Medicine (St Vincent's) - Theses
Permanent URI for this collection
Search Results
1 - 10 of 22
-
ItemEnhancing the hepatitis B care cascade in Australia: addressing barriers in the Chinese community and general practice, and evaluating cost-effectiveness( 2021)Chronic hepatitis B infection is a significant global public health concern, with untreated chronic hepatitis B leading to cirrhosis, liver failure and liver cancer. In 2015, an estimated 257 million people worldwide were living with chronic hepatitis B, of whom only around 10% were diagnosed, and fewer than 1% received treatment. An estimated 870,000 deaths are attributed to hepatitis B each year. In 2016, the World Health Organization launched the global health sector strategy on eliminating viral hepatitis, which provides guidance and frameworks for country efforts to eliminate viral hepatitis as a major public health threat by 2030. In Australia, despite a high hepatitis B vaccination rate by global standards, there are significant gaps in the coverage of service delivery among people living with chronic hepatitis B. One in three people with chronic hepatitis B are not diagnosed, and 78% are not receiving ongoing clinical care. One of the priority populations of hepatitis B infection are people born in endemic countries, with China being the most common country of birth among overseas-born people living with hepatitis B in Australia. To increase hepatitis B diagnosis, care and treatment (that is, to enhance the hepatitis B care cascade) in Australia, several critical areas for improvement have been identified, including adapting services to the affected population, building health workforce capacity to meet demands, and building the investment case to support models of care that will promote hepatitis B elimination. The overarching aim of the research presented in this thesis was to generate evidence targeting each of these three aspects, with particular emphasis on: 1) engaging the Chinese community in hepatitis B testing and clinical management; 2) engaging general practitioners (GPs) in the provision of hepatitis B-related care; and 3) formulating a robust hepatitis B investment case. To accomplish these objectives, five interlocking studies were conducted. The first two studies focused on an affected community (the Australian Chinese community), the second two on health service providers, and the final study on the cost effectiveness of hepatitis B care. More specifically: Study 1 was a randomised controlled pilot and feasibility study of the impacts of an educational program designed to improve hepatitis B testing uptake in the Australian Chinese community; Study 2 was a qualitative study to explore enablers of hepatitis B clinical management among the Australian Chinese community; Study 3 was a before-and-after evaluation of a self-guided learning package among GPs practising in Victoria; Study 4 was a nationwide survey of knowledge, attitudes, barriers and enablers to the provision of hepatitis B care among GPs in Australia; and Study 5 was a cost-effectiveness study analysing the impacts of enhancing hepatitis B care cascade to reach global and national targets in Australia. The findings of this research indicated that a culturally tailored education program can contribute to improving hepatitis B-related knowledge among the Australian Chinese community. Key messages identified to resonate most strongly among people living with chronic hepatitis B included availability of effective and cheap treatment, and that long-term engagement with clinical management has substantial benefits. A holistic response from community, healthcare providers and the public health sector is required to motivate testing and clinical management among the Australian Chinese community at risk of hepatitis B infection. Additionally, this research showed that concise, clear and practical resources can support GPs to identify who to test for hepatitis B. It also showed that GPs lack of awareness, knowledge, confidence and intention to prescribe treatment for hepatitis B, highlighting the need for interventions to increase their interest and skills in the provision of hepatitis B-related care. Economic evaluation findings suggest that an improvement in the hepatitis B care cascade is required for Australia to reach the global 2030 targets, and that it is cost-effective to spend up to AUD328 million to AUD538 million per year on demand generation activities to reach the national and global targets. Overall, this research provides novel evidence about feasible and effective interventions for improving the hepatitis B care cascade in Australia. It also provides insights into ways to enhance the global hepatitis B care cascade.
-
ItemImpaired awareness of hypoglycaemia in type 1 diabetes: Challenges to achieving metabolic control and advances in therapeutic options to replace beta cell function( 2021)Impaired awareness of hypoglycaemia (IAH) affects an estimated 20% of people living with type 1 diabetes and increases the risk of severe hypoglycaemia six-fold. The increased susceptibility to hypoglycaemia results from defective physiological defences in response to a fall in blood glucose levels, leading to IAH and a self-perpetuating cycle of recurrent hypoglycaemia. People with IAH and recurrent severe hypoglycaemia have high morbidity and mortality, though this remains to be fully defined. The management of individuals with IAH is complex. A staged clinical approach has been proposed which includes educational, technological and transplantation interventions, aiming to avoid hypoglycaemia. Novel diabetes therapies and technologies, in particular closed-loop insulin delivery systems, also known as the ‘artificial pancreas’, may be a viable alternative therapeutic option to manage these high-risk individuals. This thesis focuses on IAH in adults with type 1 diabetes, aiming to better define mortality risk in people living with IAH and recurrent severe hypoglycaemia, and to better understand strategies to address challenges to achieving optimal glycaemic control. The original research conducted in this thesis also investigates the efficacy of hybrid closed-loop technology and a novel insulin formulation to optimise overall glucose control, and specifically, for individuals with IAH, to minimise hypoglycaemia and potentially ameliorate hypoglycaemia awareness. The first study of this thesis explored mortality rates and cause of death in adults with IAH and recurrent severe hypoglycaemia who were considered for islet transplantation. This study found that hypoglycaemia-related mortality was high in those who did not undergo islet transplantation, which is considered gold standard for this vulnerable group. These findings highlight the importance of seeking alternative technology-based therapeutic options for those who are deemed not suitable for transplantation or for those awaiting transplantation. The findings from this study also justify the importance of the subsequent studies of this thesis. The following two studies of this thesis investigated whether novel technology, specifically advanced hybrid closed-loop algorithms and faster-acting insulin formulations, which are two important components critical to the success of a closed-loop system, can improve glucose control further in a well-controlled general adult population with type 1 diabetes. Overall high glucose time-in-range, high time spent in closed-loop, positive user acceptability with no major safety concerns demonstrated promising progression in the evolution of these technologies, and warrants broader evaluation in a group with IAH. The fourth randomised crossover study investigated glucose control and counterregulatory responses using a hybrid closed-loop system in adults with IAH when undertaking moderate- and high-intensity exercise. This is a particularly challenging area for people with IAH due to the risk of exercise-associated hypoglycaemia. Closed-loop use during exercise was safe and effective with minimal hypoglycaemia, despite an overall attenuated counterregulatory response to exercise, though the cortisol response to high-intensity exercise was preserved. The final study brought together elements of the preceding studies to comprehensively evaluate adults with IAH and recurrent severe hypoglycaemia, comparable to those who meet criteria for islet transplantation. Findings demonstrated that a hybrid closed-loop system improved overall glucose control without an increase in hypoglycaemia, reduced glucose variability, reduced quantitative composite hypoglycaemia scores, and partially improved glucose counterregulatory responses without restoration of hypoglycaemia awareness compared with standard diabetes therapy. This thesis adds a substantial body of knowledge towards the current understanding of IAH and its associated burden, and the strengths and limitations of hybrid closed-loop insulin delivery for the management of adults with IAH. This work contributes added knowledge towards better delineating and improving decision algorithms to allocate closed-loop systems or transplantation to the most appropriate recipients. Until a biological cure is achieved, ongoing advances in both automated insulin delivery systems and beta cell replacement with transplantation will continue to improve biological and psychosocial outcomes for this vulnerable group of people living with type 1 diabetes.
-
ItemDefining and Treating Crohn's Disease Strictures( 2021)Crohn’s disease, one of two main Inflammatory Bowel Diseases (IBD), is a relapsing and remitting inflammatory condition of the digestive tract leading to progressive and cumulative damage to the gastrointestinal tract. Strictures are the most common complication of Crohn's disease. Already at diagnosis between 11% and 30% of patients have stricturing disease and 1 in 3 will develop stricturing after five years, with many requiring bowel surgery. Previously, strictures have been regarded as a contraindication for drug therapy, based on the premise that such strictures comprise irreversible fibrosis. Treatment has been endoscopic dilation or surgery. Pathways leading to fibrosis are now more comprehensively understood and the important contribution of both acute and chronic inflammation as well as smooth muscle hyperplasia/hypertrophy are increasingly recognized as key factors in stricture pathogenesis. This thesis investigates, in a range of studies, the diagnostic, prognostic and non-surgical treatment modalities for patients with stricturing Crohn’s disease. I have comprehensively reviewed the current evidence for drug therapy in Crohn’s disease and highlighted the limited current data supporting drug treatment in the management of strictures. In addition, I have outlined the current position for endoscopic therapy, particularly endoscopic balloon dilation as part of the management of strictures. I have evaluated the key demographic, clinical, endoscopic and imaging risk factors for progression to surgery. The key role of MRI small bowel for detailed evaluation of patients with stricturing Crohn’s and its utility to predict stricture surgery has been defined. The Stricture Definition and Treatment (STRIDENT) study is the first randomised controlled study of drug treatment in stricturing Crohn’s disease. As part of this study, I have demonstrated the outcomes of drug therapy, including intensive drug treatment with treat to target dosing of adalimumab in combination with a thiopurine, and treatment with standard dosing anti-TNF monotherapy. In addition to clinical outcomes, this study prospectively and objectively demonstrates the morphological stricture changes associated with treatment using multiple imaging modalities (MRI, intestinal ultrasound, and endoscopy) and the effect on biomarkers of inflammation (CRP, faecal calprotectin). This research has demonstrated that Crohn’s disease strictures are responsive to drug therapy and that tighter control from intensive treatment results in less treatment failure and greater improvement in stricture morphology. These series of studies on the diagnosis and treatment of patients with stricturing Crohn’s disease will help change the current treatment paradigm for this disabling condition. Future scientific studies will provide further insights into the pathophysiology of strictures to further improve patient outcomes.
-
ItemNo Preview AvailableAlcohol and recreational drug use in young adults with type 1 diabetes( 2021)Navigating the transition from adolescence to young adulthood can be challenging and this period is associated with peak alcohol and drug use. For those diagnosed with type 1 diabetes, the burden of continuous blood glucose management along with the developmental tasks of young adulthood can become overwhelming. Clinicians, researchers, and consumer groups have raised concerns regarding the potential impact of alcohol and illicit drug use on the early morbidity and mortality seen in young adults with type 1 diabetes. The prevalence of alcohol and recreational drug use amongst young adults with type 1 diabetes approaches the general population and they experience more substance related harm. The experiences of young adults with type 1 diabetes while using substances and the effect of substance use on blood glucose levels remains understudied, with only a small number of short studies often conducted in a laboratory or non-naturalistic environment looking at alcohol consumption's influence on blood glucose. These studies have provided conflicting results. This thesis examines these experiences and contains two literature review and the results of four research studies performed for this doctorate. The literature reviews include a general paper pertaining to alcohol and recreational drug use in both type 1 and type 2 diabetes. The second review focuses on young adults with type 1 diabetes and a third section provides an update on important studies performed since publication of those reviews. Study 1 is a qualitative analysis of semi structured interviews (n=16) focused on substance using experiences and harm minimisation tools used by young adults with type 1 diabetes. It explores the specific experiences where substance use impedes attempts at glucose management and the tools used by young adults to mitigate this harm. Study 2 is a quantitative survey study (n= 96) of substance use prevalence, beliefs about effects of substances on blood glucose levels and harm minimisation tools in a cohort of young adults with type 1 diabetes. The results showed no consistency regarding the perceived effect of alcohol on blood glucose levels and that harm minimisation measures were recognised and used by over 50% of the cohort. Study 3 is a survey of clinicians (n=79) that explored their approach to screening and intervention. It showed greater confidence in screening and management of the interaction of alcohol with type 1 diabetes than for other recreational illicit drugs. Study 4 is a prospective experimental study using flash glucose monitoring (n=20) to explore the "real world" effect of substance use on blood glucose metrics. While there was no difference between glucose outcomes on days where substances were used compared with control days, HbA1c (a marker of 3-monthly glucose management) was found to be a less reliable predictor of glucose patterns following substance use than on non-substance using days. Overall, the results across these studies contribute to our understanding of the interaction between substance use and managing type 1 diabetes. This knowledge should aid in the approach of both young adults with type 1 diabetes and their clinicians. They document the experiences of young adults allowing for more sophisticated conversations with their care providers as well as the harm reduction measures already taken. They also highlight that even those with good metabolic control remain at risk of acute harm following drug and alcohol use. The outcomes of this thesis should encourage clinicians to screen young adults with type 1 diabetes for alcohol and drug use and to counsel them regarding potential harm reduction measures. It should also influence the educational literature and other sources of information used by young adults with type 1 diabetes on the need to monitor and respond to their glucose levels following substance use and engage in harm minimisation practices irrespective of baseline glucose management.
-
ItemUnderstanding renal clinician attitudes, experiences and practice of renal supportive care, palliative care and end of life care( 2021)Abstract: People with end stage kidney disease (ESKD) report high symptom burden, complex care needs and often have limited prognosis. Renal supportive care (RSC) also known as kidney supportive care, is a clinical approach integrating nephrology and palliative care expertise to improve symptom management, treatment decision making and quality of life (QOL) for people with advanced kidney disease. Renal supportive care and palliative care have been described to improve quality of life, symptom burden and care coordination, however in practice, across Australia, renal clinicians’ perceptions of the renal supportive care and it’s role alongside nephrology care and specialist palliative care are unknown. The period of time referred to as ‘end of life’ is defined, for the purposes of this thesis, as that time when an individual who is living with, and impaired by a serious illness is considered likely to die within 12 months. This period can be a complex and challenging for renal patients, caregivers and clinicians. Recent international quantitative and qualitative studies have articulated issues and concerns raised by nephrologists, in particular, when navigating end of life decision making. Communication about prognosis and provision of end of life care is described as wanting in routine ESKD care, with some clinicians feeling inadequately prepared to have these discussions, others describing an avoidance of raising the prospect of death with patients due to concerns of damaging the patient-doctor relationship and a desire to instil hope. Renal clinicians’ experiences of transitioning treatment goals from life sustaining treatments to care focusing on symptoms and comfort including how palliative care and renal supportive care is integrated for patients in Australia have largely been undocumented. This thesis aimed to explore renal clinicians’ experiences of providing end of life care, of palliative care and of renal supportive care and to identify the strengths, limitations and opportunities of current practice to improve clinical care. In addition, this study aimed to develop recommendations regarding core duties, features of a clinical model of renal supportive care and issues to be considered for future renal supportive care service development and integration. A sequential mixed methods study was undertaken with three phases; (1) a qualitative study of 53 Victorian renal clinicians to understand experiences of providing end of life care, of palliative care and of renal supportive care, (2) an online survey of 382 renal clinicians’ experiences across Australia and New Zealand to distil components and priorities for renal supportive care services and, (3) establishment of a multidisciplinary advisory group to oversee the integration of data and develop recommendations for establishing renal supportive care services in Victoria. This program of work has demonstrated that many clinicians viewed renal supportive care as widely accepted and valuable including at a phase in the illness before patients are imminently dying, particularly in the area of symptom management. However, variation in resources, information and communication systems and healthcare delivery of renal supportive care within and between health services contributed to a wide diversity of definitions, clinical scopes and for some clinicians, uncertainty of benefit. Palliative care was viewed as valuable, especially for the final days to weeks of life, yet, was also considered to be physically and philosophically separate from nephrology care. The majority of difficult experiences reported by clinicians in end of life care provision were associated with views of compromised decision making. Decisions that were too late, rushed, or associated with a lack of agreement between patients, families and treating teams, with concerns of patients suffering or an inability to express their wishes or preferences were most concerning. When describing their experiences of renal patients deteriorating and dying, renal clinicians described a set of shared values. These included an ongoing commitment to care for patients, the importance of clinical leadership and a respect for patient choice in decision making. Experiences of distress and professional and moral discomfort were reported by renal clinicians when one or more of these values were perceived to be threatened or compromised. The Victorian renal supportive care advisory group recommended a consensus definition of renal supportive care, an ideal renal supportive care model and dedicated resources for data collection and collaboration across nephrology units to develop renal supportive care services and improve end of life experiences for patients and clinicians. In conclusion, providing end of life care to patients was often experienced as complex, uncertain, and at times, uncomfortable and distressing for renal clinicians. This was due to multiple contributory healthcare system, clinical, and patient factors, in addition to professional pressures and expectations to continue to provide care that enhanced both quality and quantity of life. These factors were often perceived as barriers for clinicians in holding earlier discussions and planning the end of life care for patients with advanced renal disease. Challenging end of life care experiences were conceptualised in terms of a self-perpetuating cycle where difficult experiences were associated with compromised professional values, variable or limited renal supportive care and palliative care support, and with little education or specific resources which served in turn to reinforce the ongoing challenges for clinicians. Opportunities or entry points to change this cycle included reconceptualising patient education and systematic approaches to articulate and integrate renal supportive care and palliative care in nephrology care. This thesis has demonstrated the ways in which experiences of providing end of life care can be challenging and the reasons renal supportive care and palliative care have not yet been established within routine nephrology care. It has also articulated approaches to address these barriers and future aspirations of renal supportive care provision including the clinical and research priorities to improve patient and clinician experiences of receiving and providing end of life care.
-
ItemThe role of cardiac output and fluid responsive measurements in improving outcomes after major abdominal surgery in adults( 2021)Adequate delivery of oxygen to tissues is essential to tissue healing and preserving organ function following major surgery which is characterised by an increased oxygen demand. Cardiac output (CO), the flow out of the heart, can now be measured with monitors using technology that allows them to be used safely during the perioperative period. This thesis explores the monitors used to target CO, the effect of targeting CO, goal-directed therapy (GDT), and haemodynamic differences between restrictive and liberal fluid therapy. The CO technology of focus in this thesis is the oesophageal Doppler with arterial pressure waveform devices and plethysmography also assessed for their ability for agreement to clinical events. Two prospective observational studies assessed the ability of the monitors to track the clinical events of fluid and vasopressor administration. Compared to each other, the Doppler monitor and arterial pressure waveform monitor had reduced concordance to track CO changes following fluid boluses with even poorer concordance to vasopressor administration. Compared to the reference standard of thermodilution, both technologies displayed reduced precision but the Doppler tracked fluid boluses more consistently. A randomised control trial was conducted with patients having colorectal resection surgery targeting an optimal CO using fluid bolus therapy. Importantly, it was conducted within a contemporary enhanced recovery after surgery (ERAS) framework to demonstrate whether GDT can have a benefit in addition to optimal perioperative care. There was no difference in hospital length of stay or proportion of patients with major complications. A meta-analysis of other studies shows that the benefit to GDT with a Doppler technology device is effective in reducing complications but the results are less applicable with lower perioperative risk, such as patients within an ERAS framework. Finally, the haemodynamic effect of a restrictive fluid therapy compared to a modestly liberal fluid therapy was observed with CO monitoring and fluid responsive parameters. Fluid restriction resulted in a reduced CO and stroke volume which may explain a finding of increased kidney injury and surgical site infection observed in this group. In summary, targeting an increased CO in major abdominal surgery may show reductions in complications but this is not seen in low-risk patients. A Doppler CO monitor has a better ability to detect changes after a fluid bolus but measurement of CO clinically is still challenging with reduced precision observed. The demonstration of reduced CO with fluid restriction supports the importance of avoiding the harmful effects of hypovolaemia and the utility of the measurement and targeting of CO.
-
ItemA model of culturally informed integration of Diabetes Education and diabetic Eye disease Screening (iDEES) in Indigenous primary care settings( 2021)Diabetes mellitus, particularly Type 2 diabetes (T2D), is a fast-growing pandemic and leading public health problem. If not managed well, T2D can lead to serious complications, such as diabetic retinopathy (DR). DR is a retinal complication of diabetes and one of the leading causes of vision impairment and blindness in working-aged adults globally. Although there have been many attempts to treat and eradicate DR, the burden tends to fall on the most vulnerable people in low-income countries, rural settings, and indigenous populations. Indigenous Australians are more likely to have T2D and are at higher risk of being visually impaired or going blind due to DR then non-Indigenous Australians. Studies have demonstrated that early detection and management practices, such as DR screening, are effective strategies to detect and manage DR to reduce the risk of sight-threatening visual complications and blindness (NHMRC, 2008). Despite the benefits of DR screening, screening rates among Indigenous Australians are substantially lower than in non-Indigenous Australians. Thus, understanding the association between diabetes and its complications, above all DR, and the importance of regular eye screening is very important for both individuals with diabetes and healthcare clinicians involved in providing diabetes support and diabetes self-management education. Technological advances and the Medicare rebates that support the use of non-ophthalmic clinicians (general practitioners, diabetes educators, health workers and endocrinologists) to supplement coverage by ophthalmologists and optometrists can extend retinopathy screening capacity and should also facilitate improved DR screening rates among Indigenous Australians. Diabetes educators are part of a multidisciplinary healthcare team and are integral to improving diabetes support and self-management education to assist people with diabetes. Integrating ocular screening and diabetes education in primary healthcare settings has potential to synergistically improve retinopathy screening coverage, patient self-management, risk factor control, diabetes care satisfaction, health economics and sustainability of under-resourced services. Hypotheses The studies in this thesis are based on the hypotheses that Indigenous Australian with diabetes are at high risk of diabetic retinopathy due to multiple factors, including suboptimal risk factor profiles; and that a novel model of nurse-led care provision can improve diabetic retinopathy screening rates, reduce risk factors for diabetic retinopathy, and in the longer-term reduce the rates of diabetic retinopathy and related complications. The overall goal is to develop, implement and assess a novel nurse-led model of culturally informed integrated diabetic eye screening and diabetes education in Aboriginal Community Controlled Health Organisations (ACCHOs). Specific Aims 1. To develop, implement and assess a novel nurse-led model of culturally informed integrated diabetic eye screening and diabetes education for Indigenous Australian adults with diabetes in ACCHO primary care centres and related clinics in regional Victoria; including to determine (a) diabetic retinopathy screening coverage rates; (b) the prevalence of impaired vision and of diabetic retinopathy; (c) lifestyle-related risk factors for diabetes complications; (d) traditional risk factors levels including HbA1c, blood pressure and kidney function (ACCHO national key performance indicators), lipids and smoking; and (e) patient satisfaction with diabetes care. 2. To conduct a thematic review of self-management practices in Indigenous Australians related to smoking, nutrition, alcohol, physical activity and emotional wellbeing, as there is a paucity of data in this area. Methods The candidate developed a novel integrated Diabetes Education and diabetic Eye disease Screening (iDEES) model of care that was implemented and tested at three Indigenous-led primary care practices in regional Victoria, Australia. The trial was registered (ANZCTRN1261800120435) and ethics committee approved, and each participant provided written informed consent. The trial was of a pre-post design, with a single clinic visit at baseline and follow-up. Each visit included eye testing, surveys regarding lifestyle and diabetes education. Traditional risk factors, including BMI, blood pressure, smoking, HbA1c, kidney function, and lipid levels, were collected from the electronic medical record system, if available. The candidate was responsible for collecting all qualitative data, based on the surveys which, due to potential low literacy issues, she verbally administered to each study participant. This is culturally acceptable and often preferred in a culture with a strong oral tradition. The surveys were usually administered during a one-hour diabetes education and eye imaging appointment. Results were analysed using descriptive statistics, with significance taken at p < 0.05. A thematic literature review was undertaken. Results Overall 334 eligible patients, 171 (51%) participated. A high rate of 78% of the target population was screened at the main study site, in spite of COVID-19 restrictions with 76% being re-screened as per national recommendations. Smaller clinical services strived, but struggled, to embed this additional technology-based service for a range of reasons, predominantly due to understaffing, high staff turnover and management changes, with screening coverage of 18% and 27%. This study of screening coverage for diabetes eye care is one of very few available in the literature, in spite of it being a key metric for diabetes eye care. High rates of diabetic retinopathy (29%) were identified at all sites, on par with other studies of Indigenous Australians. The study also identified high rates of suboptimal self-management behaviour at all study sites, and at the main study site also identified suboptimal systemic risk factor control in adults with diabetes, with a median of four of nine traditional risk factor targets being achieved for women and three of nine for men. The vast majority participants reported being very satisfied with their current diabetes treatment. Follow-up regarding lifestyle and risk factors could not be repeated due to COVID-19 limitations. The literature review identified a knowledge gap in the areas of lifestyle and traditional risk factors among Indigenous Australians with diabetes. Hence, the data generated by the thesis contributed valuable new knowledge to the field. Conclusions An integrated nurse-led model of care was implemented in regional Australian ACCHOs and achieved diabetic retinopathy screening coverage rates of over 75% in the fully engaged sites, with much lower coverage at the less engaged sites. High rates of retinopathy and of adverse lifestyle and traditional risk factors were identified. This culturally acceptable nurse-led model of care merits longer-term follow-up and assessment in other sites, including whether it can improve long-term health outcomes for Indigenous Australians with diabetes.
-
ItemPopulation level outcomes of advancements in diabetes care( 2021)The development of diabetes-related complications is a major healthcare problem. The overall aim of this thesis is to document trends in the incidence of diabetes-related complications, focusing on those related to cardiovascular and renal disease. Diabetes care has improved significantly over past decades, resulting in improved glycaemic control and an increase in the number of patients achieving various metabolic goals. Indeed, the application of multifactorial, target driven interventions has been shown to reduce the development and progression of diabetes related complications in the clinical trial setting. Furthermore, novel glucose lowering medications have recently been shown to reduce the development of cardiovascular and renal complications in recent clinical trials. It is possible that these recent improvements in diabetes management have contributed to reductions in complications in the general diabetes population. In this thesis I examined changes in rates of diabetes related complications in people with and without diabetes over time in Victoria, Australia. The research described in this thesis is mainly centred on an analysis of trends in hospital admissions in Victoria, Australia for various diabetes related complications. This thesis shows that there was a significant decline in the cardiovascular outcomes of, incident AMI, stroke and heart failure presentations for patients with type 1 diabetes, type 2 diabetes and without diabetes between 2004 and 2016. The greatest rate of decline was observed in patients with type 2 diabetes, followed by patients with type 1 diabetes. My research also demonstrates that there was a significant decline in end stage renal disease presentations (separate to those for dialysis and transplantation) for patients with type 1 diabetes, type 2 diabetes or no diabetes. However, rates of admissions for diabetic nephropathy and specifically for dialysis and transplantation remained stable. This lack of translation of a reduction in ESRD presentations to reduced rates of dialysis and transplantation may be due to changes in clinical practices, such as greater access and eligibility for renal replacement programs. The continuing large number of patients with diabetic nephropathy represent an opportunity for the better implementation of best practice guidelines aimed at slowing the development and progression of diabetic kidney disease. In addition, I was able to show that overall rates of lower extremity amputations (LEA) declined for patients with type 2 diabetes, compared to those with type 1 diabetes who did not experience such a decline. Concerningly, a significant rise was seen in all types of LEA for younger patients with type 1 diabetes, whereas pleasingly, older patients with type 2 diabetes saw a decline in rates of LEA. While there is a large amount known on the numbers of people that experience cardiovascular events, less is known about the intravascular burden of coronary artery disease in people with and without diabetes. I was able to show a significant increase over time in the burden of coronary artery disease for patients with type 2 diabetes, compared to those without diabetes in whom no change was observed. A key finding was that following adjustment for the use of traditional cardiovascular protective medications such as statins, renin-angiotensin system inhibitors and anti-platelet drugs, there was no significant difference in the extent of intra-coronary artery disease between patients with and without type 2 diabetes. The implication of this finding is that the aggressive use of traditional preventative therapies can greatly help to reduce the excess burden of disease within the coronary arteries of patients with type 2 diabetes. The improvement in rates of traditional diabetes related complications has led to a corresponding increase of non-traditional complications, including malignancies. In the last results chapter of this thesis, I was able to show that for patients with type 2 diabetes and malignancies there was a significantly increased risk of emergency department presentations, inpatient admissions and all-cause mortality compared to patients with malignancies but without diabetes. This thesis adds to a growing body of evidence of the negative impact of diabetes, on patient outcomes and the importance of risk factor modification and multifactorial interventions. It highlights that although improvements in hospital admission rates for many diabetes related complications are occurring, the overall burden of complications still remains a major public health problem. Unfortunately, my work also shines a light on the changing face of diabetes complications and the potential problems associated with the emergence of non-traditional complications, such as malignancies.
-
ItemAddressing Controversies in the Management of Barrett’s Oesophagus Related Dysplasia( 2021)Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are safe and effective for management of Barrett’s oesophagus with dysplasia; however, some patients have a poor response to RFA, and recurrence of dysplasia can occur. There are controversies surrounding the management of Barrett’s oesophagus with low grade dysplasia (LGD) due to the conflicting data in the literature on diagnosis and progression rate. This thesis describes the long-term outcomes of endoscopic eradication therapy in management of dysplastic Barrett’s oesophagus and factors associated with poor response to RFA. In addition, this thesis also addresses the wide range of progression rate of LGD in the literature, investigates the use of specific histologic criteria to predict progression from LGD and describes a different phenotype of LGD in Barrett’s oesophagus.
-
ItemDifficult to treat populations with hepatitis C infection: Prisoners, people who inject drugs, and viral resistance( 2020)It is estimated that 71 million people are living with hepatitis C virus (HCV) infection globally. The availability of all-oral direct acting antiviral (DAA) medications for HCV infection has revolutionised treatment which is now well tolerated, short in duration and highly effective and cure rates exceed 95% in clinical trials. In this context, the World Health Organization (WHO) has proposed targets for the elimination of HCV as a public health threat by 2030. This includes an 80% reduction in HCV incidence and 65% reduction in HCV-related mortality. Achieving these targets will require sustained effort in diagnosing and treating HCV infection, as well as the development and implementation of models of care to reach populations both highly affected by HCV infection or those underserved by current models. Mathematical modelling data has demonstrated that in high and middle-income countries, HCV incidence will be most rapidly reduced if treatment is prioritised for people who inject drugs (PWID) who contribute most greatly to HCV transmission. Prison populations globally are characterised by high HCV prevalence which is estimated to exceed 15%, and, in Australia, is as high as 50% amongst incarcerated PWIDs. PWIDs also experience high rates of incarceration on account of the criminalisation of injecting drug use (IDU). Despite this, HCV treatment rates within prisons have remained low due to multiple barriers to prison-based HCV care. As individuals re-enter the community from prison, they are also confronted by multiple competing priorities and linkage to HCV care was poor in the interferon era. How we can safely and effectively increase HCV treatment rates in the prison setting and beyond is not well defined. While most people living with HCV are cured following first-line DAA therapy, there are a subset who relapse. Those with advanced liver disease, including cirrhosis, are overrepresented in this group. It is therefore important to evaluate second-line salvage therapies in individuals with advanced disease to minimise HCV-mortality and mortality, in keeping with the WHO elimination goals. This thesis includes a number of clinical studies to address the above issues. In the first study, I evaluated the safety and efficacy of HCV treatment delivered to prisoners by the Statewide Hepatitis Program which operates in all Victorian prisons. I identified that nurse-led HCV care can reach prisoners in large numbers, that it was safe, and that cure rates exceeded 95%. Importantly, over 80% of those treated had never engaged in specialist HCV care prior to incarceration, highlighting that prison-based treatment can reach a population that is poorly served by existing healthcare models. Given that approximately 70% of prisoners reported recent IDU prior to incarceration, prison-based HCV care can also potentially reduce HCV incidence and prevalence within the community more broadly via interrupting transmission. In the second study, I investigated the likelihood of community DAA initiation amongst individuals released from prison with untreated HCV infection. I performed a randomised control trial evaluating a transitional intervention aimed at enhancing continuity of care following release. I identified that amongst unsupported individuals, DAA initiation rates were low. Our transitional model, however, was able to support a greater proportion of individuals to commence HCV treatment, whilst also significantly reducing the interval between community re-entry and DAA initiation, compared to those receiving standard of care. In the third study, I investigated the performance of non-invasive fibrosis algorithms amongst prisoners with HCV, including the AST-to-Platelet Index (APRI) and FIB-4 scores, to minimise the need for transient elastography and improve prison treatment efficiencies. I identified that these algorithms achieved high negative predictive values (NPV) at previously validated thresholds and, if incorporated into HCV assessment pathways, could minimise the need for further fibrosis determination. This is relevant for the dissemination of prison-based HCV programs domestically and internationally where access to transient elastography remains a barrier to care. In the fourth study, I investigated the prevalence of HCV NS5A resistance associated substitutions (RAS) at treatment baseline in DAA-naive participants with genotype (GT)1a, GT1b and GT3 infection. I demonstrated that the baseline NS5A RAS prevalence amongst Australians with GT1a infection was lower than other international regions, but comparable for GT1b and GT3 infection, and that next generation sequencing offered little improvement in diagnostic yield over population-based sequencing at baseline. These findings endorse Australia guidelines that HCV RAS testing is not required prior to first-line DAA therapy. In the fifth study, I evaluated the safety and efficacy of sofosbuvir, elbasvir, grazoprevir and ribavirin for relapsed HCV following treatment with an NS5A-inhibitor containing DAA regimen. I demonstrated that not only was this an effective salvage regimen for GT1 and 4, for which elbasvir and grazoprevir are licensed, but also for GT3 infection by using a multitargeted approach to suppress the emergence of resistant viral variants. In the sixth study, I evaluated the safety and efficacy of sofosbuvir, velpatasvir and voxilaprevir for relapsed HCV in Australians with advanced liver disease who were treated via a pharmaceutical early access program. Despite a high prevalence of difficult to cure characteristics including GT3 infection, cirrhosis, portal hypertension and liver transplantation (LT), I identified high SVR12 rates. While treatment was generally well tolerated, there were three episodes of hepatic decompensation and protease inhibitor usage should be carefully monitored in those with advanced disease. This study provides reassuring evidence that this regimen is highly effective for relapsed HCV, irrespective of baseline characteristics.