also suggested that greater organizational maturity was required for the CHAs to operate as social enterprises. Considering these findings, we revised our initial framework, and then used it to develop a maturity model to suggest how health organizations like CHAs can achieve greater organizational maturity to operate as social enterprises that use digital technology to engage citizens in co-creating IPCHS.
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(2022)ThesisType 2 diabetes is a major global health issue. It is projected that by 2045, 783 million people worldwide will be living with diabetes, making it one of the leading contributors to premature death globally. Approximately 30 to 40% of individuals with diabetes develop chronic kidney disease (CKD), making diabetes the leading cause of CKD worldwide. Despite glucose, blood pressure and lipid lowering, and treatment with renin-angiotensin system (RAS) blockade, the risk of cardiovascular events, kidney failure and death remains high for millions of people with diabetes and CKD worldwide. Originally developed to lower blood glucose, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to have favourable effects on multiple metabolic risk factors including blood pressure, glucose, body weight and albuminuria. Large, randomized trials, including those reported herein, have demonstrated the capacity of these agents to reduce the risk of cardiovascular events, kidney failure and extend survival in increasingly diverse populations, including those without diabetes. This doctorate aims to evaluate the efficacy and safety of SGLT2 inhibitors in people with type 2 diabetes and CKD. Chapter 1 introduces the doctorate, summarizing the epidemiology of type 2 diabetes and CKD, as well as traditional approaches to improving outcomes in this population and the potential role for SGLT2 inhibition in people with diabetes. Chapter 2 provides an overview of SGLT2 inhibitors, practical considerations and evidence for their use in people with type 2 diabetes from cardiovascular outcome trials. Chapters 3 to 5 assess the efficacy and safety of the SGLT2 inhibitor, canagliflozin, across different levels of kidney function, defined by estimated glomerular filtration rate (eGFR) and albuminuria, using data from the CANVAS Program. Whilst the relative effects of canagliflozin on cardiovascular and kidney outcomes are consistent across different levels of eGFR and albuminuria, absolute risk reductions are largest for individuals with severely increased albuminuria. Further, the Kidney Disease Improving Global Outcomes classification of CKD, which combines eGFR and albuminuria to risk stratify individuals, can accurately identify those who are likely to derive the greatest absolute benefits with treatment. In Chapter 6, the results of a systematic review and meta-analysis are presented, which demonstrate that for people with type 2 diabetes, SGLT2 inhibitors substantially reduce the risk of the most important patient-centred kidney outcome – the need for dialysis, kidney transplantation or death due to kidney disease – and provide protection against acute kidney injury. The results of a meta-analysis are presented in Chapter 7, indicating that the benefits of SGLT2 inhibitors are similar with and without metformin, which is widely recommended as first-line glucose lowering therapy in type 2 diabetes. In Chapter 8, an individual participant data meta-analysis demonstrated that SGLT2 inhibitors reduce the risk of serious hyperkalaemia in people with type 2 diabetes at high cardiovascular risk and/or with CKD, which may enable better use of RAS blockade and mineralocorticoid receptor antagonists to improve cardiorenal outcomes. Chapter 9 explores questions about this class of agent that remain to be answered by ongoing randomized trials, and how SGLT2 inhibitors and other kidney protective therapies might be used for people with CKD in the future. Taken together, the findings of this doctorate provide compelling evidence that SGLT2 inhibitors should be routinely offered to individual with type 2 diabetes to safely reduce the risk of major kidney outcomes and cardiovascular events.