Medicine (St Vincent's) - Theses

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    Addressing knowledge gaps in the assessment of disease status in systemic sclerosis
    Ross, Laura ( 2022)
    Systemic sclerosis (SSc, or scleroderma) is a rare, orphan condition associated with high morbidity and mortality. There remain significant areas of unmet need in terms of the understanding of the underlying pathogenesis of the disease, how disease manifestations are identified and measured in clinical trials, as well as in clinical practice, in addition to a lack of effective, targeted therapeutics that offer improved survival and quality of life to patients. SSc is frequently a fatal disease, with a mortality risk up to seven times that of the general population and it is associated with a large burden of physical and mental ill-health, notable from the time of onset of disease. Our understanding of the disease has progressed significantly over the past 100 years, since Matsui confirmed that SSc was in fact a multi-system disease, not an exclusively dermatological condition. The importance of vascular changes and auto-inflammatory mechanisms in addition to excessive collagen deposition in the development of SSc and subsequent disease progression are now appreciated. Important pathogenic pathways that lead to the dense fibrotic extra-cellular matrix deposition and obliterative vasculopathy that characterise advanced SSc have been identified. However there is an ongoing absence of evidence to link levels and activities of cytokines and other cell mediators to specific pathogenic effects in SSc. The precise pathogenic mechanisms of specific disease manifestations remain incompletely understood and insights are often gained by working backwards through studying those individuals with advanced disease and identifying the clinical and pathogenic mechanisms that set them apart from others with mild disease. Heterogeneity, both of disease presentation and progression, is a clinical hallmark of SSc, and this has impeded efforts to both define the presence of disease and measure important changes in disease status, either in response to novel therapies in a clinical trial or in observational, longitudinal cohort studies. Important disease manifestations such as cardiac disease or gastrointestinal disease remain largely undefined and the lack of fully-validated multi-system measures of disease status have contributed to the failure of multiple randomised controlled therapeutic trials. Treatment options in SSc are limited, and it remains one of the few rheumatic diseases without a targeted treatment that alters the disease course. Optimal clinical trial design remains debated and effective recruitment strategies to identify those individuals most likely to benefit from treatment are controversial. Methodological inconsistencies remain an Achilles heel of SSc clinical trials, meaning accurate, valid measurement of disease status and comparison between study cohorts cannot be performed. In this context, this thesis aims to further our understanding of SSc by studying specific organ effects of SSc and reviewing and developing methodologically sound means of disease assessment. Specifically, this thesis will address the significant knowledge gaps that currently limit our ability to develop a global measure of disease activity in SSc. I will address the face, content and construct validity of items to measure activity within particular organ systems and will present a preliminary multi-system activity index. Additionally, I will explore SSc-associated heart involvement. This organ system was prioritised in my thesis research because of the prognostic importance of cardiac disease in SSc and the lack of understanding of the full spectrum and natural history of heart involvement, and the absence of valid methods of diagnosis. I present results that quantify the prevalence of myocardial fibrosis in SSc, evaluate the utility of commonly available cardiac investigations in the diagnosis of SSc heart involvement and the progress made in the development of classification criteria for the diagnosis of SSc-associated heart involvement.
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    Targeting cytokines involved in T cell proliferation and function in a mouse model of type 1 diabetes
    Ge, Tingting ( 2022)
    Cytokines functioning through the JAK-STAT pathway amplify immune responses in autoimmune and inflammatory diseases and drive some T cell lymphomas. Therefore, JAK inhibitors have shown efficacy in multiple autoimmune diseases as well as T cell malignancies. My PhD work focused on the role of common gamma chain cytokines in T cell proliferation and their contribution to autoimmune diabetes and T cell lymphomas. In chapter 2, I used the JAK1 selective inhibitor ABT 317 to reverse spontaneous diabetes in NOD mice. I confirmed that the JAK1 inhibitor can block IFNgamma activity to prevent MHC class I upregulation on beta cells and weaken the interaction between T cells and beta cells. More importantly, my research revealed that the JAK1 inhibitor reduced common chain cytokines, IL-21, IL-2, IL-15 and IL-7 signalling in T cells and inhibited both CD4+ and CD8+ T cell proliferation and differentiation. In a recent study by our lab, Jhala et al showed that islet autoantigen-specific T cells from NOD mice lacking IFNgamma receptors (Ifngr1 mutant mice) are present at >10-fold in number compared to wild-type NOD mice, and this expansion is due to increased response of Ifngr1 mutant T cells to common gamma chain cytokines. It emphasises reducing T-cell proliferation as an important way that JAK inhibitors preserve beta cells. In chapter 3, I studied checkpoint inhibitor-induced diabetes by injecting NOD mice with anti-PD-L1 antibodies. Diabetes was induced rapidly after the administration of anti-PD-L1 due to activation of already existing islet-specific T cells that can destroy beta cells. There is currently no effective therapy to prevent checkpoint inhibitor-induced diabetes. I used a JAK1/JAK2 inhibitor to block the effect of cytokines on T cells and beta cells. The JAK1/JAK2 inhibitor prevented anti-PD-L1 induced diabetes. Using JAK inhibitors after checkpoint inhibitors in a tumour model did not reverse or abrogate the anti-tumour effects of checkpoint inhibitors. This provides preclinical validation for using a JAK inhibitor to prevent checkpoint inhibitor-induced diabetes, a rare immune-related side effect of this cancer therapy. We observed a high incidence of lymphomas in Ifngr1 mutant mice. Phenotype studies of these lymphomas showed that most lymphomas originated from immature T cells. Lymphoma cells showed increased phosphorylation of STAT3 and STAT5. Ifngr1 mutant mice had increased proliferation of pathogenic beta cell specific CD8+ T cells due to decreased SOCS1 and increased proliferative response of T cells to IL-2. However, the expression of SOCS1 in Ifngr1 mutant thymocytes is similar to that in NOD thymocytes and IFNgamma receptor deficiency did not affect thymocyte proliferation and development. IFNgamma receptor deficiency impaired immune-mediated suppression of T cell lymphoma development. In conclusion, IFNgamma receptor deficiency does not cause increased T cell lymphomagenesis but impairs immune-mediated suppression of T cell lymphoma development. My PhD work shows that cytokines working through the JAK-STAT pathway lead to increased proliferation of pathological islet specific T cells and autoimmune diabetes. JAK inhibitor administration can reduce T cell proliferation to prevent and reverse autoimmune diabetes in NOD mice. However, increased T cell lymphomas in Ifngr1 mutant mice is not due to increased JAK-STAT signalling but due to impaired immune-mediated suppression of T cell lymphoma.
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    A genome stability pathway with dual roles in meiosis and germ cell development
    Tsui, Vanessa ( 2022)
    Chromosome segregation errors because of meiotic recombination of are a leading cause of pregnancy loss. In the case of live births can cause serious congenital aneuploidy such as trisomy 21. Meiotic recombination pairs homologous chromosomes to promote large scale exchanges of genetic information, resulting in recombinant haploid gametes (sperm or eggs). Meiotic recombination begins with many programmed DNA double strand breaks (DSBs). The vast majority of these DSBs is repaired directly and only a small subset leads to genetic exchange between the two parental chromosomes, also known as crossing over. This suggests there are factors that actively promote DSB repair as non-crossovers. In my PhD project, I studied the role of a DNA repair protein, FANCM, and how crossover rates are altered in a Fancm knockout mouse model. My results indicate that FANCM deletion leads to two distinct but related outcomes: 1) increased genome instability in the all the cells of the body and 2) increased crossover rates between homologous chromosomes in meiotic cells. As a result of overall genome instability, there is increased spontaneous DNA damage leading to perturbed germ cell production, reducing spermatogenesis in Fancm-knockout males and reduced fertility in Fancm-knockout females. The absence of FANCM alters the DSB repair pathway choice in meiotic cells, resulting in more crossovers compared to wild-type conditions. Therefore, FANCM plays an important role in regulating crossover designation and balancing the exchange of genetic information during each reproductive generation. My work and further investigations into reproductive biology will provide more insight into how DNA repair defects may cause human congenital aneuploidies and could shed light on earlier diagnostic opportunities.
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    Behavioural treatment for functional bowel symptoms in inflammatory bowel disease
    Khera, Angela Jane ( 2022)
    Inflammatory bowel diseases (IBD) are chronic relapsing and remitting inflammatory diseases of the gastrointestinal tract, with the most common sub-types being Crohn’s disease and ulcerative colitis. Despite achieving disease remission patients with inflammatory bowel disease often experience persisting bowel symptoms, considered “functional in nature”, including increased bowel frequency, urgency, faecal incontinence, constipation (low bowel frequency or difficult rectal emptying), abdominal pain, bloating, and anorectal pain. Some patients with ulcerative colitis require major surgery, involving colectomy and construction of a neo-rectum or ileoanal pouch. Many continue to have similar long-term symptoms. Poor health-related quality of life, anxiety, depression, and health-seeking behaviour are associated with these functional bowel disorders in patients with IBD. Behavioural treatment for bowel dysfunction incorporates education, muscular and sensory rehabilitation, defaecation training, practical management strategies, and psychological support. It is of proven efficacy in the non-IBD population but the evidence in patients with IBD is extremely limited. The primary aim of this thesis is to determine the efficacy of behavioural treatment, including pelvic floor muscle training, for persistent bowel symptoms in patients with quiescent IBD or an ileoanal pouch. These studies have demonstrated that behavioural treatment is an effective management strategy for patients with quiescent IBD, in both public and private healthcare settings. It reduces symptom severity and improves health-related quality of life. The long-term findings of the prospective LIBERATE study found that most patients had maintained the improvement in symptoms at 12 months after completing treatment. The cross-sectional study of patients with an ileoanal pouch confirms that many do have long-term pouch dysfunction, and most have learned to live with it. The preliminary findings of the randomised controlled RAP trial, for patients undergoing pouch surgery, demonstrate statistically significant superiority of peri-operative physiotherapist-led behavioural intervention over standard or usual care, with regard to symptoms, psychological well-being, and quality of life. This thesis includes the first studies examining pelvic floor muscle function in patients with IBD using real-time ultrasound. They are also the first studies to use transperineal ultrasound as an outcome measure following pelvic floor behavioural treatment for faecal incontinence or defaecatory dysfunction. Transperineal ultrasound identified pelvic floor muscle dysfunction and accurate displacement, although these were not associated with the primary outcomes of treatment. Real-time ultrasound examination was well tolerated and an excellent non-invasive biofeedback tool for patients with IBD and pelvic floor muscle dysfunction. The findings from this thesis provide a clear rationale for behavioural treatment to be offered to patients, particularly when other therapies have failed. This work also suggests that identifying functional bowel symptoms earlier and treating them effectively may minimise the impact on psychological well-being and quality of life, particularly for those undergoing major pouch surgery. Improving the recognition of functional bowel symptoms and providing evidence for behavioural treatment as a safe and effective management option has the potential to alter the current model of care and reduce the personal and economic burden of IBD.
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    Enhancing the hepatitis B care cascade in Australia: addressing barriers in the Chinese community and general practice, and evaluating cost-effectiveness
    Xiao, Yinzong ( 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.
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    The roles of retinoic acid receptors and target gene HOXA1 in regulating haematopoiesis and myelodysplastic syndromes
    Grace, Clea Simes ( 2022)
    Haematopoietic stem cells (HSCs) are multipotent cells responsible for the maintenance of the haematopoietic system throughout life. Dysregulation of the balance between HSC self-renewal, death and differentiation can have serious consequences such as myelodysplastic syndromes (MDS) or leukaemia. All-trans retinoic acid (ATRA), the biologically active metabolite of retinoic acid (RA) has pleiotropic effects on haematopoietic cells, maintaining haematopoiesis via complex intrinsic and extrinsic mechanisms involving retinoic acid receptor-alpha (RARalpha) and RARgamma signalling. Conditional murine Rar knockout models were utilised to determine the intrinsic and extrinsic impacts of Rara and/or Rarg deletion on HSCs and their progeny in vivo via global, postnatal deletion, haematopoietic cell-specific deletion (whole bone marrow transplants (WBMTs)) and HSC and progenitor-specific deletion (Lineage-c-Kit+Sca-1+ (LKS+) WBMTs). These data revealed novel roles of Rara in haematopoiesis, with postnatal deletion resulting in intrinsically-mediated myeloid-biased haematopoiesis, reduced numbers of CD8+ T cells and altered HSC reconstitution capacity, in addition to extrinsically-mediated aberrant BM erythropoiesis and B lymphopoiesis. Loss of either Rara and/or Rarg resulted in myeloid-biased haematopoiesis and concurrent deletion (expression of Rarb only) enhanced HSC exhaustion. Contrary to germline Rarg-/- studies, postnatal Rarg deletion had a limited impact on haematopoiesis. The observed phenotypical differences between germline and global, postnatal Rar deletions may be due to a combination of developmental and microenvironmental interactions, interactions between Rara and Rarg and their differential target genes and compensatory effects. Whilst the relative contribution of RA signalling to its haematopoietic regulation is unknown, homeoboxa1 (HOXA1) is an RARgamma target gene and its full-length isoform (HOXA1-FL) is frequently upregulated in human MDS. A series of studies utilising conditional murine haematopoietic Hoxa1 knockin mice revealed that whilst recipient mice developed MDS during serial transplantation, consistent with previous studies, the levels of Hoxa1-FL overexpression were insufficient to result in progression to secondary acute myeloid leukaemia (sAML). Additionally, Hoxa1 overexpression resulted in profound, persistent and serially transplantable macrothrombocytopenia despite a depleted yet highly megakaryocyte-primed HSC and progenitor compartment. The macrothrombocytopenia resulted from ineffective thrombopoiesis by dysfunctional, low ploidy megakaryocytes, potentially due to inflammation-mediated lineage skewing and/or late-stage developmental defect(s). Dysregulated BM erythropoiesis and granulopoiesis were also observed. These phenotypes were consistently evident early, persisted in non-transplanted pre-malignant mice and became more profound during serial transplantation and after MDS progression. Phenotypic severity also depended on Hoxa1 gene-dosage and isoform expression. Furthermore, the megakaryocyte-priming correlated to increased DNA damage and/or deficient DNA damage responses (DDR), increased expression of inflammatory markers and altered programmed cell death, suggesting that an altered inflammatory microenvironment and associated haematopoietic lineage skewing may have contributed to the Hoxa1-FL-mediated haematopoietic defects, although this remains under investigation. Whilst the precise mechanisms underlying these phenotypes therefore remain to elucidated, it is evident that Rara, Rarg and Hoxa1-FL have pleiotropic impacts on haematopoiesis that are both cell-type and maturation-stage dependent. Elucidation of these effects in murine models are critical steps in the development of targeted therapies for MDS patients with increased Hoxa1-FL expression and for other haematopoietic malignancies to which dysregulated Hoxa1 and/or RA signalling may contribute.
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    Impaired awareness of hypoglycaemia in type 1 diabetes: Challenges to achieving metabolic control and advances in therapeutic options to replace beta cell function
    Lee, Melissa Huilin ( 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.
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    Single-cell analysis of ab versus gd T cell development
    Oh, Seungyoul ( 2022)
    T cells are divided into the alphabeta and gammadelta lineages. It is currently thought both lineages develop in the thymus from common uncommitted progenitors that are seeded from the bone marrow. Over the years, studies at a population level have identified many of the specific genes that must be activated or silenced as T cell progenitors differentiate towards either lineage. Despite much effort over the years, it is still unknown whether this combination of activation and silencing occurs in each cell as they differentiate. In addition, the exact branch point at which the alphabeta and gammadelta lineages diverge remains contentious. Although the prevailing T cell developmental model assumes that the gammadelta lineage branches from the main developmental pathway around the DN2b and DN3a stages, which is when definitive gammadelta lineage markers become obvious, it is still unclear whether this is actually the case. To better understand the development of the gammadelta lineage, the kinetics of alphabeta versus gammadelta T cell development were tracked in OP9-DL1 cultures. This revealed the two lineages may develop along different pathways. Moreover, cellular barcoding analysis of CD4-CD8- double negative 1 (DN1) thymocytes, which suggested these thymocytes may in fact be a heterogenous mixture consisting of distinct subpopulations that develop into either alphabeta cells or gammadelta cells. To investigate the early alphabeta versus gammadelta T cell development more precisely, single-cell RNA-sequencing (scRNA-seq) was employed to determine the transcriptional profiles of individual DN and gammadelta thymocytes, which was then used to re-assemble de novo a model of the early stages in T cell development. >20,000 DN and gammadelta thymocytes were analysed using Chromium 10X scRNA-seq over three runs. Hierarchical clustering revealed that early thymocyte populations are much more complex than the standard view of early T cell development. Computational trajectory analyses suggested that the alphabeta versus gammadelta decision may actually be established at the DN1 stage, which is consistent with the previous cellular barcoding experiments. Eight transcriptionally distinct DN1 subpopulations were identified. One or more of these may be the bipotent precursor(s) of both alphabeta and gammadelta lineages. Alternatively, it may be that specific subpopulations are precursors of the alphabeta lineages, while others are precursors of the gammadelta lineage. To investigate this, these subpopulations were sorted and analysed for the lineage outcomes in OP9-DL1 co-cultures. I show that distinct DN1 subpopulations are in fact restricted to the alphabeta lineage, while others are restricted to the gammadelta lineage. Moreover, specific gammadelta-primed DN1 subpopulations preferentially develop into IL-17 or IFNg-producing gammadelta T cells, well before the expression of lineage-defining T cell receptors. Thus, T cell lineage decisions are already hardwired from the earliest stages of T cell development. These new insights into hardwiring of lineage commitment represents a paradigm-change in our understanding of early T cell development. This has the potential to form the basis for more comprehensive research to elucidate underlying molecular mechanisms and framework to address how the lineage decision is made. Ultimately, this will have significant implications on designing novel therapeutics targets for treating diseases.
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    Defining and Treating Crohn's Disease Strictures
    Schulberg, Julien Dion ( 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.
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    Alcohol and recreational drug use in young adults with type 1 diabetes
    Pastor, Adam Zacharia ( 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.